prr.hec.gov.pkprr.hec.gov.pk/jspui/bitstream/123456789/668/2/1039s.pdfii declaration i hereby...

SYNTHESIS, CHARACTERIZATION AND

BIOLOGICAL STUDIES OF HETEROCYCLIC

CHALCONES AND THEIR DERIVATIVES

A THESIS SUBMITTED TO

THE UNIVERSITY OF THE PUNJAB

FOR THE AWARD OF DEGREE OF

DOCTOR OF PHILOSOPHY IN

CHEMISTRY

Session 2010

SUBMITTED BY:

SYED UMAR FAROOQ RIZVI

RESEARCH SUPERVISOR

PROF. DR. HAMID LATIF SIDDIQUI

INSTITUTE OF CHEMISTRY

UNIVERSITY OF THE PUNJAB, LAHORE

i

DEDICATION

This work is dedicated to

ii

Declaration

I hereby declare that the work described in this thesis was carried out by me under

the supervision of Prof. Dr. Hamid Latif Siddiqui at the Institute of Chemistry, University

of the Punjab, Lahore.

I also hereby declare that the substance of this thesis has never been submitted

elsewhere for any other degree.

I further declare that the thesis embodies the results of my own research work or

advanced studies and that it has been composed by myself. Where appropriate, I have

made acknowledgement of the work of others.

Syed Umar Farooq Rizvi

iii

APPROVAL CERTIFICATE

This is to certify that this dissertation titled as “Synthesis, Characterization and

Biological Studies of Heterocyclic Chalcones and Their Derivatives” submitted by Mr.

Syed Umar Farooq Rizvi is accepted in its present form by the Institute of Chemistry,

University of the Punjab, Lahore, Pakistan, as satisfying the partial requirement for the

degree of Doctor of Philosophy in Organic Chemistry.

Supervisor: Dr. Hamid Latif Siddiqui

Professor of Organic Chemistry,

Institute of Chemistry,

University of Punjab,

Lahore, Pakistan.

Co-Supervisor: Dr. Saeed Ahmed

Associate Professor,

Department of Chemistry,

Gomal University,

Dera Ismail Khan, Pakistan.

iv

ACKNOWLEDGEMENTS

ll praises to the ALMIGHTY ALLAH who induced the man with

intelligence, knowledge, sight to observe, mind to think and judge. Peace

and blessings of Allah be upon the Hazrat Muhammad (S. A. W. W.) and

his pure and pious progeny who exhorted his followers to seek knowledge

from cradle to grave.

I am greatly obliged to my worthy supervisor Prof. Dr. Hamid Latif Siddiqui,

Institute of Chemistry, University of the Punjab, Lahore, whose knowledge, skillful

guidance, encouragement and kindness have helped me in each and every stage of my

research work. Indeed it is an honor and pleasure for me to work with him. I have been

fortunate to learn a great deal of chemistry from him.

I am whole-heartedly thankful to my cosupervisor Dr. Saeed Ahmed, Associate

Professor, Department of Chemistry, Gomal University, Dera Ismail Khan, who guided

me in my research work. I am especially thankful to him for his constant care and

encouragement.

I am also grateful to Dr. Saeed Ahmad Nagra, Director, Institute of Chemistry,

University of the Punjab Lahore, for providing me research facilities during my research

work. I am indeed grateful to all teachers of Chemistry section, especially Dr. Jamil

Anwar Chaudhary for providing me good working environment and research facilities.

I would like to thank Higher Education Commission (HEC) of Pakistan for

providing me the necessary funds for carrying out my research project. I also

acknowledge HEJ Research Institute of Chemistry Karachi for facilitating me regarding

the spectral and biological analysis of my compounds.

I am thankful to Dr. Masoom Yasinzai, Institute of Biochemistry, University of

Balochistan, Quetta, Pakistan for leishmanicidal studies.

I am also grateful to Dr. Raymond F. Schinazi, Center for AIDS Research,

Veterans Affairs Medical Center and Department of Pediatrics, Emory University School

of Medicine, Decatur, Georgia 30033, USA, for evaluating the synthesized compounds

for anti-HIV-1 and cytotoxic activities.

I am highly grateful to my colleagues Mehmood Akbar Siddiqui, Shehzad Nasim,

Atif Yaqoob, Tafazzul Hussain Bhutta and Raja Rizwan Nazeer, Muhammad Tariq,

Hafeez-ur-Rehman, Muhammad Liaqat and Muhammad Sadiq Hussain for their

cooperation during my thesis write-up.

A

v

I would like to express my thanks to my friends and research fellows particularly

Mujahid Hussain Bukhari, Naveed Ahmed, Irfan Ashiq, Rana Amjad Ayyub Bhatti,

Amjid Iqbal, Khizar Iqbal Malik, Shehbaz Nazeer, Muhammad Azad, Rana Altaf

Hussain, Sheikh Muhammad Israr, Muhammad Shahid, Bushra Maliha and Mrs. Sana

Matloob and Ms. Zunera for their cooperation, good wishes and moral support during the

course of my research work.

I am highly thankful to my dearest, best friends and my research fellows Mr,

Waqar Nasir and Mr. Matloob Ahmad for enlightening me with their knowledge,

opinions and most importantly their precious time.

I am highly obliged and thankful to my parents, sisters and other family members

who guided and prayed for me in every step of my life and always believed in me to

complete the task. I specially wish to thank my daughter for her love and encouragement.

I hardly find words to thank my wife “Fehmina Jabeen” for her consistent

support, cooperation and sacrifice towards the successful completion of my works. I can

never forget her untiring efforts in every step of this project and my life.

Syed Umar Farooq Rizvi

vi

CONTENTS

Chapter-1 INTRODUCTION & LITERATURE SURVEY 1

1.1 Chalcones and their Chemistry 1

1.2 Natural sources of chalcones 2

1.2.1 Dietary Chalcones 6

1.3 Pharmacological Profile of chalcones 7

1.3.1 Antimalarial Chalcones 8

1.3.2 Antibacterial Chalcones 12

1.3.3 Antifungal Chalcones 16

1.3.4 Anti-inflammatory Chalcones 19

1.3.5 Antileishmanial Chalcones 22

1.3.6 Antiviral Chalcones 24

1.3.7 Antituberculous Chalcones 26

1.3.8 Antitrichomonal Chalcones 27

1.4 Applications in Synthetic Organic Chemistry 28

1.4.1 Oxidation of Chalcones 28

1.4.2 Reduction of Chalcones 29

1.4.3 Conversion of Chalcones to 1,5-Diketones 30

1.4.4 Conversion of Chalcones to Ferrocenyl Chalcones 30

1.4.5 Conversion of Chalcones to Imidazoles and Pyrimidines 31

1.4.6 Conversion of Chalcones to 2-Pyrazolines 32

1.4.7 Conversion of Chalcones to Isoxazoles 32

1.4.8 Conversion of Chalcones to Flavanones 33

1.4.9 Conversion of Chalcones to (±)-1-(5-aryl-3-pyridin-2-yl-4,5-

dihydro-pyrazol-1-yl)-2-imidazol-1-yl-ethanone 33

1.4.10 Conversion of Chalcones to 5-amino-1,3,4-thiadiazole-2-thiol

imines and imino-thiobenzyl1 34

1.4.11 Conversion of Chalcones to 2,4,6-trisubstituted pyrimidines 35

1.4.12 Reaction of Chalcones with Diethyl Malonate 36

vii

1.4.13 Reactions of Chalcones with Thiosemicarbazide 37

1.4.14 Conversion of Chalcones to Di- and Triphenylquinoline 37

1.4.15 Conversion of Chalcones to Chromones & Chromanones 38

1.4.16 Conversion of Chalcones to 5-aryl-1-isonicotinoyl-3-(pyridin-2-

yl)-4, 5-dihydro-1H-pyrazole Derivatives 39

1.4.17 Conversion of Chalcones to Pyrazolines by Ultrasound

Irradiation 39

1.4.18 Reaction of Chalcones with Pyridine-2-carboxamidrazone 40

1.4.19 Reaction of Chalcones with 4,5,6-Triaminopyrimidine 41

1.4.20 Synthesis of Coumarinyl Derivatives of Chalcones 41

1.5 Methods of Chalcone Synthesis 42

1.5.1 Conventional Method─Claisen-Schmidt Reaction 42

1.5.2 Microwave Assisted Synthesis of Chalcones 42

1.5.3 Ultrasound Irradiation Synthesis of Chalcones 43

1.5.4 Synthesis of Chalcones Using a Solid Base Catalyst 43

1.5.5 Synthesis of Chalcones Using PTC 44

1.6 Aim of the Project 45

1.7 Plan of Work and Experimental Schemes 49

1.7.1 Scheme─I 50

1.7.2 Scheme─II 51

1.7.3 Scheme─III 51

1.7.4 Scheme─IV 52

Chapter-2 EXPERIMENTAL 53

2.1 General 53

2.1.1 Substrates and Reagents 53

2.1.2 Solvents 53

2.1.3 Instruments 53

2.2 Methods of Preparation of Precursors for Chalcones 54

2.2.1 N-acetylation of Substituted Anilines 54

2.2.2 Synthesis of 2-Chloro-3-formylquinolines (1-4) (Method-A; 54

viii

Conventional Thermal Method)

2.2.3 Synthesis of 2-Chloro-3-formylquinolines (1-4) (Method-B;

Microwave Irradiation Method) 54

2.2.4 Method for N-arylation of Piperidine (9) (Scheme─III) 56

2.3 General Method for the Synthesis of Quinolinyl Chalcones (1a-

k, 2a-k, 3a-s and 4a-s) (Scheme─I) 56

2.3.1 (2E)-3-(2-Chloro-8-methylquinolin-3-yl)-1-thien-3-ylprop-2-en-

1-one (1a) 56

2.3.2 (2E)-3-(2-Chloro-8-methylquinolin-3-yl)-1-(3-methylthien-2-

yl)prop-2-en-1-one (1b) 57


yl)prop-2-en-1-one (1c) 58


yl)prop-2-en-1-one (1d) 58

2.3.5 (2E)-3-(2-Chloro-8-methylquinolin-3-yl)-1-(2,5-dimethylthien-

3-yl)prop-2-en-1-one (1e) 59

2.3.6 (2E)-3-(2-Chloro-8-methylquinolin-3-yl)-1-(3-chlorothien-2-

yl)prop-2-en-1-one (1f) 60


yl)pr2.3.8 (2E)-3-(2-Chloro-8-methylquinolin-3-yl)-1-(2,5-

dichlorothien-3-yl)prop-2-en-1-one (1h) op-2-en-1-one (1g)

61

2.3.8 (2E)-3-(2-Chloro-8-methylquinolin-3-yl)-1-(2,5-dichlorothien-

3-yl)prop-2-en-1-one (1h) 61

2.3.9 (2E)-1-(3-Bromothien-2-yl)-3-(2-chloro-8-methylquinolin-3-

yl)prop-2-en-1-one (1i) 62


yl)prop-2-en-1-one (1j) 63

2.3.11 (2E)-3-(2-Chloro-8-methylquinolin-3-yl)-1-(5-iodothien-2-

yl)prop-2-en-1-one (1k) 63


1-one (2a) 64

ix












yl)prop-2-en-1-one (2g) 68

2.3.19 (2E)-3-(2-Chloro-7-methylquinolin-3-yl)-1-(2,5-dichlorothien-3-

yl)prop-2-en-1-one (2h) 69








1-one (3a) 71









2.3.28 (2E)-3-(2-Chloro-6-methylquinolin-3-yl)-1-(3-chlorothien-2- 75

x

yl)prop-2-en-1-one (3f)




3-yl)prop-2-en-1-one (3h) 76







2.3.34 (2E)-3-(2-Chloro-6-methylquinolin-3-yl)-1-(1H-pyrrol-2-

yl)prop-2-en-1-one (3l) 81

2.3.35 (2E)-3-(2-Chloro-6-methylquinolin-3-yl)-1-(5-methyl-2-

furyl)prop-2-en-1-one (3m) 81

2.3.36 (2E)-3-(2-Chloro-6-methylquinolin-3-yl)-1-(2,5-dimethyl-3-

furyl)prop-2-en-1-one (3n) 84

2.3.37 (2E)-1-(1-Benzofuran-2-yl)-3-(2-chloro-6-methylquinolin-3-

yl)prop-2-en-1-one (3o) 84

2.3.38 (2E)-3-(2-Chloro-6-methylquinolin-3-yl)-1-(2,3-dihydro-1,4-

benzodioxin-6-yl)prop-2-en-1-one (3p) 85

2.3.39 (2E)-3-(2-Chloro-6-methylquinolin-3-yl)-1-(1-naphthyl)prop-2-

en-1-one (3q) 88


en-1-one (3r) 91

2.3.41 (2E)-1-(9-Anthryl)-3-(2-chloro-6-methylquinolin-3-yl)prop-2-

en-1-one (3s) 91

2.3.42 (2E)-3-(2-Chloro-6-methoxyquinolin-3-yl)-1-thien-3-ylprop-2-

en-1-one (4a) 92

2.3.43 (2E)-3-(2-Chloro-6-methoxyquinolin-3-yl)-1-(3-methylthien-2-


xi





2.3.46 (2E)-3-(2-Chloro-6-methoxyquinolin-3-yl)-1-(2,5-

dimethylthien-3-yl)prop-2-en-1-one (4e) 95

2.3.47 (2E)-3-(2-Chloro-6-methoxyquinolin-3-yl)-1-(3-chlorothien-2-





dichlorothien-3-yl)prop-2-en-1-one (4h) 97

2.3.50 (2E)-1-(3-Bromothien-2-yl)-3-(2-chloro-6-methoxyquinolin-3-




2.3.52 (2E)-3-(2-Chloro-6-methoxyquinolin-3-yl)-1-(5-iodothien-2-


2.3.53 (2E)-3-(2-Chloro-6-methoxyquinolin-3-yl)-1-(1H-pyrrol-2-

yl)prop-2-en-1-one (4l) 99

2.3.54 (2E)-3-(2-Chloro-6-methoxyquinolin-3-yl)-1-(5-methyl-2-

furyl)prop-2-en-1-one (4m) 100

2.3.55 (2E)-3-(2-Chloro-6-methoxyquinolin-3-yl)-1-(2,5-dimethyl-3-

furyl)prop-2-en-1-one (4n) 101

2.3.56 (2E)-1-(1-Benzofuran-2-yl)-3-(2-chloro-6-methoxyquinolin-3-

yl)prop-2-en-1-one (4o) 101

2.3.57 (2E)-3-(2-Chloro-6-methoxyquinolin-3-yl)-1-(2,3-dihydro-1,4-

benzodioxin-6-yl)prop-2-en-1-one (4p) 102

2.3.58 (2E)-3-(2-Chloro-6-methoxyquinolin-3-yl)-1-(1-naphthyl)prop-

2-en-1-one (4q) 103

2.3.59 (2E)-3-(2-Chloro-6-methoxyquinolin-3-yl)-1-(2-naphthyl)prop- 103

xii

2-en-1-one (4r)

2.3.60 (2E)-1-(9-Anthryl)-3-(2-chloro-6-methoxyquinolin-3-yl)prop-2-

en-1-one (4s) 104

2.4 General Method for the Synthesis of 2-Pyrazolines (5a-k, 6a-k,

7a-s and 8a-s) (Scheme─II) 105

2.4.1 2-Chloro-8-methyl-3-(3-thiophen-3-yl-4,5-dihydro-1H-pyrazol-

5-yl)quinoline (5a) 105

2.4.2 2-Chloro-8-methyl-3-[3-(3-methylthiophen-2-yl)-4,5-dihydro-

1H-pyrazol-5-yl]quinoline (5b) 106


1H-pyrazol-5-yl]quinoline (5c) 107


1H-pyrazol-5-yl]quinoline (5d) 107

2.4.5 2-Chloro-3-[3-(2,5-dimethylthiophen-3-yl)-4,5-dihydro-1H-

pyrazol-5-yl]-8-methylquinoline (5e) 108

2.4.6 2-Chloro-3-[3-(3-chlorothiophen-2-yl)-4,5-dihydro-1H-pyrazol-

5-yl]-8-methylquinoline (5f) 109


5-yl]-8-methylquinoline (5g) 110

2.4.8 2-Chloro-3-[3-(2,5-dichlorothiophen-3-yl)-4,5-dihydro-1H-

pyrazol-5-yl]-8-methylquinoline (5h) 110

2.4.9 3-[3-(3-Bromothiophen-2-yl)-4,5-dihydro-1H-pyrazol-5-yl]-2-

chloro-8-methylquinoline (5i) 111


chloro-8-methylquinoline (5j) 112

2.4.11 2-Chloro-3-[3-(5-iodothiophen-2-yl)-4,5-dihydro-1H-pyrazol-5-

yl]-8-methylquinoline (5k) 113





xiii










5-yl]-7-methylquinoline (6g) 118





















2.4.29 2-Chloro-3-[3-(5-chlorothiophen-2-yl)-4,5-dihydro-1H-pyrazol- 126

xiv

5-yl]-6-methylquinoline (7g)









2.4.34 2-Chloro-6-methoxy-3-(3-thiophen-3-yl-4,5-dihydro-1H-

pyrazol-5-yl)quinoline (8a) 129

2.4.35 2-Chloro-6-methoxy-3-[3-(3-methylthiophen-2-yl)-4,5-dihydro-







pyrazol-5-yl]-6-methoxyquinoline (8e) 132


5-yl]-6-methoxyquinoline (8f) 133


5-yl]-6-methoxyquinoline (8g) 133


pyrazol-5-yl]-6-methoxyquinoline (8h) 134


chloro-6-methoxyquinoline (8i) 135


chloro-6-methoxyquinoline (8j) 135


yl]-6-methoxyquinoline (8k) 136

xv

2.5 General Method for the Synthesis of Piperidinyl Chalcones

(9a─l) (Scheme─III) 137

2.5.1 (2E)-3-(4-Piperidin-1-ylphenyl)-1-thiophen-2-ylprop-2-en-1-one

(9a) 137

2.5.2 (2E)-3-(4-Piperidin-1-ylphenyl)-1-thiophen-3-ylprop-2-en-1-one

(9b) 138

2.5.3 (2E)-1-(3-Methylthiophen-2-yl)-3-(4-piperidin-1-ylphenyl)prop-

2-en-1-one (9c) 139


2-en-1-one (9d) 139


2-en-1-one (9e) 140

2.5.6 (2E)-1-(2,5-Dimethylthiophen-3-yl)-3-(4-piperidin-1-

ylphenyl)prop-2-en-1-one (9f) 141

2.5.7 (2E)-1-(3-Chlorothiophen-2-yl)-3-(4-piperidin-1-ylphenyl)prop-

2-en-1-one (9g) 141


2-en-1-one (9h) 142

2.5.9 (2E)-1-(2,5-Dichlorothiophen-3-yl)-3-(4-piperidin-1-

ylphenyl)prop-2-en-1-one (9i) 143

2.5.10 (2E)-1-(3-Bromothiophen-2-yl)-3-(4-piperidin-1-ylphenyl)prop-

2-en-1-one (9j) 143


2-en-1-one (9k) 144

2.5.12 (2E)-1-(5-Iodothiophen-2-yl)-3-(4-piperidin-1-ylphenyl)prop-2-

en-1-one (9l) 145

2.6 General Method for the Synthesis of 2-Pyrazolines of 4-

piperidin-1-ylbenzaldehyde (10a─l) (Scheme─IV) 145

2.6.1 1-[4-(3-Thiophen-2-yl-4,5-dihydro-1H-pyrazol-5-

yl)phenyl]piperidine (10a) 146

2.6.2 1-[4-(3-Thiophen-3-yl-4,5-dihydro-1H-pyrazol-5- 146

xvi

yl)phenyl]piperidine (10b)

2.6.3 1-{4-[3-(3-Methylthiophen-2-yl)-4,5-dihydro-1H-pyrazol-5-

yl]phenyl}piperidine (10c) 147


yl]phenyl}piperidine (10d) 148


yl]phenyl}piperidine (10e) 148

2.6.6 1-{4-[3-(2,5-Dimethylthiophen-3-yl)-4,5-dihydro-1H-pyrazol-5-

yl]phenyl}piperidine (10f) 149

2.6.7 1-{4-[3-(3-Chlorothiophen-2-yl)-4,5-dihydro-1H-pyrazol-5-

yl]phenyl}piperidine (10g) 150


yl]phenyl}piperidine (10h) 150

2.6.9 1-{4-[3-(2,5-Dichlorothiophen-3-yl)-4,5-dihydro-1H-pyrazol-5-

yl]phenyl}piperidine (10i) 151

2.6.10 1-{4-[3-(3-Bromothiophen-2-yl)-4,5-dihydro-1H-pyrazol-5-

yl]phenyl}piperidine (10j) 152


yl]phenyl}piperidine (10k) 152

2.6.12 1-{4-[3-(5-Iodothiophen-2-yl)-4,5-dihydro-1H-pyrazol-5-

yl]phenyl}piperidine (10l) 153

2.7 Protocols for Biological Studies 154

2.7.1 Antimicrobial Assay 154

2.7.2 Antileishmanial Assay 154

2.7.3 Determination of IC50 values of the titled compounds (1a-k, 2a-

k, 3a-s, 4a-s, 5a-k, 6a-k and 9a-l) 155

2.7.4 Anti-HIV-1 Assay 155

2.7.5 Cytotoxic Assay 155

2.7.6 Determination of EC50 and EC90 156

2.8 X-Ray Crystallography 156

xvii

Chapter-3 RESULTS & DISCUSSION 158

3.1 Chemistry of Quinolyl Chalcones and their 2-Pyrazoline

Derivatives 158

3.1.1 Chemistry of Quinolyl Chalcones (1a-k, 2a-k, 3a-s and 4a-s) 158

3.1.2 Chemistry of Pyrazolines of Quinolyl Chalcones (5a-k, 6a-k, 7a-

k and 8a-k) 160

3.2 Chemistry of Piperidyl Chalcones and their 2-Pyrazoline

Derivatives 162

3.2.1 Chemistry of Piperidyl Chalcones (9a-l) 162

3.2.2 Chemistry of Pyrazolines of Piperidyl Chalcones (10a-l) 163

3.3 Biological Activities of Chalcones 164

3.3.1 Antimicrobial Studies of Quinolyl Chalcones (3a-s and 4a-s) 165

3.3.2 Antileishmanial Studies of Quinolyl Chalcones (3a-s and 4a-s) 167

3.3.3 Antileishmanial Studies of Quinolyl Chalcones (1a-k and 2a-k)

and their 2-pyrazoline derivatives (5a-k and 6a-k) 169

3.3.4 Anti-HIV-1 and Cytotoxic Studies of 2-Pyrazoline Derivatives

of Quinolyl Chalcones (5a-k and 7a-k) 171

3.3.5 Antileishmanial Studies of Piperidyl Chalcones (9a-l) 172

3.3.6 Cytotoxic Studies of Piperidyl Chalcones and their 2-Pyrazoline

Derivatives (10a-l) 172

3.4 Achievements and Problems 175

3.5 Conclusion 175

3.6 Future Perspectives 177

BIBLIOGRAPHY 178

LIST OF PUBLICATIONS 193

xviii

LIST OF TABLES

Page No

Table 1 Natural sources of chalcones and their derivatives 3

Table 2 Contents of dihydrochalcones in apple juices and other apple

products 7

Table 3 Experimental results of MW irradiation synthesis of chalcones 43

Table 4 Experimental results of synthesis of chalcones using HT-OtBu

catalyst 44

Table 5 A comparison of the methods producing chloroquinoline-

carbaldehyde, in terms of yields & reaction kinetics 55

Table 6 Results of antimicrobial activity of compounds 3a-s and 4a-s 165

Table 7 Results of antileishmanial activity of the series 3a-s and 4a-s 167

Table 8 Results of antileishmanial activity of the series 1a-k, 2a-k, 5a-k and

6a-k 169

Table 9 Results of anti-HIV-1 activity in human PBM cells and cytotoxicity

of the series 5a-k and 7a-k 171

Table 10 Results of antileishmanial activity of the series 9a-l 172

Table 11 Results of anti-HIV-1 activity and cytotoxicity of the Series 9a-l

and 10a-l 173

Table 12 Significantly active antimicrobial agents 176

Table 13 Categories of antileishmanial chalcones (1a-k, 2a-k, 3a-s, 4a-s and

9a-l) 176

Table 14 Categories of antileishmanial pyrazoline derivatives 5a-k and 6a-k 177

Table 15 Categories of antiviral/cytotoxic compounds 5a-k, 7a-k, 9a-l and

10a-l 177

xix

LIST OF FIGURES

Page No.

Figure 1 1,3-Diphenyl-2-propene-1-one or chalcone 1

Figure 2 Mesityl oxide 1

Figure 3 Conversion of flavone to chalcone 2

Figure 4 Structures of chalcone based drugs 45

Figure 5 Structures of quinoline based drugs 46

Figure 6 Structures of two piperidine-based drugs 47

Figure 7 Structures of some thiophene based drugs 47

Figure 8 Structures of some thiophene based drugs 48

Figure 9 Synthesis of quinolinyl chalcones 50

Figure 10 Synthesis of 2-pyrazoline derivatives of chalcones 51

Figure 11 Synthesis of piperidyl chalcones 51

Figure 12 Conversion of piperidyl chalcones to 2-pyrazoline derivatives 52

Figure 13 ORTEP diagram of compound 3k 79

Figure 14 ORTEP diagram of compound 3m 82

Figure 15 ORTEP diagram of compound 3p 86

Figure 16 ORTEP diagram of compound 3q 89

xx

LIST OF ABBREVITIONS

HIV-1 Human immunodeficiency virus type 1

DMSO Dimethylsulphoxide

DMF Dimethylformamide

MeOH Methanol

EtOH Ethanol

FDA Food and Drug Administration

EU European Union

DHC’s Dihydrochalcones

RBC’s Red Blood Cells

MIC Minimum Inhibitory Concentration

GST’s Glutathione-S-transferase

HIV Human immunodeficiency virus

TB Tuberculosis

TN Thallic Nitrate

THF Tetrahydrofuran

DCM Dichloromethane

PTC Phase Transfer Catalyst

AcOEt Ethyl acetate

CDCl3 Deuterated Chloroform

CTAB Cetyltrimethylammonium bromide

NSAID Non-steroidal Anti-inflammatory Drug

TLC Thin Layer Chromatography

MW

HEPES

Microwave

4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid

AIDS Acquired immunodeficiency syndrome

xxi

SUMMARY

Four series, consisting of sixty (60) new heterocyclic chalcones were

synthesized by the condensation of methyl/methoxy substituted formylquinolines

with various substituted heteroaromatic ketones. The precursors

(formylquinolines) were prepared by Vilsmeier Haack formylation of substituted

acetanilides, which in turn were synthesized by N-acetylation of various

substituted anilines with the help of acetic acid in the presence of ortho

phosphoric acid. Another series of piperidyl-thienyl chalcones was synthesized.

For this purpose, the precursor 4-piperidin-1-ylbenzaldehyde was prepared by N-

arylation of piperidine with 4-fluorobenzaldehyde in the presence of K2CO3 and a

phase transfer catalyst CTAB in DMF solvent. The 4-piperidin-1-ylbenzaldehyde

was then condensed with various thienyl ketones in alkaline medium with

constant stirring at room temperature to give the fifth series consisting of twelve

(12) new chalcones. The ketoethylinic group of chalcones was then cyclized into

2-pyrazolines by refluxing them with hydrazine hydrate in ethanolic solution. In

this way fifty six (56) new pyrazoline derivatives of chalcones were obtained.

Finally all of the synthesized compounds (128 in number) were screened for their

antibacterial, antifungal, antileishmanial, anti-HIV-1 and cytotoxic activities.

Many of the prepared chalcones as well as their 2-pyrazoline derivatives were

proved to be potent biologically active compounds.

Chapter – 1

Chapter -1 Introduction & Literature Survey

1

Chapter 1

INTRODUCTION & LITERATURE SURVEY

1.1 Chalcones and their Chemistry

Chalcone is the trivial name given to the α,β-unsaturated ketones obtained by

condensing an aromatic aldehyde with an aryl methyl ketone in the presence of a

base. They are designated structurally as Ar CH=CHC(O) Ar´ and their IUPAC name

is 1,3-Diphenyl-2-propene-1-one.1 The substituents attached to the benzene rings of

chalcone are numbered as shown in the figure below (Figure 1).

O

R1 B A R2

23

4

6 6'

5'

4'

3'

2'

5

Figure 1. 1,3-Diphenyl-2-propene-1-one or chalcone

In this structure, the group ─CH=CHC(=O)─ is known as the chalcone

functionality or chalcone moiety or ketoethylenic group.2 Due to this functionality,

chalcones are also called α,β-unsaturated carbonyl systems or α,β-unsaturated

ketones. The parent member of the chalcone series is benzylideneacetophenone. Other

names given to chalcone are phenyl styryl ketone, β-phenylacrylophenone, γ-oxo-α, γ-

diphenyl-α-propylene, and α-phenyl-β-benzoylethylene.3 The term “chalcone” was

first used by Kostanecki.4 All the α,β-unsaturated ketones are not necessarily be

chalcones but all the chalcones are α,β-unsaturated ketones e.g. Mesityl oxide (Figure

2) is an α,β-unsaturated ketone (but not a chalcone) with the formula

CH3C(O)CH=C(CH3)2. This compound is a colorless, volatile liquid with a strong

peppermint odor.5

O

Figure 2. Mesityl oxide

http://en.wikipedia.org/wiki/Carbonyl#.CE.B1.2C.CE.B2-Unsaturated_carbonyl_compounds

http://en.wikipedia.org/wiki/Liquid

http://en.wikipedia.org/wiki/Peppermint


2

The difference is the “aromaticity” on position 1 and 3 of the α,β-unsaturated

carbonyl system. If the groups attached to ─CH=CHC(=O)─ moiety do not possess

aromaticity, then the resulting compound is just α,β-unsaturated ketone and not the

chalcone.

Chalcones have a diverse array of groups on the two aromatic rings of 1,3-

Diaryl-2-propene-1-one, as shown in the Figure1 above, where the substituents R1 and

R2 may be same or different and they may be present anywhere on the two rings.

Moreover, R1 or R2 may not necessarily be a single substituent i.e. more than one

substituent may be present on any of the two rings. Also, the two aromatic rings may

be homocyclic or heterocyclic.6,7

Chalcones belong to flavonoid family. Structurally, chalcones are open-chain

flavonoids, which were derived by the cleavage of the C ring in the flavonoids,7 as

shown below (Figure 3).

O

O

AR

B R'

C

OH

O

AR

B R'

Figure 3. Conversion of flavone to chalcone

1.2 Natural sources of chalcones

Chalcones are abundantly present in nature, from ferns to higher plants.

During 1960‟s and 70‟s many chalcones have been reported to be isolated from the

various parts of plants: buds, leaves, blossoms, heart wood, roots, seeds, flowers, and

inflorescence. These compounds exist both in free and combined states either in the

form of chalcones or glycosides respectively. These compounds have been found to

carry many different substituents like methyl, isopentyl, methoxy and hydroxyl,

which may be present either on ring A and/or ring B of the chalcone molecule. Many

higher plants have been found to contain dihydrochalcones, as given in the table 1.8


3

Table 1. Natural sources of chalcones and their derivatives

No Plant Source Chalcones/ Derivatives of Chalcones Ref

1 Alpinia

speciosa

(seeds)

OH OH

OMeO

2‟,4‟-Dihydroxy-6‟-methoxychalcone (Cardamonin)

9

2 Angelica keiskei

(roots)

O

OH

OH

MeO

Hydroxyderricin

10

3 Coreopsis

tinctoria

(ray flowers)

OH

OH

O

OH

OH

Glu-O

4‟-glucocidoxy-2‟,3‟,3,4-tetrahydroxychalcone (marein)

11

4 Gossypium

hirsutum

“Cotton”

(flowers)

O

OHOHMeO

O

OHOH

OH

O

H

OHH

H

H

6‟-glucocidoxy-2‟,4-dihydroxychalcone

12

5 Cryptocarya

bourdilloni

(roots)

O

OH

OH

H

O

5-hydroxy-4-[(2E)-3-phenylprop-2-enoyl]- 3a,7a-dihydro-1-benzofuran-2(3H)-one

13

14


4

6 Flemingia

stricta

(leaves)

O

OHOH

(2E)-1-[2,4-dihydroxy-3-(3-methylbut-2-en-1-yl) phenyl]-3-phenylprop-2-en-1-one

15

7 Flemingia

congesta

(Inflorescences)

O

OHOH

OH

O

(Chromenochalcone)

16

8 Flemingia

wallichii

(leaves)

OH

OH

O

R1

R2

OH

OH

Homoflemingin: R1

= H, R2 = OMe

Flemiwallichin: R1

= OMe, R2 = H

17

9 Gnaphalium

affine

(flowers) O

OHOH

OH

O

H

OHH

H

H

O

OH

OH

OH

OMe

4‟-glucocidoxy-3‟,6,4-trihydroxychalcone

18

10 Lindera

umbellate

(leaves)

O OH

OH OMe

2‟,6‟-Dihydroxy-4‟-methoxychalcone

19


5

11 Lonchocarpus

sericeus

(seeds and

roots)

O

OH

OH

O

(2E)-1-(5-hydroxy-2,2-dimethyl-2H-chromen-6-yl)- 3-(4-hydroxyphenyl)prop-2-en-1-one

20

12 Myrica gale

(fruits)

O OH

OH OMe

CH3

CH3

2‟,6‟-Dihydroxy-4‟-methoxy-3‟,5‟-dimethyldihydro-

Chalcone

21

13 Prunus cerasus

L.

(heart wood)

O OMe

OH OMeOMeMeO

2‟-Hydroxy-2,4,4‟,6‟-tetramethoxychalcone (cerasidin);

O OMe

OH OHOMeMeO

2‟,4‟-Dihydroxy-2,4,6‟-trimethoxychalcone (cerasin)

22

14 Psorelea

corylifolia

(seeds)

O

OMe

4‟-O-methylchalcone O OH

OH OMeOH

CHO

5‟-Formyl-2‟,4-dihydooxy-4‟-methoxychalcone

23,

24


6

15 Glycyrrhiza

glabra

(root bark)

O

OH

OH

OMe

OH

(2E)-3-(3,4-dihydroxy-2-methoxyphenyl)-1-

(4-hydroxyphenyl)prop-2-en-1-one

25

1.2.1 Dietary Chalcones

Chalcones is one of the major classes of natural products which are widely

distributed in spices, tea, beer, fruits and vegetables and have been recently a subject

of great interest for their pharmacological activities.26

According to Francisco A. et al. the major dietary source of dihydrochalcones

is apples.27

The US FDA (Food and Drug Administration) and EU (European Union)

have approved the neohesperidin dihydrochalcone to be used as sweetener in various

foods like non-alcoholic soft drinks, desserts and confectionery etc. at concentrations

in the range 10-400 mg kg-1

(or mg l-1

),28

or as a flavor modifier at concentrations of

up to 5 mg kg-1

.29

Native chalcone glycosides tend to convert to flavanone glycosides during

extraction. Due to this characteristic, chalcones by themselves have limited

occurrence in foods. Naringenin chalcone is found in tomato skin but it is present in

traces in its juice, paste and ketchup.30-33

Mixtures of retrochalcones (e.g. echinatin,

licochalcones A and B) are present in licorice (liquorice) root (Glycyrrhiza spp) and

some medicines based on licorice. Also, the confectionery containing licorice root

extracts, might contain these chalcones.34-38

Similarly prenyl-chalcones (e.g.

xanthohumol, desmethylxanthohumol) occur in hops and beer.39

Mixture of

Flavanone-chalcone (e.g. cerasinone, cerasin) have also been shown to exist in Prunus

spp.40

Dihydrochalcones (DHCs) are characteristic of apples and derived products

(apple juice, cider, pomace, etc).

Phloretin 2'-glucoside (phloridzin) content of apples varies widely depending

upon the cultivar.41-43

Some English cider apples contain phloridzin as much as 190

mgkg-1

, while cultivar Verde Doncella contains less than 0.1 mgkg-1

.44

They are

present in the skin, pulp and especially the seeds, but the skin is 5-10 times richer than

that of flesh.45


7

While eating an apple, we usually discard its core and seeds, thus some of the

apple dihydrochalcones are not ingested. If fruits are eaten without peel, then the

DHC‟s intake is smaller.

Table 2. Contents of dihydrochalcones in apple juices and other apple products.

Values are mg L-1

(juices) or mg kg-1

(jams, etc)__________________________

Content (mg L-1

or mg kg-1

as appropriate)

Commodity and method of preparation Phloridzin Total DHC _ Juice (domestic extractor) 4.4 8.4

Juice (experimental) 13-18 40-51

Juice (experimental) 5.4 9.2

Juice (commercial) 2.7-3.3 4.8-5.6

Jam (commercial) 2.3 4.0

Compote (commercial) 9.1 14.3

Jelly (commercial) 1.0 1.4

Juice (domestic extractor) 4 9

Juice commercial clear 38 72

Juice commercial cloudy 12 39

Mash commercial 33 86

Nectar commercial 12 29

Juice (domestic) 83-196 97-223

_________________________________________________________________

The DHCs contents in clear or cloudy commercial apple juices may be 5-10

times more than those in the juices obtained in a domestic juice extractor.46

This is

due to the fact that in industrial process, the whole apples (seeds, core and peels) are

extracted and the use of thermal treatments make the degrading enzymes

(polyphenoloxidases) inactive, which is clear from the table 2.47

1.3 Pharmacological Profile of chalcones

Chalcones, either natural or synthetic, are known to exhibit a broad spectrum

of various biological activities. The presence of α,β-unsaturated carbonyl moiety as

well as of substituted aromatic rings render the chalcones biologically active. Some

substituted chalcones and their derivatives, including some of their heterocyclic

analogues have been reported to possess strong biological properties which have been

proved detrimental to the growth of microbes,48,49

tubercle bacilli,50,51

malarial

parasites52

and intestinal worms.53`

Many chalcones have been claimed to be toxic to

various animals54,55

and insects56,57

and have also shown inhibitory effects on several

enzymes58,59

and herbaceous plants.60

A few major biological activities which have

been reported to be associated with chalcones include: anti-inflammatory,61,62


8

antifungal,63-66

antioxidant,67-70

antimalarial,71-74

antituberculosis,75

analgesic,76

anti-

HIV77

and antitumor activities77-79

. Some of them act as anticancer,80

antiviral,81

and

anti-AIDS agents.82

Quinoline-based chalcones have been reported to possess

antimalarial activity.83

1.3.1 Antimalarial Chalcones

Malaria is becoming a major public health problem in more than one hundred

tropical and subtropical countries of the world. An estimated 400 to 900 million

people are affected by it each year, and it causes one to three million deaths

annually.84,85

The causal organisms of human malaria are following protozoan

parasites: Plasmodium falciparum, P. malariae, P. vivax and P. ovale. However, P.

falciparum is the most pervasive of these, and it causes about 80% of infections and

90% of deaths.86

Many drugs have been developed for the treatment of malaria, of

which chloroquine is most commonly used, but P. falciparum has become resistant to

conventional antimalarial drugs, and the search for new antimalarial drugs is still

underway.87,88

(16) R1R

2= H R

3= CF 3

R1

R2

O

H3CO

OCH 3

(18) R1R

2= OCH3

(20) R1= H R

2= CF 3

(21) R1R

2= F

(19) R1= H R

2= C2H5

R1

R3

R2

O

H3CO

OCH 3

H3CO

(17) R1R

3= Cl R

2= H

According to Liu et al.89

and Go et al.,90

the properties of ring „A‟ of

chalcones, determine the in vitro antimalarial activity against human malarial parasite,

P. falciparum. The important parameters are the size as well as the hydrophobicity of

the substituents. For instance, the alkoxylated chalcones 16-21 (IC50 < 6.5 μM) were

proven to be more active than their corresponding hydroxylated derivatives.

The compound 22, among the hydroxylated chalcones, was found to be the

most active (IC50= 12.3 μM). The IC50 values of other hydroxylated chalcones 23-26

were below 20 μM.


9

R2

O

OHR

1

OOH

OH

R4

R3

R2

R1

(22) R1R

2R

4= H R

3= Cl

(23) R1R

3= F R

2R

4= H

(24) R1= pyridinyl R

2R

3R

4= H

(26) R1= H R

2= N(CH 3)2

(25) R1R

2= Cl

Inhibitors of sorbitol-induced hemolysis of RBCs have been proven to be good

antiplasmodial agents as well. The mode of action of alkoxylated and those of

hydroxylated chalcones is also the same. They seem to inhibit sorbitol-induced

hemolysis of infected erythrocytes at a concentration of 10 μM.90

Yenesew et al.91

have reported the antiplasmodial activity of 27-29 with IC50

10.3-16.1 μM.

O

OH

OH

OH

OH

(27) 5-prenylbutein

OCH3

OH

O

OH

(28) Licoagrochalcone A

OH

OOH

OH

OCH 3

(29) Homobutein

Domínguez et al.92

reported phenylurenyl chalcone derivatives, with

substitution in ring B (IC50 = 1.76-10 μM) as potent growth inhibitors against in vitro

cultured P. falciparum. The data suggests that the activity depends on the substituents

on ring B. The para-position in the urenyl ring of 4‟-phenylurenyl chalcones 30-32

plays a crucial role in their antimalarial activity e.g. chloro-substituted compounds at

this position showed good activity.

O

N N

R1

O

R3

R2

R4

HH

Cl

(30) R1R

3= Cl R

2R

4= H

(31) R1R

3= F R

2R

4= H

(32) R1= H R

2R

3R

4= OCH3


10

3‟-phenylurenylchalcone derivatives 33-36 displayed better activity than

corresponding 4‟-phenylurenyl chalcones.92

(33) R2R

3R

4= OCH3 R

1= H

(34) R1R

3= Cl R

2R

4= H

(35) R1R

2R

4= H R

3= CH3

R1

O

R3

R2

R4

O

N N

HH

(36) R1R

4= H R

2R

3= OCH3

An outstanding antimalarial agent 37 was reported by Chen et al.93

which

exhibited antimalarial activity not only against human (in vitro) but also against

rodent (in vivo) parasites without any toxicity.

H9C4O

OCH 3

O

OCH 3

(37)

Naturally occurring chalcone crotaorixin (38) isolated from Crotalaria

orixensis has 100% inhibitory effect on the maturation of P. falciparum parasites at

concentrations 50 μg/ml and 10 μg/ml from ring stage to schizont stage. Medicagenin

(39) is a diprenylated chalcone, extracted from Crotalaria medicagenia roots showed

100% inhibition at 2.0 μg/ml.94


11

OH

O

OH

OCH 3

OH

(38) crotaorixin

OH

O

OH

OH

(39) medicagenin

Chromenodihydrochalcones (100, 40 and 41) extracted from Crotalaria

ramosissima were proved to be weaker antimalarial agents.94

OH

OOH

O

CH3

CH3

(100)

(40) R1= H R

2= OCH3

OH O

R2

R1OCH3

CH3

(41) R1R

2= OH

(42) xanthohumol

OCH 3 O

OH

OH

OH

Prenylated chalcone (xanthohumol, 42), isolated from hops (Humulus

lupulus), was screened for antiplasmodial activity by Frölich et al.95

against poW

(chloroquine-sensitive strain) and Dd2 (Multiresistant clone), exhibited significant

activity (IC50 = 8.2 ± 0.3 and 24.0 ± 0.8 μM for poW and Dd2 respectively)


12

N Cl

MeO

MeO

O

ClCl

(43)

Domínguez et al.96

reported the synthesis of twelve novel quinolyl chalcones

and found their biological activity against a chloroquine resistant strain of P.

falciparum. Only the compound (2E)-3-(2-chloro-6,7-dimethoxyquinolin-3-yl)-1-

(2,4-dichlorophenyl)prop-2-en-1-one (43) was found to be the most promising

compound with IC50 = 19.0 μM.

MeO

MeO

O

OMeOH

(44)

Lim et al.97

prepared twenty derivatives of flavonoids and chalcones. In the

chalcone series the compound (44) was found to be the most active, EC50 = 1.0 μg/mL

with 100% inhibition against P. falciparum and at the final concentration of 5.4

μg/ml.

1.3.2 Antibacterial Chalcones

Antibacterial activity of chalcones is being studied extensively. Researchers

have not only identified the structures of the bactericidal chalcones, isolated from

various plants, but have also synthesized or modified them. The antibacterial effects

depend upon the binding of the chalcone moiety to a nucleophilic group, like thiol

group of an essential protein98

(An essential protein is a protein that cannot be

synthesized de novo by the organism, usually referring to humans, and therefore must

be supplied in the diet.) The increase in the number of multi-drug resistant

microorganisms, has reached to an alarming level all over the world. Many resistant

strains of Staphylococcus aureus and other antibiotic-resistant pathogenic bacteria

have already been reported. A series of quinolinyl chalcones have been tested for

their in vitro antibacterial activity against different strains of gram negative and gram


13

positive bacteria, which have shown significant activity aginst Staphylococcus aureus,

Bacillus subtilis, Escherichia coli and Salmonella typhosa.99

Retrochalcones (chalcones which do not have an oxygen function at the 2-

positin) isolated from Glycyrrhiza inflata e.g. licochalcone A (45) and licochalcone C

(46) have been found to possess potent antibacterial activity especially to

Staphylococcus aureus, Bacillus subtillis and Micrococcus luteus.98

Kromann et al.100

observed that the free hydroxyl group at 4‟-posision in ring A is responsible for the

antibacterial effect of licochalcone A.

O

OH

OCH 3

OH

CH3

CH3

Licochalcone A

O

OH

OCH 3

OH

CH3

CH3

Licochalcone C

(45) (46)

Conversely, the activity of (45), with hydroxyl group at position 4 of ring B

has not affected if the hydroxyl group is replaced by chloro group (47, MIC= 10 μΜ

against S. aureus), or blocked by a methyl group or even removed permanently.

Complete elimination of activity has been observed when both the hydroxyl groups

are either removed or blocked by methylation. Also the removal of the lipophilic

prenyl group results in the total loss of activity.100

OCH 3

R2

R1

O

OH

(47) R1= C(CH 3)2CH=CH 2 R

2=Cl

(48) R1= C6H13 R

2=OH


14

A more potent chalcone (48) than licochalcone A (45) results by the

incorporation of a longer hexyl group which means that a direct relationship is present

between the lipophilicity and bactericidal activity.100

Compound 49-52 form a novel class of chalcones due to the presence of

aliphatic amino substituents.101

Aliphatic amines positioned in the ring A, has a minor

effect on the activity. The activity is not affected by the distance between aliphatic

amino group and the aromatic ring A, whereas in case ring B, this distance plays an

important role towards the activity. The most potent compound in this study is 49

(MIC= 2 μM against methicillin-resistant S. aureus, and MIC= 5 μΜ against E.

faecium and E. coli). Again the lipophilicity is an important parameter that controls

the antibacterial activity in chalcones. Another property observed, is the bulkiness of

the substituent in position 5 of ring B. There observed a direct relationship between

the antibacterial activity and the bulkiness of the substituent in position 5 of ring B.

(50) R1= 4-methylpiperazine R

3= NHCH2CH2N(CH)3 R

2R

4= H

(51) R1= OCH2CH2N(CH3)2 R

2= F R

3= H R

4= OCH3

(52) R1= OCH2CH2N(CH3)2 R

2= CH2N(CH3)2 R

3= H R

4= OCH3

(49) R1= piperazine R

3= NHCH2CH2N(CH)3 R

2R

4= H

R1

O

CH3 CH3

R2

R3

R4

Machado et al.102

have reported the antibacterial activity of isoliquiritigenine

(53) against S. aureus, S. epidermidis and S. heamolyticus, with MIC= 250 μg ml-1

.

Pinocembrin chalcone (54) was found active against S. aureus.103

Belofsky et al.104

isolated chalcones (55) from Dalea versicolor, which was

found to be active individually as well as in combination with other common

antibiotics (berberin, tetracycline and erythromycin) against human pathogen S.

aureus and B. cereus.


15

R5

R4

CH3OH

R3

OH

R2

R1

(53) R1R

3R

4R

5= H R

2= OH

(54) R2R

3R

4R

5= H R

1= OH

(55) R1R

2= H R

3R

4= CH 3 R

5= OCH 3

Chalcones (56 and 57) have been shown to possess bateriostatic profile i.e.

they exhibited inhibitory effect rather than killing of bacteria even at higher

concentrations (16 times MIC). The difference between the mechanisms of carboxy

and hydroxychalcones is that the later are bactericidal ( cause killing of bacteria) and

the former are bateriostatic (inhibit the growth).105

Lin et al.106

reported that chalcones (58 and 59) with the 2-hydroxy group in

ring A and 3-chloro- or 3-iodo- group in ring B, exhibited the strongest activity, with

a growth inhibition of 90-92%.

CH3R3

R4

R1

R2

(56) R1 R

2 = CF 3 R

3 = H R

4 = COOH

(57) R1R

2 = Br R

3 = H R

4 = COOH

(58) R1 = Cl R

2 R

4 = H R

3 = OH

(59) R1 = I R

2 R

4 = H R

3 = OH

The bioassay of dihydrochalcones (60-63) showedthat these compounds have

relatively good activity against Gram-positive bacteria S. aureus an B. subtilis, and

the Gram-negative bacterium Pseudomonas aeruginosa.107-109


16

OHR2

R1

OH O

R3

(60) R1R

3= H R

2= OCH 3

(61) R1= CH 3 R

2= OH R

3= H

(62) R1= CHO R

2= OH R

3= H

(63) R1= H R

2= OCH 3 R

3= OH

1.3.3 Antifungal Chalcones

Candida albicans is a well known human pathogen, responsible for the oral

and vaginal infections. It is a major cause of invasive fungal disease. The intensive

use of antifungal drugs results in the generation of new resistant strains of Candida

species, due to which there is an increasing interest to develop new suitable

therapeutics.110

Chalcones seem to be a solution to all these problems, because the mechanism

of antifungal action of chalcones is the inhibition of cell wall.111

As far as the

therapeutic viewpoint is concerned, chalcones inhibit glutathione-S-transferases

(GSTs) enzymes that are apparently involved in drug resistance.112

It has also been

reported that thiol alkylation is one of the steps involved in chalcones detoxification

action in yeasts.113

Chalcone functionality is fundamental for growth inhibition against Candida

species, but some conflicting results have also been obtained about the fungicidal

effects of hydroxyl-chalcones. The antifungal activity of chalcones largely depends on

their potential to interact with sulfhydryl groups.114

Tsuchiya H. et al. have reported

that the cyclization of chalcones to flavones or reduction to dihydrochalcones results

in the loss of their antifungal properties.115

Chalcones devoid of phenolic groups, have also been reported to possess

either low or no activity.116

Some natural hydroxyl-chalcones have exhibited low

activity against C. Albicans.117,118

On the other hand some plant-derived chalcones

after hydroxylation in ring A are strong candidates as antifungal agents,111

and the

position of the hydroxyl group in the ring B is largely associated with its antifungal

activity.


17

Lopez et al.119

examined the antifungal activity of chalcones (64-67) against a

group of dermatophytic fungi. The presence of electron-donating groups on ring B,

make them weak antifungal agent. Conversely, electron-withdrawing groups in the

para position increase the activity. The presence of α,β-unsaturated carbonyl group

enhances the antifungal activity, but it is not sufficient alone.

The compound 67 is the most active one, although it neither possesses any electron-

withdrawing group, in the para position of ring „B‟, nor does it have any substituent

in ortho position. This compound showed antifungal activities against Microsporum

canis (MIC = 25 μgml-1

), Microsporum gypseum (1.5 μgml-1

), Trichophyton

mentagrophytes (3 μgml-1

), Trichophyton rubrum (3 μgml-1

) and Epidermophyton

floccosum (0.5 μgml-1

).119

ElSohly et al.120

isolated the prenylated chalcones (isobavachalcone 68) and

69 from the leaves of Maclura tinctoria were found active against the two fungal

pathogens Candida albicans (IC50 of 3 and 15 mg ml-1

, respectively) and

Cryptococcus neoformans (IC50 = 7 mg ml-1

).

R3

O

R2

R1

(64) R1R

3= H R

2= NO 2

(65) R1= OCH 3 R

2R

3= H

(66) R1R

3= H R

2= CH 3

(67) R1= OCH 3 R

2= H R

3= Br

OH

O

R1

R2

OH

(68) R1= OH R

2= CH 2CH=C(CH 3)2

(69) R1= OH R

2= CH 2CH(OH)C(CH 3)=CH 2

(70) R1= H R

2= OCH 3

(71) R1R

2= H


18

Svetaz et al.121

reported that the compounds 70 and 71 exhibited very good

antifungal activities, which they extracted from Zuccagnia punctata. Their MIC

values were found to be 6.25 μgml-1

and 3.12 μgml-1

respectively, against Phomopsis

longicolla Hobbs CE117, whereas against Collectotrichum truncatum CE175 the MIC

= 6.25 μgml-1

.

The chalcone 72 (crotmadine) has been reported to be extracted from the

leaves and stems of Crotalaria madurensis. This compound displayed antifungal

property against T. mentagrophytes at a concentration 62.5 μgml-1

.122

(72) crotmadine

O O

OH

OH

Okunade et al. reported that the dihydrochalcone 60 was found to be a good

antifungal agent against two AIDS-related fungal pathogens C. albicans and C.

neoformans.107

Compound 61 displayed promising antifungal activity against T.

mentagrophytes at 60 μg/disk.108

Miles D. H. et al.123

showed that dihydrochalcone 62

exhibited potent antifungal activity against Rhizoctonia solani and Helminthosporium

teres, and antibacterial activity against Xanthomonas campestris.

OHR2

R1

OH OH

R3

(60) R1R

3= H R

2= OCH 3

(61) R1= CH 3 R

2= OH R

3= H

(62) R1= CHO R

2= OH R

3= H


19

1.3.4 Anti-inflammatory Chalcones

The procedures adopted in the treatment of various inflammatory diseases

include inhibition of prostaglandin E2 (PGE2) and nitric oxide (NO) production.

Excessive amounts of NO cause tissue damage. Rheumatoid arthritis, an

inflammatory disorder, is caused due to excessive NO production by activated

macrophages. Therefore, it is necessary to produce potent and selective NO inhibitors

for potential therapeutic use.98

A series of chalcones was screened for anti-inflammatory effect by Herencia

et al.124-127

Chalcone 73 was found to be significantly as a superoxide anion

scavenger, with IC50 value of 0.1 μM. It also inhibits the inducible NO synthase

expression via a superoxide-dependent mechanism in stimulated mouse peritoneal

macrophages, and secluded the cells against oxidant stress.

Rojas et al.128

reported the concentration-dependent inhibition of the NO

production of the chalcones 74 and 75 with IC50 = 0.6 and 0.7 μM, respectively.

R5

R4

R3

R2

R1

O

N

CH3

CH3

(73) R1R

4R

5= H R

2R

3= OCH 3

(74) R1R

5= OCH 3 R

2R

3R

4= H

(75) R1R

4= OCH 3 R

2R

3R

5= H

A series of Trimethoxychalcones with diverse patterns of fluorination, was

prepared by Rojas et al.129

The chalcone 76 showed inhibitory effect (76.3%

inhibition at 10 μM) on the generation of NO as well as of prostaglandin E2 in

lipopolysaccharide-stimulated RAW 264.7 macrophage cells. The inhibition depends

on amount of dose with no cytotoxicity.


20

OCF3

OCH 3

OCH 3H3CO

(76)

The chalcone derivatives 77-79 extracted from the fruits of Mallotus

philippinensis130

and 42, 80-82 from hops (H. lupulus),131

displayed inhibition in the

generation of NO, induced by lipopolysaccharide (LPS) and INF-γ in murine

macrophage-type cell line, RAW 264.7.

R2

OH OH

OH

R1

OO

CH3R3

(77) R1= H R

2= CH 2CH=C(CH 3)CH2CH2CH=C(CH 3)2 R

3= CH 3 (Mallotophilippens C)

(78) R1= OH R

2= CH 2CH=C(CH 3)CH2CH2CH=C(CH 3)2 R

3= CH 3 (Mallotophilippens D)

(79) R1= OH R

2= CH 2CH=C(CH 3)2 R

3= CH 2CH2CH=C(CH 3)2 (Mallotophilippens E)

(42) xanthohumol

OCH 3 O

OH

OH

OH

O OCH 3

OOH

OH

OH

(80) xanthohumol B

OCH 3

OH

OHOH

O

OH

OCH 3

OH

OH O

OH

(81) xanthohumol D (82) dihydroxanthohumol


21

Madan et al.132

reported that the 2‟-Hydroxychalcone 83 has the ability to

control cell trafficking by the blockage in the expression of cell adhesion molecules.

Its inhibitory effect on both TNF-α and LPS-induced expression of leukocyte

adhesion molecules was almost the same.

OOH

(83)

The potential of all the hydroxyl and alkoxychalcones (84-92) to inhibit the

release of β-glucuronidase and lysozyme has been reported133-136

from rat neutrophils

stimulated with formyl-Met-Leu-Phe/cytochalasin B (fMLP/CB). Among the

hydroxychalcones, compound 86 is found to be the most active one in the inhibition

of release of β-glucuronidase (IC50= 1.6 μM) and lysozyme (IC50= 1.4 μM) from

fMLP/CB stimulated rat neutophils.

The mode of action of dialkokxychalcones (90-92) as anti-inflammatory

agents is not the inhibition of mast cells and neutophils degranulation. They actually

suppress NO formation from N9 cells. Compound 90 showed the greatest ability to

inhibit NO formation from LPS-stimulated murine microglial cell lines (IC50 = 0.7

μM). Compound 92 exhibited strong activity in dose-dependent inhibition of β-

glucuronidase from peritoneal mast cells of rats stimulated with compounds: 30/74

(10 μg/ml).135

R1

R3

R2

OOH

(84) R1R

2= H R

3= OH

(85) R1= H R

2R

3= Cl

(86) R1= OH R

2R

3= H

OR1

ClR

2

(89) R1R

2= OC 3H7

(90) R1R

2= OC 4H9

(91) R1R

2= OC 2H5

(92) R1R

2= OH


22

OH

OOH

OH

CH3

O

O

R1

OH

(87) R1= H

(88) R1= OCH 3

1.3.5 Antileishmanial Chalcones

Leishmaniasis is a group of diseases caused by various species of protozoan

parasites which belong to the genus Leishmania. Over 12 million people of 88

countries are affected by it, with an annual increase of 2-3 million cases. According to

a careful investigation, a population of 350 million is under threat of infection.137

Amphotericin B and pentamidine have been used for medication of the disease.138

During the past decade, chalcones emerged as a new class of antileishmanial

agents.139-141

Licochalcone A, extracted from a Chinese plant Glycyrrhiza spp is one

of the most studied leishmanicidal chalcones, which inhibits the parasite enzyme

fumarate reductase.142,143

Chen et al.144

studied that licochalcone A not only inhibited

the in vitro growth of the parasites L. major and L. donovani promastigotes but also

killed the intracellular amastigotes of both. The in vivo study was carried out in mice

and hamsters infected with L. major and L. donovani parasites respectively. The

results exhibited the inhibition in growth of these parasites, both in mice and

hamsters. The study supports the importance of licochalcone A and its analogues in

the development of new antileishmanial drugs.


23

O

OH

OCH 3

OH

CH3

CH3

Licochalcone A

O

OH

OCH 3

OH

CH3

CH3

Licochalcone C(45) (46)

As far as licochalcone C is concerned, its extent of growth inhibition of the L.

major parasite is the same as that of the licochalcone A.145

Chalcones 93 and 94 displayed potent antileishmanial activity against both

extracellular and intracellular forms (IC50 = 153 and 118 μM, respectively). Some new

oxygenated chalcones 95-98 and 1 were found to inhibit the in vitro growth of L.

major promastigotes (IC50 = 4.0-10.5 μM) and L. donovani amastigotes (IC50 = 0.65-

6.1 μM) in human monocyte-derived macrophages (MDM).146

OCH 3

OCH 3

O

R2

R1

(93) R1= H R

2=OCH2CH=CH2

(95) R1= OH R

2= H

(96) R1R

2= H

(97) R1= H R

2= OH

(98) R1= H R

2= OCH2CH=CH2

(94) R1= H R

2= OC4H9

Torres-Santos et al. screened in vitro the dihydoxychalcone 99 against

promastigotes and intracellular amastigotes of L. amazonensis and found ED50 = 0.5

and 24 µg/mL respectively. The ultrastructural studies indicate that this chalcone

enlarges and disorganizes the mitochondria of promastigotes. The inhibitory effect on

intracellular amastigotes is a direct effect on parasites, without any disarrangement of

macrophage organelles, even at 80 µg/mL of 99.147


24

O

H3CO

OH

OH

(99)

OH

OOH

O

CH3

CH3

(100)

The extracellular promastigotes of L. donovani and intracellular amastigotes

residing within murine macrophages were tested with chromeno chalcone 100

(crotaramosmin). It was observed that 100 was found potent, with 84% and 74%

inhibition against promastigotes and amastigotes respectively at 50 µg/mL dose.148,149

Hermoso et al.150

synthesized dihydrochalcones 101-103 and screened them

against L. braziliensis, L. tropica and L. infantum. The activity as well as toxicity

increases by substituting the methoxy group at C-4‟ (ring A) with an acetate group.

R1

O

H3CO

R2

R3

(101) R1

= H R2

R3

= OCOCH3

(102) R1R

3= OCOCH3 R

2= OH

(103) R1R

2R

3= OCOCH3

Neilson et al.151

reported the fact that the pharmacophore consists of two

aromatic rings, while the propanone chain‟s function is just to provide space. The

tendency of a chalcone to act as an antileishmanial agent depends upon the

substituents on both the rings as well as the ratio of their lipophilicity to

hydrophilicity. Also the substitutions on ring A did not play a major role towards

antileishmanial activity, but replacing acetate groups with hydroxyl groups not only

enhances the activity but also reduces the cytotoxicity to murine macrophages.

1.3.6 Antiviral Chalcones

In the studies of inhibitory effects of chalcones against plant viruses and

human rhinoviruses, the antiviral property of chalcones was discovered. The antiviral

activity specifically depends on the substitution patterns.98

Onyilagha et al.152,153


25

tested a few hydroxy and methoxy chalcones for activity against tomato ringspot

nepovirus (ToRSV) infectivity. The chalcones‟ ability of inducing resistance against

ToRSV was analyzed in time course experiments. It was observed that the application

of chalcones before or after ToRSV infection, results in a loss of activities.

Compounds 71 and 104-107 were found to be most effective antiviral agents.

OH

O

R1

R2

OH

(71) R1R

2= H

R2

OCH 3

OCH 3

R1

O

R3

(104) R1R

3= H R

2= OCH 3

(105) R1R

2= OH R

3= OCH 3

OH

R2

OH O

R1

(106) R1R

2= OH

(107) R1= H R 2= OCH 3

Xanthohumol 42 has been reported by Wang et al.154

as a selective inhibitor of

HIV-1 and it may represent a new therapeutic agent against HIV-1 infection. The

EC50 values of 42 on HIV-1 p24 antigen inhibition and RT production were 1.28 and

0.50 μg/ml, respectively.

(42) xanthohumol

OCH 3 O

OH

OH

OH


26

Wu and coworkers155

determined that chalcone 108, extracted from the genus

Desmos, exhibited potent anti-HIV activity.with EC50 = 0.022 μg/ml.

CHO

H3CO OH

OOH

CH3

OH

(108)

OH

R2 R

3

R4

R1

O

OH

(109) R1R

4= OH R

2R

3= H

(110) R1R

2= H R

3= OCH 3 R

4= OH

(111) R1= H R

2R

4= OH R

3= OCH 3

The chalcone 109 (butein) was tested for inhibitory effect on HIV-1 by Xu et

al.156

using fluorescence and HPLC assays. The results suggested that butein 109

applied at 50 μg/ml caused more than 50% inhibition of HIV-1 protease.

Licochalcones A 45 and B 110 as well as 111 screened by Uchiumi et al.,157

were found to reduce the TPA-induced HIV promoter, while they didn‟t cause a

decrease in the Luc activity in pCMVLuc transfected cells. These chalcones displayed

a negative effect on HIV transcription, possibly due to their binding with some

specific protein factors. Moreover, cardamonin 112 showed significant anti-HIV-1 PR

activity (75.1% inhibition) with an IC50 = 31 μg/ml.158-160

OH OCH 3

OOH

(112)

1.3.7 Antituberculous Chalcones

A very frequently encountered disease caused by mycobacterium, is

Tuberculosis (TB). Although it is almost wiped out significantly from industrially

more developed countries, it is still a major health problem in most developing

countries. The infection rate of TB in developing countries is 0.1−0.3 % annually,

with high mortality rate. Mycobacterium tuberculosis has developed resistance against


27

conventional anti-TB drugs, and for the past 40 years no new drug with different

mode of action has been developed. Therefore, new anti-TB drugs are needed to be

developed, which have potential to reduce the therapy duration, treatment of multiple

drug resistant tuberculosis (MDR-TB) by single dosage regiment and of course

reduction in total expenditure.161

Two approaches can be adopted to develop new pharmacophore, which have

anti-TB activity: (i) synthesis of new compounds better than those of existing ones,

(ii) Searching for those novel compounds which have never been exposed to M.

tuberculosis strains to address multi-drug resistant tuberculosis.162

Shahar Yar et al. synthesized a novel series of eleven chalcones, which were

tested for antimycobacterial activity against M. tuberculosis H37RV using a BACTEC-

460 radiometric system. Among the eleven chalcones, only six were found to be

active. The compounds 114 and 118 exhibited largest efficacy and displayed >90%

inhibition at MIC ≈ 6.25 μg/ml in the primary screen, whereas the chalcones 113, 115,

116 and 117 displayed ≈ 90% inhibition with MIC values greater than 6.25 μg/ml.

OH

O

CH3

R1

R2

R3R

4

(113) R1R

2R

4= H R

3= Cl

(114) R1R

2R

4= H R

3= NMe 2

(115) R1R

4= H R

2R

3= OMe

(116) R1R

2R

4= H R

3= F

(117) R2R

3R

4= H R

1= Cl

(118) R2R

3= H R

1R

4= Cl

The data suggest that dimethylaminophenyl substituted chalcones are good

antitubercular agents.161

1.3.8 Antitrichomonal Chalcones

Trichomonas gallinae, a flagellated protozoan, parasitizes upper digestive tract

and different organs of various birds and urogenital duct in humans. The domestic

pigeon and some dove species like white-wing doves are primary hosts of this

parasite.


28

Metronidazole was proven to be effective against T. gallinae [Bussieras et al.

1961]163

and therefore, used in the treatment of human urogenital trichomonosis since

its discovery [Krieger et al. 1985].164

Despite of their extensive use worldwide, cases

of clinical resistance to nitroimidazoles are very rare in man. Oyedapo et al.165

synthesized a series of ten chalcones and examined them for antitrichomonal

activities. Five of the prepared chalcones 119-123 were found active at concentrations

≤100 μg/ml. Chalcones 119-121 showed activity (MLC = 100±0, 0.78±0 and 50±0

μg/ml) due to the presence of 2‟-hydroxyl group which would form flavones or

isoflavones via intramolecular cyclization. Compound 122 displayed same MLC

value as that of 121 i.e. 50±0 μg/ml. The dihydroxychalcone 123 was found to be the

2nd

most active compound (MLC = 3.13±0 μg/ml) after compound 120 which was

proven to be the most active one, with MLC value of 0.78±0 μg/ml equal to the

standard drug metronidazole.

(119) R1R

3R

5= H R

2= OH R

4= OMe

(120) R4R

5= H R

2= OH R

1R

3= OMe

(121) R1R

3R

5= H R

2= OH R

4= Cl

(122) R2R

3= H R

1R

4R

5= OMe

(123) R1R

2R

3= H R

4R

5= OH

R1

R2

R3

R5

R4

O

1.4 Applications in Synthetic Organic Chemistry

Chalcones are very reactive organic compounds and most of their reactions are

due to α,β-unsaturated carbonyl moiety. They undergo oxidation,166-170

reduction,171-

174 Michael addition, Suzuki cross coupling reactions etc. They serve as precursors for

the synthesis of various heterocyclic compounds like pyrimidines177

, imidazoles177

, 2-

pyrazolines178

, isoxazoles179

, flavonoids.180

A few examples of various reactions of

chalcones are given under the following schemes.

1.4.1 Oxidation of Chalcones166-170

Chalcones can easily and smoothly be oxidized to their corresponding

flavones by employing selenium dioxide.166-168


29

Cl

OH

O

OMe

OMe

SeO2

Cl

O

O

OMe

OMe

Scheme 1(i). Oxidation of chalcones to flavones using SeO2

Another very convenient and efficient method of oxidation of chalcones to prepare

symmetrical169

and unsymmetrical170

benzils, is with thallic nitrate (TN).

O

O

O

R1

R2

R1

R2

TN

in aq acid/glyme

Scheme 1(ii). Oxidation of chalcones to benzyls using thallic nitrate (TN)

The yield of this reaction is 45-70%. However, the reaction fails due to the presence

of electron-withdrawing groups.

1.4.2 Reduction of Chalcones171-174

Selective reduction of double bond in chalcone takes place upon reacting with

sodium borohydride in pyridine.171

Reduction of chalcones by lithium amalgam172

produces a small quantity of its

corresponding alcohol. Sodium metal reduces chalcone to corresponding

benzylacetophenone.173

Another reducing agent is zinc metal in ethanol-acetic acid

system, which reduces butein to corresponding flavan.174

OH

O

OH

OH

OH

OOH

OH

OH

OHH

(Butein) 4,7,3',4'-Tetrahydroxyflavan

Zn

CH3COOH

Scheme 2. Reduction of butein to 4,7,3’,4’-Tetrahydroxyflavan using Zn in CH3COOH


30

1.4.3 Conversion of Chalcones to 1,5-Diketones175

Ceylan and Gezegen reported the synthesis of a series of eight 1,5-diketones

through Michael-type addition reaction. Different chalcones (1mol) were treated with

cyclohexanone (2mol) in the presence of KOH (6% mol) under solvent-free

conditions by employing phase transfer catalyst (benzyltriethylammonium chloride;

6% mol). The mixture was stirred at r. t. and gave good yields i.e. 40-83%.

O O O O

+X X 6%KOH, 6%PTC

r.t., 3-4 h

(1a-h) (2) (3a-h)

3a) X = H; b) X = o-Cl; c) X = m-Cl; d) X = p-Cl

e) X = o-Br; f) X = o-OMe; g) X = m-OMe; h) X = p-OMe

Scheme 3. Synthesis of 1,5-Diketones by addition of cyclohexanone to chalcones

It was observed that the yield was affected by the position of substituents. Low

yields were obtained in o-substituted products, due to steric hindrance.

1.4.4 Conversion of Chalcones to Ferrocenyl Chalcones176

Song et al. synthesized two new organometallic derivatives of chalcones by

Suzuki cross-coupling reaction. Acetyl ferrocene was treated first with 3-

Bromobenzaldehyde to give chalcone (1) which upon refluxing in inert atmosphere

with aryl boronic acid in the presence of Pd(0) in aqueous Na2CO3 soln. gave the

corresponding 3-biaryl-1-ferrocenyl-2-propene-1-ones (2a-b).


31

(1)

(2a-b)

Fc

O

CH3

+

O

BrFc

Br

O

Fc = ferrocenyl

Ar =

O

,

ArB(OH) 2Pd(0)

Ar

O

Fe

Scheme 4. Synthesis of 3-biaryl-1-ferrocenyl-2-propene-1-ones

1.4.5 Conversion of Chalcones to Imidazoles and Pyrimidines177

Varga et al. reported the conversion of chalcones into two major classes of

organic compounds, i.e. imidazoles and pyrimidines. The reagent used for cyclization

was guanidine in the presence of 50% KOH and 30% hydrogen peroxide. The type of

product depends on the order of addition of H2O2. If H2O2 is added at initial stage then

imidazole would be the final product.

Ar1 Ar

2

O

+ NH2 NH2

NH

NH

N

O

NH2

Ar1

Ar2

Imidazoles

EtOH, 50% aq. KOH,

30% aq. H2O2, 80 °C

Scheme 5 (i). Conversion of chalcones to imidazoles using H2O2 in Ist step

But if H2O2 is added to the reaction mixture after 1h refluxing, in small

portions and over a period of 1h, then the final product is pyrimidine.

Ar1 Ar

2

O

+ NH2 NH2

NH

NN

NH2

Ar2Ar1

Pyrimidines

1) EtOH, 50% KOH,

rflx., 1-3h

2) 30% aq. H2O2

Scheme 5 (ii). Conversion of chalcones to pyrimidines using H2O2 in IInd

step


32

1.4.6 Conversion of Chalcones to 2-Pyrazolines178

Lévai reported the synthesis of chlorinated 3,5-diaryl-2-pyrazolines

derivatives from chlorochalcones. He treated different chalcones with hydrazine

hydrate or phenyl hydrazine in acetic acid, and the reaction mixture was refluxed for

3h. The crude product was obtained by filtration and recrystallized from methanol.

N N

X

H H

H

X= H, C 6H5

O

R1

R2

XNHNH2

MeCOOH

R1

R2

The groups R1 and R

2 may be H, Cl, di-Cl, Me or OMe.

Scheme 6. Conversion of chalcones to 2-Pyrazolines using hydrazine or phenylhydrazine

1.4.7 Conversion of Chalcones to Isoxazoles179

Kidwai M. et al (2006) reported the synthesis of six isoxazole derivatives via

Michael addition of hydroxylamine hydrochloride over chalcones under microwave

irradiations using K2CO3 as solid support. O

X

Y N O

Y

X

(a-f)

X Y

a:

b:

c:

d:

e:

f:

H H

p-CH3O

m-NO2

p-Me 2N

H

p-CH3O

H

H

H

p-Cl

p-Cl

+Anhydrous K2CO3

EtOH, MW 140 °CNH2OH

Scheme 7. Synthesis of isoxazole under MW irradiations


33

The above reactions were highly regioselective irrespective of the nature of the groups

attached to the two rings in the chalcones.

1.4.8 Conversion of Chalcones to Flavanones180

Sagrera and Seoane prepared flavanones by MW irradiation under solvent-free

conditions. For this purpose, they used common household microwave oven and

examined various mineral supports and catalysts. Irradiating with 30% TFA over

silica gel, chalcones produced flavanones in high yields.

R2

OH

R3

R5

R6

R4

OR1

R2

O

R3

R5

R6

R4

OR1

30% TFA / silica gel

microwave, 9min

69 - 80%

Scheme 8. Synthesis of flavonones from o-hydroxychalcones under MW irradiations

1.4.9 Conversion of Chalcones to (±)-1-(5-aryl-3-pyridin-2-yl-4,5-

dihydro-pyrazol-1-yl)-2-imidazol-1-yl-ethanone181

Mamolo et al. prepared (±)-1-(5-aryl-3-pyridin-2-yl-4,5-dihydro-pyrazol-1-

yl)-2-imidazol-1-yl-ethanone derivatives according to the following scheme.

Chalcones (1) first treated with hydrazine hydrate to give corresponding (±)-5-aryl-3-

(pyridin-2-yl)-4,5-dihydro-1H-pyrazoles (2). Upon stirring these pyrazoles (2) with

equimolar bromoacetyl chloride and triethylamine in benzene at r. t. for 4 h and

finally concentrating the mixture under reduced pressure the corresponding (±)-2-

bromo-1-(5-aryl-3-pyridin-2-yl-4,5-dihydro-pyrazol-1-yl)-ethanone derivatives (3)

were obtained. Ultimately, (3) were refluxed with imidazole (in 1:2 mole ratio) for 2

h, in acetonitrile. After long work up (±)-1-(5-aryl-3-pyridin-2-yl-4,5-dihydro-

pyrazol-1-yl)-2-imidazol-1-yl-ethanone derivatives (4) were obtained in pure form.


34

O

H

N

O

+ RN

O

R

(1)

NH2NH2.H2O

(2)

O

ClBr

NN

N

O

Br

R

NNH

NR

N

NH

NN

N

O

N N

R

(4)(3)

Scheme 9. Conversion of chalcones to (±)-1-(5-aryl-3-pyridin-2-yl-4,5-dihydro-

pyrazol-1-yl)-2-imidazol-1-yl-ethanone

and finally tested for their in vitro antifungal activity. The compounds exhibited

moderate antifungal activity against strains of Candida parapsilosis, C.

pseudotropicalis and C. glabrata.

1.4.10 Conversion of Chalcones to 5-amino-1,3,4-thiadiazole-2-thiol

imines and imino-thiobenzyl182

Yusuf et al. synthesized a series of 5-amino-1,3,4-thiadiazole-2-thiol imines

and imino-thiobenzyl derivatives by treating different chalcones with 5-amino-1,3,4-

thiadiazole-2-thiols under reflux in absolute ethanol for 5-8 h. The reaction mixture

was concentrated in vacuum, and the crude product was recrystallized from methanol.

The starting material 5-amino-1,3,4-thiadiazole-2-thiol was prepared by refluxing

thiosemicarbazide with carbon disulphide.


35

S

NH

NH2

NH2

+ SS

N N

SNH2

SH

OR1

R2

N NN

S

SH

R1

R2

Cl

Cl

Cl

NN

N

S

S

R1

R2

NN

N

S

S

Cl

R1

R2

(1)(2)

(3i) (3ii)

R1 = H, OMe, (Me)2N, Cl, OH

R2 = H, Cl

Scheme 10. Synthesis of 5-amino-1,3,4-thiadiazole-2-thiol imines and imino-

thiobenzyl derivatives

1.4.11 Conversion of Chalcones to 2,4,6-trisubstituted pyrimidines183

Agarwal et al. reported the synthesis of 2,4,6-trisubstituted pyrimidines (3).

For this purpose chalcones (1), prepared by the reaction of 4-acetylpyridine with

different aldehydes, were treated with morpholine-4-carboxamidine hydrochloride

(2), which in turn was prepared by refluxing morpholine with S-methylisothiourea

sulfate in water. The chalcones (1) cyclized with morpholine-4-carboxamidine

hydrochloride (2) in the presence of sodium isopropoxide (which appeared by adding

sodium metal in isopropanol in situ) to yield first dihydropyrimidine (A) which

further oxidizes to give a series of 2,4,6-trisubstituted pyrimidines (3).


36

O

CH3

+ CHOR

O

R

+ NO

NH

NH2

. HCl

NH

NH2

SMe

2

.H2SO4

NH

O

N

N

NH

N

O

R

N

N

N

N

O

R

(1) (2)

(3)(A)

Scheme 11. Conversion of chalcones to 2,4,6-trisubstituted pyrimidines

1.4.12 Reaction of Chalcones with Diethyl Malonate184

Zhang et al. proposed the use of K2CO3 as an efficient catalyst in Michael

addition reactions of chalcones and azachalcones with equimolar amount of diethyl

malonate under high-speed vibration milling (HSVM) conditions.

X

O

+R

(1a-o) (2) (3a-o)

X = CH, N

R = H, 4-Me, 4-OMe, 4-NO 2, 3-NO 2, 4-CN, 4-Cl, 3,4-Cl, 3,4-(OCH 2O)-

CH2(COOEt) 2X

O

EtO2C CO2Et

R K2CO3 (10% equiv.)

HSVM

Scheme 12. Michael additionof diethyl malonate catalyzed by K2CO3 under

HSVM conditions

Amazing results were obtained in terms of yields. Except compounds 3c, 3i

and 3m all the other compounds were obtained in 98-99% yield. The yields of 3c, 3i

and 3m were 91%, 76% and 92% respectively.


37

1.4.13 Reactions of Chalcones with Thiosemicarbazide185

Özdemir et al. synthesized pyrazoline derivatives of chalcones with

thiosemicarbazide. It was done by heating each chalcone with thiosemicarbazide (in

slight excess) in the presence of NaOH (double) in ethanol. The crude product (2) was

obtained by pouring the reaction mixture in ice cold water, and then filtration. It was

crystallized from proper solvent.

O

O

HAr

O

+OH-

O

Ar

O

NHNH2

NH2S

O

N N

Ar

S NH2

Ar = C6H5-, 2-furyl-

(1)(2)

Scheme 13. Reactions of chalcones with thiosemicarbazide

1.4.14 Conversion of Chalcones to Di- and Triphenylquinoline186

Qi et al. reported a seven step procedure for the synthesis of 2,5,7-

triphenylquinoline (8). In the second last (6th) step 5,7-diphenylquinoline (7) was

obtained by heating a mixture containing m-terphenylamine (3.7 mmol), nitrobenzene

(2.78 ml), FeSO4 (11 mmol), glycerol (60 mmol), conc. H2SO4 (3 ml) and glacial

acetic acid (3.33 ml) at 145 ºC for 4 h. After work up 33% yield of 5,7-

diphenylquinoline (7) was obtained. Finally, 5,7-diphenylquinoline (7) was added to a

solution of phenyl lithium in THF and the mixture was refluxed for 4 h.. The 2,5,7-

triphenylquinoline (8) was obtained (34.8%) after work up.


38

HPh

O

+ OH-

(1) (2)

CH3

O

Ph

OOO

OEt

O

COOEt

Ph

(3)

O

H2NOH.HCl

NOH

NH2

AcCl/Ac2O

Py

(4) (5) (6)

N N

PhLiGlycerol

PhNO2

(7) (8)

Scheme 14. Synthesis of 5,7-diphenylquinoline and 2,5,7-triphenylquinoline from

chalcones

1.4.15 Conversion of Chalcones to Chromones & Chromanones187

Prakash et al. reported the synthesis of 2,3-dimethoxy-3-hydroxy-2-(1-phenyl-

3-aryl-4-pyrazolyl)chromanones (5) by the oxidation of 3-hydroxy-2-(1-phenyl-3-

aryl-4-pyrazolyl)chromones (4) using IDB (iodobenzene diacetate) in MeOH, which

in turn were prepared by the cyclization of pyrazolyl derivatives of 2-

hydroxychalcone (3) with H2O2 in KOH─MeOH.

+

(1) (2)

CH3

OH

O

NN

O

Ph

H Ar

KOH-MeOH

THF

OH

O

N

N

Ar

Ph

(3)

H2O2 KOH-MeOH

N

N

O

O

OH

Ph

ArIBD

MeOH

N

N

O

O

OH

Ph

Ar

OMe

OMe

(4)(5)

Ar = a, C6H5; b, 4-MeC 6H4; c, 4-OMeC 6H4; d, 4-ClC 6H4; e, 4-BrC6H4; f, 4-FC 6H4; g, 4-NO 2C6H4

Scheme 15. Conversion of chalcones to chromones & chromanones using IBD


39

1.4.16 Conversion of Chalcones to 5-aryl-1-isonicotinoyl-3-(pyridin-

2-yl)-4,5-dihydro-1H-pyrazole Derivatives188

Mamolo et al. prepared a series of 5-aryl-1-isonicotinoyl-3-(pyridin-2-yl)-4,5-

dihydro-1H-pyrazole derivatives according to the scheme given below. Chalcones (1)

first treated with hydrazine hydrate to give corresponding 5-aryl-3-(pyridin-2-yl)-4,5-

dihydro-1H-pyrazoles (2). Solution of (2) in ethanol was mixed with isonicotinoyl

bromoacetyl chloride (in DCM) at r. t. To this solution triethylamine was added

dropwise and allowed to stir for another 3 h. The final product (3) was obtained by

filtration and recrystallized from ethanol.

O

H

N

O

+N

O(1)

(2)

NNH

N

(3)

NN

N

O

N

N

Cl

O

NH2NH2.H2O

R

R

R R

Scheme 16. Synthesis of 5-aryl-1-isonicotinoyl-3-(pyridin-2-yl)-4,5-dihydro-1H-

pyrazole derivatives of chalcones

1.4.17 Conversion of Chalcones to Pyrazolines by Ultrasound

Irradiation189

Li et al. introduced an improved and efficient method for the ring pyrazoline

ring insertion reaction on chalcone moiety. Owing to the extensive use of ultrasound

in synthetic organic chemistry, they employed this technique to synthesize

pyrazolines. A series of 1,3,5-triaryl-2-pyrazolines was prepared by treating different

chalcones with phenylhydrazine hydrochloride in high yields of 83-96%. The reaction

was carried out at 28-36 ºC for 1.5-2 h in CH3COONa-CH3COOH aqueous soln. The

ultrasound frequency was adjusted at 25 kHz in most cases.


40

(1) (2)

O

Ar1 Ar2

+

NH NH2.HCl N

N

Ar1

Ar2

(3)

CH3COONa-CH3COOH

H2O/ U.S.

Ar1 Ar2

a. C6H5 4-CH3OC6H4

b. C6H5 4-CH3C6H4

c. C6H5 C6H5

d. C6H5 4-ClC6H4

e. C6H5 3-ClC6H4

f. C6H5 2-ClC6H4

g. C6H5 3-BrC6H4

h. C6H5 4-O2NC6H4

i. 4-ClC6H4 C6H5

j. 3-O2NC6H4 C6H5

Scheme 17. Synthesis of 1,3,5-triaryl-2-pyrazolines under ultrasonic irradiations

1.4.18 Reaction of Chalcones with Pyridine-2-carboxamidrazone190

Mamolo et al. reported the synthesis of three series of N1-[1-[3-aryl-1-

(pyridine-2-, 3-, or 4-yl)-3-oxo]propyl]-2-pyridinecarboxamidrazones (2a-t) by

stirring a mixture of different chalcones (1a-t) at r. t. in ethanol with 2-

pyridinecarboxamidrazone, which in turn was prepared by direct reaction of

hydrazine with 2-cyanopyridine.

+

(1a-t)

Het

O

H

O

Het

O

R R

N CN

NH2NH2

N

NH

NH NH2

ONH

Het

NH

NHN

R

(2a-t)

Het = 2-pyridyl, 3-pyridyl, 4-pyridyl

R = H, 3-Cl, 4-Cl, 3,4-Cl2, 3-Me, 4-Me, 4-Ph

Scheme 18. Synthesis of pyridine-2-carboxamidrazone from chalcones


41

1.4.19 Reaction of Chalcones with 4,5,6-Triaminopyrimidine191

Insuasty et al. synthesized a series of 4-amino-6-aryl-8-(1,3-benzodioxol-5-

yl)-8,9-dihydro-7H-pyrimido[4,5-b][1,4]diazepines (4a-f) and 4-amino-8-aryl-6-(1,3-

benzodioxol-5-yl)-8,9-dihydro-7H-pyrimido[4,5-b][1,4]diazepines (5a-f) by treatment

under microwave irradiation of equimolar quantity of 4,5,6-triaminopyrimidin 1 with

two series of chalcones 2a-f and 3a-f. DMF was used as a catalyst. Microwaves were

irradiated for 2-5 min at a power range of 100-300 W.

N

N

NH2

NH2

NH2

O

O

O

R

O

O

O

R(2a-f) (3a-f)

1

N

NH

N

N

NH2

O

O

R

N

NH

N

N

NH2

O

O

R(4a-f) (5a-f)

R = a, NO2; b, Cl; c, Br; d, H; e, Me; f, OMe

Scheme 19. Synthesis of novel derivatives of 8,9-dihydro-7H-pyrimido[4,5-

b][1,4]diazepines

1.4.20 Synthesis of Coumarinyl Derivatives of Chalcones192

Trivedi et al. reported an improved and rapid synthesis of coumarinyl

derivatives of chalcones. For this purpose, malonic acid was treated with substituted

phenols in the presence of ZnCl2 and POCl3, to yield substituted coumarins, which

were then acetylated using POCl3 and glacial acetic acid. Finally the prepared

acetylcoumarins were treated with different aromatic aldehydes to give the title

compounds. Chalcone synthesis was different in the way that CHCl3 was used as

solvent unlike conventional solvents MeOH and EtOH and a mild organic base

piperidine was used instead of NaOH or KOH.


42

+

OHC

R

(4a-i) and (5a-i)

OH

R4

R3

R2

R1

COOH

COOH

(1)

O

R1

R2

R3

R4

OH

O

glacial acetic acid POCl3

O

R1

R2

R3

R4

OH

O

COCH3

O

R1

R2

R3

R4

OH

O

O

R

(2)

(3)

CHCl3, piperidine, 80 °C

Anhydrous ZnCl2

POCl3, 70 °C

R = H, 4-H, 4-OMe, 3-OC6H5, 2-NO2, 3-NO2, 4-N(Me)2, 3-OMe and 4-OH, 3,4-di OMe

4 a-i , R1= Me, R

2= H, R

3= H, R

4= CH(Me)2

5 a-i , R1= H, R

2= Cl, R

3= Me, R

4= H

Scheme 20. Synthesis of coumarinyl derivatives of chalcones

1.5 Methods of Chalcone Synthesis

A variety of methods are available for the synthesis of chalcones. A few are

being discussed here, which are most efficient, convenient and give high yield in

shorter reaction time.

1.5.1 Conventional Method─Claisen-Schmidt Reaction193

Claisen-Schmidt condensation is a conventional and convenient method for

the synthesis of chalcones. In this reaction equimolar quantities of substituted

aromatic aldehydes are condensed with substituted aromatic ketones in aqueous

alcoholic alkali. The reaction is usually carried out in the temperature range of 20-

50ºC, and the reaction time is 12-15 hours. Some other condensing agents are also

employed e.g. alkali metal alkoxide, magnesium tert-butoxide, hydrogen chloride,

anhydrous aluminium chloride, boron trifluoride, phosphorus oxychloride, boric

anhydride, amino acids, borax and organometallic compounds (e.g. CdEt2 in butyl

ether)

1.5.2 Microwave Assisted Synthesis of Chalcones194

Reddy et al. reported the synthesis of chalcones by microwave irradiations

using domestic household oven (600 W) in high yields and very short reaction time as

compared to that needed under thermal conditions. In this reaction catalytic amount of

ZnCl2. The results are given in table 3.


43

(1) (2)

O

Ph CH3 +

CHO

R (3a-e)

ZnCl2

MW

O

Ph

R

R : a= H; b=Cl; c= OMe; d= Me; e= NO2

Scheme 21. Synthesis of chalcones under MW irradiations

Table 3. Experimental results of MW irradiation synthesis of chalcones

3 R Time (min) Yield (%)

a H 5 85

b Cl 3 82

c OCH3 3 90

d CH3 4 87

e NO2 5 85

1.5.3 Ultrasound Irradiation Synthesis of Chalcones195

Li et al. reported the synthesis of chalcones under ultrasound irradiation, using

catalyst pulverized KOH or KF-Al2O3. The results showed that the yield obtained in

case KOH was 52-97% while those in KF-Al2O3 was found to be 83-98%.

(1) (2)

+

(3a-k)

O

Ph Ar

Ar : a= C6H5; b= 4-MeOC 6H4; c= 3,4-(OCH 2O)C6H3; d= 3-O2NC6H4; e= 4-ClC 6H4

HAr

O

CH3Ph

O

f= 3-ClC 6H4; g= 4-MeC 6H4; h= 2,4-Cl 2C6H3; i= 4-O2NC6H4; j= 4-Me 2NC6H4; k= C6H5CH=CH

KF-Al2O3 or KOH

U. S.

Scheme 22. Synthesis of chalcones under ultrasonic irradiations

Moreover, this procedure needs less reaction time along with easier work-up. The

reaction temperatures were between 20-45 ºC

1.5.4 Synthesis of Chalcones Using a Solid Base Catalyst196

Kantam and coworkers introduced a new catalyst Mg-Al-OtBu hydrotalcite

(HT-OtBu), for the synthesis of chalcones. This new catalyst was designated as a solid


44

base. The advantage of this catalyst over others is that it gives higher yields and

proceeds with faster rates. The results are given in table 4.

(1) (2)

O

Ar2

CH3+

Ar1

O

H

(3a-l)

Ar2

Ar1

OHT-OtBu catalyst

Toluene, reflux

Scheme 23. Synthesis of chalcones HT-OtBu catalyst

Table 4. Experimental results of synthesis of chalcones using HT-OtBu catalyst

3 Ar1 Ar

2 Time (h) Yield (%)

a C6H5 C6H5 3.5 90

b C6H5 C4H3N 8.0 77

c C6H5 C8H8 5.0 88

d C6H5 4-MeC6H4 2.0 85

e C6H5 4-OMeC6H4 2.0 91

f 4-OmeC6H4 C6H5 1.5 92

g C4H3O C6H5 1.0 92

h 4-ClC6H4 C6H5 5.0 90

i C6H5 4-ClC6H4 2.0 87

j 3-OmeC6H4 C6H5 1.5 91

k 3-BrC6H4 C6H5 2.0 93

l 4-OphC6H4 C6H5 2.0 91

Other advantages of this procedure are; firstly there is no aldol-type by-

product has been observed, and secondly the catalyst can be recycled from the

reaction mixture by an easy procedure and can be reused at least three times.

1.5.5 Synthesis of Chalcones Using PTC197

Basaif et al. proposed a stereoselective synthesis of chalcones in water as

environmental friendly solvent. Excellent yields were obtained in the presence of a

phase transfer catalyst (PTC) cetyltrimethylammonium bromide (CTAB). Three

different series of chalcones were synthesized by employing three hetarylketones: 2-

Acetylpyrrole, 2-Acetylthiophene and 2-Acetylpyridine and a variety of aromatic

aldehydes. The yields were 62-95%.

(1a-c) (2)

O

Ar1

CH3

+Ar

2

O

H

(3a-h)

Ar1 Ar

2

O

(4a-h)

(5a-e)Ar1: a= 2-Acetylpyrrol; b= 2-Acetylthiophene; c= 2-Acetylpyridine

NaOH (2%), r. t.

CTAB

Scheme 24. Synthesis of chalcones using PTC


45

This method offers many significant advantages over the conventional

methods:

i) Faster rates

ii) Higher yields

iii) No side reactions

iv) Stereo-selectivity of product

v) Safe, neat and simple methodology

vi) Cheap and environmental friendly solvent

vii) Easier work-up and lower reaction temperature

viii) Alkoxides substituted aq. Alkali metal hydroxides

1.6 Aim of the Project

In the last two decades, chalcones have appeared as an effective class of biologically

active compounds. Research work is extensively being done throughout the world, in

order to search for the new biologically active chalcones. The aim of this project is to

synthesize novel biologically active heterocyclic chalcones, which might prove to be

more active and cheaper therapeutic agents than those of conventional ones. Literature

studies have strongly revealed the fact that chalcone derivatives (natural or synthetic)

possess a broad spectrum of biological activities including anti-inflammatory,198

antifungal,199

antioxidant,200

antimalarial,201

antituberculosis,202

analgesic,203

antitumor,204

anticancer,205

antiviral,206

anti-AIDS207

and antileishmanial agents.208

Structures of two chalcone drugs sofalcone209

and sophoradin210

are given in the

foolowing Figure 4.

OO

O

OH

O

CH3CH3 O

CH3CH3

OOH

OH

OH

CH3

CH3 CH3

CH3

CH3 CH3

Sofalcone (anti-ulcer) Sophoradin (a chinese herbal medicine)

Figure 4. Structures of chalcone based drugs


46

Quinolines and their derivatives, which represent a major class of

heterocycles,211

are widely found in natural products212

and drugs213-215

They exhibit

significant role in medicinal chemistry. Several quinoline derivatives have been

reported to exhibit bactericidal,216

antimalarial,217

antiallergenic,218

and anti-

inflammatory219

properties. Some of the famous antimalarial drugs, containing

quinoline ring system; available in the market are plasmoquine,220

primaquine and

chloroquine.221

Many quinoline derivatives are found to possess anticancer and

antitumor activities.222

A common anticancer drug (OSI-930) is based on quinolyl-

thienyl system (Figure 5).223

Among the quinolines, 2-chloro-3-formylquinolines find

an important place in synthetic organic chemistry, as these are key intermediates for

further β-annelation of a wide variety of ring systems and for the inter conversions of

many functional groups.224

Quinoline-based chalcones have been reported to possess

antimalarial activity.225

N

NHN

Cl N

NH

SNH

OO

F

F

F

Chloroquine (Antimalarial) OSI-930 (Anticancer)

Figure 5. Structures of quinoline based drugs

In the present work, various substituted 2-chloro-3-formylquinoline nuclei and

chalcone functionality have been incorporated in a single molecule (1a-k, 2a-k, 3a-s

and 4a-s).

Similarly piperidine nucleus is frequently recognized in the structure of

numerous naturally occuring alkaloids,226

pharmaceutical, agrochemicals and

synthetic intermediate with interesting biological, physical and pharmacological

properties like neuroleptic, antihypertensive, antiinflammatory, antitumor, anti-HIV

and anticonvulsant activities.227

A very large number of compounds have been

prepared for testing as local anestheties, the structure of which were patterned after

cocaine and contained the piperidine nucleus.228

Other reported biological and

enzyme inhibition activities of piperidine derivatives are antibacterial,229

antifungal,230


47

antimalarial,231

antioxidant232

antiestrogenic,233

antidepressant,234

anticancer235

and

cytotoxic activities.236

In view of the biological properties, a series of piperidyl

chalcones (9a-l) is also prepared. Two very common drugs used in the treatment of

alzheimer's disease237

and schizophrenia238

are given in the Figure 6.

N

N

N

O

N

O

O

O

Ampalex (alzheimer) CX-546 (schizophrenia)

Figure 6. Structures of two piperidine-based drugs

Thiophene and its derivatives find applications in the pharmaceutical area over

a wide range of drug types.239

They are of current interest due to their wide spectrum

of pharmacological properties. Some of the common biological activities shown by

thiophene derivatives include antibacterial,240,241

antifungal,240,241

anti-

inflammatory,242

anticancer243

and antitumor244

activities. The structures of some

thiophene-based drugs used as antiasthmatic245

(ketotifen), antifungal246

(tioconazole)

and non-steroidal anti-inflammatory247

drug (tenoxicam) are given in figure 7.

S

O

N

CH3

Cl

Cl

O

N

N

S

Cl

N OH

NH

O

SN

S

CH3

OO

Ketotifen (Antiasthmatic) Tioconazole (Antifungal) Tenoxicam (NSAID)

Figure 7. Structures of some thiophene based drugs

Looking at such a significant role of thiophene derivatives in the field of

pharmaceutical chemistry, we used a variety of substituted aetylthiophenes to be

condensed with various heteroaromatic aldehydes to form libraries of heterocyclic

chalcones.

http://en.wikipedia.org/wiki/Alzheimer%27s_disease

http://en.wikipedia.org/wiki/Schizophrenia

http://en.wikipedia.org/wiki/Schizophrenia


48

On the other hand Pyrazoline derivat have been reported to possess a

widespread range of biological activities like antibacterial,248

antifungal,249

antidepressant,250

antitumor,251

antimicrobial,252

anti-inflammatory,253

molluscicidal

activity,254

antiamoebic,255

anticonvulsant256

activities. One of the most famous

pyrazole-based drugs used as a non-steroidal anti-inflammatory drug (NSAID) is

celecoxib257

and a poisoning treatment drug (i.e. antidote) is fomepizole258

(Figure 8).

Considerable attention has been focused on the pyrazoline family in the last two

decades. Among various pyrazoline derivativs, 2-pyrazolines seem to be the most

frequently studied pyrazoline type compounds.259

N

N

S

NH2

O

O

F F

F

NH

N

CH3

celecoxib (NSAID) fomepizole (antidote)

Figure 8. Structures of some thiophene based drugs

This precedent for broad bioactivity profiles for these different heterocyclic

pharmacophores led us to perceive that fusion of quinolyl and piperidyl chalcones

with pyrazole nuclei, may result in new bioactive molecules which might exhibit

enhanced biological activities. For this purpose, the prepared chalcones were refluxed

with hydrazine hydrate in ethanol to yield five series of new 2-pyrazoline derivatives

of chalcones (5a-k, 6a-k, 7a-k, 8a-k and 10a-l) based on quinolyl, piperidyl and

thienyl ring systems. In the end all the compounds were tested for their antimicrobial,

antileishmanial anti-HIV-1 and cytotoxic activities.

A short account of research work is being presented here in the field of

synthetic organic chemistry.


49

1.7 Plan of Work and Experimental Schemes

The synthesis of biologically active, novel heterocyclic chalcones consists of

the following phases:

I) Thorough literature survey, in order to design various experimental

schemes.

II) Purchase of the chemicals according to the proposed schemes.

III) Synthesis of the heteroaromatic precursors: substituted 2-chloro-3-

formylquinolines i.e. 1, 2, 3 and 4 (scheme-I, Figure 4) and 4-

piperidin-1-ylbenzaldehyde i.e. 9 (scheme-III, Figure 6).

IV) Condensation of the prepared precursors with various aromatic and

heteroaromatic ketones in the presence of a base to yield new

chalcones, as given in the scheme-I and scheme-III.

V) Pyrazoline ring insertion on the chalcone-moiety using hydrazine

hydrate in ethanol, as given in scheme-II (Figure 5) and scheme-IV

(Figure 7).

VI) Screening of all the prepared compounds (chalcones and their

pyrazoline derivatives) for various biological activities.


50

1.7.1 Scheme─I

(1) R1= CH 3 R

2R

3= H

NH2

R1

R2

R3 AcOH

o-H3PO4

NH

R1

R2

R3

O

CH3

POCl3

DMF

N

H

Cl

R3

R2

R1

O

(2) R2= CH 3 R

1R

3= H

(3) R3= CH 3 R

1R

2= H

(4) R3= OCH 3 R

1R

2= H

N

H

Cl

R3

R2

R1

O

NaOH/EtOH

r. t.N Cl

R3

R2

R1

O

Ar

(1a-k) R1= CH 3 R

2R

3= H

(2a-k) R2= CH 3 R

1R

3= H

(3a-s) R3= CH 3 R

1R

2= H

(4a-s) R3= OCH 3 R

1R

2= H

Ketones Ar Ketones Ar

a Thien-3-yl k 5-I-thien-2-yl

b 3-Me-thien-2-yl l 1H-pyrrol-2-yl

c 4-Me-thien-2-yl m 5-Me-furan-2yl

d 5-Me-thien-2-yl n 2,5-diMe-furan-3-yl

e 2,5-diMe-thien-3-yl o Benzofuran-2-yl

f 3-Cl-thien-2-yl p 2,3-diH-1,4-benzodioxin-6-yl

g 5-Cl-thien-2-yl q 1-Naphthyl

h 2,5-diCl-thien-3-yl r 2-Naphthyl

i 3-Br-thien-2-yl s 9-Anthryl

j 5-Br-thien-2-yl

+ ArCH3

O

Figure 9. Synthesis of quinolinyl chalcones


51

1.7.2 Scheme─II

N

Ar

O

ClR2

R1

R3

NH2NH

2.H

2O

EtOHN ClR

2

R1

NH N

ArR

3

(1a-k) R1= CH 3 R

2R

3= H

(2a-k) R2= CH 3 R

1R

3= H

(3a-k) R3= CH 3 R

1R

2= H

(4a-k) R3= OCH 3 R

1R

2= H

(5a-k)

(6a-k)

(7a-k)

(8a-k)


a Thien-3-yl g 5-Cl-thien-2-yl

b 3-Me-thien-2-yl h 2,5-diCl-thien-3-yl

c 4-Me-thien-2-yl i 3-Br-thien-2-yl

d 5-Me-thien-2-yl j 5-Br-thien-2-yl

e 2,5-diMe-thien-3-yl k 5-I-thien-2-yl

f 3-Cl-thien-2-yl

Figure 10. Synthesis of 2-pyrazoline derivatives of chalcones

1.7.3 Scheme─III

NH

NaOH/EtOH

r. t.+ Ar

O

O

H

F+ N

O

H

N

O

H

N

O

Ar

(9)

(9) (9a-l)



b Thien-3-yl h 5-Cl-thien-2-yl

c 3-Me-thien-2-yl i 2,5-diCl-thien-3-yl


e 5-Me-thien-2-yl k 5-Br-thien-2-yl

f 2,5-diMe-thien-3-yl l 5-I-thien-2-yl

K2CO3, CTAB

DMF, 100 °C

Figure 11. Synthesis of piperidyl chalcones


52

1.7.4 Scheme─IV

N

O

Ar

(10a-l)

N

Ar

NH N

+

(9a-l)

NH2 NH2EtOH

reflux








Figure 12. Conversion of piperidyl chalcones to 2-pyrazoline derivatives

Chapter – 2

Chapter -2 Experimental

53

Chapter 2

EXPERIMENTAL

2.1 General

All the chemicals (solvents and reagents) were purchased from foreign

companies (Merck, Wako, Sigma/Aldrich and Alpha Aesar), and were used as such

with no further purification and distillation. No local chemical has been used in the

research work. The purity of these chemicals was 98-99.9%.

2.1.1 Substrates and Reagents

Various substituted and unsubstituted aromatic ketones (Alpha Aesar and

Sigma/Aldrich), p-anisidine (Sigma/Aldrich), o-toluidine (Merck), m-toluidine

(Sigma/Aldrich), p-toluidine (Sigma/Aldrich), piperidine (Wako), p-

fluorobenzaldehyde (Wako), were used as received. The reagents used were:

Phosphoryl chloride (Sigma/Aldrich and Merck), Glacial Acetic Acid (Merck),

orthophosphoric Acid (Sigma/Aldrich), Aliquat (Wako) sodium hydroxide (Merck)

and hydrazine (Merck).

2.1.2 Solvents

Analytical grade solvents like N,N-Dimethylformamide (DMF), dimethyl

sulfoxide (DMSO), ethanol (EtOH), methanol (MeOH), ethyl acetate (AcOEt)

chloroform (CHCl3) and n-hexane were used as such without further distillation.

2.1.3 Instruments

Melting points were obtained on Gallenkamp melting point apparatus and were

uncorrected.

IR spectra were recorded in KBr pellets on Perkin Elmer infrared spectrophotometer.

1H NMR spectra were recorded in CDCl3 on Brücker/XWIN NMR (400 MHz) and

TMSwas used as internal standard. Chemical shifts are given in δ (ppm).

Mass spectra were recorded on a Jeol MS Route instrument.

Elemental analyses were performed by C.S.I.C., Madrid Spain and were within ±

0.4% of predicted values for all the compounds.


54

All the reactions were monitored with the help of pre-coated aluminium TLC plates

(0.2mm, 60 HF254, Merck).

2.2 Methods of Preparation of Precursors for Chalcones

2.2.1 N-acetylation of Substituted Anilines260

To 0.1 mol of substituted aniline, 0.2 mol of glacial acetic acid was added in a

250 ml flask. To this mixture, catalytic amount of orthophosphoric acid was added

and the mixture was refluxed for 5-6 hrs. At the completion of the reaction (TLC

monitoring), the mixture was poured in ice-cold water and stirred well. The crude

product was precipitated out at once. The precipitates were filtered and washed with

cold water. The pure product was obtained by recrystallization from boiling water.

2.2.2 Synthesis of 2-Chloro-3-formylquinolines (1-4) (Method-A;

Conventional Thermal Method)261

Vilsmeier reagent was prepared by adding POCl3 (107.4 g, 64.4 mL, 0.70 mol)

dropwise in DMF (18.26 g, 19.2 mL, 0.25 mol) at 0 ºC with constant stirring. To this

solution was added the acetanilide (0.10 mol) and the mixture was stirred (15 min) at

room temperature. Then this mixture was stirred at 70-80 ºC for the time period as

mentioned in table-5. After the completion of the reaction (TLC monitoring), the

mixture was poured in ice cold water (500 mL) and stirred vigorously (30 min) at 0-

10 °C. The 2-Chloro-3-quinolinecarbaldehyde was precipitated out, which was

filtered off, washed with water (200 mL), dried and recrystallised from ethyl acetate.

2.2.3 Synthesis of 2-Chloro-3-formylquinolines (1-4) (Method-B;

Microwave Irradiation Method)

Vilsmeier reagent was prepared by adding POCl3 (107.4 g, 64.4 mL, 0.70 mol)

dropwise in DMF (18.26 g, 19.2 mL, 0.25 mol) at 0 ºC with constant stirring. To this

solution was added the acetanilide (0.10 mol) and the mixture was stirred (15 min) at

room temperature. Then this mixture was subjected to microwave irradiation at 350

W for the time period as mentioned in table-5. After the completion of the reaction

(TLC monitoring), the mixture was poured in ice cold water (500 mL) and stirred

vigorously (30 min) at 0-10 °C. The 2-Chloro-3-quinolinecarbaldehyde was

precipitated out, which was filtered off, washed with water (200 mL), dried and

recrystallised from ethyl acetate.


55

Table 5. A comparison of the methods producing chloroquinolinecarbaldehyde, in terms of yields & reaction kinetics

Thermal Condition Microwave Irradiation

Entry Acetanilide 2-Chloro-3-formylquinoline (70-80°C) (350W)

Reaction Yield Reaction Yield

(R) (R) Time/hr (%) Time/sec (%)

1 2-Me 8-Me 15.5 67 100 82

2 3-Me 7-Me 6 66 30 79

3 4-Me 6-Me 16 70 120 88

4 4-OMe 6-OMe 16 56 120 85


56

2.2.4 Method for N-arylation of Piperidine 262 (9) (Scheme─III)

A mixture of piperidine (50 mmol, 4.25 g, 4.93 mL) and para-

fluorobenzaldehyde (50 mmol, 6.205g, 5.275 mL) in DMF (25 mL), was stirred at

100 ºC in the presence of K2CO3 (50 mmol, 6.9 g) and cetyl trimethylammonium

bromide (CTAB, 10 mg). After the completion of reaction (TLC monitoring), the

mixture was poured into ice-cold water (100 mL). Crude product 4-piperidin-1-

ylbenzaldehyde was precipitated out, which was filtered and recrystallized from

methanol.

2.3 General Method for the Synthesis of Quinolinyl

Chalcones (1a-k, 2a-k, 3a-s and 4a-s) (Scheme─I)

A mixture of quinolinecarbaldehyde (1, 2, 3 or 4, 10 mmol) and an aromatic

ketone (a-k or a-s, 10 mmol) in methanol (50 ml) was stirred at room temperature,

followed by dropwise addition of aq. NaOH (4 ml, 10%). The stirring was continued

for 2 h and the reaction mixture was then kept at 0°C (24 h). Subsequently, it was

poured onto ice-cold water (200 ml). The precipitates were collected by filtration,

washed with cold water followed by cold MeOH. The resulting chalcones (1a-k, 2a-

k, 3a-s and 4a-s) were recrystallised from CHCl3.


1-one (1a)

N

O

S

Cl

CH3

Yield : 60%

State : Pale yellow solid

M.P. : 128-130°C

IR : υmax(KBr) cm-1

1649 (C=O), 1591 (C=C), 1561 (C=N

of quinoline ring).


57

1H-NMR : (CDCl3) δ: 2.76 (3H, s, Me), 7.39 (1H, dd, H4', J = 5.1

Hz, 2.9 Hz), 7.46 (1H, d, Hα, J = 15.6 Hz), 7.47 (1H, t,

H6, J = 7.6 Hz), 7.60 (1H, d, H7, J=7.0 Hz), 7.69 (1H,

d, H5', J = 4.7 Hz, 1.1 Hz), 7.70 (1H, d, H5, J = 6.7 Hz),

8.20 (1H, d, Hβ, J = 15.7 Hz), 8.20 (1H, dd, H2', J = 2.8

Hz, 1.1 Hz), 8.42 (1H, s, H4).

MS : (m/z): 313 (M+, 1.9%), 111 (M

+−C12H9NCl, 100 %).

CHN : Anal. Calculated for C17H12NOClS: C, 65.07; H, 3.85;

N, 4.46. Found: C, 65.04; H, 3.78; N, 4.44.


yl)prop-2-en-1-one (1b)

N

O

S

Cl CH3

CH3

Yield : 56%

State : Yellow solid

M.P. : 174-175°C


1654 (C=O), 1594 (C=C), 1563 (C=N

of quinoline ring).

1H-NMR : (CDCl3) δ: 2.66-2.76 (s, Me x 2), 7.02 (1H, d, H4', J =

4.9 Hz), 7.41 (1H, d, Hα, J = 15.4 Hz), 7.47 (1H, t, H6, J

= 7.6 Hz), 7.49 (1H, d, H5', J = 5.3 Hz), 7.59 (1H, d,

H7, J = 7.0 Hz), 7.71 (1H, d, H5, J = 8.0 Hz), 8.20 (1H,

d, Hβ, J = 15.4 Hz), 8.40 (1H, s, H4).

MS : (m/z): 327 (M+, 6.74%), 125 (M

+−C12H9NCl, 100 %).


N, 4.27. Found: C, 65.90; H, 4.27; N, 4.27.


58


yl)prop-2-en-1-one (1c)

N

O

S

Cl

CH3CH3

Yield : 49%


M.P. : 146-147°C


1655 (C=O), 1593 (C=C), 1565 (C=N

of quinoline ring).

1H-NMR : (CDCl3) δ: 2.33-2.76 (s, Me x 2), 7.31 (1H, s, H5'), 7.46

(1H, d, Hα, J = 15.5 Hz), 7.47 (1H, t, H6, J = 7.6 Hz),

7.60 (1H, d, H7, J = 7.0 Hz), 7.70 (1H, d, H5, J = 7.0

Hz), 7.71 (1H, s, H3'), 8.23 (1H, d, Hβ, J = 15.6 Hz),

8.42 (1H, s, H4).

MS : (m/z): 327 (M+, 5.02%), 292 (M

+−Cl, 100 %).


N, 4.27. Found: C, 65.85; H, 4.23; N, 4.22.


yl)prop-2-en-1-one (1d)

N

O

S

Cl

CH3

CH3


59

Yield : 55%


M.P. : 180-181°C


1652 (C=O), 1596 (C=C), 1563 (C=N

of quinoline ring).

1H-NMR : (CDCl3) δ: 2.57-2.75 (s, Me x 2), 6.86 (1H, d, H4',

J=3.1 Hz), 7.43 (1H, d, Hα, J = 15.6 Hz), 7.46 (1H, t,

H6, J = 7.7 Hz), 7.59 (1H, d, H7, J = 7.0 Hz), 7.69 (1H,

d, H5, J = 8.2 Hz), 7.72 (1H, d, H3' J = 3.8 Hz), 8.19

(1H, d, Hβ, J = 15.6 Hz), 8.40 (1H, s, H4).

MS : (m/z): 327 (M+, 5.56%), 125 (M

+−C12H9NCl, 100 %).


N, 4.27. Found: C, 65.86; H, 4.25; N, 4.25.


3-yl)prop-2-en-1-one (1e)

N

O

S

Cl

CH3

CH3CH3 1

Yield : 67%


M.P. : 138-140°C


1648 (C=O), 1585 (C=C), 1565 (C=N

of quinoline ring).


(1H, d, Hα, J = 15.7 Hz), 7.46 (1H, t, H6, J = 7.7 Hz),

7.59 (1H, d, H7, J = 7.0 Hz), 7.68 (1H, d, H5, J = 8.1

Hz), 8.10 (1H, d, Hβ, J = 15.7 Hz), 8.37 (1H, s, H4).

MS : (m/z): 341 (M+, 7.71%), 139 (M

+−C12H9NCl, 100 %).


60


N, 4.10. Found: C, 66.66; H, 4.62; N, 4.02.



N

O

S

Cl Cl

CH3

Yield : 73%


M.P. : 162-163°C


1650 (C=O), 1592 (C=C), 1570 (C=N

of quinoline ring).

1H-NMR : (CDCl3) δ: 2.76 (3H, s, Me), 7.07 (1H, d, H4', J = 5.3

Hz), 7.47 (1H, t, H6, J=7.7 Hz), 7.59 (1H, d, H7, J = 7.0

Hz), 7.60 (1H, d, H5', J = 5.3 Hz), 7.71 (1H, d, H5, J =

8.1 Hz), 7.82 (1H, d, Hα, J = 15.5 Hz), 8.24 (1H, d, Hβ,

J = 15.6 Hz), 8.42 (1H, s, H4).

MS : (m/z): 312 (M+−Cl, 40.18%), 145 (M

+−C12H9NCl, 100

%).

CHN : Anal. Calculated for C17H11NOCl2S: C, 58.63; H, 3.18;

N, 4.02. Found: C, 58.59; H, 3.12; N, 3.98.


61


yl)prop-2-en-1-one (1g)

N

O

S

Cl

Cl

CH3

Yield : 85%


M.P. : 166-168°C


1656 (C=O), 1598 (C=C), 1572 (C=N

of quinoline ring).

1H-NMR : (CDCl3) δ: 2.76 (3H, s, Me), 7.02 (1H, d, H4', J=4.0

Hz), 7.39 (1H, d, Hα, J = 15.5 Hz), 7.48 (1H, t, H6, J =

7.6 Hz), 7.61 (1H, d, H7, J = 7.0 Hz), 7.68 (1H, d, H3', J

= 4.2 Hz), 7.70 (1H, d, H5, J = 8.1 Hz), 8.23 (1H, d, Hβ,

J = 15.6 Hz), 8.41 (1H, s, H4).

MS : (m/z): 312 (M+−Cl, 30.24%), 145 (M

+−C12H9NCl, 100

%).


N, 4.02. Found: C, 58.55; H, 3.13; N, 3.97.

2.3.8 (2E)-3-(2-Chloro-8-methylquinolin-3-yl)-1-(2,5-dichlorothien-3-

yl)prop-2-en-1-one (1h)

N

O

S

Cl

Cl

ClCH3

Yield : 69%


62

State : White solid

M.P. : 120-121°C


1664 (C=O), 1596 (C=C), 1570 (C=N

of quinoline ring).

1H-NMR : (CDCl3) δ: 2.76 (3H, s, Me), 7.15 (1H, s, H4'), 7.45 (1H,

d, Hα, J = 15.7 Hz), 7.47 (1H, t, H6, J = 7.7 Hz), 7.61

(1H, d, H7, J = 6.8 Hz), 7.70 (1H, d, H5, J = 8.1 Hz),

8.17 (1H, d, Hβ, J = 15.7 Hz), 8.39 (1H, s, H4).

MS : (m/z): 383 (M+, 1.8%), 179 (M

+−C12H9NCl, 100 %).


N, 3.66. Found: C, 53.24; H, 2.55; N, 3.60.


yl)prop-2-en-1-one (1i)

N

O

S

Cl Br

CH3

Yield : 86%


M.P. : 210-212°C


1652 (C=O), 1592 (C=C), 1568 (C=N

of quinoline ring).


Hz), 7.47 (1H, t, H6, J = 7.6 Hz), 7.58 (1H, d, H5', J =

5.2 Hz), 7.60 (1H, d, H7, J = 7.1 Hz), 7.71 (1H, d, H5, J

= 8.0 Hz), 7.81 (1H, d, Hα, J = 15.6 Hz), 8.25 (1H, d,

Hβ, J = 15.5 Hz), 8.44 (1H, s, H4).

MS : (m/z): 393 (M+, 1.0%), 82 (M

+−C13H9NOClBr, 100 %).

CHN : Anal. Calculated for C17H11NOClSBr: C, 51.99; H,

2.82; N, 3.57. Found: C, 51.98; H, 2.77; N, 3.59.


63


yl)prop-2-en-1-one (1j)

N

O

S

Cl

Br

CH3

Yield : 71%

State : Off white solid

M.P. : 204-206°C


1653 (C=O), 1588 (C=C), 1566 (C=N

of quinoline ring).


Hz), 7.39 (1H, d, Hα, J = 15.6 Hz), 7.48 (1H, t, H6, J =

7.6 Hz), 7.61 (1H, d, H7, J = 7.1 Hz), 7.63 (1H, d, H3', J

= 4.0 Hz), 7.70 (1H, d, H5, J = 8.0 Hz), 8.23 (1H, d, Hβ,

J = 15.6 Hz), 8.41 (1H, s, H4).

MS : (m/z): 393 (M+, 2%), 82 (M

+−C13H9NOClBr, 100 %).


2.82; N, 3.57. Found: C, 51.93; H, 2.75; N, 3.55.


yl)prop-2-en-1-one (1k)

N

O

S

Cl

I

CH3

Yield : 86%


64


M.P. : 196-198°C


1649 (C=O), 1596 (C=C), 1565 (C=N

of quinoline ring).


Hz), 7.38 (1H, d, Hα, J = 15.6 Hz), 7.47 (1H, t, H6, J =

7.6 Hz), 7.51 (1H, d, H3', J = 3.9 Hz), 7.61 (1H, d, H7, J

= 7.0 Hz), 7.70 (1H, d, H5, J = 8.1 Hz), 8.23 (1H, d, Hβ,

J = 15.6 Hz), 8.41 (1H, s, H4).

MS : (m/z): 439 (M+, 1%), 82 (M

+−C13H9NOICl, 100 %).

CHN : Anal. Calculated for C17H11NOClSI: C, 46.44; H, 2.52;

N, 3.19. Found: C, 46.39; H, 2.42; N, 3.13.

2.3.12 (2E)-3-(2-Chloro-7-methylquinolin-3-yl)-1-thien-3-ylprop-2-

en-1-one (2a)

N

O

S

ClCH3

Yield : 65%

State : White solid

M.P. : 180-182°C


1649 (C=O), 1594 (C=C), 1565 (C=N

of quinoline ring);

1H-NMR : (CDCl3) δ: 2.57 (3H, s, Me), 7.39 (1H, dd, H4', J = 5.1

Hz, 2.9 Hz), 7.42 (1H, dd, H5, J = 8.2 Hz, 1.2 Hz), 7.45

(1H, d, Hα, J = 15.7 Hz), 7.69 (1H, dd, H5', J = 5.1 Hz,

1.0 Hz), 7.76 (1H, d, H6, J = 8.3 Hz), 7.79 (1H, s, H8),

8.19 (1H, d, Hβ, J = 15.6 Hz), 8.20 (1H, dd, H2', J = 2.9

Hz, 1.0 Hz), 8.42 (1H, s, H4);

MS : (m/z): 313 (M+, 1.86%), 111 (M

+−C12H9NCl, 100 %).


65


N, 4.46. Found: C, 65.03; H, 3.76; N, 4.43.



N

O

S

Cl CH3CH3

Yield : 51%


M.P. : 208-210°C


1653 (C=O), 1594 (C=C), 1563 (C=N

of quinoline ring).


4.9 Hz), 7.40 (1H, d, Hα, J = 15.4 Hz), 7.42 (1H, dd, H5,

J = 8.2 Hz, 1.3 Hz), 7.49 (1H, d, H5' J = 4.9 Hz), 7.77

(1H, d, H6, J = 8.6 Hz), 7.78 (1H, s, H8), 8.18 (1H, d,

Hβ, J = 15.4 Hz), 8.40 (1H, s, H4).

MS : (m/z): 327 (M+, 10%), 125 (M

+−C12H9NCl, 100 %).


N, 4.27. Found: C, 65.92; H, 4.25; N, 4.25.



N

O

S

Cl

CH3

CH3


66

Yield : 56%


M.P. : 173-174°C


1655 (C=O), 1594 (C=C), 1564 (C=N

of quinoline ring).


(1H, dd, H5, J = 8.2 Hz, 1.3 Hz), 7.44 (1H, d, Hα, J =

15.5 Hz), 7.71 (1H, s, H3'), 7.76 (1H, d, H6, J = 8.3 Hz),

7.79 (1H, s, H8), 8.21 (1H, d, Hβ, J = 15.6 Hz), 8.42

(1H, s, H4).

MS : (m/z): 327 (M+, %), 125 (M

+−C12H9NCl, 100 %).


N, 4.27. Found: C, 65.85; H, 4.24; N, 4.23.



N

O

S

Cl

CH3

CH3

Yield : 52%


M.P. : 173-175°C


1652 (C=O), 1595 (C=C), 1563 (C=N

of quinoline ring).


3.3 Hz), 7.42 (1H, d, Hα, J = 15.6 Hz), 7.43 (1H, dd, H5,

J = 8.2 Hz, 1.2 Hz), 7.71 (1H, d, H3', J = 3.7 Hz), 7.75

(1H, d, H6, J = 8.3 Hz), 7.78 (1H, s, H8), 8.18 (1H, d,

Hβ, J = 15.6 Hz), 8.40 (1H, s, H4).

MS : (m/z): 327 (M+, 3.61%), 125 (M

+−C12H9NCl, 100 %).


67


N, 4.27. Found: C, 65.89; H, 4.26; N, 4.25.



N

O

S

Cl

CH3

CH3

CH3

Yield : 70%


M.P. : 183-185 °C


1648 (C=O), 1590 (C=C), 1565 (C=N

of quinoline ring).


(1H, d, Hα, J = 15.7 Hz), 7.41 (1H, dd, H5, J = 8.4 Hz,

1.2 Hz), 7.74 (1H, d, H6, J = 8.3 Hz), 7.78 (1H, s, H8),

8.08 (1H, d, Hβ, J = 15.7 Hz), 8.37 (1H, s, H4).

MS : (m/z): 341 (M+, 10.31%), 306 (M

+−Cl, 100 %).


N, 4.10. Found: C, 66.65; H, 4.68; N, 4.08.



N

O

S

Cl ClCH3


68

Yield : 66%


M.P. : 160-162 °C


1650 (C=O), 1591 (C=C), 1569 (C=N

of quinoline ring).


Hz), 7.28 (1H, dd, H5, J = 8.3 Hz, 1.1 Hz), 7.60 (1H, d,

H5', J = 5.2 Hz), 7.77 (1H, d, H6, J=8.6 Hz), 7.82 (1H,

d, Hα, J = 15.5 Hz), 7.96 (1H, s, H8), 8.23 (1H, d, Hβ, J

= 15.5 Hz), 8.42 (1H, s, H4).

MS : (m/z): 348 (M+, 1.8%), 145 (M

+−C12H9NCl, 100 %).


N, 4.02. Found: C, 58.53; H, 3.16; N, 3.97.



N

O

S

Cl

Cl

CH3

Yield : 80%


M.P. : 170-171 °C


1656 (C=O), 1598 (C=C), 1570 (C=N

of quinoline ring).


Hz), 7.35 (1H, dd, H5, J = 8.3 Hz, 1.2 Hz), 7.39 (1H, d,

Hα, J = 15.6 Hz), 7.57 (1H, d, H3', J = 4.1 Hz), 7.64

(1H, d, H6, J = 8.3 Hz), 7.72 (1H, s, H8), 8.20 (1H, d,

Hβ, J=15.6 Hz), 8.39 (1H, s, H4).

MS : (m/z): 348 (M+, 2.41%), 145 (M

+−C12H9NCl, 100 %).


69


N, 4.02. Found: C, 58.57; H, 3.14; N, 3.96.


3-yl)prop-2-en-1-one (2h)

N

O

S

Cl

Cl

Cl

CH3

Yield : 63%


M.P. : 163 °C


1662 (C=O), 1596 (C=C), 1572 (C=N

of quinoline ring).


dd, H5, J = 8.3 Hz, 1.0 Hz), 7.45 (1H, d, Hα, J = 15.7

Hz), 7.76 (1H, d, H6, J = 8.3 Hz), 7.79 (1H, s, H8), 8.15

(1H, d, Hβ, J = 15.7 Hz), 8.39 (1H, s, H4).

MS : (m/z): 383 (M+, 1.7%), 346 (M

+−Cl, 100 %).


N, 3.66. Found: C, 53.26; H, 2.58; N, 3.67.



N

O

S

Cl BrCH3

Yield : 79%


70


M.P. : 164-165 °C


1652 (C=O), 1592 (C=C), 1568 (C=N

of quinoline ring).


Hz), 7.42 (1H, dd, H5, J = 8.3 Hz, 1.3 Hz), 7.58 (1H, d,

H5', J = 5.2 Hz), 7.78 (1H, d, H6, J = 8.6 Hz), 7.82 (1H,

d, Hα, J = 15.6 Hz), 7.79 (1H, s, H8), 8.23 (1H, d, Hβ, J

= 15.5 Hz), 8.43 (1H, s, H4).

MS : (m/z): 393 (M+, 1.5%), 82 (M

+−C13H9NOClBr, 100 %).


2.82; N, 3.57. Found: C, 51.94; H, 2.76; N, 3.56.



N

O

S

Cl

Br

CH3

Yield : 75%


M.P. : 162-164 °C


1653 (C=O), 1588 (C=C), 1566 (C=N

of quinoline ring).


Hz), 7.38 (1H, d, Hα, J = 15.6 Hz), 7.42 (1H, dd, H5, J =

8.3 Hz, 1.0 Hz), 7.63 (1H, d, H3', J = 4.0 Hz), 7.76 (1H,

d, H6, J = 8.3 Hz),7.79 (1H, s, H8), 8.21 (1H, d, Hβ, J =

15.6 Hz), 8.40 (1H, s, H4).

MS : (m/z): 393 (M+, 1.5%), 82 (M

+−C13H9NOClBr, 100 %).


71


2.82; N, 3.57. Found: C, 51.95; H, 2.79; N, 3.56.



N

O

S

Cl

I

CH3

Yield : 90%

State : Deep yellow solid

M.P. : 164-165 °C


1650 (C=O), 1596 (C=C), 1565 (C=N

of quinoline ring).


Hz), 7.37 (1H, d, Hα, J = 15.5 Hz), 7.42 (1H, dd, H5, J =

8.4 Hz, 1.2 Hz), 7.50 (1H, d, H3', J = 4.0 Hz), 7.76 (1H,

d, H6, J = 8.3 Hz), 7.79 (1H, s, H8), 8.21 (1H, d, Hβ, J =

15.6 Hz), 8.40 (1H, s, H4).

MS : (m/z): 439 (M+, 1.5%), 82 (M

+−C13H9NOICl, 100 %).


N, 3.19. Found: C, 46.44; H, 2.43; N, 3.18.

2.3.23 (2E)-3-(2-Chloro-6-methylquinolin-3-yl)-1-thien-3-ylprop-2-

en-1-one (3a)

N

O

S

Cl

CH3


72

Yield : 72%


M.P. : 183-185 °C


1648 (C=O), 1592 (C=C).

1H-NMR : (CDCl3) δ: 2.54 (3H, s, Me), 7.39 (1H, dd, H4', J=2.8

Hz), 7.44 (1H, d, Hα, J=15.7 Hz), 7.6 (1H, d, H7, J=8.6

Hz), 7.62 (1H, s, H5), 7.70 (1H, d, H5', J=4.7 Hz), 7.91

(1H, d, H8, J=8.5 Hz), 8.18 (1H, d, Hβ, J=15.8 Hz), 8.20

(1H, dd, H2', J=2.2 Hz), 8.36 (1H, s, H4).

MS : (m/z): 313 (M+, 7.9%), 278 (M

+−Cl, 100 %).


N, 4.46. Found: C, 65.02; H, 3.75; N, 4.41.



N

O

S

Cl CH3

CH3

Yield : 53%


M.P. : 172-173 °C


1654 (C=O), 1594 (C=C).


J=4.9 Hz), 7.40 (1H, d, Hα, J=15.4 Hz), 7.49 (1H, d,

H5', J=4.9 Hz), 7.58 (1H, dd, H7, J=8.6 Hz), 7.64 (1H,

s, H5), 7.90 (1H, d, H8, J=8.6 Hz), 8.18 (1H, d, Hβ,

J=15.4 Hz), 8.35 (1H, s, H4).

MS : (m/z): 327 (M+, 25.8%), 292 (M

+−Cl, 100 %).


N, 4.27. Found: C, 65.89; H, 4.29; N, 4.25.


73



N

O

S

Cl

CH3

CH3

Yield : 45%

State : White solid

M.P. : 150 °C


1656 (C=O), 1593 (C=C).


(1H, d, Hα, J=15.5 Hz), 7.48 (1H, dd, H7, J=8.6 Hz),

7.51 (1H, s, H5), 7.71 (1H, s, H3'), 7.83 (1H, d, H8,

J=8.5 Hz), 8.21 (1H, d, Hβ, J=15.6 Hz), 8.41 (1H, s,

H4).

MS : (m/z): 328 (M+, 11.4%), 125 (M

+−C12H9NCl, 100 %).


N, 4.27. Found: C, 65.87; H, 4.24; N, 4.26.



N

O

S

Cl

CH3

CH3

Yield : 44%

State : Bright yellow solid

M.P. : 198 °C


1652 (C=O), 1596 (C=C).


74


J=3.6 Hz), 7.42 (1H, d, Hα, J=15.6 Hz), 7.58 (1H, dd,

H7, J=8.6 Hz), 7.62 (1H, s, H5), 7.71 (1H, d, H3' J=3.8

Hz), 7.90 (1H, d, H8, J=8.6 Hz), 8.18 (1H, d, Hβ, J=15.6

Hz), 8.35 (1H, s, H4).

MS : (m/z): 327 (M+, 12.1%), 292 (M

+−Cl, 100 %).


N, 4.27. Found: C, 65.89; H, 4.27; N, 4.22.



N

O

S

Cl

CH3

CH3

CH3

Yield : 67%


M.P. : 128-130 °C


1648 (C=O), 1585 (C=C).


(1H, d, Hα, J=15.7 Hz), 7.58 (1H, dd, H7, J=8.6 Hz),

7.62 (1H, s, H5), 7.90 (1H, d, H8, J=8.6 Hz), 8.08 (1H,

d, Hβ, J=15.7 Hz), 8.33 (1H, s, H4).

MS : (m/z): 341 (M+, 48.2%), 306 (M

+−Cl, 100 %).


N, 4.10. Found: C, 66.61; H, 4.63; N, 4.05.


75



N

O

S

Cl Cl

CH3

Yield : 74%


M.P. : 184-186 °C


1650 (C=O), 1592 (C=C).


Hz), 7.50 (1H, d, H5', J=5.2 Hz), 7.59 (1H, dd, H7,

J=8.5 Hz), 7.64 (1H, s, H5), 7.82 (1H, d, Hα, J=15.6

Hz), 7.90 (1H, d, H8, J=8.6 Hz), 8.22 (1H, d, Hβ, J=15.5

Hz), 8.37 (1H, s, H4).

MS : (m/z): 347 (M+, 4.2%), 312 (M

+−Cl, 100 %).


N, 4.02. Found: C, 58.54; H, 3.16; N, 3.99.



N

O

S

Cl

Cl

CH3

Yield : 89%


M.P. : 180 °C


1656 (C=O), 1598 (C=C).


76


Hz), 7.39 (1H, d, Hα, J=15.6 Hz), 7.60 (1H, dd, H7,

J=8.6 Hz), 7.63 (1H, s, H5), 7.68 (1H, d, H3', J=4.0 Hz),

7.91 (1H, d, H8, J=8.5 Hz), 8.21 (1H, d, Hβ, J=15.6 Hz),

8.36 (1H, s, H4).

MS : (m/z): 347 (M+, 6.9%), 312 (M

+−Cl, 100 %).


N, 4.02. Found: C, 58.57; H, 3.13; N, 3.99.


3-yl)prop-2-en-1-one (3h)

N

O

S

Cl

Cl

Cl

CH3

Yield : 53%


M.P. : 128 °C


1664 (C=O), 1595 (C=C).


d, Hα, J=15.7 Hz), 7.60 (1H, dd, H7, J=8.6 Hz), 7.63

(1H, s, H5), 7.90 (1H, d, H8, J=8.6 Hz), 8.14 (1H, d, Hβ,

J=15.7 Hz), 8.34 (1H, s, H4).

MS : (m/z): 383 (M+, 5.7%), 346 (M

+−Cl, 100 %).


N, 3.66. Found: C, 53.22; H, 2.58; N, 3.62


77



N

O

S

Cl Br

CH3

Yield : 64%


M.P. : 189-191 °C


1650 (C=O), 1591 (C=C).


Hz), 7.58 (1H, d, H5', J=5.1 Hz), 7.59 (1H, dd, H7,

J=8.6 Hz), 7.65 (1H, s, H5), 7.83 (1H, d, Hα, J=15.5

Hz), 7.91 (1H, d, H8, J=8.6 Hz), 8.22 (1H, d, Hβ,

J=15.5 Hz), 8.38 (1H, s, H4).

MS : (m/z): 393 (M+, 5.1%), 356 (M

+−Cl, 100 %).


2.82; N, 3.57. Found: C, 51.96; H, 2.79; N, 3.58.



N

O

S

Cl

Br

CH3

Yield : 55%

State : Pale brown solid

M.P. : 160-161 °C


1653 (C=O), 1588 (C=C).


78


Hz), 7.17 (1H, d, H3', J=4.0 Hz), 7.38 (1H, d, Hα,

J=15.6 Hz), 7.60 (1H, dd, H7, J=8.5 Hz), 7.63 (1H, s,

H5), 7.91 (1H, d, H8, J=8.3 Hz), 8.21 (1H, d, Hβ, J=15.6

Hz), 8.36 (1H, s, H4).

MS : (m/z): 393 (M+, 10.9%), 358 (M

+−Cl, 100 %).


2.82; N, 3.57. Found: C, 51.98; H, 2.77; N, 3.56.



N

O

S

Cl

I

CH3

Yield : 87%


M.P. : 178 °C


1648 (C=O), 1596 (C=C).


Hz), 7.37 (1H, d, Hα, J=15.5 Hz), 7.50 (1H, d, H3',

J=3.9 Hz), 7.59 (1H, dd, H7, J=8.7 Hz), 7.62 (1H, s,

H5), 7.90 (1H, d, H8, J=8.5 Hz), 8.20 (1H, d, Hβ, J=15.6

Hz), 8.35 (1H, s, H4).

MS : (m/z): 439 (M+, 12.6%), 404 (M

+−Cl, 100 %).


N, 3.19. Found: C, 46.41; H, 2.45; N, 3.17.

The ORTEP diagram of the compound 3k is given in the Figure 13 below.


79

Figure 13. ORTEP-3 diagram of compound 3k with the numbering scheme. Displacement ellipsoids

are drawn at the 50% probability level, H atoms are represented by circles of arbitrary radii.


80

Crystal Data:

C17H11ClINOS

Mr = 439.68

Monoclinic, P21/c

a = 17.112 (6) Å

b = 7.636 (3) Å

c = 13.174 (5) Å

β = 111.29 (2)°

V = 1603.9 (10) Å3

Z = 4

Mo Kα radiation

µ = 2.29 mm-1

T = 173 (2) K

0.26 X 0.07 X 0.06 mm

Data collection:

Nonius KappaCCD diffractometer

Absorption correction: multi-scan

(SORTAV; Blessing, 1997)

Tmin = 0.587, Tmax = 0.875

6042 measured reflections

3652 independent reflections

2663 reflections with I > 2σ(I)

Rint = 0.036

Refinement:

R[F2 > 2σ(F

2)] = 0.041

wR(F2) = 0.097

S = 1.03

3652 reflections

200 parameters

H-atom parameters constrained

Δρmax = 0.52 e Å-3

Δρmin = -0.63 e Å-3


81

2.3.34 (2E)-3-(2-Chloro-6-methylquinolin-3-yl)-1-(1H-pyrrol-2-

yl)prop-2-en-1-one (3l)

N

O

NH

Cl

CH3

Yield : 70%


M.P. : 214 °C


1654 (C=O), 1594 (C=C).

1H-NMR : (CDCl3) δ: 2.47 (3H, s, Me), 6.24 (1H, dd, H4', J=3.5

Hz), 6.70 (1H, d, H3', J=3.5 Hz), 7.05 (1H, d, H5', J=4.2

Hz), 7.41 (1H, d, Hα, J=15.6 Hz), 7.57 (1H, dd, H7,

J=8.6 Hz), 7.63 (1H, s, H5), 7.91 (1H, d, H8, J=8.6 Hz),

8.18 (1H, d, Hβ, J=15.7 Hz), 8.35 (s, 1H, H4).

MS : (m/z): 295 (M+, 8.5%), 260 (M

+−Cl, 100 %).

CHN : Anal. Calculated for C17H13N2OCl: C, 68.81; H, 4.42;

N, 9.44. Found: C, 68.72; H, 4.36; N, 9.40.

2.3.35 (2E)-3-(2-Chloro-6-methylquinolin-3-yl)-1-(5-methyl-2-

furyl)prop-2-en-1-one (3m)

Yield : 95%


M.P. : 158 °C


82


1664 (C=O), 1594 (C=C).

1H-NMR : (CDCl3) δ: 2.45-2.54 (s, Me x 2), 6.24 (1H, dd, H4',

J=3.4 Hz), 7.29 (1H, d, H3', J=3.5 Hz), 7.45 (1H, d, Hα,

J=15.7 Hz), 7.58 (1H, dd, H7, J=8.6 Hz), 7.63 (1H, s,

H5), 7.90 (1H, d, H8, J=8.6 Hz), 8.22 (1H, d, Hβ, J=15.8

Hz), 8.38 (1H, s, H4).

MS : (m/z): 311 (M+, 8.3%), 276 (M

+−Cl, 100 %).

CHN : Anal. Calculated for C18H14NO2Cl: C, 69.34; H, 4.53;

N, 4.49. Found: C, 69.32; H, 4.47; N, 4.48.

The ORTEP diagram of the compound 3m is given in the Figure 14 below.

Figure 14. ORTEP-3 diagram of compound 3m with the numbering scheme. Displacement ellipsoids



83

Crystal Data:

C18H14ClNO2

Mr = 311.75

Monoclinic, C2/c

a = 36.228 (10) Å

b = 7.372 (3) Å

c = 11.214 (5) Å

β = 99.70 (2)°

V = 2952 (2) Å3

Z = 8

Mo Kα radiation

µ = 0.27 mm-1

T = 173 (2) K

0.22 X 0.20 X 0.07 mm

Data collection:




Tmin = 0.944, Tmax = 0.982




Rint = 0.038

Refinement:

R[F2 > 2σ(F

2)] = 0.044

wR(F2) = 0.110

S = 1.01

3355 reflections

200 parameters


Δρmax = 0.25 e Å-3

Δρmin = -0.24 e Å-3


84

2.3.36 (2E)-3-(2-Chloro-6-methylquinolin-3-yl)-1-(2,5-dimethyl-3-

furyl)prop-2-en-1-one (3n)

Yield : 92%


M.P. : 145-147 °C


1648 (C=O), 1596 (C=C).

1H-NMR : (CDCl3) δ: 2.29-2.62 (s, Me x3), 6.34 (1H, s, H4'), 7.22

(1H, d, Hα, J=15.9 Hz), 7.58 (1H, dd, H7, J=8.6 Hz),

7.61 (1H, s, H5), 7.90 (1H, d, H8, J=8.6 Hz), 8.08 (1H,

d, Hβ, J=15.8 Hz), 8.31 (1H, s, H4).

MS : (m/z): 325 (M+, 38.1%), 290 (M

+−Cl, 100 %).


N, 4.30. Found: C, 69.99; H, 4.94; N, 4.22.

2.3.37 (2E)-1-(1-Benzofuran-2-yl)-3-(2-chloro-6-methylquinolin-3-

yl)prop-2-en-1-one (3o)

Yield : 56%


M.P. : 162 °C


85


1660 (C=O), 1592 (C=C).

1H-NMR : (CDCl3) δ: 2.47 (3H, s, Me), 7.28 (1H, t, Ar-H), 7.36

(1H, d, Hα, J=15.8 Hz), 7.42-7.53 (4H, m, Ar-H), 7.62

(1H, s, H5), 7.68 (1H, dd, H7, J=8.5 Hz), 7.83 (1H, d,

H8, J=8.6 Hz), 8.04 (1H, d, Hβ, J=15.6 Hz), 8.11 (1H, s,

H4).

MS : (m/z): 348 (M+, 12.5%), 313 (M

+−Cl, 100 %).


N, 4.03. Found: C, 72.49; H, 3.98; N, 4.01.

2.3.38 (2E)-3-(2-Chloro-6-methylquinolin-3-yl)-1-(2,3-dihydro-1,4-

benzodioxin-6-yl)prop-2-en-1-one (3p)

Yield : 46%


M.P. : 158-160 °C


1658 (C=O), 1595 (C=C).

1H-NMR : (CDCl3) δ: 2.54 (3H, s, Me), 4.32 (4H, m, Dioxane

Ring), 6.96 (1H, d, Ar-H, J=8.8 Hz), 7.42 (1H, m, Ar-

H), 7.55 (1H, d, Hα, J=15.7 Hz), 7.58 (1H, dd, H7,

J=8.6 Hz), 7.62 (1H, s, H5), 7.70 (1H, m, Ar-H), 7.90

(1H, d, H8, J=8.6 Hz), 8.15 (1H, d, Hβ, J=15.7 Hz), 8.36

(1H, s, H4).

MS : (m/z): 365 (M+, 24.1%), 330 (M

+−Cl, 100 %).


N, 3.83. Found: C, 68.91; H, 4.36; N, 3.79.

The ORTEP diagram of the compound 3p is given in the Figure 15 below.


86

Figure 15. ORTEP-3 diagram of compound 3p with the numbering scheme. Displacement ellipsoids



87

Crystal Data:

C21H16ClNO3

Mr = 365.80

Monoclinic, P21/c

a = 6.370 (3) Å

b = 38.735 (9) Å

c = 7.409 (4) Å

β = 114.93 (2)°

V = 1657.8 (12) Å3

Z = 4

Mo Kα radiation

µ = 0.25 mm-1

T = 173 K

0.18 X 0.16 X 0.14 mm

Data collection:




Tmin = 0.956, Tmax = 0.966




Rint = 0.037

Refinement:

R[F2 > 2σ(F

2)] = 0.037

wR(F2) = 0.091

S = 1.03

2933 reflections

236 parameters


Δρmax = 0.19 e Å-3

Δρmin = -0.23 e Å-3


88


en-1-one (3q)

Yield : 97%


M.P. : 138 °C


1659 (C=O), 1587 (C=C).

1H-NMR : (CDCl3) δ: 2.53 (3H, s, Me), 7.38 (1H, d, Hα, J=15.9

Hz), 7.53-7.60 (5H, m, Ar-H), 7.85 (1H, d, Ar-H, J=6.8

Hz), 7.90 (1H, d, H7, J=8.6 Hz), 7.93 (1H, s, H5), 8.02

(1H, d, H8, J=8.1 Hz), 8.04 (1H, d, Hβ, J=16.2 Hz), 8.37

(1H, s, H4), 8.39 (1H, d, Ar-H, J=8.3 Hz).

MS : (m/z): 357 (M+, 17.2%), 322 (M

+−Cl, 100 %).

CHN : Anal. Calculated for C23H16NOCl: C, 77.20; H, 4.51; N,

3.91. Found: C, 77.13; H, 4.47; N, 3.85.

The ORTEP diagram of the compound 3q is given in the Figure 16 below.


89

Figure 16. ORTEP-3 diagram of compound 3q with the numbering scheme. Displacement ellipsoids



90

Crystal Data:

C23H16ClNO

Mr = 357.82

Monoclinic, P21/c

a = 16.919 (8) Å

b = 7.146 (3) Å

c = 14.829 (5) Å

β = 103.29 (2)°

V = 1744.9 (13) Å3

Z = 4

Mo Kα radiation

µ = 0.23 mm-1

T = 173 K

0.14 X 0.12 X 0.05 mm

Data collection:




Tmin = 0.968, Tmax = 0.989




Rint = 0.039

Refinement:

R[F2 > 2σ(F

2)] = 0.051

wR(F2) = 0.131

S = 1.01

3988 reflections

236 parameters


Δρmax = 0.24 e Å-3

Δρmin = -0.29 e Å-3


91

2.3.40 (2E)-3-(2-Chloro-6-methylquinolin-3-yl)-1-(2-naphthyl)prop-

2-en-1-one (3r)

Yield : 65%


M.P. : 138 °C


1654 (C=O), 1589 (C=C).


Hz), 7.53-7.56 (2H, m, Ar-H), 7.60 (1H, dd, H7, J= 8.1

Hz), 7.63 (1H, s, H5), 7.86-7.93 (4H, m, Ar-H), 8.03

(1H, dd, H8, J=8.6 Hz), 8.06 (1H, d, Hβ, J=16.1 Hz),

8.44 (1H, s, H4), 8.46 (1H, s, Ar-H).

MS : (m/z): 357 (M+, 1.7%), 127 (M

+−C13H9NOCl, 100 %).


3.91. Found: C, 77.18; H, 4.48; N, 3.91.

2.3.41 (2E)-1-(9-Anthryl)-3-(2-chloro-6-methylquinolin-3-yl)prop-2-

en-1-one (3s)

Yield : 86%


M.P. : 232-233 °C


92


1662 (C=O), 1586 (C=C).


Hz), 7.47-7.57 (4H, m, Ar-H), 7.60 (1H, dd, H7, J=8.5

Hz), 7.63 (1H, s, H5), 7.77 (1H, d, Hβ, J=16.1 Hz), 7.84

(1H, d, H8, J=8.6 Hz), 7.92-7.95 (2H, m, Ar-H), 8.05-

8.07 (2H, m, Ar-H), 8.31 (1H, s, H4), 8.56 (1H, s, Ar-

H).

MS : (m/z): 407 (M+, 83%), 177 (M

+−C13H9NOCl, 100 %).


3.43. Found: C, 7979.46; H, 4.41; N, 3.39.

2.3.42 (2E)-3-(2-Chloro-6-methoxyquinolin-3-yl)-1-thien-3-ylprop-2-

en-1-one (4a)

N

O

S

Cl

O

CH3

Yield : 82%

State : Yellowish grey solid

M.P. : 182 °C


1648 (C=O), 1593 (C=C).

1H-NMR : (CDCl3) δ: 3.94 (3H, s, OMe), 7.11 (1H, d, H5, J=2.6

Hz), 7.39 (1H, d, H4', J=2.9 Hz), 7.45 (1H, d, Hα,

J=15.7 Hz), 7.60 (1H, dd, H7, J=9.1 Hz), 7.69 (1H, d,

H5', J=4.6 Hz), 7.91 (1H, d, H8, J=9.2 Hz), 8.17 (1H, d,

Hβ, J=15.9 Hz), 8.20 (1H, dd, H2', J=2.2 Hz), 8.36 (1H,

s, H4).

MS : (m/z): 329 (M+, 19.7%), 294 (M

+−Cl, 100 %).

CHN : Anal. Calculated for C17H12NO2ClS: C, 61.91; H, 3.67;

N, 4.25. Found: C, 61.90; H, 3.61; N, 4.23.


93



N

O

S

Cl CH3

O

CH3

Yield : 64%

State : Greenish yellow solid

M.P. : 180 °C


1654 (C=O), 1594 (C=C).

1H-NMR : (CDCl3) δ: 2.67 (3H, s, Me), 3.94 (3H, s, OMe), 7.02

(1H, d, H4', J=4.9 Hz), 7.13 (1H, d, H5, J=2.6 Hz), 7.36

(1H, d, H8, J=9.2 Hz), 7.40 (1H, d, Hα, J=15.5 Hz), 7.49

(1H, d, H5', J=4.9 Hz), 7.58 (1H, dd, H7, J=8.6 Hz),

7.90 (1H, d, H8, J=9.2 Hz), 8.17 (1H, d, Hβ, J=15.4 Hz),

8.33 (1H, s, H4).

MS : (m/z): 343 (M+, 63.5%), 308 (M

+−Cl, 100 %).


N, 4.07. Found: C, 62.75; H, 4.02; N, 4.03.



N

O

S

Cl

CH3

O

CH3

Yield : 74%



94

M.P. : 146 °C


1656 (C=O), 1594 (C=C).


(1H, d, H4', J=4.9 Hz), 7.12 (1H, d, H5, J=2.5 Hz), 7.31

(1H, s, H5'), 7.40 (1H, dd, H7, J=9.3 Hz), 7.44 (1H, d,

Hα, J=15.6 Hz), 7.70 (1H, s, H3'), 7.91 (1H, d, H8,

J=9.2 Hz), 8.19 (1H, d, Hβ, J=15.6 Hz), 8.35 (1H, s,

H4).

MS : (m/z): 343 (M+, 21.4%), 308 (M

+−Cl, 100 %).


N, 4.07. Found: C, 62.79; H, 4.04; N, 4.04.



N

O

S

Cl

CH3

O

CH3

Yield : 57%


M.P. : 152-153 °C


1648 (C=O), 1588 (C=C).


(1H, d, H4' J=4.4 Hz), 7.11 (1H, d, H5, J=2.6 Hz ), 7.33

(1H, d, Hα, J=15.6 Hz), 7.42 (1H, dd, H7, J=9.2 Hz),

7.68 (1H, d, H3' J=4.4 Hz), 7.90 (1H, d, H8, J=9.2 Hz),

8.12 (1H, d, Hβ, J=15.6 Hz), 8.36 (1H, s, H4).

MS : (m/z): 343 (M+, 29.6%), 308 (M

+−Cl, 100 %).


N, 4.07. Found: C, 62.81; H, 4.03; N, 4.01.


95


dimethylthien-3-yl)prop-2-en-1-one (4e)

N

O

S

Cl

CH3

CH3

O

CH3

Yield : 94%


M.P. : 116 °C


1648 (C=O), 1585 (C=C).

1H-NMR : (CDCl3) δ: 2.44-2.72 (s, Me x 2), 3.93 (3H, s, OMe),

7.09 (1H, s, H4'), 7.10 (1H, d, H5, J=2.9), 7.33 (1H, d,

Hα, J=15.7 Hz), 7.39 (1H, dd, H7, J=9.2 Hz), 7.90 (1H,

d, H8, J=9.2 Hz), 8.07 (1H, d, Hβ, J=15.7 Hz), 8.31 (1H,

s, H4).

MS : (m/z): 357 (M+, 56.4%), 322 (M

+−Cl, 100 %).


N, 3.91. Found: C, 63.62; H, 4.44; N, 3.85.



N

O

S

Cl Cl

O

CH3

Yield : 67%

State : Greyish green solid

M.P. : 136-138 °C


96


1651 (C=O), 1594 (C=C).

1H-NMR : (CDCl3) δ: 3.94 (3H, s, OMe), 7.08 (1H, d, H4', J=5.2

Hz), 7.12 (1H, d, H5, J=2.7 Hz), 7.41 (1H, dd, H7,

J=9.2 Hz), 7.61 (1H, d, H5', J=5.2 Hz), 7.83 (1H, d, Hα,

J=15.5 Hz), 7.91 (1H, d, H8, J=9.2 Hz), 8.22 (1H, d, Hβ,

J=15.6 Hz), 8.36 (1H, s, H4).

MS : (m/z): 363 (M+, 24.9%), 328 (M

+−Cl, 100 %).

CHN : Anal. Calculated for C17H11NO2Cl2S: C, 56.06; H, 3.04;

N, 3.84. Found: C, 56.02; H, 3.01; N, 3.78.



N

O

S

Cl

Cl

O

CH3

Yield : 95%


M.P. : 178-180 °C


1654 (C=O), 1594 (C=C).


Hz), 7.11 (1H, d, H5, J=2.7 Hz), 7.36 (1H, dd, H7, J=9.2

Hz), 7.42 (1H, d, Hα, J=15.6 Hz), 7.50 (1H, d, H3',

J=4.1 Hz), 7.89 (1H, d, H8, J=9.2 Hz), 8.12 (1H, d, Hβ,

J=15.6 Hz), 8.36 (1H, s, H4).

MS : (m/z): 363 (M+, 13.7%), 328 (M

+−Cl, 100 %).

CHN : Anal. Calculated for C17H11NO2Cl2S: 56.06; H, 3.04; N,

3.84. Found: C, 56.01; H, 2.98; N, 3.79.


97


dichlorothien-3-yl)prop-2-en-1-one (4h)

N

O

S

Cl

Cl

Cl

O

CH3

Yield : 96%


M.P. : 144 °C


1664 (C=O), 1591 (C=C).


Hz), 7.16 (1H, s, H4'), 7.41 (1H, dd, H7, J=9.2 Hz), 7.46

(1H, d, Hα, J=15.7 Hz), 7.91 (1H, d, H8, J=9.2 Hz), 8.14

(1H, d, Hβ, J=15.7 Hz), 8.33 (1H, s, H4).

MS : (m/z): 397 (M+, 14.3%), 362 (M

+−Cl, 100 %).

CHN : Anal. Calculated for C17H10NO2Cl3S: C, 51.21; H, 2.53;

N, 3.51. Found: C, 51.19; H, 2.42; N, 3.46.



N

O

S

Cl Br

O

CH3

Yield : 73%


M.P. : 148-150 °C


1650 (C=O), 1591 (C=C).


98


Hz), 7.16 (1H, d, H4', J=5.1 Hz), 7.41 (1H, dd, H7,

J=9.2 Hz), 7.59 (1H, d, H5', J=5.1 Hz), 7.83 (1H, d, Hα,

J=15.6 Hz), 7.91 (1H, d, H8, J=9.2 Hz), 8.22 (1H, d, Hβ,

J=15.6 Hz), 8.36 (1H, s, H4).

MS : (m/z): 408 (M+, 16.2%), 374 (M

+−Cl, 100 %).

CHN : Anal. Calculated for C17H11NO2ClSBr: C, 49.96; H,

2.71; N, 3.43. Found: C, 49.92; H, 2.70; N, 3.33.



N

O

S

Cl

Br

O

CH3

Yield : 84%


M.P. : 178 °C


1654 (C=O), 1589 (C=C).


Hz), 7.10 (1H, d, H5, J=2.6 Hz), 7.36 (1H, dd, H7, J=9.2

Hz), 7.42 (1H, d, Hα, J=15.6 Hz), 7.45 (1H, d, H3',

J=4.1 Hz), 7.89 (1H, d, H8, J=9.2 Hz), 8.13 (1H, d, Hβ,

J=15.6 Hz), 8.36 (1H, s, H4).

MS : (m/z): 409 (M+, 20.4%), 374 (M

+−Cl, 100 %).

CHN : Anal. Calculated for C17H11NO2ClSBr: C, 49.96; H,

2.71; N, 3.43. Found: C, 49.87; H, 2.68; N, 3.41


99

2.3.52 (2E)-3-(2-Chloro-6-methoxyquinolin-3-yl)-1-(5-iodothien-2-


N

O

S

Cl

I

O

CH3

Yield : 91%


M.P. : 184 °C


1648 (C=O), 1594 (C=C).


Hz), 7.10 (1H, d, H5, J=2.7 Hz), 7.36 (1H, dd, H7, J=9.2

Hz), 7.43 (1H, d, Hα, J=15.5 Hz), 7.46 (1H, d, H3',

J=4.1 Hz), 7.89 (1H, d, H8, J=9.2 Hz), 8.14 (1H, d, Hβ,

J=15.6 Hz), 8.36 (1H, s, H4).

MS : (m/z): 455 (M+, 11.2%), 237 (M

+−C12H9NOCl, 100 %).

CHN : Anal. Calculated for C17H11NO2ClSI: C, 44.81; H, 2.43;

N, 3.07. Found: C, 44.75; H, 2.39; N, 3.02.

2.3.53 (2E)-3-(2-Chloro-6-methoxyquinolin-3-yl)-1-(1H-pyrrol-2-

yl)prop-2-en-1-one (4l)

N Cl

NH

O

OCH3

Yield : 90%


M.P. : 172 °C

IR: : υmaxυmax(KBr) 1648 (C=O), 1596 (C=C) cm

-1


100

1H-NMR: : (CDCl3) δ: 2.47 (3H, s, OMe), 6.34 (1H, dd, H4', J=3.4

Hz), 6.64 (1H, d, H3', J=3.4 Hz), 7.0 (1H, d, H5', J=4.0

Hz), 7.44 (1H, d, Hα, J=15.5 Hz), 7.52 (1H, dd, H7,

J=8.6 Hz), 7.12 (1H, d, H5, J=2.7 Hz), 7.90 (1H, d, H8,

J=8.6 Hz), 8.20 (1H, d, Hβ, J=15.6 Hz), 8.34 (1H, s,

H4).

MS : (m/z) 311 (M+, 13.3%), 276 (M

+−Cl, 100 %).

CHN : Anal. Calculated for C17H13N2O2Cl C, 65.28; H, 4.19;

N, 8.96. Found: C, 65.27; H, 4.11; N, 8.92.

2.3.54 (2E)-3-(2-Chloro-6-methoxyquinolin-3-yl)-1-(5-methyl-2-

furyl)prop-2-en-1-one (4m)

N Cl

O

O

OCH3 CH3

Yield : 98%


M.P. : 168 °C


1664 (C=O), 1594 (C=C).


(1H, dd, H4', J=3.0 Hz), 7.29 (1H, d, H3', J=3.4 Hz),

7.45 (1H, d, Hα, J=15.8 Hz), 7.40 (1H, dd, H7, J=9.1

Hz), 7.12 (1H, d, H5, J=2.7 Hz), 7.90 (1H, d, H8, J=8.2

Hz), 8.22 (1H, d, Hβ, J=15.8 Hz), 8.36 (1H, s, H4).

MS : (m/z): 327 (M+, 28.7%), 292 (M

+−Cl, 100 %).


N, 4.27. Found: C, 65.94; H, 4.31; N, 4.26.


101

2.3.55 (2E)-3-(2-Chloro-6-methoxyquinolin-3-yl)-1-(2,5-dimethyl-3-

furyl)prop-2-en-1-one (4n)

N Cl

O

O

OCH3

CH3

CH3

Yield : 69%


M.P. : 122 °C


1649 (C=O), 1596 (C=C).

1H-NMR : (CDCl3) δ: 2.27-2.61 (s, Me x 2), 3.93 (3H, s, OMe),

6.97 (1H, s, H4'), 7.11 (1H, d, H5, J=2.7 Hz), 7.24 (1H,

d, Hα, J=15.9 Hz), 7.40 (1H, dd, H7, J=9.2 Hz), 7.90

(1H, d, H8, J=9.2 Hz), 8.12 (1H, d, Hβ, J=15.8 Hz), 8.36

(1H, s, H4).

MS : (m/z): 341 (M+, 22.5%), 306 (M

+−Cl,100 %).


N, 4.10. Found: C, 66.74; H, 4.68; N, 4.09.

2.3.56 (2E)-1-(1-Benzofuran-2-yl)-3-(2-chloro-6-methoxyquinolin-3-

yl)prop-2-en-1-one (4o)

N Cl

O

O

OCH3

Yield : 62%


M.P. : 158 °C


102


1658 (C=O), 1587 (C=C).


Hz), 7.29 (1H, t, Ar-H) 7.36 (1H, d, Hα, J=15.8 Hz),

7.42-7.52 (4H, m, Ar-H), 7.67 (1H, d, H7, J=9.2 Hz),

7.82 (1H, d, H8, J=9.2 Hz), 8.06 (1H, d, Hβ, J=15.8 Hz),

8.10 (1H, s, H4).

MS : (m/z): 363 (M+, 10.5%), 328 (M

+−Cl, 100 %).


N, 3.85. Found: C, 69.31; H, 3.82; N, 3.81.

2.3.57 (2E)-3-(2-Chloro-6-methoxyquinolin-3-yl)-1-(2,3-dihydro-1,4-

benzodioxin-6-yl)prop-2-en-1-one (4p)

Yield : 92%


M.P. : 163-164 °C


1658 (C=O), 1596 (C=C).

1H-NMR : (CDCl3) δ: 3.93 (3H, s, OMe), 4.34 (4H, m, Dioxane

Ring), 6.94 (1H, d, Ar-H, J=8.1 Hz), 7.12 (1H, d, H5,

J=2.6 Hz), 7.36 (1H, d, Ar-H, J=3.9 Hz), 7.50 (1H, d,

Hα, J=15.6 Hz), 7.58 (1H, dd, H7, J=9.1 Hz), 7.70 (1H,

m, Ar-H), 7.91 (1H, d, H8, J=9.2 Hz), 8.18 (1H, d, Hβ,

J=15.6 Hz), 8.35 (1H, s, H4).

MS : (m/z): 381 (M+, 7.5%), 346 (M

+−Cl, 100 %).


N, 3.67. Found: C, 66.02; H, 4.18; N, 3.63.


103


2-en-1-one (4q)

Yield : 90%


M.P. : 162 °C


1659 (C=O), 1587 (C=C).


Hz), 7.38 (1H, d, Hα, J=15.9 Hz), 7.40 (1H, dd, H7,

J=9.2 Hz), 7.53-7.61 (3H, m, Ar-H), 7.83-7.92 (3H, m,

Ar-H), 7.98 (1H, d, H8, J=9.2 Hz), 8.03 (1H, d, Hβ,

J=16.1 Hz), 8.35 (1H, s, H4), 8.40 (1H, d, Ar-H, J=8.3

Hz).

MS : (m/z): 373 (M+, 57.0%), 338 (M

+−Cl, 100 %).


N, 3.75. Found: C, 73.87; H, 4.27; N, 3.72.


2-en-1-one (4r)

Yield : 55%

State : Light grey solid


104

M.P. : 140 °C


1659 (C=O), 1586 (C=C).


Hz), 7.41 (1H, dd, H7, J=9.2 Hz), 7.55-7.64 (2H, m, Ar-

H), 7.73 (1H, d, Hα, J=15.7 Hz), 7.89-8.00 (4H, m, Ar-

H), 8.11 (1H, dd, H8 J=9.2 Hz), 8.23 (1H, d, Hβ, J=15.7

Hz), 8.42 (1H, s, H4), 8.56 (1H, s, Ar-H).

MS : (m/z): 373 (M+, 34.9%), 338 (M

+−Cl, 100 %).


N, 3.75. Found: C, 73.88; H, 4.27; N, 3.71.

2.3.60 (2E)-1-(9-Anthryl)-3-(2-chloro-6-methoxyquinolin-3-yl)prop-2-

en-1-one (4s)

Yield : 97%


M.P. : 220-222 °C


1660 (C=O), 1588 (C=C).


Hz), 7.40 (1H, d, Hα, J=16.1 Hz), 7.47-7.56 (4H, m, Ar-

H), 7.84 (1H, dd, H7, J=7.2 Hz), 7.90-7.93 (2H, m, Ar-

H), 7.96 (1H, d, Hβ, J=16.1 Hz), 8.03 (1H, d, H8, J=7.4

Hz), 8.54 (1H, s, Ar-H) 8.06-8.08 (2H, m, Ar-H).

MS : (m/z): 423 (M+, 16.3%), 177 (M

+−C13H9NO2Cl, 100 %).


N, 3.30. Found: C, 76.42; H, 4.27; N, 3.27.


105

2.4 General Method for the Synthesis of 2-Pyrazolines263

(2.4.1─2.4.44) (Scheme─II)

A mixture of Chalcone (1a-k, 2a-k, 3a-k or 4a-k, 1.0 mmol) and hydrazine

hydrate (3.0 mmol) in ethanol (10 mL) was refluxed. The crude product was

precipitated out in the reaction flask within 8-15 min. Subsequently, it was poured

onto ice-cold water (50 ml). The precipitates were collected by filtration, washed with

cold water followed by cold EtOH to obtain 2-pyrazolines which were recrystallised

from EtOH (95%) to obtain pure compounds 5a-k, 6a-k, 7a-k and 8a-k.


5-yl)quinoline (5a)

S

N

NH

N

Cl

CH3

Yield : 72%

State : White solid

M.P. : 195-196 °C


3274 (N-H), 1595 (C=N of pyrazoline

ring), 1550 (C=N of quinoline ring).

1H-NMR : (CDCl3) δ: 2.70 (3H, s, Me), 2.97 (1H, dd, J = 16.4, 9.4

Hz, 4-Ha), 3.75 (1H, dd, J = 16.4, 10.7 Hz, 4-Hb), 5.39

(1H, t, J = 9.9 Hz, 5-H), 7.32 (1H, dd, H4', J = 5.0 Hz,

2.8 Hz), 7.45 (1H, t, H6, J = 7.6 Hz), 7.55 (1H, d, H7, J

= 7.0 Hz), 7.60 (1H, d, H5', J = 4.6 Hz, 1.0 Hz), 7.67

(1H, d, H5, J = 6.6 Hz), 8.08 (1H, dd, H2', J = 2.7 Hz,

1.0 Hz), 8.39 (1H, s, H4).

MS : (m/z): 328 (M+, 100 %).


106

CHN : Anal. Calculated for C17H14N3ClS: C, 62.28; H, 4.30; N,

12.82. Found: C, 62.22; H, 4.22; N, 12.78.


1H-pyrazol-5-yl]quinoline (5b)

S

N

NH

N

Cl CH3

CH3

Yield : 67%

State : White solid

M.P. : 130-131 °C




1H-NMR : (CDCl3) δ: 2.63-2.73 (s, Me x 2), 2.86 (1H, dd, J =

16.3, 9.4 Hz, 4-Ha), 3.66 (1H, dd, J = 16.3, 10.5 Hz, 4-

Hb), 5.31 (1H, t, J = 9.9 Hz, 5-H), 6.82 (1H, d, H4', J =

5.1 Hz), 7.45 (1H, t, H6, J = 7.6 Hz), 7.33 (1H, d, H5', J

= 5.1 Hz), 7.54 (1H, d, H7, J = 7.0 Hz), 7.69 (1H, d, H5,

J = 7.9 Hz), 8.38 (1H, s, H4).

MS : (m/z): 342 (M+, 100 %).


12.29. Found: C, 63.22; H, 4.75; N, 12.23.


107


1H-pyrazol-5-yl]quinoline (5c)

S

N

NH

N

Cl CH3

CH3

Yield : 71%

State : White solid

M.P. : 182 °C





16.3, 9.3 Hz, 4-Ha), 3.69 (1H, dd, J = 16.3, 10.5 Hz, 4-

Hb), 5.31 (1H, t, J = 9.9 Hz, 5-H) 7.11 (1H, s, H5'), 7.44

(1H, t, H6, J = 7.5 Hz), 7.55 (1H, d, H7, J = 7.0 Hz),

7.69 (1H, d, H5, J = 7.0 Hz), 7.52 (1H, s, H3'), 8.37 (1H,

s, H4).

MS : (m/z): 342 (M+, 100 %).


12.29. Found: C, 63.20; H, 4.69; N, 12.25.


1H-pyrazol-5-yl]quinoline (5d)

S

N

NH

N

Cl

CH3

CH3


108

Yield : 80%


M.P. : 209-210 °C





16.3, 9.3 Hz, 4-Ha), 3.67 (1H, dd, J = 16.3, 10.5 Hz, 4-

Hb), 5.31 (1H, t, J = 9.9 Hz, 5-H), 6.66 (1H, d, H4', J =

3.0 Hz), 6.86 (1H, d, H3' J = 3.4 Hz), 7.44 (1H, t, H6, J

= 7.6 Hz), 7.54 (1H, d, H7, J = 7.0 Hz), 7.62 (1H, d, H5,

J = 8.1 Hz), 8.33 (1H, s, H4).

MS : (m/z): 342 (M+, 100 %).


12.29. Found: C, 63.23; H, 4.70; N, 12.27.


pyrazol-5-yl]-8-methylquinoline (5e)

S

N

NH

N

Cl

CH3

CH3

CH3

Yield : 88%

State : Brown solid

M.P. : 126-127 °C





16.3, 9.7 Hz, 4-Ha), 3.68 (1H, dd, J = 16.3, 10.6 Hz, 4-

Hb), 5.30 (1H, t, J = 10.0 Hz, 5-H), 6.86 (1H, s, H4'),


109

7.42 (1H, t, H6, J = 7.7 Hz), 7.54 (1H, d, H7, J = 7.0

Hz), 7.68 (1H, d, H5, J = 8.1 Hz), 8.34 (1H, s, H4).

MS : (m/z): 356 (M+, 100 %).


11.81. Found: C, 64.10; H, 5.08; N, 11.79.


5-yl]-8-methylquinoline (5f)

S

N

NH

N

Cl Cl

CH3

Yield : 81%

State : Yellowish brown solid

M.P. : 152 °C




1H-NMR : (CDCl3) δ: 2.72 (3H, s, Me), 3.11 (1H, dd, J = 16.9,

10.2 Hz, 4-Ha), 3.94 (1H, dd, J = 16.9, 10.8 Hz, 4-Hb),

5.39 (1H, t, J = 10.4 Hz, 5-H), 6.87 (1H, d, H4', J = 5.4

Hz), 7.41 (1H, t, H6, J = 7.6 Hz), 7.54 (1H, d, H7, J =

7.0 Hz), 7.32 (1H, d, H5', J = 5.4 Hz), 7.65 (1H, d, H5, J

= 8.1 Hz), 8.37 (1H, s, H4).

MS : (m/z): 362 (M+, 100 %).

CHN : Anal. Calculated for C17H13N3Cl2S: C, 56.36; H, 3.62;

N, 11.60. Found: C, 56.34; H, 3.58; N, 11.54.


110



S

N

NH

N

Cl

Cl

CH3

Yield : 80%


M.P. : 230-232 °C





10.1 Hz, 4-Ha), 3.62 (1H, dd, J = 16.3, 10.7 Hz, 4-Hb),

5.39 (1H, t, J = 10.3 Hz, 5-H), 6.85 (1H, d, H4', J = 4.2

Hz), 7.42 (1H, t, H6, J = 7.6 Hz), 7.56 (1H, d, H7, J =

7.0 Hz), 7.48 (1H, d, H3', J = 4.4 Hz), 7.63 (1H, d, H5, J

= 8.0 Hz), 8.35 (1H, s, H4).

MS : (m/z): 362 (M+, 100 %).


N, 11.60. Found: C, 56.31; H, 3.56; N, 11.55.


pyrazol-5-yl]-8-methylquinoline (5h)

S

N

NH

N

Cl

Cl

Cl

CH3


111

Yield : 75%


M.P. : 153 °C





10.0 Hz, 4-Ha), 4.00 (1H, dd, J = 16.8, 10.5 Hz, 4-Hb),

5.40 (1H, t, J = 10.3 Hz, 5-H), 6.96 (1H, s, H4'), 7.41

(1H, t, H6, J = 7.6 Hz), 7.56 (1H, d, H7, J = 6.8 Hz),

7.62 (1H, d, H5, J = 8.1 Hz), 8.35 (1H, s, H4).

MS : (m/z): 397 (M+, 100 %).


N, 10.59. Found: C, 51.41; H, 3.00; N, 10.56.


chloro-8-methylquinoline (5i)

S

N

NH

N

Cl Br

CH3

Yield : 77%


M.P. : 166-168 °C





10.2 Hz, 4-Ha), 4.10 (1H, dd, J = 16.8, 10.8 Hz, 4-Hb),

5.32 (1H, t, J = 10.4 Hz, 5-H), 6.86 (1H, d, H4', J = 5.5

Hz), 7.43 (1H, t, H6, J = 7.6 Hz), 7.21 (1H, d, H5', J =


112

5.5 Hz), 7.54 (1H, d, H7, J = 7.1 Hz), 7.65 (1H, d, H5, J

= 8.0 Hz), 8.39 (1H, s, H4).

MS : (m/z): 407 (M+, 100 %).

CHN : Anal. Calculated for C17H13N3ClSBr: C, 50.20; H, 3.22;

N, 10.33. Found: C, 50.14; H, 3.18; N, 10.29.


chloro-8-methylquinoline (5j)

S

N

NH

N

Cl

Br

CH3

Yield : 80%


M.P. : 215-216 °C





Hz, 4-Ha), 3.61 (1H, dd, J = 16.2, 10.6 Hz, 4-Hb), 5.28

(1H, t, J = 10.3 Hz, 5-H), 6.87 (1H, d, H4', J = 4.2 Hz),

7.42 (1H, t, H6, J = 7.6 Hz), 7.55 (1H, d, H7, J = 7.1

Hz), 7.43 (1H, d, H3', J = 4.2 Hz), 7.63 (1H, d, H5, J =

8.0 Hz), 8.36 (1H, s, H4).

MS : (m/z): 407 (M+, 100 %).


N, 10.33. Found: C, 50.19 H, 3.17; N, 10.28.


113

2.4.11 2-Chloro-3-[3-(5-iodothiophen-2-yl)-4,5-dihydro-1H-pyrazol-

5-yl]-8-methylquinoline (5k)

S

N

NH

N

Cl

I

CH3

Yield : 82%


M.P. : 178 °C





Hz, 4-Ha), 3.73 (1H, dd, J = 16.3, 10.6 Hz, 4-Hb), 5.31

(1H, t, J = 10.2 Hz, 5-H), 6.71 (1H, d, H4', J = 4.0 Hz),

7.42 (1H, t, H6, J = 7.6 Hz), 7.16 (1H, d, H3', J = 4.1

Hz), 7.56 (1H, d, H7, J = 7.0 Hz), 7.63 (1H, d, H5, J =

8.1 Hz), 8.36 (1H, s, H4).

MS : (m/z): 454 (M+, 100 %).

CHN : Anal. Calculated for C17H13N3ClSI: C, 45.00; H, 2.89;

N, 9.26. Found: C, 44.98; H, 2.81; N, 9.25.


5-yl)quinoline (6a)

S

N

NH

N

ClCH3

Yield : 80%


114

State : White solid

M.P. : 180-181 °C




1H-NMR : (CDCl3) δ: 2.50 (3H, s, Me), 2.95 (1H, dd, J=16.3, 9.4

Hz, 4-Ha), 3.74 (1H, dd, J = 16.4, 10.6 Hz, 4-Hb), 5.38

(1H, t, J = 9.9 Hz, 5-H), 7.31 (1H, dd, H4', J = 5.0 Hz,

2.8 Hz), 7.40 (1H, d, H5, J = 8.1 Hz), 7.62 (1H, dd, H5',

J = 4.9 Hz, 0.9 Hz), 7.73 (1H, d, H6, J = 8.3 Hz), 7.75

(1H, s, H8), 8.08 (1H, dd, H2', J = 2.8 Hz, 1.0 Hz), 8.40

(1H, s, H4).

MS : (m/z): 327 (M+, 100 %).


12.82. Found: C, 62.24; H, 4.25; N, 12.80.



S

N

NH

N

Cl CH3CH3

Yield : 78%


M.P. : 160-161 °C





16.3, 9.4 Hz, 4-Ha), 3.64 (1H, dd, J = 16.3, 10.4 Hz, 4-

Hb), 5.29 (1H, t, J = 9.9 Hz, 5-H), 6.82 (1H, d, H4', J =

5.0 Hz), 7.35 (1H, d, H5, J = 8.1 Hz), 7.35 (1H, d, H5', J


115

= 4.9 Hz), 7.74 (1H, d, H6, J = 8.5 Hz), 7.76 (1H, s, H8),

8.39 (1H, s, H4).

MS : (m/z): 342 (M+, 100 %).


12.29. Found: C, 63.14; H, 4.65; N, 12.29.



S

N

NH

N

Cl CH3CH3

Yield : 83%

State : White solid

M.P. : 200 °C





16.3, 9.3 Hz, 4-Ha), 3.66 (1H, dd, J = 16.3, 10.5 Hz, 4-

Hb), 5.30 (1H, t, J = 9.9 Hz, 5-H), 7.11 (1H, s, H5'),

7.37 (1H, d, H5, J = 8.1 Hz), 7.51 (1H, s, H3'), 7.74 (1H,

d, H6, J = 8.3 Hz), 7.76 (1H, s, H8), 8.41 (1H, s, H4).

MS : (m/z): 342 (M+, 100 %).


12.29. Found: C, 63.21; H, 4.69; N, 12.25.


116



S

N

NH

N

Cl

CH3

CH3

Yield : 87%

Stat : Pale yellow solid

M.P. : 198°C





16.3, 9.3 Hz, 4-Ha), 3.66 (1H, dd, J = 16.3, 10.5 Hz, 4-

Hb), 5.31 (1H, t, J = 9.9 Hz, 5-H), 6.66 (1H, d, H4', J =

3.2 Hz), 6.85 (1H, d, H3', J = 3.5 Hz), 7.37 (1H, d, H5, J

= 8.1 Hz), 7.74 (1H, d, H6, J = 8.3 Hz), 7.76 (1H, s, H8),

8.40 (1H, s, H4).

MS : (m/z): 342 (M+, 100 %).


12.29. Found: C, 63.23; H, 4.69; N, 12.31.



S

N

NH

N

Cl

CH3

CH3CH3

Yield : 86%



117

M.P. : 116-117 °C





16.2, 9.7 Hz, 4-Ha), 3.65 (1H, dd, J = 16.3, 10.5 Hz, 4-

Hb), 5.28 (1H, t, J = 10.0 Hz, 5-H), 6.86 (1H, s, H4'),

7.41 (1H, d, H5, J = 8.3 Hz), 7.72 (1H, d, H6, J = 8.3

Hz), 7.76 (1H, s, H8), 8.34 (1H, s, H4).

MS : (m/z): 356 (M+, 100 %).


11.81. Found: C, 64.08; H, 5.05; N, 11.76.



S

N

NH

N

Cl ClCH3

Yield : 79%

State : White solid

M.P. : 166-167 °C





10.1 Hz, 4-Ha), 4.00 (1H, dd, J = 16.9, 10.8 Hz, 4-Hb),

5.39 (1H, t, J = 10.4 Hz, 5-H), 6.86 (1H, d, H4', J = 5.2

Hz), 7.21 (1H, d, H5, J = 8.3 Hz), 7.32 (1H, d, H5', J =

5.2 Hz), 7.76 (1H, d, H6, J = 8.6 Hz), 7.89 (1H, s, H8),

8.37 (1H, s, H4).

MS : (m/z): 362 (M+, 96.20%) 185 (M

+−C10H7NCl, 100 %).


N, 11.60. Found: C, 56.32; H, 3.61; N, 11.58.


118



S

N

NH

N

Cl

Cl

CH3

Yield : 83%


M.P. : 205-207 °C





10.0 Hz, 4-Ha), 3.71 (1H, dd, J = 16.2, 10.7 Hz, 4-Hb),

5.36 (1H, t, J = 10.3 Hz, 5-H), 6.82 (1H, d, H4', J = 4.3

Hz), 7.28 (1H, d, H5, J = 8.3 Hz), 7.47 (1H, d, H3', J =

4.3 Hz), 7.65 (1H, d, H6, J = 8.3 Hz), 7.69 (1H, s, H8),

8.34 (1H, s, H4).

MS : (m/z): 362 (M+, 100 %).


N, 11.60. Found: C, 56.34 H, 3.59; N, 11.52.


119



S

N

NH

N

Cl

Cl

ClCH3

Yield : 75%


M.P. : 178-179 °C





Hz, 4-Ha), 3.98 (1H, dd, J = 16.7, 10.5 Hz, 4-Hb), 5.39

(1H, t, J = 10.2 Hz, 5-H), 6.97 (1H, s, H4'), 7.35 (1H, d,

H5, J = 8.3 Hz), 7.72 (1H, d, H6, J = 8.2 Hz), 7.75 (1H,

s, H8), 8.33 (1H, s, H4).

MS : (m/z): 397 (M+, 100 %).


N, 10.59. Found: C, 51.45; H, 3.02; N, 10.54.



S

N

NH

N

Cl BrCH3

Yield : 92%

Stat : White solid


120

M.P. : 170-171 °C





10.1 Hz, 4-Ha), 4.06 (1H, dd, J = 16.8, 10.8 Hz, 4-Hb),

5.39 (1H, t, J = 10.4 Hz, 5-H), 6.95 (1H, d, H4', J = 5.5

Hz), 7.35 (1H, d, H5, J = 8.2 Hz), 7.21 (1H, d, H5', J =

5.5 Hz), 7.72 (1H, d, H6, J = 8.6 Hz), 7.74 (1H, s, H8),

8.38 (1H, s, H4).

MS : (m/z): 407 (M+, 100 %).


N, 10.33. Found: C, 50.12; H, 3.14; N, 10.30.



S

N

NH

N

Cl

Br

CH3

Yield : 76%

State : White solid

M.P. : 195 °C





Hz, 4-Ha), 3.71 (1H, dd, J = 16.2, 10.7 Hz, 4-Hb), 5.36

(1H, t, J = 10.3 Hz, 5-H), 6.86 (1H, d, H4', J = 4.2 Hz),

7.36 (1H, d, H5, J = 8.3 Hz), 7.43 (1H, d, H3', J = 4.2

Hz), 7.74 (1H, d, H6, J = 8.3 Hz), 7.75 (1H, s, H8), 8.35

(1H, s, H4).

MS : (m/z): 407 (M+, 100 %).


121


N, 10.33. Found: C, 50.15; H, 3.19; N, 10.25.


yl]-7-methylquinoline (6k)

S

N

NH

N

Cl

I

CH3

Yield : 85%

State : White solid

M.P. : 212 °C





Hz, 4-Ha), 3.71 (1H, dd, J = 16.2, 10.7 Hz, 4-Hb), 5.36

(1H, t, J = 10.3 Hz, 5-H), 6.71 (1H, d, H4', J = 4.2 Hz),

7.15 (1H, d, H3', J = 4.2 Hz), 7.34 (1H, d, H5, J = 8.4

Hz), 7.74 (1H, d, H6, J = 8.3 Hz), 7.75 (1H, s, H8), 8.35

(1H, s, H4).

MS : (m/z): 454 (M+, 100 %).


N, 9.26. Found: C, 44.95; H, 2.85; N, 9.23.


122


5-yl)quinoline (7a)

S

N

NH

N

CH3

Cl

Yield : 75%

State : White solid

M.P. : 178-179 °C





Hz, 4-Ha), 3.77 (1H, dd, J = 16.2, 10.4 Hz, 4-Hb), 5.38

(1H, t, J = 9.9 Hz, 5-H), 7.32 (1H, dd, H4', J=2.7 Hz),

7.56 (1H, d, H7, J=8.6 Hz), 7.60 (1H, s, H5), 7.63 (1H,

d, H5', J=4.7 Hz), 7.87 (1H, d, H8, J=8.5 Hz), 8.10 (1H,

dd, H2', J=2.2 Hz, 1.0 Hz), 8.34 (1H, s, H4).

MS : (m/z): 328 (M+, 100 %).


12.82. Found: C, 62.22; H, 4.22; N, 12.78.



S

N

NH

N

CH3

Cl CH3

Yield : 70%



123

M.P. : 179-180 °C




1H-NMR : (CDCl3) 2.42-2.64 (s, Me x 2), 2.84 (1H, dd, J = 16.2,

9.3 Hz, 4-Ha), 3.67 (1H, dd, J = 16.2, 10.3 Hz, 4-Hb),

5.29 (1H, t, J = 9.8 Hz, 5-H), 6.84 (1H, d, H4', J=4.9

Hz), 7.34 (1H, d, H5', J=4.9 Hz), 7.54 (1H, dd, H7,

J=8.5 Hz), 7.64 (1H, s, H5), 7.88 (1H, d, H8, J=8.6 Hz),

8.34 (1H, s, H4).

MS : (m/z): 342 (M+, 100 %).


12.29. Found: C, 63.22; H, 4.75; N, 12.23.



S

N

NH

N

CH3

Cl CH3

Yield : 69%

State : White solid

M.P. : 210 °C





16.3, 9.3 Hz, 4-Ha), 3.67 (1H, dd, J = 16.3, 10.4 Hz, 4-

Hb), 5.29 (1H, t, J = 9.8 Hz, 5-H) 7.96 (1H, s, H5'), 7.14

(1H, s, H3'), 7.49 (1H, dd, H7, J=8.6 Hz), 7.60 (1H, s,

H5), 7.86 (1H, d, H8, J=8.6 Hz), 8.38 (1H, s, H4).

MS : (m/z): 342 (M+, 100 %).


12.29. Found: C, 63.20; H, 4.69; N, 12.25.


124



S

N

NH

N

CH3

Cl

CH3

Yield : 72%


M.P. : 185-187 °C





16.3, 9.3 Hz, 4-Ha), 3.66 (1H, dd, J = 16.3, 10.5 Hz, 4-

Hb), 5.30 (1H, t, J = 9.8 Hz, 5-H), 6.79 (1H, d, H4',

J=3.5 Hz), 7.07 (1H, d, H3' J=3.8 Hz), 7.56 (1H, dd,

H7, J=8.6 Hz), 7.61 (1H, s, H5), 7.88 (1H, d, H8, J=8.6

Hz), 8.34 (1H, s, H4).

MS : (m/z): 342 (M+, 100 %).


12.29. Found: C, 63.23; H, 4.70; N, 12.27.



S

N

NH

N

CH3

Cl

CH3

CH3

Yield : 79%



125

M.P. : 117-119 °C





16.3, 9.6 Hz, 4-Ha), 3.65 (1H, dd, J = 16.3, 10.6 Hz, 4-

Hb), 5.29 (1H, t, J = 9.9 Hz, 5-H), 6.89 (1H, s, H4'),

7.59 (1H, dd, H7, J=8.6 Hz), 7.60 (1H, s, H5), 7.88 (1H,

d, H8, J=8.6 Hz), 8.36 (1H, s, H4).

MS : (m/z): 356 (M+, 100 %).


11.81. Found: C, 64.10; H, 5.08; N, 11.79.



S

N

NH

N

CH3

Cl Cl

Yield : 75%


M.P. : 170-172 °C





Hz, 4-Ha), 4.04 (1H, dd, J = 16.9, 10.7 Hz, 4-Hb), 5.35

(1H, t, J = 10.3 Hz, 5-H), 6.88 (1H, d, H4', J=5.2 Hz),

7.48 (1H, d, H5', J=5.2 Hz), 7.60 (1H, dd, H7, J=8.6

Hz), 7.64 (1H, s, H5), 7.87 (1H, d, H8, J=8.6 Hz), 8.36

(1H, s, H4).

MS : (m/z): 362 (M+, 100 %).


126

CHN : Anal. Calculated. for C17H13N3Cl2S: C, 56.36; H, 3.62;

N, 11.60. Found: C, 56.34; H, 3.58; N, 11.54.

2.4.29 2-Chloro-3-[3-(5-chlorothiophen-2-yl)-4,5-dihydro-1H-

pyrazol-5-yl]-6-methylquinoline (7g)

S

N

NH

N

CH3

Cl

Cl

Yield : 66%


M.P. : 224-225 °C





Hz, 4-Ha), 3.70 (1H, dd, J = 16.3, 10.5 Hz, 4-Hb), 5.38

(1H, t, J = 10.3 Hz, 5-H), 6.94 (1H, d, H4', J=4.0 Hz),

7.60 (1H, dd, H7, J=8.6 Hz), 7.63 (1H, s, H5), 7.67 (1H,

d, H3', J=4.0 Hz), 7.88 (1H, d, H8, J=8.6 Hz), 8.38 (1H,

s, H4).

MS : (m/z): 362 (M+, 100 %).


N, 11.60. Found: C, 56.31; H, 3.56; N, 11.55.



S

N

NH

N

CH3

Cl

Cl

Cl


127

Yield : 69%


M.P. : 178-180 °C





10.0 Hz, 4-Ha), 4.00 (1H, dd, J = 16.8, 10.5 Hz, 4-Hb),

5.40 (1H, t, J = 10.3 Hz, 5-H), 7.15 (1H, s, H4'), 7.60

(1H, dd, H7, J=8.6 Hz), 7.63 (1H, s, H5), 7.90 (1H, d,

H8, J=8.6 Hz), 8.34 (1H, s, H4).

MS : (m/z): 397 (M+, 100 %).


N, 10.59. Found: C, 51.41; H, 3.00; N, 10.56.



S

N

NH

N

CH3

Cl Br

Yield : 81%

State : White solid

M.P. : 187-188 °C





10.2 Hz, 4-Ha), 4.10 (1H, dd, J = 16.8, 10.8 Hz, 4-Hb),

5.40 (1H, t, J = 10.4 Hz, 5-H), 7.16 (1H, d, H4', J=5.16

Hz), 7.58 (1H, d, H5', J=5.1 Hz), 7.59 (1H, dd, H7,

J=8.6 Hz), 7.65 (1H, s, H5), 7.91 (1H, d, H8, J=8.6 Hz),

8.38 (1H, s, H4).

MS : (m/z): 407 (M+, 100 %).


128


N, 10.33. Found: C, 50.14; H, 3.18; N, 10.29.



S

N

NH

N

CH3

Cl

Br

Yield : 83%;


M.P. : 215-216 °C





Hz, 4-Ha), 3.71 (1H, dd, J = 16.2, 10.6 Hz, 4-Hb), 5.36

(1H, t, J = 10.3 Hz, 5-H), 7.10 (1H, d, H4', J=4.0 Hz),

7.17 (1H, d, H3', J=4.0 Hz), 7.60 (1H, dd, H7, J=8.5

Hz), 7.63 (1H, s, H5), 7.91 (1H, d, H8, J=8.3 Hz), 8.36

(1H, s, H4).

MS : (m/z): 407 (M+, 100 %).


N, 10.33. Found: C, 50.19 H, 3.17; N, 10.28.


yl]-6-methylquinoline (7k)

S

N

NH

N

CH3

Cl

I


129

Yield : 74%

State : White solid

M.P. : 192 °C





Hz, 4-Ha), 3.73 (1H, dd, J = 16.3, 10.6 Hz, 4-Hb), 5.37

(1H, t, J = 10.2 Hz, 5-H), 7.36 (1H, d, H4', J=3.9 Hz),

7.50 (1H, d, H3', J=3.9 Hz), 7.59 (1H, dd, H7, J=8.7

Hz), 7.62 (1H, s, H5), 7.90 (1H, d, H8, J=8.5 Hz), 8.35

(1H, s, H4).

MS : (m/z): 454 (M+, 100 %).


N, 9.26. Found: C, 44.98; H, 2.81; N, 9.25.

2.4.34 2-Chloro-6-methoxy-3-(3-thiophen-3-yl-4,5-dihydro-1H-

pyrazol-5-yl)quinoline (8a)

S

N

NH

N

MeO

Cl

Yield : 70%


M.P. : 170-172 °C




1H-NMR : (CDCl3) δ: 2.95 (1H, dd, J=16.3, 9.4 Hz, 4-Ha), 3.74

(1H, dd, J = 16.4, 10.6 Hz, 4-Hb), 3.94 (3H, s, OMe),

5.38 (1H, t, J = 9.9 Hz, 5-H), 7.11 (1H, d, H5, J=2.6

Hz), 7.39 (1H, d, H4', J=2.9 Hz), 7.60 (1H, dd, H7,

J=9.1 Hz), 7.69 (1H, d, H5', J=4.6 Hz), 7.91 (1H, d, H8,


130

J=9.2 Hz), 8.20 (1H, dd, H2', J=2.2 Hz), 8.36 (1H, s,

H4).

MS : (m/z): 343 (M+, 100 %).


12.82. Found: C, 62.24; H, 4.25; N, 12.80.



S

N

NH

N

MeO

Cl CH3

Yield : 82%


M.P. : 164-166 °C





Hz, 4-Ha), 3.64 (1H, dd, J = 16.3, 10.4 Hz, 4-Hb), 3.94

(3H, s, OMe), 5.29 (1H, t, J = 9.9 Hz, 5-H), 7.02 (1H,

d, H4', J=4.9 Hz), 7.13 (1H, d, H5, J=2.6 Hz), 7.36 (1H,

d, H8, J=9.2 Hz), 7.49 (1H, d, H5', J=4.9 Hz), 7.58 (1H,

dd, H7, J=8.6 Hz), 7.90 (1H, d, H8, J=9.2 Hz), 8.33 (1H,

s, H4).

MS : (m/z): 356 (M+, 100 %).


12.29. Found: C, 63.14; H, 4.65; N, 12.29.


131



S

N

NH

N

MeO

Cl CH3

Yield : 81%


M.P. : 180 °C





Hz, 4-Ha), 3.66 (1H, dd, J = 16.3, 10.5 Hz, 4-Hb), 3.94

(3H, s, OMe), 5.30 (1H, t, J = 9.9 Hz, 5-H), 7.02 (1H,

d, H4', J=4.9 Hz), 7.12 (1H, d, H5, J=2.5 Hz), 7.31 (1H,

s, H5'), 7.40 (1H, dd, H7, J=9.3 Hz), 7.70 (1H, s, H3'),

7.91 (1H, d, H8, J=9.2 Hz), 8.35 (1H, s, H4).

MS : (m/z): 356 (M+, 100 %).


12.29. Found: C, 63.21; H, 4.69; N, 12.25.



S

N

NH

N

MeO

Cl

CH3

Yield : 75%



132

M.P. : 170 °C





Hz, 4-Ha), 3.66 (1H, dd, J = 16.3, 10.5 Hz, 4-Hb), 3.93

(3H, s, OMe), 5.31 (1H, t, J = 9.9 Hz, 5-H), 7.06 (1H,

d, H4' J=4.4 Hz), 7.11 (1H, d, H5, J=2.6 Hz ), 7.42 (1H,

dd, H7, J=9.2 Hz), 7.68 (1H, d, H3' J=4.4 Hz), 7.90 (1H,

d, H8, J=9.2 Hz), 8.36 (1H, s, H4).

MS : (m/z): 356 (M+, 100 %).


12.29. Found: C, 63.23; H, 4.69; N, 12.31.


pyrazol-5-yl]-6-methoxyquinoline (8e)

S

N

NH

N

MeO

Cl

CH3

CH3

Yield : 74%

State : White solid

M.P. : 122-124 °C





16.2, 9.7 Hz, 4-Ha), 3.65 (1H, dd, J = 16.3, 10.5 Hz, 4-

Hb), 3.93 (3H, s, OMe), 5.28 (1H, t, J = 10.0 Hz, 5-H),

7.09 (1H, s, H4'), 7.10 (1H, d, H5, J=2.9), 7.39 (1H, dd,

H7, J=9.2 Hz), 7.90 (1H, d, H8, J=9.2 Hz), 8.31 (1H, s,

H4).

MS : (m/z): 372 (M+, 100 %).


133


11.81. Found: C, 64.08; H, 5.05; N, 11.76.


5-yl]-6-methoxyquinoline (8f)

S

N

NH

N

MeO

Cl Cl

Yield : 79%


M.P. : 198-200 °C




1H-NMR : (CDCl3) δ: 3.15 (1H, dd, J = 16.9, 10.1 Hz, 4-Ha), 3.94

(3H, s, OMe), 4.00 (1H, dd, J = 16.9, 10.8 Hz, 4-Hb),

5.39 (1H, t, J = 10.4 Hz, 5-H), 7.08 (1H, d, H4', J=5.2

Hz), 7.12 (1H, d, H5, J=2.7 Hz), 7.41 (1H, dd, H7,

J=9.2 Hz), 7.61 (1H, d, H5', J=5.2 Hz), 7.91 (1H, d, H8,

J=9.2 Hz), 8.36 (1H, s, H4).

MS : (m/z): 378 (M+, 100 %)

CHN : Anal. Calculated. for C17H13N3Cl2S: C, 56.36; H, 3.62;

N, 11.60. Found: C, 56.32; H, 3.61; N, 11.58.


5-yl]-6-methoxyquinoline (8g)

S

N

NH

N

MeO

Cl

Cl


134

Yield : 57%


M.P. : 204-206 °C





(1H, dd, J = 16.2, 10.7 Hz, 4-Hb), 3.91 (3H, s, OMe),

5.36 (1H, t, J = 10.3 Hz, 5-H), 6.95 (1H, d, H4', J=4.1

Hz), 7.11 (1H, d, H5, J = 2.7 Hz), 7.36 (1H, dd, H7,

J=9.2 Hz), 7.50 (1H, d, H3', J=4.1 Hz), 7.89 (1H, d, H8,

J = 9.2 Hz), 8.36 (1H, s, H4).

MS : (m/z): 378 (M+, 100 %).


N, 11.60. Found: C, 56.34 H, 3.59; N, 11.52.


pyrazol-5-yl]-6-methoxyquinoline (8h)

S

N

NH

N

MeO

Cl

Cl

Cl

Yield : 87%


M.P. : 190-191 °C





(3H, s, OMe), 3.98 (1H, dd, J = 16.7, 10.5 Hz, 4-Hb),

5.39 (1H, t, J = 10.2 Hz, 5-H), 7.11 (1H, d, H5, J=2.7

Hz), 7.16 (1H, s, H4'), 7.41 (1H, dd, H7, J=9.2 Hz), 7.91

(1H, d, H8, J=9.2 Hz), 8.33 (1H, s, H4).

MS : (m/z): 313 (M+, 100 %).


135


N, 10.59. Found: C, 51.45; H, 3.02; N, 10.54.


chloro-6-methoxyquinoline (8i)

S

N

NH

N

MeO

Cl Br

Yield : 81%


M.P. : 157-159 °C





(3H, s, OMe), 4.06 (1H, dd, J = 16.8, 10.8 Hz, 4-Hb),

5.39 (1H, t, J = 10.4 Hz, 5-H), 7.12 (1H, d, H5, J=2.7

Hz), 7.16 (1H, d, H4', J=5.1 Hz), 7.41 (1H, dd, H7,

J=9.2 Hz), 7.59 (1H, d, H5', J=5.1 Hz), 7.91 (1H, d, H8,

J=9.2 Hz), 8.36 (1H, s, H4).

MS : (m/z): 423 (M+, 100 %).


N, 10.33. Found: C, 50.12; H, 3.14; N, 10.30.


chloro-6-methoxyquinoline (8j)

S

N

NH

N

MeO

Cl

Br


136

Yield : 87%

State : White solid

M.P. : 203-205 °C





(1H, dd, J = 16.2, 10.7 Hz, 4-Hb), 3.91 (3H, s, OMe),

5.36 (1H, t, J = 10.3 Hz, 5-H), 6.95 (1H, d, H4', J=4.1

Hz), 7.10 (1H, d, H5, J=2.6 Hz), 7.36 (1H, dd, H7, J=9.2

Hz), 7.45 (1H, d, H3', J=4.1 Hz), 7.89 (1H, d, H8, J=9.2

Hz), 8.36 (1H, s, H4).

MS : (m/z): 423 (M+, 100 %).


N, 10.33. Found: C, 50.15; H, 3.19; N, 10.25.


yl]-6-methoxyquinoline (8k)

S

N

NH

N

MeO

Cl

I

Yield : 69%


M.P. : 216-218 °C





(1H, dd, J = 16.2, 10.7 Hz, 4-Hb), 3.91 (3H, s, OMe),

5.36 (1H, t, J = 10.3 Hz, 5-H), 6.92 (1H, d, H4', J=4.1

Hz), 7.10 (1H, d, H5, J=2.7 Hz), 7.36 (1H, dd, H7, J=9.2


137

Hz), 7.46 (1H, d, H3', J=4.1 Hz), 7.89 (1H, d, H8, J=9.2

Hz), 8.36 (1H, s, H4).

MS : (m/z): 470 (M+, 100 %).


N, 9.26. Found: C, 44.95; H, 2.85; N, 9.23.

2.5 General Method for the Synthesis of Piperidinyl

Chalcones (9a─l) (Scheme─III)

A mixture of 4-piperidin-1-ylbenzaldehyde (9) (10 mmol) and an aromatic

ketone (a-l, 10 mmol) in methanol (50 ml) was stirred at room temperature, followed

by dropwise addition of aq. NaOH (4 ml, 10%). The stirring was continued for 2 h

and the reaction mixture was then kept at 0 °C (24 h). Subsequently, it was poured

onto ice-cold water (200 ml). The precipitates were collected by filtration, washed

with cold water followed by cold MeOH. The resulting chalcones (9a-l) were

recrystallised from CHCl3.

2.5.1 (2E)-3-(4-Piperidin-1-ylphenyl)-1-thiophen-2-ylprop-2-en-1-

one (9a)

O

S

N

2

3

4

5

6

1

7

8

9

10

11

12

2'

3'4'

5'1'

Yield : 80%

State : Orange red

M.P. : 141 °C

IR : υmax(KBr) 1652 (C=O), 1598 (C=C) cm

-1

1H-NMR : (CDCl3) δ: 1.63-1.68 (6H, m, H3/H4/H5), 3.29-3.30 (4H,

m, H2/H6), 6.87 (2H, d, H9/H11, J = 8.8 Hz ), 7.15 (1H, t,

H4', J = 4.2 Hz), 7.23 (1H, d, Hα, J = 15.2 Hz), 7.52

(2H, d, H8/H12, J = 8.8 Hz), 7.62 (1H, d, H3', J = 4.8


138

Hz), 7.79 (1H, d, Hβ, J = 15.6 Hz), 7.82 (1H, d, H3', J =

3.6 Hz).

MS : (m/z) 297 (M+, 100 %)

CHN : Anal. Calculated for C18H19NOS: C, 72.69; H, 6.44; N,

4.71. Found: C, 72.62; H, 6.48; N, 4.68.

2.5.2 (2E)-3-(4-Piperidin-1-ylphenyl)-1-thiophen-3-ylprop-2-en-1-

one (9b)

O

S

N

Yield : 85%

State : Orange

M.P. : 160 °C


-1


m, H2/H6), 6.87 (2H, d, H9/H11, J = 8.8 Hz ), 7.21 (1H,

d, Hα, J = 15.2 Hz), 7.33 (1H, t, H4', J = 4.0 Hz), 7.51

(2H, d, H8/H12, J = 8.4 Hz), 7.64 (1H, d, H5', J = 4.8

Hz), 7.76 (1H, d, Hβ, J = 15.6 Hz), 8.10 (1H, s, H2').

MS : (m/z) 297 (M+, 100 %)


4.71. Found: C, 72.60; H, 6.40; N, 4.64 .


139

2.5.3 (2E)-1-(3-Methylthiophen-2-yl)-3-(4-piperidin-1-

ylphenyl)prop-2-en-1-one (9c)

O

S

CH3N

Yield : 90%

State : Orange yellow

M.P. : 125 °C


-1

1H-NMR : (CDCl3) δ: 1.63-1.68 (6H, m, H3/H4/H5), 2.56 (3H, s,

Me), 3.29-3.31 (4H, m, H2/H6), 6.87 (2H, d, H9/H11, J =

8.4 Hz ), 7.12 (1H, d, H5', J = 5.2 Hz), 7.18 (1H, d, Hα, J

= 15.2 Hz), 7.52 (2H, d, H8/H12, J = 8.4 Hz), 7.60 (1H,

d, H4', J = 5.2 Hz), 7.78 (1H, d, Hβ, J = 15.2 Hz)

MS : (m/z) 311 (M+, 100 %)


4.50. Found: C, 73.22; H, 6.78; N, 4.44.


ylphenyl)prop-2-en-1-one (9d)

O

S

CH3

N

Yield : 82%

State : Orange

M.P. : 110 °C


-1


140


Me), 3.29-3.31 (4H, m, H2/H6), 6.87 (2H, d, H9/H11, J =

8.8 Hz ), 7.20 (1H, d, Hα, J = 15.2 Hz), 7.21 (1H, s,

H5'), 7.52 (2H, d, H8/H12, J = 8.8 Hz), 7.63 (1H, s, H3', J

= 4.8 Hz), 7.77 (1H, d, Hβ, J = 15.2 Hz)

MS : (m/z) 311 (M+, 100 %)

CHN : Anal. Calculated forC19H21NOS: C, 73.27; H, 6.80; N,

4.50. Found: C, 73.32; H, 6.83; N, 4.48.


ylphenyl)prop-2-en-1-one (9e)

O

S

CH3

N

Yield : 79%

State : Yellowish Brown

M.P. : 90 °C


-1


Me), 3.28-3.30 (4H, m, H2/H6), 6.81 (1H, d, H4', J = 3.2

Hz), 6.87 (2H, d, H9/H11, J = 8.4 Hz ), 7.19 (1H, d, Hα, J

= 15.2 Hz), 7.51 (2H, d, H8/H12, J = 8.4 Hz), 7.64 (1H,

d, H3', J = 3.2 Hz), 7.75 (1H, d, Hβ, J = 15.6 Hz).

MS : (m/z) 311 (M+, 100 %)

CHN : Anal. Calculated for C19H21NOS: C, 73.27 H, 6.80; N,

4.50. Found: C, 73.21; H, 6.76; N, 4.53.


141

2.5.6 (2E)-1-(2,5-Dimethylthiophen-3-yl)-3-(4-piperidin-1-

ylphenyl)prop-2-en-1-one (9f)

O

S

CH3

CH3

N

Yield : 72%

State : Orange

M.P. : 115-117 °C


-1


s, 2xMe), 3.30-3.31 (4H, m, H2/H6), 6.86 (2H, d,

H9/H11, J = 8.8 Hz ), 7.10 (1H, s, H4'), 7.09 (1H, d, Hα,

J = 15.6 Hz), 7.48 (2H, d, H8/H12, J = 8.4 Hz), 7.67

(1H, d, Hβ, J = 15.6 Hz)

MS : (m/z) 325 (M+, 100 %)


4.10. Found: C, 73.82; H, 7.10; N, 4.12.


2-en-1-one (9g)

O

S

ClN

Yield : 82%

State : Crimson

M.P. : 85 °C


-1


142


m, H2/H6), 6.87 (2H, d, H8/H12, J = 8.8 Hz ), 7.02 (1H,

d, H5', J = 5.2 Hz), 7.51 (1H, d, H4', J = 5.2 Hz), 7.52

(2H, d, H9/H11, J = 8.8 Hz), 7.55 (1H, d, Hα, J = 15.6

Hz), 7.80 (1H, d, Hβ, J = 15.2 Hz)

MS : (m/z) 332 (M+, 48 %), 334 (M

++2, 12 %), 331 (M

+-1,

100 %)

CHN : Anal. Calculated for C18H18ClNOS: C, 65.15; H, 5.47;

N, 4.22. Found: C, 65.18; H, 5.43; N, 4.19.


2-en-1-one (9h)

O

S

Cl

N

Yield : 76%

State : Bright Yellow

M.P. : 162 °C


-1


m, H2/H6), 6.87 (2H, d, H9/H11, J = 8.8 Hz ), 6.97 (1H,

d, H4', J = 4.0 Hz), 7.12 (1H, d, Hα, J = 15.2 Hz), 7.51

(2H, d, H8/H12, J = 8.4 Hz), 7.58 (1H, d, H3', J = 3.6

Hz), 7.77 (1H, d, Hβ, J = 15.2 Hz).

MS : (m/z) 332 (M+, 44 %), 33 (M

+-1, 100 %)

CHN : Anal. Calculated for C18H18ClNOS: C, 65.15; H, 5.47;

N, 4.22. Found: C, 65.27; H, 5.42; N, 4.26.


143

2.5.9 (2E)-1-(2,5-Dichlorothiophen-3-yl)-3-(4-piperidin-1-

ylphenyl)prop-2-en-1-one (9i)

O

S

Cl

Cl

N

Yield : 62%

State : Yellowish Brown

M.P. : 84 °C


-1


m, H2/H6), 6.85 (2H, d, H9/H11, J = 8.8 Hz ), 7.11 (1H,

s, H4'), 7.13 (1H, d, Hα, J = 15.6 Hz), 7.48 (2H, d,

H8/H12, J = 8.4 Hz), 7.67 (1H, d, Hβ, J = 15.6 Hz)

MS : (m/z) 368 (M++2, 24 %), 365 (M

+-1, 100 %),

CHN : Anal. Calculated for C18H17Cl2NOS: C, 59.02; H, 4.68;

N, 3.82. Found: C, 58.70; H, 4.70; N, 3.75.

2.5.10 (2E)-1-(3-Bromothiophen-2-yl)-3-(4-piperidin-1-

ylphenyl)prop-2-en-1-one (9j)

O

S

BrN

Yield : 69%

State : Orange Red

M.P. : 93 °C


-1


m, H2/H6), 6.87 (2H, d, H9/H11, J = 8.4 Hz ), 7.10 (1H,


144

d, H5', J = 5.2 Hz), 7.48 (1H, d, H4', J = 5.2 Hz), 7.52

(2H, d, H8/H12, J = 8.8 Hz), 7.55 (1H, d, Hα, J = 15.6

Hz), 7.79 (1H, d, Hβ, J = 15.6 Hz)

MS : (m/z) 376 (M+, 100 %)

CHN : Anal. Calculated for C18H18BrNOS: C, 57.45; H, 4.82;

N, 3.72. Found: C, 57.54; H, 4.76; N, 3.76.


2-en-1-one (9k)

O

S

Br

N

Yield : 88%

State : Deep Yellow

M.P. : 162 °C

IR: : υmax(KBr) 1650 (C=O), 1595 (C=C) cm

-1


m, H2/H6), 6.86 (2H, d, H9/H11, J = 8.4 Hz ), 7.11 (1H,

d, H4', J = 4.0 Hz), 7.12 (1H, d, Hα, J = 15.2 Hz), 7.50

(2H, d, H8/H12, J = 8.4 Hz), 7.54 (1H, d, H3', J = 3.6

Hz), 7.78 (1H, d, Hβ, J = 15.2 Hz).

MS : (m/z) 375 (M+-1, 100 %) 376 (M

+, 67 %)

CHN : Anal. Calculated for C18H18BrNOS: C, 57.45; H, 4.82;

N, 3.72. Found: C, 57.38; H, 4.16; N, 3.61.


145

2.5.12 (2E)-1-(5-Iodothiophen-2-yl)-3-(4-piperidin-1-ylphenyl)prop-2-

en-1-one (9l)

O

S

I

N

Yield : 92%

State : Deep Yellow

M.P. : 142 °C

IR: : υmax(KBr) 1652 (C=O), 1602 (C=C) cm

-1


m, H2/H6), 6.86 (2H, d, H9/H11, J = 8.4 Hz ), 7.31 (1H,

d, H4', J = 3.6 Hz), 7.11 (1H, d, Hα, J = 15.2 Hz), 7.50

(2H, d, H8/H12, J = 8.8 Hz), 7.43 (1H, d, H3', J = 4.0

Hz), 7.77 (1H, d, Hβ, J 15.2 Hz).

MS : (m/z) 423 (M+, 100 %)

CHN : Anal. Calculated for C19H22INOS: C, 51.94; H, 5.05, N,

3.19. Found: C, 52.04; H, 5.12; N, 3.26.

2.6 General Method for the Synthesis of 2-Pyrazolines of 4-

piperidin-1-ylbenzaldehyde (10a─l) (Scheme─IV)

A mixture of Chalcone (9a-l, 1.0 mmol) and hydrazine hydrate (3.0 mmol) in

ethanol (10 mL) was refluxed. After completion of the reaction (4-6 h, TLC

monitoring) the crude product was precipitated out when the reaction mixture was

poured onto ice-cold water (50 ml). The precipitates were collected by filtration,

washed with cold water followed by cold EtOH to obtain 2-pyrazolines which were

recrystallised from EtOH (95%) to obtain pure compounds 10a-l.


146


yl)phenyl]piperidine (10a)

S

N

NNH

Yield : 65%

State : Red solid

M.P. : 132 °C

IR : υmax(KBr) 3313 (N-H) 1585 (C=N) cm

-1

1H-NMR : (CDCl3) δ: 1.60-1.65 (6H, m, H3/H4/H5), 2.87 (1H, dd, J

= 16.3, 9.3 Hz, 4-Ha),3.30-3.31 (4H, m, H2/H6), 3.68

(1H, dd, J = 16.2, 10.2 Hz, 4-Hb), 5.33 (1H, t, J = 9.8

Hz, 5-H), 6.85 (2H, d, H9/H11, J = 8.8 Hz ), 7.10 (1H, t,

H4', J = 4.2 Hz), 7.49 (2H, d, H8/H12, J = 8.8 Hz), 7.55

(1H, d, H5', J = 4.8 Hz), 7.75 (1H, d, H3', J = 3.6 Hz)

MS : (m/z) 311 (M+, 100 %)

CHN : Anal. Calculated for C18H21N3S: C, 69.42; H, 6.80; N,

13.49. Found: C, 69.35; H, 6.86; N, 13.56.


yl)phenyl]piperidine (10b)

S

N

NNH

Yield : 69%


M.P. : 125 °C


147


-1


= 16.4, 9.4 Hz, 4-Ha), 3.27-3.29 (4H, m, H2/H6), 3.71

(1H, dd, J = 16.2, 10.2 Hz, 4-Hb), 5.39 (1H, t, J = 9.8

Hz, 5-H), 6.81 (2H, d, H9/H11, J = 8.7 Hz ), 7.23 (1H, t,

H4', J = 4.0 Hz), 7.42 (2H, d, H8/H12, J = 8.4 Hz), 7.51

(1H, d, H5', J = 4.8 Hz), 8.02 (1H, s, H2').

MS : (m/z) 311 (M+, 100 %).


13.49. Found: C, 69.47; H, 6.72; N, 13.44.


yl]phenyl}piperidine (10c)

S

CH3N

NNH

Yield : 61%


M.P. : 119-120 °C

IR: : υmax(KBr) 3307 (N-H) 1610 (C=N) cm

-1


Me), 2.81 (1H, dd, J = 16.1, 9.3 Hz, 4-Ha), 3.30-3.31

(4H, m, H2/H6), 3.62 (1H, dd, J = 16.1, 10.2 Hz, 4-Hb),

5.28 (1H, t, J = 9.8 Hz, 5-H), 6.81 (2H, d, H9/H11, J =

8.4 Hz ), 7.04 (1H, d, H5', J = 5.2 Hz), 7.42 (2H, d,

H8/H12, J = 8.4 Hz), 7.48 (1H, d, H4', J = 5.2 Hz).

MS : (m/z) 325 (M+, 100 %).


12.91. Found: C, 70.09; H, 7.07; N, 12.84.


148


yl]phenyl}piperidine (10d)

S

CH3

N

NNH

Yield : 74%


M.P. : 145 °C


-1


Me), 2.84 (1H, dd, J = 16.3, 9.3 Hz, 4-Ha), 3.30-3.32

(4H, m, H2/H6), 3.60 (1H, dd, J = 16.3, 10.4 Hz, 4-Hb),

5.28 (1H, t, J = 9.9 Hz, 5-H), 6.77 (2H, d, H9/H11, J =

8.5 Hz ), 7.21 (1H, s, H5'), 7.43 (2H, d, H8/H12, J = 8.6

Hz), 7.54 (1H, s, H3', J = 4.8 Hz),

MS : (m/z) 325 (M+, 100 %).

CHN : Anal. Calculated C19H23N3S: C, 70.11; H, 7.12; N,

12.91. Found: C, 70.14; H, 7.07; N, 12.88.


yl]phenyl}piperidine (10e)

Yield : 75%.

State : Orange red solid.

M.P. : 157 °C.

S

CH3

N

NNH


149


-1


Me), 2.84 (1H, dd, J = 16.2, 9.1 Hz, 4-Ha), 3.30-3.32

(4H, m, H2/H6), 3.57 (1H, dd, J = 16.2, 10.0 Hz, 4-Hb),

5.23 (1H, t, J = 9.8 Hz, 5-H), 6.72 (1H, d, H4', J = 3.2

Hz), 6.77 (2H, d, H9/H11, J = 8.4 Hz ), 7.41 (2H, d,

H8/H12, J = 8.4 Hz), 7.51 (1H, d, H3', J = 3.2 Hz).

MS : (m/z) 325 (M+, 100 %).

CHN : Anal. Calculated for C19H23N3S : C, 70.11; H, 7.12; N,

12.91. Found: C, 70.03; H, 7.18; N, 12.97.

2.6.6 1-{4-[3-(2,5-Dimethylthiophen-3-yl)-4,5-dihydro-1H-pyrazol-5-

yl]phenyl}piperidine (10f)

S

CH3

CH3

N

NNH

Yield : 73%


M.P. : 144 °C


-1


s, 2xMe), 2.77 (1H, dd, J = 16.3, 9.5 Hz, 4-Ha), 3.30-

3.32 (4H, m, H2/H6), 3.55 (1H, dd, J = 16.3, 10.2 Hz, 4-

Hb), 5.24 (1H, t, J = 10.0 Hz, 5-H), 6.78 (2H, d, H9/H11,

J = 8.7 Hz ), 7.02 (1H, s, H4'), 7.45 (2H, d, H8/H12, J =

8.4 Hz).

MS : (m/z) 339 (M+, 100 %).


12.38. Found: C, 70.69; H, 7.37; N, 12.37.


150


yl]phenyl}piperidine (10g)

S

ClN

NH N

Yield : 65%


M.P. : 151 °C


-1


= 16.6, 10.2 Hz, 4-Ha), 3.30-3.32 (4H, m, H2/H6), 3.96

(1H, dd, J = 16.7, 10.2 Hz, 4-Hb), 5.37 (1H, t, J = 10.2

Hz, 5-H), 6.80 (2H, d, H8/H12, J = 8.7 Hz ), 7.02 (1H, d,

H5', J = 5.2 Hz), 7.47 (1H, d, H4', J = 5.2 Hz), 7.49 (2H,

d, H9/H11, J = 8.8 Hz).

MS : (m/z) 346 (M+, 12 %), 311 (M

+−Cl, 100 %).

CHN : Anal. Calculated for C19H24ClN3S : C, 62.50; H, 5.83;

N, 12.15. Found: C, 62.48; H, 5.76; N, 12.21.


yl]phenyl}piperidine (10h)

S

Cl

N

NNH

Yield : 80%

State : Brown solid

M.P. : 147 °C


151


-1


= 16.3, 10.1 Hz, 4-Ha), 3.29-3.30 (4H, m, H2/H6), 3.65

(1H, dd, J = 16.3, 10.4 Hz, 4-Hb), 5.35 (1H, t, J = 10.3

Hz, 5-H), 6.86 (2H, d, H9/H11, J = 8.7 Hz ), 6.92 (1H, d,

H4', J = 4.0 Hz), 7.47 (2H, d, H8/H12, J = 8.4 Hz), 7.53

(1H, d, H3', J = 3.6 Hz).

MS : (m/z) 346 (M+, 18 %), 311 (M

+−Cl, 100 %).

CHN : Anal. Calculated for C18H20ClN3S: C, 62.50; H, 5.83; N,

12.15. Found: C, 62.42; H, 5.91; N, 12.09.

2.6.9 1-{4-[3-(2,5-Dichlorothiophen-3-yl)-4,5-dihydro-1H-pyrazol-5-

yl]phenyl}piperidine (10i)

S

Cl

Cl

N

NNH

Yield : 65%


M.P. : 175 °C


-1


= 16.3, 10.0 Hz, 4-Ha), 3.30-3.32 (4H, m, H2/H6), 3.95

(1H, dd, J = 16.4, 9.5 Hz, 4-Hb), 5.35 (1H, t, J = 10.3

Hz, 5-H), 6.82 (2H, d, H9/H11, J = 8.5 Hz ), 7.09 (1H, s,

H4'), 7.46 (2H, d, H8/H12, J = 8.4 Hz).

MS : (m/z) 380 (M+, 100 %).

CHN : Anal. Calculated for C18H19Cl2N3S: C, 56.84; H, 5.04;

N, 11.05. Found: C, 56.74; H, 5.14; N, 11.09.


152


yl]phenyl}piperidine (10j)

S

BrN

NH N

Yield : 77%


M.P. : 180 °C


-1


= 16.5, 10.2 Hz, 4-Ha), 3.25-3.28 (4H, m, H2/H6), 4.02

(1H, dd, J = 16.5, 10.6 Hz, 4-Hb), 5.35 (1H, t, J = 10.4

Hz, 5-H), 6.78 (2H, d, H9/H11, J = 8.4 Hz ), 7.05 (1H, d,

H5', J = 5.2 Hz), 7.46 (1H, d, H4', J = 5.2 Hz), 7.49 (2H,

d, H8/H12, J = 8.6 Hz).

MS : (m/z) 390 (M+, 100 %).

CHN : Anal. Calculated for C18H20BrN3S: C, 55.39; H, 5.16; N,

10.76. Found: C, 55.30; H, 5.20; N, 10.72.


yl]phenyl}piperidine (10k)

S

Br

N

NNH

Yield : 78%

State : Brown solid

M.P. : 140 °C


153


-1


= 16.2, 9.6 Hz, 4-Ha), 3.30-3.32 (4H, m, H2/H6), 3.65

(1H, dd, J = 16.2, 9.6 Hz, 4-Hb), 5.32 (1H, t, J = 10.3

Hz, 5-H), 6.82 (2H, d, H9/H11, J = 8. Hz ), 7.05 (1H, d,

H4', J = 4.0 Hz), 7.49 (2H, d, H8/H12, J = 8.4 Hz), 7.39

1H, d, H3', J = 3.6 Hz).

MS : (m/z) 390 (M+, 8%), 310 (M

+−Br, 100 %).

CHN : Anal. Calculated for C18H20BrN3S: C, 55.39; H, 5.16; N,

10.76. Found: C, 55.34; H, 5.14; N, 10.71.

2.6.12 1-{4-[3-(5-Iodothiophen-2-yl)-4,5-dihydro-1H-pyrazol-5-

yl]phenyl}piperidine (10l)

S

I

N

NNH

Yield : 72%


M.P. : 167 °C

IR : υmax(KBr) 3312 (N-H), 1608 (C=N) cm

-1


= 16.3, 9.7 Hz, 4-Ha), 3.30-3.32 (4H, m, H2/H6), 3.64

(1H, dd, J = 16.2, 10.1 Hz, 4-Hb), 5.29 (1H, t, J = 10.2

Hz, 5-H), 6.79 (2H, d, H9/H11, J = 8.4 Hz ), 7.15 (1H, d,

H4', J = 3.6 Hz), 7.50 (2H, d, H8/H12, J = 8.5 Hz), 7.32

(1H, d, H3', J = 4.0 Hz).

MS : (m/z) 437 (M+, 100 %).

CHN : Anal. Calculated for C18H20IN3S: C, 49.43; H, 4.61; N,

9.61. Found: C, 49.47; H, 4.55; N, 9.56.


154

2.7 Protocols for Biological Studies

2.7.1 Antimicrobial Assay

The in vitro antimicrobial activity was done by the reported method.264

All

compounds (1a-k, 2a-k, 3a-s, 4a-s, 5a-k, 6a-k, and 9a-l) were screened for

antibacterial activity against Escherichia coli, Miicrococus luteus and Staphylococus

aureus using Chloramphenicol (1.00 mmol/ml) as standard. The antifungal activity

was investigated against Aspergellus flavus, Aspergellus niger and Curvuliaria lunata

using Flucanazole (1.00 mmol/ml) as standard. At the end of 24 h and 48 h for

bacteria and fungi respectively, the inhibition was recorded measuring the diameter of

the inhibition zone. Each experiment was repeated thrice and the average of the three

independednt determinations was recorded. The results are summarized in table 6.

2.7.2 Antileishmanial Assay

All compounds (1a-k, 2a-k, 3a-s, 4a-s, 5a-k, 6a-k and 9a-l) were tested for

the antileishmanial activity using L. major promastigotes as parasites for in vitro

screening. Parasites were cultured at 24C in Shaking incubator on M 199 medium

containing foetal bovine serum (10%); HEPES (25 mM), and penicillin and

streptomycin (0.22g each).265

Each compound (1 mg) was dissolved in DMSO (1 ml) and Amphotericin B

(1 mg) taken in DMSO (1 ml) was used as a positive control. Parasites were taken

from lag phase of their growth and were centrifuged at 3000 rpm for 3 minutes. The

parasite density was maintained at 2x106

cells/ml by diluting with fresh culture

medium. In 96-well plates, 180 l of medium was added in different wells. The

experimental compound (20 l) was added in medium and serially diluted. Parasite

culture (100 l) was added in all wells. In Negative controls, DMSO was serially

diluted in medium while the positive control contained varying concentrations of

standard antileishmanial compound i.e. Amphotericin B. The plates were incubated

for 72 h at 24 C. The culture was examined microscopically on an improved neubaur

counting chamber and IC50 values of compounds possessing antileishmanial activity

were calculated. All assays were run in duplicate. The results are summarized in table

7, 8 and 10.


155

2.7.3 Determination of IC50 values of the titled compounds (1a-k, 2a-

k, 3a-s, 4a-s, 5a-k, 6a-k and 9a-l)

Prism windows-based software is used to run different biological screening

activity to find out IC50 / LD50.

In case of antileishmanial activity, after running the samples and calculating

the % of inhibition in serial dilution methods (It depends on the activity of the

compounds; some of them show in 4-6-7 or 10 dilution the inhibitory concentration).

After that we count the number of parasite in neubauer chamber (0,0025 mm2) and we

implement the result manually in the prism windows-based software.

2.7.4 Anti-HIV-1 Assay

The antiviral assays in human PBMCs were performed according to the

reported procedure.266,267

According to the procedure phytohemagglutinin- stimulated

human PBMCs were made infected with LAV-1 strain of HIV-1. The tested

compounds were then added to cultures. Uninfected and untreated PBMCs were

grown as controls in parallel at equivalent cell concentrations. The cultures were

incubated for 6 days after infection, in a humidified 5% CO2-95% air incubator at

37°C at which point all cultures were sampled for Anti-HIV-1 activity. The

supernatant was clarified, and the viral particles were then pelleted at 40,000 rpm for

30 min by using a rotor (70.1 Ti; Beckman Instruments, Inc., Fullerton, Calif.) and

suspended in virus-disrupting buffer. The RT assay was performed by a modification

of the method of Spira et al. in 96-well microdilution plates by using (rA)n . (dT)12-18

as the template primer. The RT results were expressed in disintegrations per minute

per milliliter of originally clarified supernatant. The results are summarized in table 9

and 11.

2.7.5 Cytotoxic Assay

The cytotoxic activity were also performed according to the literature

method.268,269

The compounds were evaluated for their potential toxic effects on

uninfected PHA-stimulated human PBM cell, CEM (T-lymphoblastoid cell line

obtained from American Type Culture Collection, Rockville, MD) and Vero (African

green monkey kidney) cells. Log phase Vero, CEM and PHA stimulated human PBM

cells were seeded at a density of 5×103, 2.5×103, and 5×104 cells/well, respectively.

All of the cells were plated in 96-well cell culture plates containing 10-fold serial

dilutions of the test drug. The cultures were incubated for 2, 3, and 4 days for Vero,


156

CEM, and PBM cells, respectively, in a humidified 5% CO2–air at 37 ◦C. At the end

of incubation, MTT tetrazolium dye solution (cell titer 96, Promega, Madison, WI)

was added to each well and incubated overnight. The reaction was stopped with stop

solubilization solution (Promega, Madison, WI). The plates were incubated for 5 h to

ensure that the formazan crystals were dissolved. The plates were read at 570 nm

using an ELISA plate reader (Bio-Tek Instruments, Inc., Winooski, VT, Model EL

312e). The 50% inhibition concentration (IC50) was determined from the

concentration–response curve using the median effect method.270,271

The results are

summarized in table 9 and 11.

2.7.6 Determination of EC50 and EC90

The median effective concentrations (EC50s) and inhibitory concentrations

(IC50s) were derived from the computer-generated median effect plot of the dose

effect data, as described previously.272,273

From the slope of the dose-effect plot and

the EC50, the computer program also generated the 90% effective concentration

(EC90). The ratios of the drugs selected for the combination studies were based on the

relative potencies of the individual compounds. The combination index (CI) for the

combined effects of the drugs was also determined by using the same computer

program. For the analyses we used constant ratios of the drugs. The CI values were

determined from the median effect plot by using a conservative, mutually

nonexclusive equation. CI values of <1, 1, or >1 indicate synergism, additive ism, or

antagonism, respectively

2.8 X-Ray Crystallography

A colorless prismatic crystal of (3k, 3m, 3p and 3q) was coated with Paratone

8277 oil (Exxon) and mounted on a glass fiber. All measurements were made on a

Nonius KappaCCD diffractometer with graphite monochromated Mo-K radiation.

The data were collected274

using and scans. The data were corrected for Lorentz

and polarization effects and for absorption using multi-scan method.275

The structure was solved by the direct methods276

and expanded using Fourier

techniques.277

The non-hydrogen atoms were refined anisotropically. The H-atoms

were included at geometrically idealized positions and were not refined. The final

cycle of full-matrix least-squares refinement using SHELXL97278

converged with

unweighted and weighted agreement factors, R = 0.037 and wR = 0.086 (for 2933


157

observed data with I > 2.0σ(I)), respectively, and goodness of fit, S = 1.01. The

weighting scheme was based on counting statistics and the final difference Fourier

map was essentially featureless. The figure was plotted with the aid of ORTEP-3 for

Windows.279

Chapter – 3

Chapter -3 Results & Discussion

158

Chapter 3

RESULTS AND DISCUSSION

3.1 Chemistry of Quinolyl Chalcones and their 2-

Pyrazoline Derivatives

3.1.1 Chemistry of Quinolyl Chalcones (1a-k, 2a-k, 3a-s and 4a-s)

All the chalcones were prepared by Claisen-Schmidt condensation reaction

between equimolar quantities of 6-OMe or 6/7/8-Me-substituted 2-Chloro-3-

formylquinolines with various aromatic and heteroaromatic ketones in methanol in the

presence of 10% NaOH solution. The product was precipitated out by stirring the

mixture at room temperature. The crude product was obtained by filtration and

washing first with water and then with cold methanol. It was then recrystallized from

EtOH to give pure compounds (1a-k, 2a-k, 3a-s and 4a-s). The general structure of

these chalcones is given below:

N

O

Ar

Cl

R1

R2

R3


a Thien-3-yl k 5-I-thien-2-yl

b 3-Me-thien-2-yl l 1H-pyrrol-2-yl

c 4-Me-thien-2-yl m 5-Me-furan-2yl

d 5-Me-thien-2-yl n 2,5-diMe-furan-3-yl

e 2,5-diMe-thien-3-yl o Benzofuran-2-yl

f 3-Cl-thien-2-yl p 2,3-diH-1,4-benzodioxin-6-yl

g 5-Cl-thien-2-yl q 1-Naphthyl

h 2,5-diCl-thien-3-yl r 2-Naphthyl

i 3-Br-thien-2-yl s 9-Anthryl

j 5-Br-thien-2-yl

(1a-k): R2R

3 = H, R

1 = CH 3, Ar = a-k

(2a-k): R1R

3 = H, R

2 = CH 3, Ar = a-k

(3a-s): R1R

2 = H, R

3 = CH 3, Ar = a-s

(4a-s): R1R

2 = H, R

3 = OMe, Ar = a-s

1

3

2

45

6

7

8


159

All the prepared compounds were characterized by spectroscopic techniques

(NMR, IR, MS) and elemental analysis. The MS was employed only for the molecular

mass confirmation. For structure elucidation, 1H NMR spectroscopy was used. The X-

ray crystallographic study of 3k, 3m, 3p and 3q was also performed for the structure

confirmation. Elemental analyses were done after the recrystallization of the

compounds in appropriate solvents.

IR Spectra

Selected diagnostic bands of the IR spectra of the chalcones (1a-k, 2a-k, 3a-s

and 4a-s) showed useful information about the structure of the compounds. Two

significant stretching bands due to ethylenic group C=C and carbonyl group C=O

were observed at 1585-1598 and 1648-1664 cm-1

respectively, which are typical

stretching regions for chalcone moiety. The quinoline C=N stretching appeared at

1563-1572 cm-1

in all of the title compounds. The characteristic band for thiophene

(a-k derivatives) was observed at 750-700 cm-1

. The C─O─C stretching of furyl ring

in (3m-o and 4m-o) appeared at 1040-1075 cm-1

. In addition, the spectra of (3l and 4l)

showed a stretching band resulting from the NH stretching of the pyrrole moiety at

3215 cm-1

.

Mass Spectra

The molecular ion, observed in the mass spectra for all the chalcones,

confirmed their molecular masses. The base peak in the mass spectra of most of

compounds was obtained by the cleavage of C-Cl bond in 2-Chloroquinoline moiety.

1NMR Spectra

The 1H-NMR spectra of the chalcones (1a-k, 2a-k, 3a-s and 4a-s) reveal, that

the Cα-H and Cβ-H protons are so much deshielded that their signal is shifted

considerably downfield to such an extent that they appear in the aromatic region (δ

7.22-8.23). As a result, two very sharp doublets around 7.4 ppm for Hα and 8.2ppm

for Hβ, with a coupling constant 15.4-16.2 Hz for the trans chalcones were observed,

except (1f/1i, 2f/2i, 3f/3i and 4f/4i). Interestingly, Hα showed a doublet relatively in

the downfield at δ 7.82-7.83 in chalcones (1f/1i, 2f/2i, 3f/3i and 4f/4i). This was

attributed to an additional (-)I of the groups like Cl/Br in the vicinity i.e. on the 3‟

position of thiophene ring.

The thiophenyl protons appear in the region δ 6.24-8.20 ppm. The

unsubstituted thiophenyl derivatives (1a, 2a, 3a and 4a) show three signals, for

protons H2', H4' and H5'. The most deshielded of these is H2', which appears as


160

doublets of doublet at δ 8.20 ppm with J = 2.9, 1.0 Hz. This large δ value is due to the

presence of carbonyl oxygen atom in the vicinity, which increases Other two protons

H4' and H5' both appear as dd at δ 7.39

S

O

NCl

H2'

H4'

H

H

H5' R

(J = 5.1 and 2.9 Hz) and 7.70 ppm (J = 5.1 and 1.0 Hz) respectively. Similarly, 3-

substituted thiophenyl derivatives (1-4 b, f and i) show two doublets, representing H4',

H5' at δ 7.10 and 7.49 ppm respectively, with J = 4.9 Hz for both the protons. In case

of 5-substituted thiophenyl derivatives (1-4 d, g, j and k) two doublets appear at δ

6.87-7.36 and 7.51-7.72 ppm for protons H4' and H3' with J = 4.0 for both the protons.

For 4-substituted thiophenyl derivatives (1-4 c) two sharp singlets are observed at δ

7.31 and 7.71 ppm for H5' and H3' respectively. In case of disubstituted thiophenyl

derivatives (1-4 e and h) a sharp singlet appeared at δ 7.10 ppm.

The aromatic protons of quinolyl, thienyl, furyl, pyrrolyl, naphthyl and anthryl

rings appeared in the expected region δ 6.24-8.56 ppm.

X-Ray Crystallography

The E-configuration of chalcones was confirmed by X-ray structure of 3k,

3m, 3p and 3q and have already been reported.280-282

3.1.2 Chemistry of Pyrazolines of Quinolyl Chalcones (5a-k, 6a-k,

7a-k and 8a-k)

The pyrazoline derivatives of the synthesized chalcones were prepared by

refluxing them with hydrazine hydrate in ethanolic solution. The product was

precipitated within the reaction flask, which was filtered, washed (first with water and

then with cold ethanol), dried and ultimately recrystallized from ethanol.


161

N

Ar

O

ClR2

R1

R3

NH2NH

2.H

2O

EtOHN ClR

2

R1

NH N

ArR

3

(1a-k) R1= CH 3 R

2R

3= H

(2a-k) R2= CH 3 R

1R

3= H

(3a-k) R3= CH 3 R

1R

2= H

(4a-k) R3= OCH 3 R

1R

2= H

(5a-k)

(6a-k)

(7a-k)

(8a-k)



b 3-Me-thien-2-yl h 2,5-diCl-thien-3-yl

c 4-Me-thien-2-yl i 3-Br-thien-2-yl


e 2,5-diMe-thien-3-yl k 5-I-thien-2-yl

f 3-Cl-thien-2-yl

IR Spectra

The formation of product (5a-k, 6a-k, 7a-k and 8a-k) was confirmed by the

disappearance of C=O peak at 1648-1664 cm-1

and appearance of characteristic ring

stretching bands of C=N at 1590-1500 cm-1

. In addition, another stretching band of N-

H at 3274-3288 cm-1

confirmed the ring closure at chalcone moiety. Moreover, the

absorption bands at 1020-1108 cm-1

were attributed to the C─N stretching vibrations,

which also confirmed the formation of desired pyrazoline ring in all the compounds.

Mass Spectra

The molecular ion M+, observed in the mass spectra for all the pyrazolines,

confirmed their molecular masses. The base peak, in all of the mass spectra (except

for 6f, where the quinoline nucleus fragments to give M+−C10H7NCl), was exhibited

by M+ itself.

1NMR Spectra

In proton NMR spectra, the disappearance of ethylenic protons between δ

7.22-8.23 ppm and appearance of a peak at δ 1.5 (±0.02) for CH2 in pyrazolines,

further confirmed the formation of proposed compounds. Th 1H-NMR signal for N-H

proton is so weak that it does not appear in the spectra. In the 1H-NMR spectra of the

pyrazolines (5a-k, 6a-k, 7a-k and 8a-k) reveal the presence of two doublets of

doublet signals due to CH2 protons Ha (upfield H of CH2) at δ 2.82-3.21 ppm region,

and Hb (downfield H of CH2) at 3.64-4.10 ppm. The CH proton appeared as a triplet

at δ 5.28-5.40 ppm region.


162

3.2 Chemistry of Piperidyl Chalcones and their 2-

Pyrazoline Derivatives

3.2.1 Chemistry of Piperidyl Chalcones (9a-l)

The precursor 4-piperidin-1-ylbenzaldehyde was prepared by N-arylation of

piperidine with 4-fluorobenzaldehyde in the presence of K2CO3 and CTAB, in DMF

as solvent. The 4-piperidin-1-ylbenzaldehyde was then condensed with various

thienyl ketones in alkaline medium with constant stirring at room temperature. The

title compounds (9a-l) were precipitated out within the reaction flask, which were

then filtered washed with water and then with cold methanol. The pure products were

obtained after recrystallization from methanol.

NH

NaOH/EtOH

r. t.+ Ar

O

O

H

F+ N

O

H

N

O

H

N

O

Ar

(9)

(9) (9a-l)








K2CO3, CTAB

DMF, 100 °C

IR Spectra

Selected bands of the IR spectra of the chalcones (9a-l) showed significant

information about their structures. Two typical stretching bands of chalcone moiety,

due to ethylenic group C=C and carbonyl group C=O were observed at 1590-1607

and 1650-1658 cm-1

respectively. The characteristic band for thiophene (a-l

derivatives) was observed at 750-700 cm-1

.


163

Mass Spectra

Very interesting mass spectra of compounds (9a-l) were obtained, in terms

that the base peak, in all the spectra was exhibited by M+ itself. This gives information

about the stability of the piperidyl chalcone nucleus. Molecular masses of compounds

(9a-l) were also confirmed by their mass spectra.

1NMR Spectra

The 1H-NMR spectra of the chalcones (9a-l) show that the Hα and Hβ protons

appear in the aromatic region (δ 7.09-7.79). As a result, two very sharp doublets

around 7.10 ppm for Hα and 7.79 ppm for Hβ, with a coupling constant 15.2-15.6 Hz

for the trans chalcones were observed. Here also, the signals of the Hα, for chalcones

(9g and 9j) appeared relatively in the downfield at δ 7.55. This again was attributed to

an additional (-)I of the groups like Cl/Br in the vicinity i.e. on the 3‟ position of

thiophene ring.

3.2.2 Chemistry of Pyrazolines of Piperidyl Chalcones (10a-l)

The pyrazoline derivatives of the synthesized piperidyl chalcones were

prepared by refluxing them with hydrazine hydrate in ethanolic solution. The product

(10a-l) was precipitated within the reaction flask, which was filtered, washed (first

with water and then with cold ethanol), and recrystallized from ethanol.

N

O

Ar

(10a-l)

N

Ar

NH N

+

(9a-l)

NH2 NH2EtOH

reflux








IR Spectra

The formation of product (10a-l) was confirmed by the disappearance of C=O

peak at 1650-1658 cm-1

and appearance of characteristic ring stretching bands of C=N


164

at 1610-1580 cm-1

. Moreover, an additional stretching band of N-H at 3305-3317 cm-1

confirmed the ring closure at chalcone moiety.

Mass Spectra

The molecular ion M+, observed in the mass spectra for all the pyrazolines,

confirmed their molecular masses. Again, the base peak, in all of the mass spectra

(except for 10g-h and 10k where the M+−Cl and M

+−Br gave the base peak,

respectively), was exhibited by M+ itself.

1NMR Spectra

The disappearance of signals between δ 7.22-8.23 ppm for olefinic protons in

the 1H NMR spectra and appearance of peaks at δ 2.77-3.14, 3.55-4.02, and 5.24-5.39

for CH2 (Ha and Hb respectively) and H-5 in pyrazoline ring, further confirmed the

formation of target compounds. The 1H-NMR spectra of pyrazolines (10a-l), show the

presence of two doublets of doublet signals due to CH2 protons, Ha (upfield H of CH2)

at δ 2.82-3.21 ppm region and Hb at 3.64-4.10 ppm. The CH proton appeared as a

triplet at δ 5.28-5.40 ppm region.

3.3 Biological Activities of Chalcones

The prepared chalcones were screened for various biological properties like

antifungal, antibacterial, antileishmanial, anti-HIV-1 and cytotoxicity.

Panels of Micro-organisms:

Bacteria: E. coli, M. luteus and S. aureus

Fungii: A. flaves, A. niger and C. lunata

Leishmania: L. major

Anti-HIV-1: Human PBM cells.

Cytotoxicity: Human PBM, CEM and VERO

The panel of the microorganisms was chosen following the literature (See

chapter 1). Actually, these are very common and highly pathogenic microorganisms

which are commonly found anywhere in the world, especially in Pakistan.

The results of these assays are tabulated below.


165

3.3.1 Antimicrobial Studies of Quinolyl Chalcones (3a-s and 4a-s)

Table 6. Antimicrobial activity of compounds (3a-s and 4a-s) Antibacterial activity Zone of Antifungal activity Zone of

Inhibition in mm Inhibition in mm

Compound E. coli M. luteus S. aureus A. flaves A. niger C. lunata

3a 21 31 34 10 11 12

3b 16 23 25 8 10 11

3c 14 27 31 7 9 8

3d 13 22 26 4 10 9

3e 11 20 22 3 8 5

3f 30 28 30 20 15 11

3g 32 30 38 18 17 15

3h 36 35 39 13 15 10

3i 28 34 40 16 17 12

3j 20 22 31 10 9 10

3k 15 21 19 7 9 11

3l 36 33 37 10 11 14

3m 1 6 27 31 12 13 10

3n 11 17 15 3 5 6

3o 36 30 31 8 16 11

3p 37 30 39 11 12 15

3q 11 25 35 10 15 13

3r 15 17 25 11 10 11

3s 10 15 11 10 12 10

4a 22 32 35 11 12 13

4b 20 28 29 7 6 5

4c 16 23 37 10 11 9

4d 14 27 30 8 8 10

4e 12 22 24 4 7 6

4f 31 30 33 22 17 10

4g 33 32 39 20 21 18

4h 38 35 41 25 22 20

4i 37 34 40 12 14 11

4j 21 20 30 9 6 11

4k 14 18 12 6 8 10

4l 30 36 41 16 16 13

4m 18 30 32 10 10 11

4n 13 19 12 2 3 8

4o 37 34 33 11 17 18

4p 38 32 41 12 13 16

4q 12 27 37 13 16 14

4r 25 30 35 10 11 11

4s 17 20 13 11 13 12

Standarad 39 36 43 17 18 16

DMF +ve +ve +ve +ve +ve +ve +ve indicates microbial growth. Control: DMF (0.01% solution in distilled water). Standard for

antibacterial:

Chloramphenicol (1.00 mmol/ml). Standard for antifungal: Flucanazole (1.00 mmol/ml)


166

Antibacterial Activity

Compounds 4h, and 4o-p, from substituted heteroaryl derivatives have shown

promising antibacterial activities (almost equivalent to standard) against all the three

bacterial strains i.e., E. coli, M. luteus and S. aureus. Among the two series of

compounds, unsubstituted thiophenyl derivatives (3a and 4a) exhibited almost

equivalent antibacterial activities to that of the standard (Table 6). Activity decreases

considerably by the substitution of methyl and halo groups at position 5 of thiophenyl

ring (3d, 4d, 3g, 4g, 3j, 4j, 3k and 4k; Table 6). Incorporation of chlorine at position

5 of thiophenyl ring (3g and 4g) enhanced the activity to a considerable extent; it is

further increased by the incorporation of another chlorine atom at position 2 (3h and

4h). However, incorporation of same groups at positions 3 and 4 (3b, 3c, 3f, 3i, 4b,

4c, 4f, and 4i) exhibited no difference in activity except of bromo derivatives. In case

of furanyl derivatives, incorporation of a second methyl group at position 2 (3n and

4n) considerably decreases the activity than of the mono substituted one (3m and

4m). In general, activity enhances by the substitution of aromatic rings with electron

withdrawing groups and is suppressed by the incorporation of electron donating

methyl groups. No systematic change has been observed in antibacterial activities for

the rest of the compounds (Table 6).

Antifungal Activity

Among the compounds under investigation, un-substituted thiophenyl

derivatives (3a and 4a) are found almost equivalent in their antifungal activities to the

standard. In general, activity decreases in the compounds having substitution at

position 2, 3 and 5 by the incorporation of electron donating methyl groups at

aromatic rings while it enhances by the substitution of electron withdrawing groups.

Among the electron withdrawing groups, activity increases with the electronegativity

of the substituent. However, such substitutions at position 4 (3c and 4c) displayed no

marked difference in the activities. No systematic change has been observed in

antibacterial activities for the rest of the compounds (Table 6).


167

3.3.2 Antileishmanial Studies of Quinolyl Chalcones (3a-s and 4a-s)

Table 7. Antileishmanial activity of the series 3a-s and 4a-s (IC50 values)

Compounds IC50 µg/ml Compounds *IC50 µg/ml

3a 0.58±0.02 4a 0.59±0.01

3b 0.75±0.05 4b 0.82±1.25

3c 0.27±0.02 4c 0.84±0.35

3d 0.34±0.06 4d 0.61±0.05

3e 0.16±0.19 4e 0.93±0.08

3f 0.78±0.07 4f 0.68±0.56

3g 0.23±0.50 4g 0.23±0.50

3h 0.81±0.45 4h 0.69±0.06

3i 0.57±0.01 4i 0.79±0.78

3j 0.42±0.62 4j 0.32±0.62

3k 0.31±0.03 4k 0.41±0.03

3l 0.33±0.06 4l 0.33±0.06

3m 0.37±0.10 4m 0.27±0.10

3n 0.84±0.58 4n 0.29±0.03

3o 0.87±1.25 4o 0.22±0.19

3p 0.26±0.08 4p 0.46±0.08

3q 0.91±1.69 4q 0.57±0.02

3r 0.21±0.04 4r 0.31±0.04

3s 0.29±0.03 4s 0.39±0.03

Standard Drug

MIC(µg/ml±S.D)

(Amphotericin B)

0.56±0.20 Standard Drug

MIC(µg/ml±S.D)

(Amphotericin B)

0.56±0.20

Antileishmanial Activity

According to the results obtained, it is evident that unsubstituted thiophenyl

derivatives (3a and 4a) are almost equally active (IC50=0.58±0.02µg/ml for 3a and

IC50=0.59±0.01µg/ml for 4a), comparable to the standard, amphotericin B

(IC50=0.56±0.20µg/ml) while the activity enhances considerably by the substitution of

methyl and halo groups at position 5 of thiophenyl ring (3d, 4d, 3g, 4g, 3j, 4j, 3k and

4k; Table 7). Among the compounds, derivatized at position 5, chloro analogues (3g


168

and 4g) are the most active. However, incorporation of these functionalities at

position 3 of thiophenyl ring (3b, 4b, 3f, 4f, 3i and 4i) instead of position 5,

deactivates the compounds except of bromo derivative (3i) perhaps due to electronic

and steric reasons. Incorporation of methyl group at position 4 (3c) in category 3

increases the activity than its analogue 3b, derivatized at position 3

(IC50=0.75±0.05µg/ml for 3b and IC50=0.27±0.02µg/ml for 3c), while no prominent

difference in activities is observed by the same change in category 4 (4b and 4c

respectively, Table 7). Similarly, the replacement of two methyl groups at position 2

and 5 of thiophenyl ring (3e and 4e) by two chloro groups (3h and 4h), significantly

decreases the activity (by about 5 times) in category 3; reverse is observed in case of

category 4. In case of furanyl derivatives, incorporation of a second methyl group at

position 2 considerably decreases the activity (3n) than of the mono substituted one

(3m) in category 3, whereas in category 4 no marked difference is observed whether

one (4m) or two (4n) methyl groups are present on the furanyl ring. For the rest of the

compounds, no systematic change in anti-leishmanial activities is observed (Table 7).


169

3.3.3 Antileishmanial Studies of Quinolyl Chalcones (1a-k and 2a-k)

and their 2-pyrazoline derivatives (5a-k and 6a-k)

Table 8. Antileishmanial activity of series 1a-k, 2a-k, 5a-k and 6a-k (IC50 values)

Antileishmanial Activity

According to the results obtained, among the two series of chalcones (1a-k

and 2a-k), the unsubstituted thiophenyl derivatives (1a and 2a) have prominent

Compounds IC50 µg/ml Compounds *IC50 µg/ml

1a 0.61±0.81 5a 0.67±0.09

1b 0.94±0.10 5b 0.78±0.23

1c 0.59±0.09 5c 0.74±0.09

1d 0.61±1.25 5d 0.89±0.10

1e 0.73±0.08 5e 0.93±0.16

1f 0.78±0.15 5f 0.84±0.07

1g 0.65±0.14 5g 0.75±0.02

1h 0.85±0.18 5h 0.79±0.03

1i 0.93±0.99 5i 0.94±0.20

1j 0.78±0.032 5j 0.93±0.20

1k 0.67±0.23 5k 0.77±0.02

2a 0.88±0.20 6a 0.94±0.02

2b 0.92±0.11 6b 0.76±0.05

2c 0.83±0.05 6c 0.87±0.08

2d 0.74±0.31 6d 0.89±0.03

2e 0.62±0.24 6e 0.76±0.19

2f 0.59±0.20 6f 0.78±0.07

2g 0.81±0.09 6g 0.83±0.50

2h 0.78±0.14 6h 0.71±0.45

2i 0.71±0.18 6i 0.85±0.18

2j 0.91±0.31 6j 0.93±0.62

2k 0.84±0.22 6k 0.88±0.27

Standard Drug

MIC(µg/ml±S.D)

(Amphotericin B)

0.56±0.20 Standard Drug

MIC(µg/ml±S.D)

(Amphotericin B)

0.56±0.20


170

difference in antileishmanial activities i.e. 1a is more active than 2a

(IC50=0.61±0.81µg/ml for 1a and IC50=0.88±0.20µg/ml for 2a), while the activity

decreases considerably by the introduction of methyl group at position 3 of thiophenyl

ring (1b and 2b; Table 8), but replacement of methyl group by halo groups (Cl and

Br) at position 3 (1f, 1i, 2f and 2i) enhances the activity except for 1i. Moreover, the

activity decreases in the order Cl>Br>Me. However, incorporation of these

functionalities at position 5 of thiophenyl ring (1d, 1g, 1j, 1k, 2d, 2g, 2j and 2k)

instead of position 3, activates the compounds except of 2g and 2j, perhaps due to

electronic and steric reasons. Among the compounds, derivatized at position 5, methyl

analogues (1d and 2d) are the most active and the order of activity is; Me>Cl>I>Br.

Incorporation of methyl group at position 4 (2c) in series 2 increases the activity a

little bit than its analogue 2b, derivatized at position 3 (IC50=0.92±0.11µg/ml for 2b

and IC50=0.83±0.05µg/ml for 2c), while very large difference in activities is observed

by the same change in series 1 (1b and 1c respectively, Table 8). Similarly, the

replacement of two methyl groups at position 2 and 5 of thiophenyl ring (1e and 2e)

by two chloro groups (1h and 2h), significantly decreases the activity in both the

series. Lastly, the order of activity by the incorporation of methyl group at three

different positions i.e. 3-, 4- and 5- of thiophenyl ring is; -5 > -4 > -3 in both the series

(1a-k and 2a-k).

It is clear from the Table 8, that the conversion of the two series of chalcones

(1a-k and 2a-k) to their corresponding 2-pyrazoline derivatives (5a-k and 6a-k), there

is an overall decrease in the antileishmanial activity. Moreover, the order of

antileishmanial activity w.r.t different substituents at different positions of thiophenyl

ring also changes. For instance, 3-substituted thiophenyl derivatives (5b, 5f, 5i, 6b, 6f

and 6i) exhibit the following order of activity; Me>Cl>Br. In case of 5-substituted

thiophenyl derivatives (5d, 5g, 5j, 5k, 6d, 6g, 6j and 6k), the activity decreases in the

order; Cl>I>Me>Br. Similarly, 2,5-Dichloro derivatives (5h and 6h) are more active

than the corresponding dimethyl ones (5e and 6e). Lastly, the order of activity by the

incorporation of methyl group at three different positions of thiophenyl ring is; -4 > -3

> -5 in both the series (5a-k and 6a-k).


171

3.3.4 Anti-HIV-1 and Cytotoxic Studies of 2-Pyrazoline Derivatives

of Quinolyl Chalcones (5a-k and 7a-k)

Table 9. Anti- HIV-1 activity in human PBM cells and cytotoxicity (IC50, μM)

Anti- HIV-1 Activity in PBM cells Cytotoxicity (IC50, μM) in:

Code EC50, μM EC90, μM PBM CEM VERO

5a 8.5 21.0 20.2 39.7 26.0

5b 9.1 42.0 31.1 32.8 52.4

5c 7.7 34.5 13.4 30.4 52.6

5d 41.2 98.2 > 100 (0.8) ≥100 (45.3) 29.3

5e 14.5 42.4 42.2 42.1 41.0

5f 6.0 25.9 16.1 60.8 53.1

5g 66.9 ≥100 (72.5) >100 (1.7) > 100 (40.5) 58.8

5h 5.4 23.2 30.1 18.1 27.5

5i 7.3 28.0 17.1 29.1 25.5

5j 79.0 ≥100 (65.9) >100 (-11.0) 44.9 35.5

5k*

7a 22.7 77.6 44.1 44.0 28.6

7b 30.3 51.5 31.5 34.5 34.7

7c 3.4 18.4 49.7 8.8 >100 (38.7)

7d 26.3 64.2 50.5 33.4 32.9

7e 16.9 66.5 37.0 35.5 14.3

7f 14.5 43.6 >100 (1.6) 36.5 15.9

7g 5.5 68.3 29.6 16.3 27.2

7h 22.8 39.9 >100 (4.6) > 100 (35.5) 15.0

7i 3.7 20.0 13.4 31.1 32.6

7j*

7k* *Not Determined

Anti-HIV-1 and Cytotoxicity

The results show that unsubstituted thiophenyl derivative in series 5 displays

moderate activity while that in series 7 no activity has been observed. Incorporation

of Me/Cl/Br group at position 3 renders the resulting compound moderately active in

series 5, whereas in series 7 no activity is observed in 7b, weak activity in 7f and

moderate activity in 7i. If methyl group is present at position 4 then the resulting

compound (5c and 7c) showed moderate activity in both the series. Incorporation of

Me/Cl/Br group at position 5 imparts no antiviral activity in series 5 (5d, 5g and 5j)

whereas in case series 7 only Chloro substituted (7f) showed moderate activity. In

case of dimethyl-substituted thiophenyl derivatives (5e and 7e) weak activity is

observed, whereas dichloro-substituted thiophenyl derivatives (5h and 7h) exhibited

moderate activity in series 5 and no activity in series 7.


172

It is concluded that none of the compounds of the two series (5a-k and 7a-k)

have been proved to be good antiviral agent, although moderate activities have been

exhibited by a few ones (5a-c, 5f, 5h, 5i, 7c, 7g and 7i).

3.3.5 Antileishmanial Studies of Piperidyl Chalcones (9a-l)

The piperidine-based chalcones (9a-l) have not been proven to be good

antileishmanial agents. The results of the assays are given in the table 10.

Table 10. Antileishmanial activity of the series (9a-l) (IC50)

The compounds are classified into four categories as far as their

antileishmanial activities are concerned i.e. IC50 = 0.59-0.56 or below as significantly

active, 0.69-0.60 as good activity, 0.79-0.70 as moderately active and 0.95-0.80 as

low activity. On this basis, it is concluded that the piperidyl chalcones are inactive

towards leishmaniasis.

Compounds IC50 µg/ml

9a > 1.00

9b > 1.00

9c > 1.00

9d > 1.00

9e > 1.00

9f > 1.00

9g > 1.00

9h > 1.00

9i > 1.00

9j > 1.00

9k > 1.00

9l > 1.00


173

3.3.6 Cytotoxic Studies of Piperidyl Chalcones (9a-l) and their 2-

Pyrazoline Derivatives (10a-l)

Table 11. Anti-HIV-1 activity in human PBM cells (EC50 & EC90) and

cytotoxicity in PBM, CEM and Vero cells (IC50) of the series 9a-l and 10a-l

Anti-HIV-1 activity in Human PBM cells Cytotoxicity (IC50, µM) in:

Code EC50, μM EC90, μM PBM CEM VERO

ZDV 0.0029 ± 0.0020 0.026 ± 0.013 >100 14.3 56.0

1a 73.8 ≥100 >100 11.6 65.5

1b 56.0 ≥100 >100 32.1 34.4

1c 2.5 ± 1.8 19.6 ± 20.4 26.4 9.9 63.9

1d 11.6 23.1 68.8 33.3 56.3

1e 17.9 30.9 77.8 21.2 50.5

1f 11.6 ± 4.6 23.6 ± 4.9 38.2 16.6 42.3

1g 8.4 ± 7.8 29.0 ± 25.4 32.1 12.2 18.1

1h 35.4 ≥100 >100 41.5 32.4

1i 11.8 ± 2.9 24.7 ± 1.8 42.8 15.0 24.9

1j 5.8 ± 2.8 27.8 ± 16.8 39.3 12.5 18.0

1k 46.5 ≥100 >100 52.8 69.5

1l 11.6 ≥100 >100 22.0 56.5

2a 7.3 26.8 20.8 6.9 3.2

2b 11.3 ≥100 >100 27.0 29.5

2c 5.1 ± 3.9 15.5 ± 11.1 11.0 2.3 11.4

2d 13.0 24.9 24.4 16.3 31.6

2e 7.2 ± 0.5 52.9 ± 11.9 86.4 15.3 52.0

2f 16.9 ± 11.7 29.8 ± 12.9 77.5 20.1 83.4

2g 2.4 ± 1.4 13.1 ± 7.8 34.2 10.2 31.6

2h 75.3 >100 >100 >100 >100

2i 32.5 >100 59.0 37.7 53.9

2j 17.4 30.4 57.0 31.6 24.8

2k 9.0 ± 0.4 33.3 ± 17.5 80.0 21.5 25.8

2l 14.5 43.6 >100 36.5 15.9

Anti-HIV-1 Activity

According to the results obtained, it is evident that the unsubstituted

thiophenyl derivatives (9a and 9b) of chalcones (9a-l) have shown no anti-HIV


174

activity (EC50 >20 µM) while the activity enhances considerably by the substitution of

methyl and halo groups at position 3 of the thiophenyl ring (9c, 9g and 9j). However,

incorporation of these functionalities at position 5 of thiophenyl ring (9e, 9h, 9k and

9l) instead of position 3, the chloro and bromo derivatives (1h and 1k) displayed no

activity whereas methyl and iodo derivatives (9e and 9l) were proven to be weakly

active anti-HIV agents. Incorporation of methyl group at position 4 of thiophenyl ring

(9d) also exhibited weak activity. Moreover, the two disubstituted derivatives (9f and

9i) also showed weak activity. In short, in the chalcones series (9a-l), only three

compounds (9c, 9g and 9j) proved to be active anti-HIV-1 agents.

In case of pyrazoline derivatives (10a-l) the unsubstituted thiophenyl

derivatives (10a and 10b) showed enhanced activities (EC50 = 7.3 µM and 11.3 µM

respectively) as compared to their chalcones analogues (9a and 9b with EC50 = 73.8

µM and 56.0 µM respectively). The compounds 10c and 10g also proved to be active

anti-HIV agents like their starting analogues (9c and 9g), whereas the activity of 10j

(EC50 = 17.4 µM) decreased than that of 9j (EC50 = 5.8±2.8 µM). The compounds in

which methyl and halo groups are present at position 5 of thiophenyl ring (10e, 10h,

10k and 10l), only 10e and 10k displayed improved activity (EC50 = 7.2±0.5 µM and

9.0±0.4 µM respectively) than their corresponding chalcones (9e and 9k, EC50 = 17.9

µM and 46.5 µM respectively). Rest of the compounds (10d, 10f and 10i) showed no

or weak activities (Table 11).

Cytotoxic Activity

Among the compounds under investigation, the unsubstituted thiophenyl

derivatives (9a and 9b) of chalcones (9a-l) showed no toxicity against PBM cells. As

in case of anti-HIV assays, here also the activity enhances by the incorporation of

methyl and halo groups at position 3 of thiophenyl ring (9c, 9g and 9j). These three

compounds (i.e. 9c, 9g and 9j) were found to be active against PBM, CEM and Vero

cells, except that of 1c, which showed no toxicity against Vero cells only. Moreover,

both the disubstituted derivatives (9f and 9i) showed cytotoxicity against all three

types of cells (i.e. PBM, CEM and Vero cells). In rest of the compounds 9d, 9e, 9h,

9k and 9l exhibited no toxicity against PBM cells, 9k was non-toxic only against

CEM cells while 9d, 9e, 9k and 9l displayed no toxicity against Vero cells.

In case of pyrazoline derivatives (10a-l), only the compounds 10a, 10c, 10d and 10g

showed cytotoxicity against PBM cells. All of the pyrazoline derivatives (10a-l) were


175

active except 10h, while four compounds (10e, 10f, 10h and 10i) showed no cytotoxic

activity against Vero cells.

3.4 Achievements and Problems

The present study is a very petite effort in the field of research. However, we

have been successeful in achieving a few things, that could be a contribution for the

benefits of the human beings, e.g.,

Discovering some highly potent antileishmanial agents

Designing a new MW irradiated method for the synthesis of substituted 2-

chloro-3-formylquinoline derivatives in very high yields and very short

reaction times.

Synthesizing libraries of new chalcones and their 2-pyrazoline derivatives.

Besides these achievements, we also had to face some problems and difficulties, e.g.,

Failed to synthesize 2-chloro-3-acetylquinolines using DMA and POCl3, by

employing different methods like thermal, MW and US irradiation techniques.

Purification of the synthesized compounds was also a very tedious job.

Getting the required chemicals and reagents on the shelf took a long time i.e.

3-6 months or more.

Getting spectroscopic results in 1-3 months.

Obtaining some of the bio-assay results in approximately a year.

3.5 Conclusion

In summary, we have synthesized hybrids of chalcones and pyrazole nuclei,

which have potential biological activities.

All the synthesized chalcone derivatives were tested for a range of biological studies,

like antimicrobial, antileishmanial, anti-HIV and cytotoxic.

Antimicrobial Agents

Amongst the compounds tested for antibacterial study (3a-s and 4a-s), 3f-i, 3l,

3o-p, 4f-i, 4l, and 4o-p showed remarkable antibacterial activity. Especially,

compounds 3h, 3l, 3o-p, 4h-i, and 4o-p showed significant activity against E. coli and

3h-i, 4h-i and 4o against M. luteus while 3h-i, 3p, 4g, 4h-i, 4l and 4p were found

most active against S. Aureus. Compunds 3g, and 4g-h displayed more antifungal


176

activity, against all the fungi, than the standard flucanazole. The table 12 below

categorized the synthesized compounds in the form of significant active compounds.

Table 12. Significantly active antimicrobial agents (3a-s and 4a-s)

Activity Microbes Compounds

Antibacterial E. coli 3h, 3l, 3o-p, 4h-i, and 4o-p

M. luteus 3h-i, 4h-i and 4o

S. Aureus 3h-i, 3p, 4g, 4h-i, 4l and 4p

Antifungal A. Flaves 3f-g, 3i, 4f-h and 4l

A. Niger 3g, 3i, 4f-h and 4o

C. lunata 3g, 3p, 4g-h and 4o-p

Antileishmanial Agents

As far as antileishmanial activity is concerned, the chalcones (1a-k, 2a-k, 3a-

s, 4a-s and 9a-l) were tested for it. The compounds 3c-e, 3g, 3j-m, 3p, 3r-s, 4g, 4j-p,

and 4r-s exhibited significant antileishmanial activity, while others showed moderate

activity. The table 13 below categorized the synthesized compounds in the form of

significant active compounds, moderately active and weekly active.

Table 13 Categories of antileishmanial chalcones (1a-k, 2a-k, 3a-s, 4a-s and 9a-l)

Category Compounds

Significant 1c, 2f, 3a, 3c, 3d, 3e, 3g, 3i, 3j, 3k, 3l, 3m, 3p, 3r, 3s, 4a, 4g, 4j-s

Good 1a, 1d, 1g, 1k, 2e, 4d, 4f, 4h

Moderate 1e-f, 1j, 2d, 2h-i, 3b, 3f, 4i

Weak 1b, 1h-i, 2a-c, 2g, 2j-k, 3h, 3n-o, 3q, 4b-c, 4e, 9a-l

The above table 13, shows that the compounds 1c, 2f, 3a, 3c, 3d, 3e, 3g, 3i, 3j,

3k, 3l, 3m, 3p, 3r, 3s, 4a, 4g, and 4j-s were found potentially active antileishmanial

agents. It is also concluded that the piperidyl chalcones are inactive towards

leishmaniasis.

Furthermore, the conversion of chalcones (1a-k and 2a-k) to their

corresponding pyrazoline derivatives (5a-k and 6a-k), resulted in no significant

increase in their leishmanicidal properties (table 14).


177

Table 14. Categories of antileishmanial pyrazoline derivatives 5a-k and 6a-k

Category Compounds

Significant nil

Good 5a

Moderate 5b-c, 5g-h, 5k, 6b, 6e-f, 6h

Low 5d-f, 5i-j, 6a, 6c-d, 6g, 6i-k

From the above table 14, it is evident that only one compound displayed good activity

and none of the tested pyrazoline derivatives (5a-k and 6a-k) of chalcones (1a-k and

2a-k) exhibited significant antileishmanial activity.

Antiviral/Cytotoxic Activity

Amongst the compounds tested for anti-HIV-1 and cytotoxicity (5a-k, 7a-k,

9a-l and 10a-l), no compound was proved to be significantly active anti-HIV-1 and/or

cytotoxic agent. However, some of them showed moderate activity (table15).

Table 15. Categories of antiviral/cytotoxic compounds 5a-k, 7a-k, 9a-l and 10a-l

Category Compounds

Moderate 5a, 5b, 5c, 5f, 5h, 5i, 7c, 7g,7i, 9g, 9j, 10a, 10e, 10k,

Weak 5e,7e,7f, 9c, 9d, 9e, 9i, 9l, 10b, 10c,10h

Inactive 5d, 5g, 5j, 7a, 7b, 7d,7h, 9a, 9b, 9h, 9k, 9c, 10f, 10g, 10j

3.6 Future Perspectives

This research work has very great potential from pharmacological point of

view. Thats why we are planning to

Test our compounds for more biological activities like antiinflammatory,

antioxidant, antimalarial etc.

A few series have already been sent to University of Peshawar for enzymatic

activities studies, and many others for anti-HIV-1 and cytotoxic srudies.

We are also planning to synthesize pyrimidine, benzothiazine and isoxazole

derivatives of the prepared chalcones.

All of the prepared chalcones along with their derivatives and bio-assays will

be published in eminent journals, so as to lift up the name of the university (in

general) and that of the country (in particular) in the field of research.

Bibliography

178

BIBLIOGRAPHY

1. Sharp, D. W .A. The Penguin Dictionary of Chemistry. 5, 89 (1983).

2. Mistry, R. N., Desai, K. R. E-J.Che. 2, 30-41 (2005).

3. Beilstein, F. Handbuch der Organischen Chemie. 7, 428 (1925).

4. Kostanecki, S. V., Tambor, J. Chem. Ber. 32, 1921 (1899).

5. Merck Index, 11th Edition, 5811

6. El-hashash M. A. El-nagdy S., Amine M. S., Phosphorus, Sulfur, and Silicon and

the Related Elements, 55(1), (1991)

7. Lim S. S., Kim H. S., Lee D. U., Bull Korean Chem. Soc. 28(12), (2007)

8. The Chemistry of Chalcones and Related Compounds, By D. N. Dhar, John

Willey & Sons, Inc. Book p#201

9. Krishena, B. M., and Chaganty, R.B., Phytochemistry, 12, 238 (1973).

10. Kozawa M., Morita, N., Baba, K., and Hata, K., Yakugaku Zasshi, 98, 210 (1978);

Chem. Abstr., 88,191090 (1978).

11. Shimokoriyama, M., J. Am. Chem. Soc., 79, 214 (1957).

12. Pakudina, Z. P., Rakhimov, A. A., and Sadykov, A. S., Khim. Prir. Soedin (2),

126 (1969); Chem. Abstr., 71, 88425s (1969).

13. Govindachari, T. R., and Parthasarthy, P. C. Tetrahedron Letters, 3419 (1972).

14. Govindachari, T. R., and Parthasarthy, P. C., Desai, H. K., and Shanbhag, M. N.,

Tetrahedron. 29, 3091 (1973).

15. Rao, J. M., Subrahmanyam, K., and Rao, K. V. J., Curr. Sci. (India), 44, 158

(1975).

16. Cardillo, B., Gennaro, A., Merlini, L., Nasini, G., and Servi, S., Phytochemistry,

12, 2027 (1973).

17. Rao, J. M., Subrahmanyam, K., and Rao, K. V. J., Curr. Sci. 47, 584 (1978).

18. Aritomi, M., and Kawasaki, T., Chem. Pharm. Bull., 22, 1800 (1974); Chem

Abstr., 81, 166401d (1974).

19. Hayashi, N., Takeshita, K., Nishio, N., and Hayashi, S., Chem. Ind. (London), 49,

1779 (1969).

20. Baudrenghien, J., Jadot, J., and Huls, R., Bull. Classe Sci., Acad. Roy. Bleg. 39,

105 (1953); Chem. Abstr. 48, 10744d (1954).

21. Fraser, A. W., and Lewis, J. R., Phytochemistry, 13, 1561 (1954).

22. Nagarajan, G. R., and Parmar, V. S., Phytochemistry. 16, 1317 (1977).

Bibliography

179

23. Bajwa, B. S., Khanna, P L., Seshadri, T. R. Current Sci. 41, 814 (1972).

24. Gupta, S. R., Seshadri, T. R., Sood, G. R., Indian J. Chem. 13, 632 (1975).

25. Saitoh, T. and Shibata, S. Tetrahedron Letters, 4461, (1975).

26. Dicarlo, G.,ascolo, N.,Izzo, A.A.,Capasso, F. Life Sci., 65, 337–353 (1999).

27. Francisco, A Toma´s-Barbera´n and Clifford, M. N J Sci Food Agric 80, 1073-

1080 (2000)

28. European Parliament and Council Directive 94/35/EC. Sweeteners for use in

foodstuffs. Off J Eur Commun 237, 3-12 (1994).

29. LindleyMG, NHDC: recent ®ndings and technical advances, in Advances in

Sweeteners, Ed by Grenby TH. Blackie Academic and Professional, London, pp

240-252 (1996).

30. Geodakyan, S. V., Voskoboinikova, IV., Kolesnik, J. A., Tjukavkina, N. A.,

Litvinenko, VI.., Glyzin VI. J Chromatogr. 577, 371-375 (1992).

31. Krause, M., Galensa, R. Z Lebensm Untersuch Forsch 194, 29-32 (1992).

32. Justesen, U., Knuthsen. P, Leth. T. J. Chromatogr. A 799, 101-110 (1998).

33. Macheix, J. J., Fleuriet, A., Billot, J. Fruit Phenolics. CRC Press, Boca Raton, FL.

(1990).

34. Hayashi, H., Hiraoka, N., Ikeshiro, Y., Yamamoto, H., Yoshikawa T. Biol.

Pharmaceut. Bull. 21, 987-989 (1998).

35. Homma, M., Oka, K., Taniguchi, C., Niitsuma, T., Hayashi, T. Biomed.

Chromatogr. 11, 125-131 (1997).

36. Vaya, J., Belinky, P. A., Aviram, M. Free Radic. Biol. Med. 23, 302-313 (1997).

37. Zeng, L., Zhang, R.Y., Meng, T., Lou, Z. C. J. Chromatogr. 513, 247-254 (1990).

38. Saitoh, T., Shibata, S. Tetrahedron Lett. pp 4461-4462 (1975).

39. Ferreira, D., Kamara, B. I., Brandt, E. V., Joubert, E. J Agric Food Chem. 46,

3406-3410 (1998).

40. Nagarajan, G.R., Parmar, V. S. Phytochemistry. 16, 1317-1318 (1977).

41. Burda, S., Oleszek, W., Lee, C. Y. J. Agric. Food Chem. 38, 945-948 (1998).

42. Amiot, M. J., Tacchini, M., Aubert. S, Nicolas, J. J. Food Sci. 57, 958-962

(1992).

43. McRae, K. B., Lidster, P. D., de Marco, A. C., Dick, A. J. J. Sci. Food Agric. 50,

329-342 (1990).

44. SuaÂrez, B., Santamaria-Victorero, J., Mangas, J. J., Blanco, D. J. Agric. Food

Chem.42, 2732-2736 (1999).

Bibliography

180

45. Lu, Y. Foo, Y. Food Chem 59, 187-194 (1997).

46. Versari, A., Biesenbruch, S., Barbanti, D. Farnell, P. J. Lebensm Wiss. Technol.

30, 585-589 (1997).

47. Francisco, A., Barbera´n, T., Clifford, M. N. J. Sci. Food Agric. 80, 1073-1080

(2000).

48. Kishimoto, Y., Akabori, Y., Horiguchi, T. Yakugaku Zassi. 78, 447 (1958);

Chem. Abstr. 52, 13863b (1958).

49. Lespagnol, A., Lespagnol, C., Lesieur, D., Cazin, J. C., Cazin, M., Beerens, H.,

Romond, C. Chim. Ther. 7, 365 (1972); Chem. Abstr. 78, 52753c (1973).

50. Buu-Hoi, N. P., Xuong, N. D., Sy, M. Bull. Soc. Chim. France. 1646 (1956);

Chem Abstr. 51, 120631 (1957).

51. Tomcufcik, A. s., Wilkinson, R. G., Child, R. G. German Patent, 2,502,490

(1975); Chem. Abstr. 83, 179067r (1975).

52. Henry, D. W. U.S. Patent, 3,726,920 (1973); Chem. Abstr. 79, 18450n (1973).

53. Laliberte, R., Campbell, D., Bruderlein, F. Can. J. Pharm. Sci. 2, 37 (1967);

Chem. Abstr. 67, 98058f (1967).

54. Jeney, E., Zsolnai, T., Lazar, J. Zetr. Bakteriol. Parasitenk, Abt. I, Orig. 163, 291

(1955); Chem. Abstr. 49, 15074g (1955).

55. Narasimhachari, N., Seshadri, T. R. Proc. Indian Acad. Sci. 27A, 128 (1948).

56. Nakanishi, M., Tsuda, A. Japanese Patent. 74 46, 056; Chem. Abstr. 83, 38818z

(1975).

57. Ruchkin, V. E., Shvetsova, K. D., Melnikov, N. N. Probl. Poluch. Poluprod.

Prom. Org. Sin., Akad. Nauk. SSSR, Otd. Obshch. Tekh. Khim. 66 (1967); Chem.

Abstr. 68, 95417g (1968).

58. Hase, J., Kobashi, K., Kobayashi, R. Chem. Parm. Bull. 21, 1076 (1973); Chem.

Abstr. 80, 10261b (1974).

59. Lesieur, D. I., Mizon, J., Osteux, R. Ann. Pharm. Frac. 31, 705 (1973); Chem.

Abstr. 81, 59921b (1974).

60. Cross, B. U.S. Patent 3,925,408 (1975); Chem. Abstr. 84, 135646v (1975).

61. Ballesteros, J. F., Sanz, M. J., Ubeda, A., Miranda, M. A., Iborra, S., Paya, M.,

Alcaraz, M. J. Med. Chem. 38, 2794-2797 (1995).

62. Hsieh, H. K., Lee, T. H., Wang, J. P., Wang, J. J., Lin, C. N. Pharm. Res. 15, 39-

46 (1998).

Bibliography

181

63. Dimmock, J. R., Elias, D. W., Beazely, M. A., Kandepu, N. M. Curr. Med. Chem.

6, 1125-1149 (1999).

64. Go, M. L., Wu, X., Liu, X. L. Curr. Med. Chem. 12, 483-499 (2005).

65. Nowakowska, Z. Eur. J. Med. Chem. 42, 125-137 (2007).

66. Bhakuni, D. S., Chaturvedi, R. J. Nat. Prod. 47, 585-591 (1984).

67. John, A. R., Sukumaran, K., Kuttan, G., Rao, M. N. A., Subbaraju, V., Kuttan R.

Cancer Lett. 97, 33-37 (1995).

68. Vaya, R., Belinky, P. A., Aviram, M. Free Radic. Biol. Med. 23, 302-313 (1997).

69. Mukherjee, S., Kumar, V., Prasad, A. K., Raj, H. G., Brakhe, M. E., Olsen, C. E.,

Jain, S. C., Parmar, V. P. Bioorg. Med. Chem. 9, 337-339 (2001).

70. Arty, I. S., Timmerman, H., Samhoedi, M., Sastrohami, D., Sugiyanto, H., Van

Der Goot, H. Eur. J. Med. Chem. 35, 449-457 (2000).

71. Narender, T., Shweta, Tanvir K., Rao, M. S., Srivastava, K., Puri, S. K. Bioorg.

Med. Chem. Lett., 15, 2453-2455 (2005).

72. Liu, M.., Wilairat, P., Croft, S. L., Tan, A. L., Go, M. Bioorg. Med. Chem., 11,

2729-2738 (2003).

73. Wu, X., Wilairat, P., Go, M. Bioorg. Med. Chem. Lett., 12, 2299-2302 (2002).

74. Ram, V. J., Saxena, A. S., Srivastava, S., Chandra, S. Bioorg. Med. Chem. Lett.,

10, 2159-2161 (2000).

75. Sivakumar, P. M., Geetha Babu, S. K., Mukesh, D. Chem. Pharm. Bull. 55, 44-49

(2005)

76. Viana, G. S., Bandeira, M. A., Matos, F. J. Phytomedicine, 10, 189-195 (2003).

77. Tiwar, N., Dwivedi, B., Nizamuddin. Boll. Chim. Farm., 128, 332-335 (1989).

78. Xia, Y., Yang, Z. Y., Xia, P., Bastow, K. F., Nakanishi, Y., Lee, K. H. Bioorg.

Med. Chem. Lett., 10, 699-701 (2000).

79. Ducki, S., Forrest, R., Hadfield, J. A., Kendall, A., Lawrence, N. J., McGown, A.

T., Rennison, D. Bioorg. Med. Chem. Lett., 8, 1051-1056 (1998).

80. Francesco, E., Salvatore, G., Luigi, M., Massimo, C. Phytochem., 68, 939-953

(2007).

81. Trivedi, J. C., Bariwal, J. B., Upadhyay, K. D., Naliapara, Y. T., Joshi, S. K.,

Pannecouque, C. C., Clercq, E. D., Shah, A. K. Tetrahedron Lett., 48, 8472-8474

(2007).

82. Wu, J. H., Wang, X. H., Yi, Y. H., Lee, K. H. Bioorg. Med. Chem. Lett., 13, 1813-

1815 (2003).

Bibliography

182

83. Domínguez, J. N., Charris, J. E., Lobo, G., Domínguez, N. G., Moreno, M. M.,

Riggione, F., Sanchez, E., Olson, J., Rosenthal, P. J. Eur. J. Med. Chem. 36, 555-

560 (2001).

84. Weekly Epidermicological Record, W.H.O. 72 (No I, II, III), 269(1997) 292ـ.

85. Berman, J. Am. J. Trop. Med. Hyg. 1, 64 (2001).

86. Mendis, K., Sina, B., Marchesini, P., Carter, R. Am. J. Trop. Med. Hyg. 97, 64

(2001).

87. Gessler, M. C., Nkunya, M. H. H., Mwasumbi, L. B., Heinrick, M., Tanner, M.

ACTA Tropica 65, 56(1994).

88. Tran, Q. L., Tezuka, Y., Ueda, J. Y., Nguyen, N. T., Maruyama, Y., Begum, K..,

Kim, H. S., Wataya, Y., Tran, Q. K., Kadota, S. J. Enthopharmacol. 249, 86

(2003).

89. M. Liu, P. Wilairat, M.-L. Go, M. Liu, J. Med. Chem. 44, 4443e 4452 (2001).

90. M.-L. Go, M. Liu, P. Wilairat, P.J. Rosenthal, K.J. Saliba, K. Kirk, Antimicrob.

Agents Chemother. 48, 3241e3245 (2004).

91. A. Yenesew, M. Duli, S. Derese, J. O. Midiwo, M. Heydenreich, M. G. Peter, H.

Akala, J. Wangui, P. Liyala, N. C. Waters, Phytochemistry 65, 3029-3032 (2004).

92. J.N. Domıńguez, C. Leoń, J. Rodrigues, N. Gamboa de Domıńguez, J. Gut, P.J.

Rosenthal, J. Med. Chem. 48 3654e3658 (2005).

93. M. Chen, S.B. Christensen, L. Zhai, M.H. Rasmussen, T. Theander, s. Frokjaer, B.

Steffansen, J. Davidsen, A. Kharazmi, J. Infect. Dis. 176, 1327e1333 (1997).

94. T. Narender, Shweta, K. Tanvir, M. Srinivasa Rao, K. Srivastava, S.K. Puri,

Bioorg. Med. Chem. Lett. 15, 2453e2455 (2005).

95. S. Frölich, C. Schubert, U. Bienzle, K. Jenett-Siems, J. Antimicrob. Chemother.

55, 883e887 (2005).

96. J. Dominguez, J. Charris, G. Lobo, N. G. Dominguez, M. M. Moreno, F.

Riggione, E.Sanchez, J. Olson, P. J. Rosenthal. Eur. J. Med. Chem. 36, 555565ـ

(2001).

97. S. S. Lim, H. S. Kim, and D. U. Lee. Bull. Korean Chem. Soc. 28, No. 12, 2495

(2007).

98. Z. Nowakowska. Eur. J. Med. Chem. 42, 125e137 (2007).

99. K. H. Chikhalia, M. J. Patel, D. B. Vashi, ARKIVOC. 8, 189 (2008) 197ـ.

100. H. Kromann, M. Larsen, T. Boesen, K. Schønning, S.F. Nielsen, Eur. J. Med.

Chem. 39, 993e1000 (2004).

Bibliography

183

101. S.F. Nielsen, M. Larsen, T. Boesen, K. Schønning, H. Kromann, J. Med. Chem.

48, 2667e2677 (2005).

102. T.B. Machado, I.C.R. Leal, R.M. Kuster, A.C.F. Amaral, V. Kokis, M.G. de Silva,

K.R.N. Santos, Phytother. Res. 19, 519e525 (2005).

103. P.D. Bremner, J.J.M. Meyer, Planta Med. 64, 777 (1998).

104. G. Belofsky, D. Percivill, K. Lewis, G.P. Tegos, J. Ekart, J. Nat. Prod. 67,

481e484 (2004).

105. S.F. Nielsen, T. Boesen, M. Larsen, K. Schønning, H. Kromann, Bioorg. Med.

Chem. 12, 3047e3054 (2004).

106. Y.-M. Lin, Y. Zhou, M.T. Flavin, L.-M. Zhou, W. Nie, F.-Ch. Chen, Bioorg. Med.

Chem. 10, 2795e2802 (2002).

107. A.L. Okunade, D. Ch.Hufford, A.L. Clark, D. Lentz, Phytother. Res. 11, 142e144

(1997).

108. K.A. Mustafa, H.G. Kjaergaard, N.B. Perry, R.T. Weavers, Tetrahedron. 59,

6113e6120 (2003).

109. A.S. Joshi, X.-C. Li, A.C. Nimrod, H.N. ElSohly, L.A. Walker, A.M. Clark,

Planta Med. 67, 186e188 (2001).

110. E. I. Crocco, L. M. J. Mimica, L. H. Muramati, C. Garcia, V. M. Souza, L. R. B.

Ruiz,, C. Zaitz, An. Bras. Dermatol. 79, 689 (2004).

111. P. Boeck, P. C. Leal, R. A. Yunes, V. C. Fliho, S. Lopez, M. Sortino, A.

Escalante, R. L. E. Fluran, S. Zacchino, Arch. Pharm. Chem. Life Sci.. 338, 87

(2005).

112. J. R. Dimmock, D. W. Elias, M. A. Beazely, N. M. Kandepu, Curr. Med. Chem. 6,

1125 (1999).

113. K. L. Lahtchev, D. I. Batovska, St. P. Parushev, Bioorg. Med. Chem., 18,135-137

(2007).

114. D. Batovska, St. Parushev, A. Slavova,V. Bankova , I. Tsvetkova, M. Ninova, H.

Najdenski, Euro. J. Med. Chem, 42, 87(2007) 92 ـ.

115. H. Tsuchiya, M. Sato, M. Akagiri, N. Takagi, T. Tanaka, M. Iinuma, Pharmaize

49, 756 (1994).

116. M. Sato, H. Tsuchiya, M. Akagiri, S. Fujiwara, T. Fujii, N. Takagi, N. Matsuura,

M. Iinuma, Lett. Apple. Microbiol. 18, 53 (1994).

117. H. Elsohly, A. Joshi, A. Nimrod, A. Walker, Planta Med. 67, 87 (2001).

118. A. Lopez, D. Ming, G. J. Towers, J. Nat. Prod. 65, 62 (2002).

Bibliography

184

119. S. Lopez, M.V. Castelli, S. Zacchino, J.N. Dominguez, G. Lobo, J. Charris-

Charris, J.C.C. Coetrs, J.C. Ribas, C. Devia, A.M. Rodrigues, R.D. Enriz, Bioorg.

Med. Chem. 9, 1999-2013 (2001).

120. H.N. ElSohly, A.S. Joshi, A.C. Nimrod, L.A. Walker, A.M. Clark, Planta Med.

67, 87-89 (2001).

121. L. Svetaz, A. Tapia, S.N. Lopez, R.L.E. Furlan, E. Petenatti, R. Pioli, G.

Schmeda-Hirschmann, S.A. Zacchino, J. Agric. Food Chem. 52, 3297-3300

(2004).

122. D.S. Bhakuni, R. Chaturvedi, J. Nat. Prod. 47, 585-591 (1984).

123. D.H. Miles, J.M.R. Del Medeiros, V. Chittawong, P.A. Hedin, C. Swithenbank, Z.

Lidert, Phytochemistry 30, 1131-1132 (1991).

124. F. Herencia, M.L. Ferrandiz, A. Ubeda, J.N. Dominguez, J.E. Charris, G.M. Lobo,

M.J. Alcaraz, Bioorg. Med. Chem. Lett. 8, 1169-1174 (1998).

125. F. Herencia, M.L. Ferrandiz, A. Ubeda, I. Guillen, J.N. Dominguez, J.E. Charris,

G.M. Lobo, M.J. Alcaraz, Free Radic. Biol. Med. 30, 43-50 (2001).

126. F. Herencia, M.L. Ferrandiz, A. Ubeda, I. Guillen, J.N. Dominguez, J.E. Charris,

G.M. Lobo, M.J. Alcaraz, FEBS Lett. 453, 129-134 (1999).

127. F. Herencia, M.P. Lopez-Garcia, A. Ubeda, M.L. Ferrandiz, Nitric Oxide. 6, 242-

246 (2002).

128. J. Rojas, J.N. Dominguez, J.E. Charris, G.M. Lobo, M. Paya, M.L. Ferrandiz, Eur.

J. Med. Chem. 37, 699-705 (2002).

129. J. Rojas, M. Paya, J.N. Dominguez, M.L. Ferrandiz, Eur. J. Pharm. 465, 183-189

(2003).

130. Daikonya, S. Katsuki, S. Kitanaka, Chem. Pharm. Bull. 52, 1326-1329 (2004).

131. F. Zhao, H. Nozawa, A. Daikonnya, K. Kondo, S. Kitanaka, Biol. Pharm. Bull.

26, 61-65 (2003).

132. B. Madan, S. Batra, B. Ghosh, Mol. Pharmacol. 58, 526-534 (2000).

133. S.-J. Won, C.-T. Liu, L.-T. Tsao, J.-R. Weng, H.-H. Ko, J.-P. Wang, C. - N. Lin,

Eur. J. Med. Chem. 40, 103-112 (2005).

134. H.-K. Hsieh, L.-T. Tsao, J.-P. Wang, C.-N. Lin, J. Pharm. Pharmacol. 52, 163-

171 (2000).

135. M.-I. Chung, J.-R.Weng, J.-P. Wang, C.-M. Teng, C.-N. Lin, Planta Med. 68, 25-

29 (2002).

Bibliography

185

136. H.-K. Hsieh, T.-H. Lee, J.-P. Wang, J.-J. Wang, Ch.-N. Lin, Pharm. Res. 15, 39-

46 (1998).

137. M. M. Iwu, J. E. Jackson and B. G. Schuster, Parasitol. Today, 1994, 10, 65.

138. J. D. Berman and L. S. Lee, Am. J. Trop. Med. Hyg., 32, 947, (1983).

139. O. Kayser, A. F. Kiderlen, Phytother. Res. 15, 148 (2001) 152 ـ.

140. A. Hermoso, I. A. Jimenez, Z. A. Mamani, I. L. Bazzocchi, J. E. Pineiro, A. G.

Ravelo, B. Valladares, Bioorg. Med. Chem. Lett. 11, 3975 (2003) 3980 ـ.

141. Lunardi, F. G. M., Rodrigues, A. T., Correa, R., Eger-Mangrich, I., Stendel, M.,

Grisard, E. C., Assevery, J., Calixto, J. B., Santos, A. R. S. Antimicrob. Agents

Chemother. 47, 1449-1451 (2003).

142. Chen, M.; Christensen, S. B.; Blom, J.; Lemmich, E.; Nadelmann, L.; Fich, K.;

Theander, T. G.; Kharazmi, Antimicrob. Agents Chemother. 37, 2550-2556

(1993)

143. Chen, M., Zhai, L., Christensen, S. B., Theander, T. G., Kharazmi, A. Antimicrob.

Agents Chemother. 45, 2023(2001) 2029ـ.

144. M. Chen, S. B. Christensen, T. G. Theander, A. Kharazmi, Antimicrob. Agents

Chemother. 38, 1339(1994) 1344ـ.

145. Nielsen, S.F., Chen, M., Theander, T.G., Kharazmi, A., Christensen, S.B. Bioorg.

Med. Chem. Lett. 5, 449-452 (1995).

146. Zhai, L., Chen, M., Blom, J., Theander, T. G., Christensen, S. B., Kharazmi, A. J.

Antimicrob. Chemother. 43, 793-803 (1999).

147. Torres-Santos, E.C., Moreira, D.L., Kaplan, M. A. C., Meirelles, M. N., Rossi-

Bergmann, B. Antimicrob. Agents Chemother. 43, 1234-1241 (1999).

148. Narender, T., Shweta, Gupta, S. Bioorg. Med. Chem. Lett. 14, 3913-3916 (2004).

149. Kayser., Kiderlen, A. F., Felbens, L., Kalodzvaj, H. Planta Med. 65, 316 (1998).

150. Hermoso, A., Jimenez, I. A., Mamani, Z. A., Bazzocchi, I. L., Pinero, J. E.,

Ravelo, A. G., Valladares, B. Bioorg. Med. Chem. 11, 3975-3980 (2003).

151. Nielsen, S. F., Kharazmi, A., Christensen S. B. Bioorg. Med. Chem. 6, 937-945

(1998).

152. Onyilagha, J. C., Malhotra, B., Elder, M., French, Ch.J., Towers, G.H.N. Can. J.

Plant. Pathol. 19, 133-137 (1997).

153. Malhotra, B., Onyilagha, J. C., Bohm, B. A., Towers, G. H. N., James, D.,

Harborne, J. B., French, C. J. Phytochemistry 43, 1271-1276 (1996).

154. Wang, Q., Ding, Z. H., Liu, J. K., Zheng, Y. T. Antiviral Res. 64 189-194 (2004).

Bibliography

186

155. Wu, J. H., Wang, X. H., Yi, Y. H., Lee, K. H. Bioorg. Med. Chem. Lett. 13, 1813-

1815 (2003).

156. Xu, H. X. Wan, M., Dong, H., But, P., Foo, L.Y. Biol. Pharm. Bull. 23, 1072-

1076 (2000).

157. Uchiumi, F., Hatano, T., Ito, H., Yoshida, T., Tanuma, S. Antiviral Res. 58, 89-98

(2003).

158. Tewtrakul, S., Subhadhirasakul, J., Puripattanavong, T., Panphadung,

Songklanakarin J. Sci. Technol. 25, 503-508 (2003).

159. Tewtrakul, S., Subhadhirasakul, S., Kummee, S., Songklanakarin J. Sci. Technol.

25, 239-243 (2003).

160. Cheenpracha, S., Karalai, Ch., Ponglimanont, Ch., Subhadhirasakul, S.,

Tewtrakul, S. Bioorg. Med. Chem. 14, 1710-1714 (2006).

161. Shaharyar, M., Siddiqui, A. A., Ali, M. A. J. Serb. Chem. Soc. 72 , 5-11 (2007).

162. Crabb, C. Bull. World Health Organ. 80, 517 (2002).

163. Bussieras, J., Dams, R., Euze¬by, J. Bull.Soc. Sci. Vet. Lyon. 63 (1961).

164. Krieger, J. N., Dickins, C. S., Rein, M. F. Antimicrobial Agents Chemother. 27

(1985)

165. Oyedapo, A. O., Makanju, V. O., Adewunmi, C. O., Iwalewa, E. O., Adenowo, T.

K. Afr. J. Trad. CAM. 1, 55-62 (2004).

166. Mahal, H. S., Rai, H. S., Venkataraman, K. J. Chem. Soc., 866 (1935).

167. Mahal, H. S., Rai, H. S., Venkataraman, K. J. Chem. Soc., 596 (1936).

168. Chakarvarti, D., Dutta, J. J. Chem. Soc., 16, 639 (1936).

169. McKillop, A., Swann, B. P., Taylor, E. C. Tetrahedron letters, 5281 (1970).

170. McKillop, A., Swann, B. P., Ford, M. E., Taylor, E. C. J. Chem. Soc. 95, 3641

(1973).

171. Iqbal, K., Jackson, W. R. J. Chem. Soc. 95, 3641 (1973).

172. Kametani, T., Nomura, Y., J. Pharm. Soc. Japan. 74, 1037 (1954); Chem. Abstr.

49, 11594b (1955).

173. Frederick, J., Dippy, J., Lewis, R. L. Rec. Trav. Chim. 56, 1000 (1937); Chem.

Abstr. 32, 521 (1938).

174. Russell, A. J. Chem. Soc. 218 (1934).

175. Ceylan, M., Gezegen, H. Turk. J. Chem. 32, 55-61 (2008).

176. Song, Q. B., Yang, S. D., Shen, T. H., Wang, Y. Q., Xiang, Y., Wu, X. L. Chinese

Chem. Lett. 14, 569-571 (2003).

Bibliography

187

177. Varga, L., Nagy, T., Kovesdi, I., Benet-Buchholz, J., Dorman, G., Urge, L.,

Darvas, F. Tetrahedron. 59, 655-662 (2003).

178. Levai, A. ARKIVOC. 9, 344-352 (2005).

179. Kidwai, M., Kukreja, S., Thakur, R. Lett. Organic Chem. 3, 135-139 (2006).

180. Gabriel, J., Sagrera, A., Gustavo, A., Seoane. J. Braz. Chem. Soc. 16, 851-856

(2005).

181. Mamolo, G. M., Zampieri, D., Falagiani, V., Vio, L., Banfi, E. Il Farmaco.

58, 315-322 (2003).

182. Yousaf, M., Khan, R. A., Ahmed, B. Bioorg. Med. Chem. 16, 8029-8034 (2008).

183. Agarwal A., Srivastava K., Puri S.K., Chauhan P.M.S. Bioorg. Med. Chem. Lett.

15, 1881-1883 (2005).

184. Zhang, Z., Dong, W. Y., Wang, G. W., Komatsu, K. SYNLET. 1, 0061-0064 (2003).

185. Ozdemir, Z., Kandilci, H. B., Gumusel, B., Calis, U., Bilgin, A. Euro. J. Med.

Chem. 42, 373-379 (2007).

186. Qi, S., Shi, K., Gao, H., Liu, Q., Wang, H. Molecules. 12, 988-996 (2007).

187. Parkash, O., Kumar, R., Sehrawat, R. Euro. J. Med. Chem. 44, 1736-1767 (2009).

188. Mamolo, M. G., Zampieri, D., Falagiani, V., Vio, L., Banfi, Elena. II Farmaco.

56, 593-599 (2001).

189. Tai Li, J., Zhang, X. H., Lin, Z. P. Beilstein J. Org. Chem. 3, 13 (2007).

190. Mamolo, M. G., Falagiani, V., Vio, L., Banfi, Elena. II Farmaco. 54, 761-767

(1999).

191. Insuasty, B., Orozco, F., Quiroga, J., Abonia, R., Nogueras, M., Cobo, J. Euro. J.

Med. Chem. 43, 1955-1962 (2008).

192. Trivedi, J. C., Bariwal. J. P., Upadhyay, K. D., Naliapara, Y. T., Joshi, S. K.,

Pannecouque, C. C., Clercq, E. D., Shah, A. K. Tetrahedron Letters. 48, 8472-

8474 (2007).

193. Pomerantseva, L. L., Smirnova, G. A., Oleinik, A. V. Tr. Khim. Khim. Teknol. 1,

14 (1972); Chem. Abstr. 78, 159099 (1973).

194. Reddy G. V., Maitraie, D., Narsaiah, B., Rambabu, Y., Rao, P. S. Synth. Commun.

31(18), 2881-2884 (2001).

195. Li, J. T., Yang, W. Z., Wang S. X., Li, S. H., Li, T. S. Ultrason. Sonochem. 9,

237-239 (2002).

196. Kantam, L. M., Prakash, B. V., Reddy, V. C. Synth. Commun. 35, 1971-1978

(2005).

http://www.sciencedirect.com/science/journal/0960894X

Bibliography

188

197. Basaif, S. A., Sobahi, T. R., Khalil, A. K., Hassan, M. A. Bull. Korean. Chem.

Soc. 26, 1677 (2005).

198. Ballesteros J. F., Sanz M. J., Ubeda A., Miranda M. A., Iborra S., Paya M.,

Alcaraz M., J. Med. Chem. 38, 2794-2797 (1995)

199. Nowakowska Z. Eur. J. Med. Chem. 42, 125-137 (2007)

200. Mukherjee S., Kumar V., Prasad A. K., Raj H. G., Brakhe M. E., Olsen C. E., Jain

S. C., Parmar V. P., Bioorg. Med. Chem. 9, 337-339 (2001)

201. Wu X., Wilairat P., Go M., Bioorg. Med. Chem. Lett. 12, 2299-2302 (2002)

202. Sivakumar P. M., Geetha, Babu S. K., Mukesh D., Chem. Pharm. Bull. 55, 44-49

(2007)

203. Viana G. S., Bandeira M. A., Matos F., J. Phytomedicine 10, 189-195 (2003)

204. Shibata S., Stem. Cells 12, 44-52 (1994)

205. Wattenberg L. W., Coccia J. B., Galbraith A. R., Cancer Lett. 83, 165-169 (1994)

206. Trivedi J. C., Bariwal J. B., Upadhyay K. D., Naliapara Y. T., Joshi S. K.,

Pannecouque C. C., Clercq E. D., Shah A. K., Tetrahedron Lett. 48, 8472-8474

(2007)

207. Wu J. H., Wang X. H., Yi Y. H., Lee K. H., Bioorg. Med. Chem. Lett. 13, 1813-

1815 (2003)

208. Boeck P., Falcão C. A. B., Leal P. C., Yunes R. A., Filho V. C., Santos E. C. T.,

Bergmann B. R. Bioorg. Med. Chem. 14, 1538-1545 (2006)

209. Konturek S. J., Mrzozowski T., Drozdowicz D., Pawlik W., Sendur R.,

Hepatogastroenterology 34, 164–70 (1987).

210. Kyogoku K., Hatayama K., Yokamori S., Seki T., Tanaka I., Agric. Biolo. Chem.,

39, 133-138, (1975)

211. Meth-Cohn O., Narine B., Tetrahedron Lett. 23, 2045-2048 (1978)

212. Michael J. P., Nat. Prod. Rep. 476-493 (2003)

213. Alhaider A. A., Abdelkader M. A., Lien E. J., J. Med. Chem. 28, 1394–1398

(1985)

214. Campbell S. F., Hardstone J. D., Palmer M. J., J. Med. Chem. 31, 1031-1035

(1988)

215. Du, W., Tetrahedron 59, 8649-8687 (2003)

216. Awad I. M. A., Abdel-Rehman A. E., Bakhite E. A., Collect. Czech. Chem.

Commun. 56, 1749-1760 (1991)

217. Ginsburg H., Ward S. A., Bray P. G., Parasitol. Today 15, 357-360 (1999)

http://www.journalarchive.jst.go.jp/english/jnlabstract_en.php?cdjournal=bbb1961&cdvol=39&noissue=1&startpage=133

http://www.journalarchive.jst.go.jp/english/jnlabstract_en.php?cdjournal=bbb1961&cdvol=39&noissue=1&startpage=133

Bibliography

189

218. Althuis T. H., Khadin S. B., Czuba L. J., Moore P. F., Hess H. J., J. Med. Chem.

23, 262-269 (1980)

219. Dillard R. D., Pavey D. E., Benslay D. N., J. Med. Chem. 16, 251-253 (1973)

220. Manske R. H. F., Kulka M., Org. Reactions 7, 59-98 (1953)

221. Singh S. P., Parmar S. S., Stenberg V. I., J. Het. Chem. 15, 9-11 (1978)

222. Loaiza P. R., Quintero A., Rodríguez-Sotres R., Solano J. D., Rocha A. L., Eur. J.

Med. Chem. 39, 5-10 (2004)

223. Medower C., Wen L., Johnson W. W., Chem. Res. Toxicol., 21, 1570–1577 (2008)

224. Meth-Cohn O., Heterocycles 35, 539-557 (1993)

225. Domínguez J. N., Charris J. E., Lobo G., Domínguez N. G., Moreno M. M.,

Riggione F., Sanchez E., Olson J., Rosenthal P. J., Eur. J. Med. Chem., 36, 555-

560 (2001).

226. Kimpe N. D., Mark B., Jan C., Tetrahedron Lett., 37, 3171 (1996)

227. Rubiralta M., Giralt E., Diez A., Piperidine: Structure, Preparation, Reactivity,

and Synthetic Applications of Piperidine and its Derivatives (Studies in Organic

Chemistry); Elsevier: New York, Vol. 43, Chapter 1 (1991)

228. Henry, The Plant Alkaloids, 4th

Ed., Blakiston Co., Philadelphia, (1949)

229. Dang Z., Yang Y., Ji R., Zhang S., Bioorg. Med. Chem. Lett. 17, 4523-4526

(2007)

230. Jaiprakash N., Sangshetti, Devanand B., Shinde, Eur. J.Med. Chem., 46, 1040-

1044 (2011)

231. Padmanilayam M., Scorneaux B., Dong Y., Chollet J., Matile H., Charman S. A.,

Creek D. J., Charman W. N., Tomas J. S., Scheurer C., Wittlin S., Brun R.,

Vennerstrom J. L., Bioorg. Med. Chem. Lett. 16, 5542-5546 (2006)

232. Shapiro A. B., Lebedeva L. P., Suskina V. I., Antipina G. N., Smirnov L. N.,

Levin P. I., Rozantsev E. G., Polymer Science U.S.S.R. 15, 3034-3043 (1973)

233. Hendry L. B., Chu C. K., Copland J. A., Mahesh V. B., J. Steroid. Biochem Mol.

Biol. 48, 495-505 (1994)

234. Balsamo A., Giorgi I., Lapucci A., Lucacchini A., Macchia B., Macchia F.,

Martini C., Rossi A., J. Med. Chem., 30, 222–225 (1987)

235. Henderson N. D., Plumb J. A., Robins D. J., Workman P. Anticancer Drug Des.

1996 Sep;11, 421-438 (1996).

236. Alexidis A. N., Commandeur J. N. M., Rekka E. A., Groot E., Kourounakis P. N.,

Vermeulen N. P. E., Environ. Toxicol. Pharmacol. 1, 81-88 (1996)

http://www.amazon.com/Piperidine-Preparation-Reactivity-Applications-Derivatives/dp/0444883487/ref=sr_1_1?s=books&ie=UTF8&qid=1309530353&sr=1-1




http://www.sciencedirect.com/science/journal/0960894X

http://www.sciencedirect.com/science/journal/00323950

http://www.sciencedirect.com/science?_ob=PublicationURL&_tockey=%23TOC%2312965%231973%23999849987%23429127%23FLP%23&_cdi=12965&_pubType=J&view=c&_auth=y&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=21bf08380f3e0a0bbafdabbb1ab9eed7

http://www.ncbi.nlm.nih.gov/pubmed?term=%22Henderson%20ND%22%5BAuthor%5D

http://www.ncbi.nlm.nih.gov/pubmed?term=%22Plumb%20JA%22%5BAuthor%5D

http://www.ncbi.nlm.nih.gov/pubmed?term=%22Robins%20DJ%22%5BAuthor%5D

http://www.ncbi.nlm.nih.gov/pubmed?term=%22Workman%20P%22%5BAuthor%5D

http://www.ncbi.nlm.nih.gov/pubmed/8836108

Bibliography

190

237. Nagararjan, Neuropharmacology. 41, 650 (2001)

238. Lipina T., Weiss K., Roder J., Neuropsychopharmacology 32, 745–56 (2007).

239. Fuller L. S., Pratt J. W., Yates F. S., Manufactur. Chem. Aerosol News, 49, 67

(1978).

240. El-Maghraby A. A., Mohamed N. A., J. Chem. Technol. Biotechnol. 33, 25-32

(1983)

241. El-Essawy F. A., Hawatta M. A., Abdel-Megied A. E.-S., El-Sherbeny D. A.,

Chem. Heterocycl. Compd., 46, 325-333 (2010)

242. Isloor A. M., Kalluraya B., Sridhar P. K., Eur. J. Med. Chem. 45, 825-830 (2009)

243. Gogte V. N., Shah L. G., Tilak B. D., Gadekar K. N., Sahasrabudhe M. B.,

Tetrahedron, 23, 2437-2441 (1967)

244. Valderrama J. A., Espinoza O., Rodriguez J., Theoduloz C., Lett. Org. Chem., 6,

278-281 (2009)

245. Bourquin J. P., Schwarb G., Waldvogel E., Ger. Pat. 2,111,071 (1971).

246. Gymer G. E., U.S. Pat. 4,062,966 (1977)

247. Hromatka O., Ger. Pat. 2,537,070 (1976),

248. Nauduri D., Reddy G. B., Chem. Pharm. Bull. Tokyo 46, 1254-1260 (1998)

249. Azarifar D., Shaebanzadeh M., Molecules 7, 885-895 (2002)

250. Bilgin A. A., Palaska E., Sunal R., Arzneimforsch. Drug Res. 43, 1041-1044

(1993)

251. Taylor E. C., Patel H. H., Tetrahedron 48,8089-8100 (1992)

252. Ramalingham K., Thyvekikakath G. X., Berlin K. D., Chesnut R. W., Brown R.

A., Durham N. N., Ealick S. E., Van der Helm D., J. Med. Chem. 20, 847-850

(1977)

253. Barsoum F. F., Hosni H. M., Girgis A. S., Bioorg. Med. Chem. 14, 3929-3937

(2006)

254. Mishriky N., Asaad F. M., Ibrahim Y. A., Girgis A. S. Pharmazie., 51, 544-548

(1996)

255. Budakoti A., Abid M., Azam A., Eur. J. Med. Chem. 41, 63-70 (2006)

256. Ozdemir Z., Kandilici H. B., Gumusel B., Calis U., Bilgin A. A., Eur. J. Med.

Chem. 42, 373-379 (2007)

257. Rezende R. M., Paiva-Lima P., Reis W. G. P. D., Camêlo V. M., Bakhle Y. S., de

Francischi J. N., Neuropharmacology 59, 551-557 (2010)

258. Casavant M. J., Pediatrics, 107, 170 (2001).

http://onlinelibrary.wiley.com/doi/10.1002/jctb.v33:1.chem/issuetoc

http://www.ncbi.nlm.nih.gov/pubmed?term=%22Isloor%20AM%22%5BAuthor%5D

http://www.ncbi.nlm.nih.gov/pubmed?term=%22Kalluraya%20B%22%5BAuthor%5D

http://www.ncbi.nlm.nih.gov/pubmed?term=%22Sridhar%20Pai%20K%22%5BAuthor%5D



http://onlinelibrary.wiley.com/doi/10.1002/chin.v40:47/issuetoc

http://onlinelibrary.wiley.com/doi/10.1002/chin.v40:47/issuetoc

http://www.ncbi.nlm.nih.gov/pubmed?term=%22Mishriky%20N%22%5BAuthor%5D

http://www.ncbi.nlm.nih.gov/pubmed?term=%22Asaad%20FM%22%5BAuthor%5D

http://www.ncbi.nlm.nih.gov/pubmed?term=%22Ibrahim%20YA%22%5BAuthor%5D

http://www.ncbi.nlm.nih.gov/pubmed?term=%22Girgis%20AS%22%5BAuthor%5D



Bibliography

191

259. Lévai A., ARKIVOC 9, 344-352 (2005)

260. Munawar, M.A., Azad, M., Ashraf, S. Khan, M.A. J. Sci. Res., 34, 29-32, (2005).

261. Meth-Cohn, O., Narine, B., Tarnowski, B. J. Chem. Soc. Perkin Trans. I, 1520

(1981).

262. Hussain. T., Siddiqui, H. L., Zia-ur-Rehman, M., Yasinzai, M. M., Parvez, M.

Eur. J. Med. Chem., 44(11), 4654-4660 (2009).

263. Lévai, A. Heterocycl. Commun. 9, 287 (2003).

264. Sandane, A. R., Rudresh, K., Satyanarayan, N. D., Hiremath, S. P., Indian J.

Pharm. Sci. 60, 379-383 (1998).

265. Ali, S. A.; Iqbal, J.; Yasinzai, M. M. Methods in Cell Science. 19, 107 (1997).

266. Schinazi, R. F., Cannon D. L., Arnold B. H., Martino-Saltzman D., Antimicrob.

Agents Chemother. 32, 1784-1787 (1988).

267. Spira, T. J., Bozeman L. H., Holman R. C., Warfield D. T., Phillips S. K., Feorino

P. M., J. Clin. Microbiol. 25, 97-99 (1987).

268. Schinazi, R. F., Peters J., Williams C. C., Chance D., Nahmias A. J. Antimicrob.

Agents Chemother. 22, 499-507 (1982).

269. Sommadossi, J.-P., Carlisle R., Schinazi R. F., Zhou Z. Antimicrob. Agents

Chemother. 32, 997-1001 (1988)

270. Stuyver, L. J., Lostia, S., Adams, M., Mathew, S. J., Pai, S. B. Grier, J.,

Tharnish, M. P. Choi, Y., Chong, Y., Choo, H., Chu, K. C. Otto, J. M.,

Schinazi1, F. R. Antimicrobial agents. Chemother. 3854–3860 (2002).

271. Balzarini, J., Pharm. World Sci., 16, 113-126 (1994)

272. Chou, J., and T.-C. Chou. (1985). Dose-effect analysis with microcomputers:

quantitation of ED50, LD50, synergism, antagonism, low-dose risk, receptor

binding and enzyme kinetics. A computer software for Apple II Series and IBM-

PC and instruction manual. Elsevier-Biosoft, Elsevier Science Publishers,

Cambridge.

273. Schinazi, R. F., Chou T.-C., Scott R. T., Yao X., Nahmias A. J. Antimicrob.

Agents Chemother. 30,491-498 (1986)

274. Otwinowski Z., Minor W., Methods Enzymol. 276, 307-26 (1997).

275. Hooft R., COLLECT. Nonius BV, Delft. The Netherlands, (1998).

276. Altomare A., Cascarano M., Giacovazzo C., Guagliardi A. SIR92. J. Appl. Cryst.

26, 343-350 (1993).

Bibliography

192

277. Beurskens P. T., Admiraal G., Beurskens G., Bosman W. P., de Gelder R., Israel

R., Smits J. M. M. The DIRDIF-94 program system, Technical Report of the

Crystallography Laboratory, University of Nijmegen, The Netherlands (1994).

278. Sheldrick G. M. Acta Cryst. 64, 112-122 (2008).

279. Farrugia L. J., J. Appl. Cryst. 30, 565 (1997).

280. Rizvi, U. F., Siddiqui, H. L., Ahmad, S., Ahmad, M., Parvez, M. Acta Crystallogr.

Sect. C., 64, 547 (2008).

281. Rizvi S. U. F., Siddiqui H. L., Zia-ur-Rehman M., Azam M., Parvez M., Acta

Crystallogr. Sect. E, 66, 761. (2010).

282. Rizvi S. U. F., Siddiqui H. L., Hussain T., Azam M., Parvez M., Acta Crystallogr.

Sect. E, 66, 744 (2010).

List of Publications

193

LIST OF PUBLICATIONS FROM THIS THESIS

1. Novel chalcones derived from 2-chloro-3-formyl-6-methylquinoline Umar Farooq Rizvi, Hamid Latif Siddiqui, Saeed Ahmad, Masood Parvez,

Acta Crystallogr. C, 64, 547 (2008).

2. Antimicrobial and Antileishmanial Studies of Novel (2E)-3-(2-Chloro-6-

methyl/methoxyquinolin-3-yl)-1-(Aryl)prop-2-en-1-ones

Syed Umar Farooq Rizvi, Hamid Latif Siddiqui, Masood Parvez, Matloob

Ahmad, Waseeq Ahmad Siddiqui Chem. Pharm. Bull. 58(3) 301—306 (2010)

3. (2E)-3-(2-Chloro-6-methyl-3-quinolyl)-1-(1-naphthyl)prop-2-en-1-one

Syed Umar Farooq Rizvi, Hamid Latif Siddiqui, Muhammad Zia-ur-

Rehman, Muhammad Azam and Masood Parvez, Acta Crystallogr. E, 66, 761

(2010).

4. (E)-3-(2-Chloro-6-methyl-3-quinolyl)-1-(2,3-dihydro-1,4-benzodioxin-6-

yl)prop-2-en-1-one

Syed Umar Farooq Rizvi, Hamid Latif Siddiqui, Tanvir Hussain,

Muhammad Azam and Masood Parvez, Acta Crystallogr. E, 66, 744 (2010).

5. Novel quinolyl-thienyl chalcones and their 2-pyrazoline derivatives with

diverse substitution pattern as antileishmanial agents against Leishmania

major Syed Umar Farooq Rizvi, Hamid Latif Siddiqui, Muhammad Nisar Ahmad,

Matloob Ahmad, Mujahid Hussain Bukhari Med. Chem Res. (Accepted and

Online published on 12th

April, 2011).

6. Anti-HIV-1 and Cytotoxicity Studies of Piperidyl-Thienyl Chalcones and

their 2-Pyrazoline Derivatives Syed Umar Farooq Rizvi, Hamid Latif Siddiqui, Melissa Johns, Mervi

Detorio, Raymond F. Schinazi, Med. Chem Res. (Submitted, May 2011).

prr.hec.gov.pkprr.hec.gov.pk/jspui/bitstream/123456789/668/2/1039s.pdfii declaration i hereby...

Documents