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Ugwoke Oluchi C.

(HETEROARYL

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Ugwoke Oluchi C.

FACULTY OF PHSCIAL SCIENCES

DEPARTMENT OF PURE AND INDUSTRIAL CHEMISTRY

SYNTHESIS AND ANTIMICROBIAL ACTIVITIES OF

(HETEROARYL- SUBSTITUTED)–P-TOLUENESULPHONAMIDES.

OZOH CHINWE FRANCISCA

PG/M.Sc/11/59538

1

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bmaster’s name

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YNTHESIS AND ANTIMICROBIAL ACTIVITIES OF N-

TOLUENESULPHONAMIDES.

2

TITLE PAGE

UNIVERSITY OF NIGERIA, NSUKKA

FACULTY OF PHSCIAL SCIENCES


CHM 592, RESEARCH (PROJECT).

SYNTHESIS AND ANTIMICROBIAL ACTIVITIES OFN-(HETEROARYL-

SUBSTITUTED)–P-TOLUENESULPHONAMIDES.

A RESEARCH PROJECT SUBMITTED IN PARTIAL FULFILMENT OF THE

REQIREMENT FOR THE AWARD OF MASTER OF SCIENCE (M.Sc) DEGREE.

INORGANIC CHEMISTRY

BY

OZOH CHINWE FRANCISCA

PG/M.Sc/11/59538

PROJECT SUPERVISOR: PROF. U. C. OKORO.

3

APPROVAL PAGE

This work has been approved by the Department of Pure and Industrial Chemistry, University of

Nigeria, Nsukka.

__________________ ___________________

PROF. U. C. OKOROPROF. P. O. UKOHA

Project Supervisor Head of Department

Date____________ Date______________

4

CERTIFICATION

This is to certify that the research work tittled “Synthesis and Antimicrobial activities of N-

(heteroaryl-substituted)-p–toluenesulphonamides” was carried out by OZOH CHINWE

F.(PG/M.Sc/11/59538) and has been approved by the under signed as having met the standard of

the Department of Pure and Industrial Chemistry, University of Nigeria Nsukka, submitted in

partial fulfillment of the requirements for the award of M.Sc degree in Organic Chemistry.

_______________________ _________________________

PROF. U. C. OKOROPROF. P. O. UKOHA

Prof. Supervisor Head of Department

Date______________ Date___________

5

DEDICATION

I dedicate this work to God the Father, Son and the Holy Spirit, my source of life and strength.

6

ACKNOWLEDGEMENT

My sincere gratitude goes to all the faculty members of Pure and Industrial Chemistry

Department, University of Nigeria, Nsukka. I am grateful to Professor P.O. Ukoha, Head of

Department, for providing me the facilities to carry out this work.

I am exceedingly delighted in expressing my most sincere gratitude to my respected

supervisor, teacher and guide, Professor U. C. Okoro. Throughout my research period, I received

from him constant guidance, valuable suggestions, tremendous skills and creative ideas

whenever needed. Without his loving care and priceless supervision, it could have been very

difficult for me to complete this work. For this, I will ever remain thankful to him. I am also

thankful to Professor C. O. Okafor for his advice whenever needed.

My profound gratitude goes to my parents, Mr. and Mrs. Pius ObiorahOzoh, my siblings,

Amaka, Ijeoma, Edozie and Chizoba for their great encouragement and support. I want to thank

specially my friend, Ernest for his love and care. I will never forget to appreciate my

coursemates, Thompson, Ogechi, Chinelo, David and Nonye for being there for me. May God

see us through in our project work. I also want to thank my roommates and friends, Martina,

Chizzy, Adaora, Ben and Oge for their great encouragement. I will never forget to appreciate

Catholic Association of Post-graduate Student family for their prayers and supports. May God

almighty rewards you all.

7

ABSTRACT

Sulphonamides are known to represent a class of medicinally important compounds which are

extensively used as antimicrobial agents. Hence in this present study, a series of new N-

(heteroaryl-substituted)–p-toluenesulphonamides146(a-g) were synthesized by direct

condensation of p-toluenesulphonyl chloride 144 with various readily available amino pyridines

145(a-g). The chemical structures of the products were confirmed using spectroscopic methods

which include Fourier Transform–Infrared (FT-IR) spectroscopy, proton and carbon-13 Nuclear

Magnetic Resonance (1H and

13C- NMR) spectroscopy. The antimicrobial properties of the

synthesized sulphonamides were determined on Bacillus subtilis, Bacillus cereus,

Staphylococcus aureus, Peudomonasaeruginosa, Escherichia coli, Klebsiellapneumoniae,

Candida albicans and Asperigellusniger using agar-diffusion method. Results indicated

improved biological activities over reference drugs such as Tetracycline and Fluconazole.

8

TABLE OF CONTENT

TITLE PAGE-----------------------------------------------------------------------------------------------i

APPROVAL PAGE---------------------------------------------------------------------------------------ii

CERTIFICATION-----------------------------------------------------------------------------------------iii

DEDICATION---------------------------------------------------------------------------------------------iv

ACKNOWLEDGEMENT---------------------------------------------------------------------------------v

ABSTRACT------------------------------------------------------------------------------------------------vi

TABLE OF CONTENT-------------------------------------------------------------------------------vii-ix

LIST OF ABBREVIATIONS--------------------------------------------------------------------------x-xi

LIST OF TABLES-----------------------------------------------------------------------------------------xii

LIST OF FIGURES---------------------------------------------------------------------------------------xiii

CHAPTER ONE--------------------------------------------------------------------------------------------1

1.0Introduction------------------------------------------------------------------------------------1-2

1.1 Background of the Study--------------------------------------------------------------------2-7

1.2 Statement of the Problem---------------------------------------------------------------------7

1.3 Objective of the Study-------------------------------------------------------------------------7

1.4 Justification of Study---------------------------------------------------------------------------8

CHAPTER TWO--------------------------------------------------------------------------------------------9

2.0Literature Review--------------------------------------------------------------------------------9

2.1 Synthesis of Sulphonamides as Antibacterial and Antifungal Agents----------------9-13

9

2.1.2 Synthesis of Sulphonamides as Antimalarial Agents-------------------------------14-15

2.1.3 Synthesis of Sulphonamides as an Antioxidant Agent------------------------------15-16

2.1.4 Synthesis of Sulphonamides as Anticancer and Antitumor Agents--------------16-17

2.1.5 Synthesis of sulphonamides as Anti-inflammatory Agent-------------------------17-18

2.1.6 Synthesis of Sulphonamides as Antiviral and Anti- HIV Agent-----------------18-19

2.1.7 Synthesis of Sulphonamides as Diuretic Agent------------------------------------19-20

2.1.8 Synthesis of Sulphonamides as Analgesic Agent--------------------------------------20

2.1.9 Synthesis of Sulphonamides as Anticonvulsant Agent--------------------------------21

2.1.10 Synthesis of Sulphonamides as Inhibitors of Butyryl Cholinesterase----------21-22

2.2 Applications of Sulphonamides in Synthetic Organic Chemistry-------------------22-23

2.2.1 Miscellaneous Applications of Sulphonamides-------------------------------------24-25

CHAPTER THREE---------------------------------------------------------------------------------------26

3.0 Experimental Section-------------------------------------------------------------------------26

3.1 General------------------------------------------------------------------------------------------26

3.2 General Procedure for Derivatives------------------------------------------------------26-27

3.2.1. 4-Methyl-N-(pyridin-2-yl) benzenesulphonamide-------------------------------------27

3.2.2. 4-Methyl-N-(4-methyl pyridin-2-yl) benzenesulphonamide-------------------------27

3.2.3. 4-Methyl-N-(5-nitro pyridin-2-yl) benzenesulphonamide----------------------------27

3.2.4. 4-Methyl-N-(3-nitro pyridin-2-yl) benzenesulphonamide------------------------27-28

3.2.5. N-(3-Hydroxy pyridin-2-yl)-4–methyl benzenesulphonamide-----------------------28

3.2.6. 4-Methyl–N-(6-methyl pyridin-2-yl) benzenesulphonamide-------------------------28

10

3.2.7. 4-Methyl-N-(pyridin-2-yl) benzenesulphonamide-------------------------------------28

3.3 Antimicrobial Activity--------------------------------------------------------------------28-29

3.3.1 Sensitivity Testing of Compounds-------------------------------------------------------29

3.3.2Minimium Inhibitory Concentration (MIC) Testing of Compounds----------------29

CHAPTER FOUR----------------------------------------------------------------------------------------30

4.0 Results and Discussion-----------------------------------------------------------------------30

4.1 4-Methyl –N-(pyridin-2-yl) benzenesulphonamide146a------------------------------30

4.1.1 4-Methyl–N-(4-methyl pyridin-2-yl) benzenesulphonamide146b--------------30-31

4.1.2 4-Methyl-N-(5–nitro pyridin-2-yl) benzenesulphonamide146c---------------------31

4.1.3 4-Methyl-N-(3–nitro pyridin-2-yl) benzenesulphonamide146d---------------------32

4.1.4 N-(3-Hydroxy pyridin-2-yl)-4-methyl benzenesulphonamide146e--------------32-33

4.1.5 4-Methyl–N-(6-methyl pyridin-2-yl) benzenesulphonamide146f -------------------33

4.1.6 4-Methyl–N-( pyridin-4-yl) benzenesulphonamide 146g--------------------------33-34

4.2. Antimicrobial Activity Evaluation------------------------------------------------------34-35

4.2.1. Results of Sensitivity Testing of Compounds-------------------------------------------35

4.2.2. Results of Inhibition Zone Diameter (IZD)----------------------------------------------36

4.2.3. Results of MIC Testing of Compounds----------------------------------------------36-37

CHAPTER FIVE-------------------------------------------------------------------------------------------38

5.0 Conclusion--------------------------------------------------------------------------------------38

REFERENCES-----------------------------------------------------------------------------------------39-45

11

LIST OF ABBREVIATIONS

AIDS – Acquired Immune Deficiency Syndrome

Ar – Aromatic

Asp.niger – Asperigellusniger

B.cereus – Bacillus cereus

B. subtilis – Bacillus subtilis

C. albicans – Candida albicans

Cat. - Catalysis

13C-NMR – Proton Nuclear Magnetic Resonance

DARA- Dual Action Receptor Antagonist

DMF – N,N- Dimethyl Formamide

DMSO – Dimethyl Sulphoxide

E. coli – Echerichia coli

FT-IR- Fourier Transform-InfraRay

HCV – Hepatitis C Virus

HIV – Human Immunodeficiency Virus

1H-NMR – Proton Nuclear Magnetic Resonance

J – Coupling constant symbol

K. pneumonia – Klebsiella pneumonia

12

MIC – Minimium Inhibitory Concentration

MOTA- MesoionicOxatriazoles

NO- Nitric Oxide

P. aeruginosa – Pseudomonas aeruginosa

p-TsCl – p-toluenesulphonyl chloride

RT – Room Temperature

S. aureus – Staphylococcus aureus

TEA- Triethyl amine

THF – Tetrahydro furan

Chemical Symbols

cm - centimeter

oC - degree celsius

g -gramme

mg/ml -milligramme per millilitre

mL - milliliter

mmol -millimole

13

LIST OF TABLES

TABLE 1: Results of General Sensitivity Test--------------------------------------------35

TABLE 2: Results of Inhibition Zone Diameter------------------------------------------36

TABLE 3: Results of MIC Test-------------------------------------------------------------36

14

LIST OF FIGURES

Fig 1: IR- Spectral of chart of 4-Methyl-N-(pyridin-2-yl) benzenesulphonamide-----------------46

Fig 2: IR- Spectral of chart of 4-Methyl-N-( 4-methyl-2-pyridinyl) benzenesulphonamide-----47

Fig 3: IR- Spectral of chart of 4-Methyl-N-(5-nitro-2-pyridinyl) benzenesulphonamide---------48

Fig 4: IR- Spectral of chart of 4-Methyl-N-(3-nitro-2-pyridinyl) benzenesulphonamide---------49

Fig 5: IR- Spectral of chart of N-(3-Hydroxy-2-pyridinyl)-4-methyl benzenesulphonamide----50

Fig 6: IR- Spectral of chart of 4-Methyl-N- (6-methyl-2-pyridinyl) benzenesulphonamide-----51

Fig 7: IR- Spectral of chart of 4-Methyl-N-(pyridin-4-yl) benzenesulphonamide-----------------52

Fig 8: 1H-NMR- Spectral of chart of 4-Methyl-N-(pyridin-2-yl) benzenesulphonamide---------53

Fig 9:13

C-NMR- spectral of chart of 4-Methyl-N-(pyridin-2-yl) benzenesulphonamide---------54

Fig 10: 1H-NMR -Spectral of chart of 4-Methyl-N-(4-methyl-2-pyridinyl)

benzenesulphonamide---------------------------------------------------------------------------------------55

Fig 11: 1H-NMR - Spectral of chart of 4-Methyl-N-(5-nitro-2-pyridinyl)


Fig 12: 1H-NMR - Spectral of chart of 4-Methyl-N-(3-nitro-2-pyridinyl)


Fig 13: 1H-NMR - Spectral of chart of N-(3-Hydroxy-2-pyridinyl)-4-methyl


Fig 14:13

C-NMR – Spectral of chart of N-(3-Hydroxy-2-pyridinyl)-4-methyl


Fig 15: 1H-NMR - Spectral of chart of 4-Methyl-N-(6-methyl-2-pyridinyl)


Fig 16: 1H-NMR - Spectral of chart of 4-Methyl-N-(pyridin-4-yl) benzenesulphonamide-------6

15

CHAPTER ONE

1.0 INTRODUCTION

In the olden days, people were suffering from unknown ailments until Louis

Pasteur1discovered that the cause of such illnesses was micro-organisms. Before the discovery of

antibiotics in 1940, sulphonamides were the main compounds used to treat these microbial

infections.

Sulphonamides are the amides of sulphonic acid with the general structure, 1.2

Sulphonamides belong to distinctive class of compounds that constitute at least five different

classes of pharmacologically active agents.2The basic sulphonamide group –SO2NH- occurs in

various biologically active compounds including antimicrobial agents, antimalarial agents,

antithyroid agents, antitumor and inhibitors of carbonic anhydrase.3 They were introduced into

medical practice before the discovery of penicillins. It was discovered that such compounds

could be used for the treatment of infectious diseases. As a result, many workers from various

countries started producing several derivatives of sulphonamide by modifying the substituent on

the benzene ring and also by replacement of the benzene ring with heterocyclic rings.

Furthermore, several derivatives of these compounds were synthesized, characterized and tested

by biologists and found to be useful as antimicrobial agents. They inhibit multiplication of

bacteria. They have been used against most gram-positive and many gram-negative organisms,

fungi and certain protozoa.4Sulphonamides such as mixtures of sulphamethoxazole and

trimethoprim (Septrin) have been used for the treatment of uncomplicated urinary tract

infections5, scabies, worms, wounds, infections of the eye

2, mucous membrane and skin

2 among

others. Some examples are compounds 2-6:6,7

SN R1

O

O

R3

R2

1

Where R1 = Alkyl, phenyl or aryl

R2 = H, alkyl or aryl

R3 = H, alkyl or aryl

16

1.1BACKGROUND OF THE STUDY

At the beginning of 20th

century, Paul Ehrlich8 showed that various azo dyes were

effective against trypanosomiasis in mice; however, none was effective in man. In the early

1930s, Gerhard Domagk9, Head of Bacteriological and Pathological Research at Baeyer

Company in Germany, who was trying to find an agent against Streptococci, tested a variety of

azo dyes. One of the dyes tested, Prontosil7, showed remarkable positive results when tested on

mice against streptococcal infections. Prontosil's discovery ushered in the era of antibacterial

compound and had a profound impact on pharmaceutical research, drug laws, and medical

history.

In the late 1930’s, working at the Pasteur Institute in Paris in the laboratory of Ernest Fourneau,

Jacques and ThérèseTréfouël, Daniel Bovet and Federico Nitti discovered that Prontosil is

metabolized to sulphanilamide (p-aminobenzenesulphonamide)8, a much simpler and colorless

compound, redefining Prontosil7 as a prodrug.10

It was this compound which was the true

H2N

S

O

NH2

O

H2N

S

O

NH

O

N N N N

CH3

H2N

S

O

NH

O

2Sulphanilamide

(Antibacterial Drug)3

Sulphadiazine(Treatment of Cerebral

Meningitis)

4Sulphamerazine

(Treatment of infections)

HNCCH3

O

S

O

O

HN

N

N

CH3

CH3

H2N S

O

O

NH

NN

S CH3

5Sulphamethazine

(Treatment of Pneumococcal, Sepsis and Gonorrhea)

6

Sulphamethizole(Anticancer Drug)

S

O

O

NH2O2N N

NO2

N

7

17

antibacterial agent. Sulphanilamide was then synthesized in the laboratory and became the first

synthetic antibacterial agent active against a wide range of infections.

In 1940, Woods and Fildes11

improved on the hypothesis by extending the theory to include

other sulphonamides which also proved effective against Gram-positive organisms, especially

pneumococci and meningococci. A retrospective look at sulphonamides11

leaves no doubt that

besides providing the first efficient treatment of bacterial infections; they unleashed a revolution

in chemotherapy to rationally design new therapeutic agents11

.Literally, thousands of chemical

variations were played on the sulphanilamide theme. The best therapeutic results were obtained

from compounds in which one hydrogen of the –SO2NH2 group was replaced by some other

groups, usually a heterocyclic ring.11

Till date, more than twenty thousand sulphanilamide

derivatives, analogs and related compounds especially those related to p-aminobenzoic acid,

have been synthesized. Such syntheses have resulted in the discovery of new compounds with

varying pharmacological properties.11

Further structural modifications, have led to many new

types of antibacterial agents (sulphanilamides), Leprostatic agents (sulphones), diuretics

(heterocyclic sulphonamides), hypoglycemic agents (sulphonylureas), antimalarial, antithyroid,

antitumor and antiviral agents.12

Among the most successful modification are a few derivatives

of sulphanilamide presented as compounds 3, 9,10,11 and 12.

S

O

O

NH2O2N N

NO2

N

7

H2N S

O

O

NH2

8

Reductase

18

Structure of Sulphonamide

Sulphonamides or sulpha drugs have the general structure 1. In this structure 1, R may be alkyl,

aromatic or heteroaromatic and R1,R2 may be hydrogen, alkyl, aromatic or heteroaromatic group.

However, sulphanilamide which is the first known compound of this type has the sulphonamide

base structure 13 in which R1 and R4 are hydrogen.13

Till date, about 15,000 sulphonamide

derivatives, analogues and related compounds have been synthesized.13

This has led to the

discovery of many useful drugs which are effective as diuretics, antimalarial, antithyroid agents

and so on. 13

S

NH2

O O

NH2

S

N

O O

NH2

H N

N

NH2

S OO

N

NO CH3

H

S

NH2

O

O

NH

N

S

NH2

S OO

NH N

NN

S SN

H

C

O

ONH2

R

O

2

3

9Sulphamethizole

10Sulphathalidine

11Sulphalidine

12

2-sulphanilamido-pyridine

(Phthalylsulphathiazole)

19

Classification of Sulphonamide

Moreover, various parameters have been used to classify sulphonamides though it does

not currently have a clear classification.14

These parameters include; chemical structure, duration

of action, spectrum of activity and therapeutic application. However they are grouped as

systematic (absorptive action) and local use. The obtainable one is based on therapeutic usage in

terms of the duration of action.15

They are;

1. Short-lasting Sulphonamides: They have been preferred for systemic infections as they

are rapidly absorbed and rapidly excreted.16

They are considered short lasting if the blood

concentration levels remain higher than 50 g/ml for less than 12h after a single

therapeutic dose.17

Example;

Note: Sulpadiazine, sulphamerazine and sulphamethazine used together constitute the triple

sulphonamide preparation for treating urinary tract infections etc.

N S

R4

O

O

N

H R1

H

13

Sulphonamide based structure

N

N NHSO2 NH2

3

NH2

N

N NHSO2

CH3

4

N

NH3C

CH3

NHSO2 NH2

N

N

S S

S

O

O

HO

O

O

OH

OH

O O

5

14Trisulphopyrimidine

20

2. Moderate or Intermediate-Lasting Sulphonamide: They have been used for infections

requiring prolonged treatment. They are considered lasting if the blood plasma

concentration levels remains higher than 50g/ml are obtained between 12 and 24h.17

Example;

Compound 9 in combination with 16 commonly known as septrin18

inhibits

dihydrofolicreductase, the enzyme that converts both folic and dihydrofolic acid to

tetrahydrofolic acid. Consequently, two steps in the biosynthesis of nucleic acids and proteins

(necessary for bacterial survival) are inhibited. They have been used for various infections such

as recurrent urinary tract infections and are especially active against invasive aspergillosis in

AIDS patients. Other examples are; sulphapyridine, sulphadoxine etc.

3. Long-Lasting Sulphonamide: These sulphonamides are rapidly absorbed and slowly

excreted. They are considered long lasting if the blood plasma concentration levels remains

higher than 50g/ml are obtained 24h after dosing.17

Examples are the following:

H2N SO2NH

NO CH3

H2N SO2NH

S

NN

CH3

N

N

H2N

OCH3

OCH3

OCH3

9 15Sulphamethizole

16Trimethoprim

H2N SO2NH H2N SO2NH

N

NCH3ONN

S CH3

H2N SO2NH

N N

OCH3

C

N N

O

OH

SO2NH

N

617

1819

Sulphalene (Kelfizina)

Sulphamethoxy-pyridazineSulphasalazine

21

Compound 17 is used in combination with other drugs for the treatment of patients with resistant

cases of malaria. Compound 19, has been used for the treatment of ulceration colitis. Compound

6 is used as an anticancer drug.18

Other examples are sulphadoxine, sulphadimetopyrazine etc.

4. Poorly Absorbed Sulphonamides: Some sulphonamides are poorly absorbed from the

gastrointestinal tract. Therefore this group is employed presurgically for patients undergoing

intestinal surgery to diminish the bacterial count.17

Examples are compounds 22 and 23.

1.2 STATEMENT OF THE PROBLEM

Although many sulphonamides have being prepared, tested and found active, further

modifications of these structures are still necessary. The sulphonamides thus produced by these

modifications may prove to be more active and hence useful as antimicrobial agents.

1.3 OBJECTIVE OF THE STUDY

The specific objectives of this research work were to:

i. Synthesize some new sulphonamides with different substituents on the aromatic ring.

ii. Synthesize some new sulphonamides with different substituents on the amino group.

iii. Characterize them using spectrophotometric methods, namely, FT-IR, 1H-NMR,and

13C-NMR spectroscopy.

iv. Carry out biological evaluation of their antimicrobial activities.

H2N SO2NH

20Sulphaphenazole

N

N

H2N S

O

O

NH

N N

OCH3H3CO

21Sulphadimethoxine

HO

HOOC

N N SO2NHN

C

C

O

OH

O

NH SO2NH

S

N

22Salicylazosulphapyridine (Azulphidine) 23

Phthalylsulphathiazole (Sulphathalidine)

22

1.4 JUSTIFICATION OF STUDY

A survey of the literature reveals that despite the various hazardous effects posed by deadly

microbes, it is sad to note that very few new antimicrobial drugs have been discovered in recent

times. Therefore, there is a great need to design and synthesize new antimicrobial drugs for the

control of the rapid spread of harmful microbes. Although many benzenoidsulphonamides have

been synthesized, only a few p-toluenesulphonamides were synthesized and evaluated to the best

of my knowledge. For this reason, there is the need to carry out the synthesis of such categories

of sulphonamides for the evaluation of their antimicrobial potentials.

23

CHAPTER TWO

2.0 LITERATURE REVIEW

Sulphonamides are a widely used classof organic compoundsin medicine.19

Because of their

importance in medicine; many workers have synthesized over five thousand compounds of this

class. Many of these derivatives, after series of biological evaluations, are currently used as

drugs. The synthesis and biological activities of known sulphonamides are presented below.

2.1. Synthesis of Sulphonamides as Antibacterialand Antifungal Agents.

Shivanandaet al.20

synthesized a series of sulphonamides26 derived from naphthofurans

by treating the appropriate sulphonamides25 with the naphthofurans-2-carboxylic acid at 60-

70oC. The products obtained were screened for biological activity and many of them showed

appreciable antibacterial and antifungal activities.

Priteshet al.21

synthesized a novel series of 4-acetamido-N-(substituted 1,3-benzothiazol-

2-yl) benzenesulphonamides 30and N-(substituted 1,3-benzothiazol-2-yl)-4-(substituted

aryldiazenyl) benzenesulphonamide31 inorder to determine their antibacterial and antifungal

activity. In this reaction, substituted 2-aminobenzothiazole 27 was treated with 4-acetamido

phenyl sulphonyl chloride 28 to produce the acetate sulphonamide29. This was followed by acid-

catalysed hydrolysis to the free amine 30. Diazotization of compound 30 followed by diazo-

coupling with 2-naphthol gave the final product 31 as in Scheme 1. When compounds 30 and 31

were tested for their microbial activities, they were found to possess a broad spectrum of

antibacterial and antifungal activities against some microorganisms.

O

COOH

R

S R'H2N

O

O

O

NH

O

S R'

O

O

25

24 26

POCl3,

24

More complex sulphonamides were also prepared by Navinet al.22

as in Scheme 2. The

series of quinazolonyl derivatives of 4-oxo-thiazolidinyl sulphonamides37 were screened for

antibacterial and antifungal activity and were found to have a remarkable antibacterial as well as

antifungal activity.

S

N

NH S

O

O

N=N Ar

N

S

NH2 +

NHCOCH3

SO O

Cl

N

S

NH S

O

O

NHCOCH3Pyridine, Ac2O

, 2hR R

Substituted 2-aminobenzothiazole27

284-acetamidophenylsulphonyl chloride

4-acetamido-N-(substituted 1,3-benzothiazol-2-yl)benzenesulphonamide

29

R

NH2

N

S

NH S

O

O

Acetic acid(80%)

reflux, 6h

R 4-amino-N-(substituted 1,3-benzothiazol-2-yl)30

benzenesulphonamide

HCl, NaNO2

Naphthol in NaOH

31N-(substituted 1,3-benzothiazol-2-yl)

4-(substituted aryl diazenyl) benzenesulphonamide

SCHEME 1: Synthesis of 4-Acetamido-N-(substituted 1,3-benzothiazol-2-yl) benzenesulphonamides

25

Saba and Akhyar23

synthesized two novel sulphonamides (N-(2-methoxyphenyl)-4-

methyl benzenesulphonamide40 and N-ethyl-4-methyl-N-(3-methylphenyl)

benzenesulphonamide41 by reacting the appropriate amines 39 with 4-Methyl benzenesulphonyl

chloride 38 as in Scheme 3.The products obtained in good yields were again bio-assayed to

determine their biological activities and found to be active against gram-positive and gram-

negative bacteria.

Cl

NH

Cl

CH2COOH

SOCl2Benzene

SO2-

CH2COClCl

NH

Cl

COOH

NH2

PyridineH2OHCl-

-

Cl

NH

Cl

O

N

O

H2NHNSO 2S NH2

-H2OPyridine

N

N

O

NH O2S

Cl

NH

Cl

NH2

N=CH

Cl

NH

Cl

N

N

O

NH O2SR

ROHC

MethanolH2O-

RCHN

SO

N

N

O

NH O2S

Cl

NH

Cl

DMF

ZnCl2HSCH2COOH

H2O-

37

36

34 35

32 33

SCHEME 2: Synthesis of Quinazolonyl Derivatives of 4-oxo-thiazolidinyl sulphonamides

26

Deepikaet al.,24

synthesized various derivatives of sulphonamide linked Moxifloxacinas

in Scheme 4and screened them to check the biological activities. They found the compounds to

have moderate to good antibacterial activity.

S

O

O

ClNH

O

OH

+i. Na2CO3/H2O, stir at rt, 4h

ii. 2M HCl, pH 2

S

O

O

N

OOH

NHEt2, heatS

O

O

N

N

O

CH3CH3

5051 52 53

S

O

O

Cl

+

NH2

OH

R

O50

54

i. Na2CO3/H2O, stir at rt, 4h

ii. 2M HCl, pH 2

S

O

O

NHO

OH

R

55

NHEt2, heat S

O

O

NHO

N

R

CH3CH3

56

Scheme 4: Synthesis of Derivatives of Sulphonamide Linked Moxifloxacin

Naga et al.25

synthesized a class of novel N-((2-(1H-tetrazol-5-yl) methyl substituted

sulphonamide46 from (2-(1H-tetrazol-5-yl)-biphenyl-4-yl) methanamine44, and appropriately

CH3

SO O

Cl

+

NH2

O CH3

CH3

SO O

NH

O CH3

CH3

SO O

Cl

+

N

CH3

CH3

H

CH3

SO O

HN

CH3

CH3

384-Methyl benzenesulphonyl chloride

392-Methoxy aniline

40N-(2-Methoxy phenyl)-4-methyl

benzenesulphonamide

38

39

41N-ethyl-4-methyl-N-(3-methylphenyl)

benzenesulphonamide

N-ethyl-3-methyl aniline

SCHEME 3: Synthesis of (N-(2-Methoxy phenyl)-4-methyl and N-Ethyl-methyl-N-(3-methylphenyl) benzenesulphonamides

27

substituted benzenesulphonyl chlorides 45 in the presence of mild basic conditions. They were

screened and found to have good antibacterial and antifungal activities.

In a similar reaction, Argyropoulouet al.26

acylated some benzo[d]thiazol-2-amines 47

with benzene sulphonyl chlorides 48 to give N-(benzo[d]thiazol-2-yl) benzenesulphonamides49.

The products were found to have antibacterial activities.

Ajani et al.27

synthesized a series of N,N-diethylamide bearing sulphonamides53, 56 by

amidation of easily prepared benzenesulphonamides precursors52, 55 as in Scheme 5. They also

screened the synthesized compounds for antimicrobial activity and found the compounds

exhibited marked potency as antibacterial agents.

S

O

O

ClNH

O

OH

+i. Na2CO3/H2O, stir at rt, 4h

ii. 2M HCl, pH 2

S

O

O

N

OOH

NHEt2, heatS

O

O

N

N

O

CH3CH3

5051 52 53

S

O

O

Cl

+

NH2

OH

R

O50

54

i. Na2CO3/H2O, stir at rt, 4h

ii. 2M HCl, pH 2

S

O

O

NHO

OH

R

55

NHEt2, heat S

O

O

NHO

N

R

CH3CH3

56

Scheme 5: Synthesis of N,N-dimethylamide bearing sulphonamides

NH2

N

N

NHN

+S

O

O

R ClEt3N, THF

50-60oC

N

N

NHN

HN S

O

O

R

4445 46

N

SNH2

R+ ClO2S R1

RN

SN

H

S R1

O

OPyridine

60oC

4748 49

Benzo[d ]thiazol-2-amine

28

2.1.2. Synthesis of Sulphonamides as Antimalarial Agents.

Boechatet al.28

used a rational approach to synthesized a new set of 15 1H-1,2,4-triazol-

3-yl benzenesulphonamide derivatives with the aim of developing new antimalarial lead

compounds. They synthesized 1H-1,2,4-triazol-3-yl benzenesulphonamide derivatives 60by

preparing 3-amine-1H-1,2,4-triazoles 59in excellent yield (91-99%) using aminoguanidine

bicarbonate 57to undergo condensation followed by cyclization with the appropriate carboxylic

acid 58. An equimolar mixture of the 3-amino-1H-1,2,4-triazoles59and the appropriate sulphonyl

chloride derivative 48was stirred in the presence of acetonitrile or DMF at room temperature and

yield the desired 1H-1,2,4-triazol-3-yl benzenesulphonamides60 as in Scheme 6. These

compounds possessed antimalarial activities.

Ryckebuschet al.29

synthesized and evaluated a library of 31 sulphonamides as inhibitors

of a chloroquine-resistant strain of Plasmodium falciparum according to Scheme 7. They

reported that the most potent compound displayed an activity 100-fold better than chloroquine.

They synthesized thesesulphonamides66 by amine 62obtained by aromatic substitution of 4,7-

dichloroquinoline63 by 1,4-bis(3-chloropropyl)-piperazine64, and reacted with commercially

available sulphochlorides65 or sulphofluorides.

H2N N

NH

NH2 . H2CO3

H

+R' OH

O

R'

N N

NH2

N

H

H

N

R'

N N

N

H

O2S R

S

O

O

ClR

DMF or rt, 6hCH3CN,

i. Toluene, reflux, 24h

57 58 59

48

60

SCHEME 6: Synthesis of 1H-1,2,4-triazol-3-yl benzenesulphonamide Derivatives

29

2.1.3. Synthesis of sulphonamides as an Antioxidant Agent

Further derivatives of sulphonamide bearing carbazole rings were reported by Reddy et

al.30

These compounds were prepared as in Scheme 8. They were further screened to determine

their biological activities and found to exhibit moderate to potent antimicrobial activities and

good antioxidant activities.

SCHEME 8: Synthesis of Sulphonamide Bearing Carbazole

Rindhe, et al.31

synthesized 3(Z)-{4-[4-(arylsulphonyl)piperazin-1-ylbenzylidene)-1,3-

dihydro-2H-indol-2-one 74by firstly producing t-butyl-4-{4 [Z]- (2-oxo-1,2-dihydro-3H-indol-3-

ylidene)methyl]phenyl}piperazine-1-carboxylate 72which was converted to (3Z)-3-(4-piperazin-

1-yl benzylidene)-1,3-dihydro-2H-indol-2-one 73as shown in Scheme 9. Compound 73were

dissolved in tetrahydrofuran (THF) in the presence of pyridine and catalytic amount of dimethyl

aminopyridine. The reaction mixture was stirred at room temperature for 8h and then poured in

water. The aqueous layer extracted with ethyl acetate. The ethyl acetate layer that separatedout,

N Cl

R

+ NN

NH2

H2N

N N

R

NN

NH2

H

Pentanol, reflux

18h, 85%

63 +

N

N

Cl

Cl

+ S

O

O

R Cl

HNN

N S

O O

RN N

R

H

6162

63

6465

66

CH2Cl2

r.t, 3h

SCHEME 7: Synthesis of Sulphonamide as Inhibitors of a Chloroquine-resistant

N

O

H

O O

N-

O

O

N

O

SO

O R

Na+

NaH

THF, 0-5oC

R SO2 Cl

2-3h

6768

69

30

was dried over anhydrous Na2SO4 and concentrated under vacuum. The crude product obtained

was crystallized in alcohol.

2.1.4 Synthesis of Sulphonamides as Anticancer andAntitumor Agents

Another highly substituted sulphonamide was prepared by Ghorab, et al.32

They obtained

4-oxothiazolidine benzenesulphonamides79as described earlier.33

by refluxing the Schiff base

with thioglycolic acid in dry benzene for additional 12h. In addition, one pot reaction can be

conducted via refluxing sulphanilamide8 with the required aldehyde and thioglycolic acid 78 in

dry benzene for 48h. These reactions are summarized in Scheme 10. They found these

synthesized compounds to have anticancer activities.

N

O

H

+

O

NN

O

OHN

O

NN

O

O

NHN

N

O

HHN

O

NN SR

O O

Ammonimum acetateToluene, 80o

TEA, DCM, R.T

RSO2Cl, R.T

Pyridine, THF

70 71

72

7374

SCHEME 9: Synthesis of 3(Z)-{4-(arylsulphonyl)piperazin-1-ylbenzylidene)-1,3-dihydro-2H-indol-2-one

NH2

SO O

NH2

+

CHO

R

EtOHS

O

O

H2N N=CH R

NH2

SO O

NH2

+

CHO

R3

R1

R2

+

HS

OH

O

SO O

NH2

HS

OH

O

N

SR1 R2

R3

Dry benzene12h

Dry benzene

48h

8

8

75

77

76

78

79

SCHEME 10: Synthesis of 4-Oxothiazolidine benzenesulphonamides

31

Babu34

synthesized 1-((4-chlorophenyl)(phenyl)methyl)-4-(sulphonyl)piperazine84 as

shown in Scheme 11 and N-(5-Bromo-2-chlorobenzyl)-N-cyclopropylsulphonamide derivatives

87as shown in Scheme 12. He found the synthesized compounds to have anticancer activities.

2.1.5. Synthesis of Sulphonamides as Anti-inflammatory Agent

Sondhiet al35

synthesized some methanesulphonamide derivatives89 by condensation of

3,4-diaryl-2-imino-4-thiazolines 88with methanesulphonyl chloride. They found the

compounds to have anti- inflammatory and anticancer activities.

Cl

O

NaH4

60-65oC

Cl

OH

Co

60-65Toluene

Conc. HCl

Cl

Cl

Cl

Cl

N

N

H

N

N

H

N

N

S

R

O O

RSO2Cl, TEA

35-40oC

DMF,Kl, KOH

80-85oC

80(4-Chlorophenyl)(phenyl)

methanone

81(4-Chlorophenyl)(phenyl)

methanol

821-Chloro-4-(chloro(phenyl

methyl) benzene

83

1-((4-Chlorophenyl)(phenyl)methyl) piperazine

84

SCHEME 11: Synthesis of 1-((4-Chlorophenyl)(phenyl)methyl)-4-(sulphonyl)piperazine

OH

Cl

Br

O

N

Cl

Br

O

N

Cl

Br

N

Cl

Br

SO O

R

RSO2Cl

H HBF3, etherate,THF

NaBH4, 60-65oC

TEA, 35-40oC

Oxalychloride

Cyclopropane amine

0-5oC

845-Bromo-2-chloro

benzenoic acid

5-Bromo-2-chloro-N-cyclopropyl

benzamide

85 86

87

SCHEME 12: Synthesis of N-(5-Bromo-2-chlorobenzyl)-N-cyclopropyl sulphonamide

32

Husain et al.36

synthesized various amide derivatives of sulphonamide by condensing them

with appropriate 4-oxo-4(4-substituted phenyl)butanoic acid moiety as shown in Scheme 13. The

compounds were found to have significant anti-inflammatory and antibacterial activities.

SCHEME 13: Synthesis of Amide Derivatives of Sulphonamide

2.1.6. Synthesis of Sulphonanamides as Antiviral and Anti- HIV Agent

In a six-steps synthesis, Chen et al.37

synthesized 5-(4-chlorophenyl)-N-substituted-N-1,3,4-

thiadiazole-2-sulphonamide derivatives 100. Esterification of 4-chlorobenzoic acid94 with

methanol and subsequent hydrazination, followed by reaction with carbon disulphide and

hydrogen tetraoxosulphate(vi) acid afforded 5-(4-chlorophenyl)-1,3,4-thiadiazole-2-thiol 98.

Conversion of this intermediate into its sulphonyl chloride 99, followed by nucleophilic attack of

the amines gave the title sulphonamides100 as in Scheme 14. The bioassay tests they carried out

showed that the compounds possessed certain anti-tobacco mosaic virus activity.

N

S NH

R1

R2

R3

R1

R2

R3

N

S N S

O

O

CH3

CH3SO2/K2CO3

Dry THF, r.t., stir4h

8988

R'

R +

O O

R'

R

OH

O

O

R'

SO2R'' N

O

OH

R'

R

SO2R'' NH2

POCl3

Anhyd. AlCl3

Pyridine

90 91 92

93

33

SCHEME 14: Synthesis of 5-(4-Chlorophenyl)-N-substituted-N-1,3,4-thiadiazole-2-sulphonamide

Igbalet al.38

synthesized some novel primary benzenesulphonamides bearing 2,5-

disubstituted-1,3,4-oxadiazole moiety 103 by direct chlorosulphonation at the 2-position of the

phenyl ring 102 leading to 5- mercapto-1,3,4-oxadiazoles 101 as shown in Scheme

15.Interestingly, they found the synthesized compound to have anti-HIV activity.

SCHEME 15: Synthesis of Benzenesulphonamides Bearing 2,5-disubstituted-1,3,4-oxadiazole

2.1.7. Synthesis of Sulphonamides as Diuretics Agent

A sulphonamide that has diuretic activity was reported by Vardanyan and Hruby.39

The

compound 4-chloro-N-(2-methyl-1-indolinyl)-3-sulphonylbenzamide108which he named

Inapamide was obtained from2-methylindoline104 by nitrosation to give 2-methyl-1-

nitrosoindoline 105. Reduction of compound 105 with lithium aluminum hydride led to the

formation of 1-amino-2-methyl indoline106. Acylation with 3-sulphonyl amino-4-chlorobenzoic

acid chloride107 led to compound108.40

as in Scheme 16.

Cl CO2H Cl CO2CH3 Cl CONHNH2

Cl CONHNH.CS2K Cl

N N

SSH

98

N N

SS

O

O

ClCl

N N

SS

O

O

N

R2

R1

Cl

94 95 96

97 98

99 100

reflux reflux

r.t 0oC

-2-0 oC

MeOH, H2SO4NH2NH2, H2O, EtOH

KOH, CS2, EtOH H2SO4

ClCH2CH2Cl, H2O, HCl,ClNHR1R2

CH3CN, Et3Nr.t

CR

O

NH NH2

R

SO O

Cl

NN

O SH

NN

O SHR

SO O

NHR'

CS2, KOH

EtOH,reflux

Dry NH3

CHCl3, r.t, 1.5h

101 102 103

34

SCHEME 16: Synthesis of 4-chloro-N-(2-methyl-1-indolinyl)-3-sulphonyl benzamide.

2.1.8. Synthesis of Sulphonamides as Analgesic Agent

Monoterpene-based p-toluenesulphonamide was reported by De Sousa et al.41

starting

with the naturally occurring (R)-(-)-carvone109. This was followed by 1,2-addition of KCN and

then reduction with lithium aluminum hydride to afford the amino alcohols. Tosylation of this

mixture with p-toluenesulphonyl chloride furnished thesulphonamide112(Scheme 17). The

compound was screened and found to haveanalgestic-like psychopharmacological activity.

SCHEME 17: Synthesis of Monoterpene-based p-toluenesulphonamide

N H

CH3

N NO

CH3

N NH2

CH3

Cl

SO2 NH2

C

O

Cl

N NH

CH3

O

C

SO2NH2

Cl

104 105106

107

108

Inapamide

NaNO2 LiAlH4

O O CN

CH2NH S

O

O

KCN, EtOH,

acetic acid, 0oC, 90%

H2O LiAlH4, THF

p TsCl

r.t., 89%

120oC, 69%

109 110 111

112

-

35

2.1.9. Synthesis of Sulphonamides as Anticonvulsant Agent

Devendraet al.42

synthesized 4-phthalimido-N-(4-substituted phenyl)

benzenesulphonamide119 and 4-succinimido-N-(4-substituted phenyl)

benzenesulphonamide120by condensation of substituted anilines113 with p-

acetamidobenzenesulphonyl chloride114 in the presence of dry pyridine and acetic anhydride by

heating for 2hours to give substituted 4-acetamido-N-phenyl benzenesulphonamide115. This

product, 115 was further hydrolysed in the presence of glacial acetic acid for 6hours to give

substituted 4-amino-N-phenyl benzenesulphonamide116. The products were further refluxed

with phthalic117and succinic118 anhydrides in the presence of glacial acetic acid to give the

final products 119 and 120(Scheme 18). Biological evaluation of these compounds showed that

they have anticonvulsant activities.

SCHEME 18: Synthesis of 4-phthalimido-N-(4-substituted phenyl) benzenesulphonamide

2.1.10. Synthesis of Sulphonamides as Inhibitors of Butyryl Cholinesterase

Rehmanet al.43

synthesized a series of N-substituted derivatives of 2-phenylethylamine

125 by reacting of 2-phenylethylamine 121with benzene sulphonyl chloride 122toyieldN-(2-

phenylethyl) benzenesulphonamide123, which on further on treatment with alkyl and acyl

R NH2 + ClO2S NHCOCH3 NHCOCH3R NHSO2

R NHSO2 N

O

O

N

O

O

O

O

O

O

O

O

NH2R NHSO2

R NHSO2

113 114115

116

117118

119 120

PyridineAcetic Anhydride

, 2h

Hydrolysis,

Glacial Acetic acid

36

halides 124in the present of sodium hydride gaveN-substituted sulphonamides125 (Scheme 19).

The synthesized compounds were found to be inhibitors of butyryl cholinesterase.

SCHEME 19:Synthesis of N-substituted derivatives of 2-phenylethylamine

2.2.0. Applications of Sulphonamides in Synthetic Organic Chemistry

Sulphonamides have been used in the field of synthetic chemistry, especially in highly

versatile and stereo- selective reactions. Some of these are elaborated below.

� Sulphonamides are used as a basis for distinguishing between primary, secondary and

tertiary amines. The sulphonamides formed from primary and secondary amines are

usually crystalline solids.44

Because of the remaining hydrogen atom on the nitrogen, the sulphonamide from a primary

amine is soluble in alkali, forming a salt.

CH2

CH2

NH2

+S

OO

Cl

CH2

H2C

NS

OO

H

SOOCH2

H2C

N

R

1'3'

5'

1

3

5

NaHStir at r.t

R-X (124)

121 122123

125

H2O

NaCO3

SO2Cl + RNH2

Na+OH

-

SO2NHR + Na+Cl

-+ H2O

H2O+Na+Cl

-+SO2NHR2

Na+OH

-

R2NH+SO2Cl

SO2Cl + R3NNa

+OH

-

No reaction

126

Alkylsulphonamide(soluble in base)

127Dialkylsulphonamide(insoluble in base)

SO2NHR + Na OH-. . . .

. .SO2NR

-

Na+

+ H2O

128 129

37

In practice, the amine is shaken with benzenesulphonyl chloride and alkali. Primary amines yield

clear solutions which, on acidification, precipitate the alkylsulphonamide. Secondary amines

yield an insoluble compound which is unaffected by acid. Tertiary amines also give an insoluble

compound (the unreacted amine) which, however, dissolves on acidification (forming a soluble

amine salt). This test for distinguishing between the three classes of amines is known as the

Hinsberg reaction.45

� Fukuyama and coworkers introduced the 2-nitrobenzenesulphonyl group as a new amine

protecting and activating group. As a selected example, Bowman46

reported a

monoalkylation of amino group using α-amino esters facilitated by the use of

nitrophenylsulphonamide protecting group. Formation of anion of the sulphonamide

using CS2CO3 and subsequent alkylation gave an intermediate 131. Facile removal of the

sulphonyl group using phenylthiolate anion yielded the desired secondary amine 132 as

below;

� Wang et al.47

reported that various α-ketoesters have been reduced into the corresponding

1,2- diols in high enatioselectivities using the NaBH4/ Me3SiCl system.

� Jones and coworkers48

synthesized tran-2,5-disubstituted-3-iodopyrrolidines136 from 5-

endo-trig iodocydization of the (E)-homollylicsulphonamides135 in presence of

potassium carbonate in excellent yields.

S N

H

O

O

NO2

COOR2

R1

S N

O

O

NO2

COOR2

R1

R3

R3 N

H

CO2R2

R1

ii. R3 X

i. CS2CO3, DMF, 30mins PhS-

DMF, r.t,24h, (-S )O2

130131

132

R

OR1

O

O

R

OH

OH

NaBH4/MeSiCl, DMF, reflux

Cat (25mmol)

Polymer- supported chiral sulphonamide

133134

38

2.2.1. Miscellaneous Applications of Sulphonamides

Therapeutic importance of sulphonamides, in various areas of medicinal chemistry, can be

judged from some reported examples such as: anti-apoptosis (cell death), epilepsy 13749

,dual

action receptor antagonist (DARA) for the treatment of hypertension 13850

, anti-HCV 14251

;

serotonin 5- HT (5- hydroxytryptamin) receptor, potential therapeutic agents for depression,

sleep disorder, migraine pain and hypertension 13952

; anti-cocaine-induced convulsion and

lethality 14053.

Mesoionicoxatriazoles (MOTA) 14154

, selective antiplatelet, antithrombotic

(MOTA have “NO” (nitric Oxide) donating ability). “NO” is unique messenger, play vital role in

regulation of cardio vascular system, transmission in central and peripheral nervous system and

host defense mechanism, Sivelestat (ONO-5046); Elsanol (injectable formation) 14354

, has been

reported for the treatment of lung damage.

NR1R2

SO2R3

N

SO2R3

R2

I

R1

3aq. I2

MeCNK2CO3

135 136

N

O

H

S S

O

O

N

R

S

O O

N

H

N

O

NH3C

OMe

NO CH3

CH3

137

138

S

O O

N

N

NH

N

OO

NO

O

SO O

NH2

HCH3

Cl

+N

N N

H

N

S

O

O139

140

141

39

Cl

S

O O

NH

Cl

N

H

OO

O

Cl

O

O

S

O

ON

O

N

OHO

HH

142

143

40

CHAPTER THREE

3.0 EXPERIMENTAL SECTION

3.1. GENERAL

All the starting materials and reagents were obtained from commercial sources and were

used without further purification. The melting points were determined with Fischer John’s

melting point apparatus and are uncorrected. IR spectra were recorded on 8400s Fourier

Transform Infrared (FTIR) spectrophotometer and are reported in wave number (cm-1

). IR

analysis was done at National Research Institute for Chemical Technology (NARICT), Zaria,

Kaduna State. Nuclear Magnetic Resonance (1H-NMR and

13C-NMR) were determined using

Jeol 400MHz at Strathclyde University, Scotland. Chemical shifts are reported in (δ) scale. Tests

for biological activities were carried out in the Laboratories of the Faculty of Pharmacy Sciences,

University of Nigeria Nsukka. All reagents were of technical grade. p-toluenesulphonyl chloride

and some derivatives of aminopyridine used are purchased from Sigma chemical company while

some are from Aldrich chemical company. The solvents used such as dimethylformamide

(DMF), methanol and acetone were purchased from Aldrich in sure-seal bottles and were used as

received.

3.2. General Procedure for the Preparation of the Sulphonamides

The preparation of 4-methyl-N-(pyridin-2-yl) benzenesulphonamide146a described below is a

typical procedure for the preparation of these new p-toluenesulphonamides. 2-Amino pyridine

(0.94g, 10.0mmol) was dissolved in a mixture of anhydrous acetone (20.00ml) and dry pyridine

(2.00ml). p-toluenesulphonyl chloride (1.91g, 10.0mmol) was then added later. The reaction

mixture was warmed to room temperature and allowed to stir. The reaction was left for 24 hours

and 1.50g of 4-methyl-N-(pyridin-2-yl) benzenesulphonamide146a (product) was filtered off

using suction filtration. On diluting the filtrate with distilled water, a further crop (1.25g) was

obtained. The total product was recrystallized from dimethylformamide (DMF). 4-Methyl-N-(5-

nitro pyridin-2-yl) benzenesulphonamide146c and 4-methyl-N-(3-nitro pyridin-2-yl)

benzenesulphonamide146d were recrystallized from methanol solvent and N-(3-hydroxypyridin-

41

2-yl)-4-methyl benzenesulphonamide146ewas recrystallized from ethanol solvent. The products

were dried in a hot air oven at 50oC for 6 hours.

Properties and Characteristics of these New Sulphonamides Prepared

3.2.1. 4-Methyl-N-(pyridin-2-yl) benzenesulphonamide

The compound weighed (1.64g, 66.1%) as a white needle-like solid melting at 205oC- 206

oC. IR

(KBr) Ѵmax: 3236cm-1

(N-H stret.), 3042cm-1

(Ar C-H), 1133cm-1

(SO2- functional group). 1H-

NMR [DMSO-d6] δ: 8.01 (d, J = 5.25Hz, 1H, NH), 7.76 (d, J = 8.14Hz, 2H, Ar-H), 7.70 (m, 4H,

phenyl-H), 7.33 (d, J = 8.14Hz, 2H, Ar-H), 7.14 (d, J = 8.70Hz, 1H, Ar-H), 6.86 (m, 4H, pyridyl-

H), 2.32(s, 3H, CH3-phenyl). 13

C-NMR [DMSO-d6] δ: 153.57- 144.10 (C1-C9, Ar-C), 21.49 (C10,

aliphatic carbon).

3.2.2. 4-Methyl-N-(4-methyl pyridin-2-yl) benzenesulphonamide.

This compound weighed (1.52g, 58.0%) as a white solid melting at 217oC- 218

oC. IR

(KBr)Ѵmax: 3229cm-1


(Ar C-H), 1141cm-1


NMR [DMSO-d6] δ: 7.81 (d, J = 5.87Hz, 2H, Ar- H), 7.74 (d, J = 8.20Hz, 2H, Ar-H), 7.31 (d, J

= 8.09Hz, 1H, Ar- H), 6.99 (s, 1H, Ar- H), 6.67 (d, J = 5.86Hz, 1H, Ar-H), 3.39 (s, 1H, NH),

2.32 (s, 3H, CH3-pyridyl), 2.22 (s, 3H, CH3-phenyl).

3.2.3. 4-Methyl-N-(5-nitropyridin-2-yl) benzenesulphonamide.

This compound weighed (1.58g, 53.9%) as a milky needle-like solid melting at 183oC- 184

oC. IR



(Ar C-H), 1518- 1349cm-1

(NO2stret.), 1198cm-1

(SO2- functional group). 1H-NMR [DMSO-d6] δ: 8.92 (d, J = 2.64Hz, 1H, Ar- H),8.26 (dd, J1=

2.75Hz, J2 = 9.46Hz, 1H, Ar- H), 7.50 (d, J = 8.05Hz, 2H, Ar- H), 7.13 (d, J = 7.90Hz, 2H, Ar-

H), 6.71 (d, J = 9.46Hz, 1H, Ar-H), 5.30 (s,b, 1H, NH), 2.29 (s, 3H, CH3-phenyl).

3.2.4. 4-Methyl-N-(3-nitropyridin-2-yl) benzenesulphonamide.

This compound weighed (2.14g, 73.0%) as a yellowish needle-like solid melting at 153oC-

154oC. IR (KBr)Ѵmax: 3454cm

-1- 3268cm

-1 (N-H stret.), 3110cm

-1 (Ar C-H), 1333cm

-1

(NO2stret.), 1162cm-1

(SO2- functional group). 1H-NMR [DMSO-d6] δ: 8.41 (m, 7H,

42

heteroaromatic-H), 8.00 (s, b, 1H, NH), 7.51 (dt, J = 2.65Hz, J1 = 8.07Hz, J2 = 8.07Hz, 2H, Ar-

H), 7.13 (d, J = 8.00Hz, 1H, Ar-H), 6.77 (dd, J1= 4.58Hz, J2 = 8.31Hz, 1H, Ar-H), 2.29 (s,

3H,CH3-phenyl).

3.2.5. N-(3-Hydroxy pyridin-2-yl)-4–methyl benzenesulphonamide.

This compound weighed (1.92g, 72.7%) as a pale-white needle-like solid melting at 105oC-

106oC. IR (KBr)Ѵmax: 3474cm

-1 (OH stret.), 3287cm

-1 (N-H stret.), 3138cm

-1 (Ar C-H),

1164cm-1

(SO2- functional group). 1H-NMR [DMSO-d6] δ: 7.82 (m, 7H, heteroaryl-H), 7.43 (d, J

= 8.15Hz, 1H, NH), 7.29 (dd, J1 = 1.39Hz, J2 = 7.89Hz, 1H, Ar-H), 6.50 (dd, J1 = 4.85Hz, J2 =

7.85Hz, 1H, Ar-H), 5.97 (s, 1H, OH), 2.40 (s, 3H, CH3-phenyl).13

C-NMR [DMSO-d6] δ: 153.10

– 112.40 (C1-C9, Ar-C), 21.74 (C10, aliphatic carbon).

3.2.6. 4-Methyl–N-(6-methyl pyridin-2-yl) benzenesulphonamide.

This compound weighed (1.66g, 63.3%) as an orange liquid (oil). IR (KBr)Ѵmax: 3311cm-1

(N-

H stret.), 3161cm-1

(Ar C-H), 1154cm-1

(SO2- functional group). 1H-NMR [DMSO-d6] δ: 8.09

(m, 7H, heteroaryl-H), 8.0 (s, b, 1H, NH), 7.74 (t, J = 8.06Hz, 1H, Ar-H), 7.52 (d, 8.02Hz, 1H,

Ar-H), 7.25 (d, J = 7.84Hz, 1H, Ar-H), 7.12 (d, J = 7.86Hz, 1H, Ar-H), 6.83 (d, J = 8.83Hz, 1H,

Ar-H), 6.62 (d, J = 7.03Hz, 1H, Ar-H), 2.35 (s, 3H, CH3- pyridyl), 2.24 (s, 3H, CH3- phenyl).

3.2.7. 4-Methyl -N- (pyridin-2-yl) benzenesulphonamide.

This compound weighed (1.25g, 50.4%) as a white solid melting at 213oC- 214

oC. IR



(Ar C-H), 1164cm-1


NMR [DMSO-d6] δ: 8.53 (d, J = 7.15Hz, 2H, Ar-H), 7.87 (d, J = 8.31Hz, Ar-H), 7.50 (d, J =

8.07Hz, 2H, Ar-H), 7.44 (m, 4H, heteroaromatic-H), 7.12 (d, J = 7.91Hz, NH), 2.28 (s, 3H, CH3-

phenyl).

3.3. Antimicrobial Activity

The antimicrobial properties of the sulphonamides were investigated in form of the

general sensitivity testing and minimium inhibitory concentration (MIC) with respect to freshly

cultured targeted organisms. The eight organismsused in this present study are Bacillus subtilis,

Bacillus cereus and Staphylococcus aureus as gram-positive bacteria,Klebsiellapneumoniae,

43

Pseudomonas aeruginosa and Escherichia coli as gram-negative bacteria, Candida albicansand

Asperigellusniger as fungi organisms.

3.3.1. Sensitivity Testing of Compounds.

Agar diffusion technique method as describe by Vincent (2005)55

, was used to determine

the antimicrobial activities of the synthesized compounds. Sensitivity test agar plates were

seeded with 0.1ml of 24 hours culture of each micro-organism into its corresponding petri-dish

previously labeled using the molten agar already prepared. The plates were allowed to set after

which cups were made in each sector previously drawn on the backside of the bottom- plate

using marker. Using the pipette (sterile), each cup was filled with six drops of their

corresponding antimicrobial agent in appropriate solvent at a concentration of 2mg/ml. The

plates were finally incubated at 37oC for 24 hours for bacteria and 48 hours for fungi. It should

be noted that the solubilizing solvent used was dimethyl formamide (DMF). Mueller Hinton agar

was prepared in 20ml portions kept molten at 45oC. The zone of inhibition (clearance) produced

after 24 hours on incubation at 37oC was measured.Muller Hinton agar was used for the fungi in

place of nutrient agar for bacteria. The procedure was repeated for Tetracycline and Fluconazole

drugs (bacteria and fungi standard respectively).

3.3.2. Minimium Inhibitory Concentration (MIC) Testing of Compounds.

The MIC was determined by further dilution of the test sample found to be sensitive

against a particular organism. Serial dilutions of the sulphonamides were prepared from 2mg/ml

solution of the sulphonamides to give 2.0-0.125mg/ml. After dilution, the test solutions were

added into their corresponding cups previsously made in the molten agar starting from the lowest

concentration (0.125- 1.0mg/ml). This was followed by incubation at the appropriate incubation

temperature and time. The resultant inhibition zones of diameter (IZD) were measured and the

value subtracted from the diameter of the borer (8mm) to give the inhibition zone diameter

(IZD). The MIC was also determined using graph of logarithm of concentration against IZD 2

for

each plate containing a specific compound and a microorganism. The anti-logarithm of the

intercept on x-axis gives the MIC.

44

CHAPTER FOUR

4.0. RESULTS AND DISCUSSION

4.1.0 4-Methyl –N- (pyridin-2-yl) benzenesulphonamide 146a.

On condensation reaction of p-toluene sulphonylchloride 144 and2-aminopyridine 145a in dry

pyridine and acetone at room temperature for 24hours, 4-methyl-N-(pyridin-2-yl)

benzenesulphonamide146a was obtained as a white needle-like solid with a melting point of

205oC- 206

oC.

SCl

O O

+N

NH2

-HCl

H3C

SNH

H3C

OO

N

1

2

3

4

5

6

7

7

89

10

8

Acetone, dry pyridine, r.t, 24h

144 145a146a

The proposed mechanism of this reaction is as shown in Scheme 20.

H3C

SO

O

Cl N

NH2

..

+R

Dry pyridine

H3C

SO

O

R

N+

H

H Cl-

N -HClH3C

SO

O

R

N

N

H

SCHEME 20: Proposed Mechanism of Reaction of New Synthesized Sulphonamides.

The assigned structure is supported by spectra analysis. In the IR spectrum, the absorption bands

at 3236cm-1

is due to NH, 3042cm-1

is due to aromatic C-H and 1133cm-1

is due to SO2-

functional group. In the1H-NMR spectrum, the peaks at δ8.01 is assigned to NH-proton, δ7.76 is

assigned to C7–proton, δ7.70 and δ6.86 (m, 8H) are due to heteroaromatic protons, δ7.33 is

assigned to C8 – proton, δ7.14 is assigned to C9 – proton and δ2.32 is due to CH3, aliphatic

45

hydrogen. In the13

C-NMR spectrum, peaks at δ153.57- δ114.10 are due to aromatic carbons (C1-

C9) and δ21.49 is due to aliphatic carbon (CH3). The spectrum agrees with the assigned structure.

4.1.1.4-Methyl –N-(4-methyl pyridin-2-yl) benzenesulphonamide 146b.

On condensation reaction of p-toluenesulphonyl chloride 144 and 2-amino-4-methyl pyridine

145b in acetone and dry pyridine at room temperature for 24 hours, 4-methyl-N-(4-methyl

pyridin-2-yl) benzenesulphonamide146b was obtained as a white solid with a melting point of

217oC- 218

oC.


at 3229cm-1


is assigned to Aromatic C- H and 1141cm-1

is due to SO2-

functional group. In the 1H-NMR spectrum, the peaks at δ7.81 is assigned to C7 – proton, δ7.74

is assigned to C8 – proton, δ7.31 is assigned to C3 – proton, δ6.99 is assigned to C9- proton, δ6.67

is assigned to C4- proton, δ3.39 is due to NH- proton, δ2.32 is due to C10- proton and δ2.22 is due

to C11- proton. The spectrum agrees with the assigned structure.

4.1.2. 4-Methyl -N-(5–nitro pyridin-2-yl) benznesulphonamide 146c.

On condensation reaction of p-toluenesulphonyl chloride 144 and 2-amino-5-nitro pyridine 145c

in acetone and dry pyridine at room temperature for 24 hours, 4-methyl-N-(5-nitro pyridin-2-yl)

benzenesulphonamide146c was obtained as a milky needle-like solid with a melting point of

183oC- 184

oC.

H3C

S

O O

Cl+

N

NH2

H3C

SO O

NH

H3CN

H3C

- HCl

acetone, dry pyridine, r.t., 144 145b

146b

24h

12

34

5

6

7

8

9

10

7

8

11

46


at 3259cm-1


is assigned to Aromatic C- H 1518cm-1

- 1349cm-1

is due to

NO2 group and 1198cm-1

is due to SO2- functional group. In the1H-NMR spectrum, the peaks at

δ8.92 is assigned to C4 – proton, δ8.26 is assigned to C9 – proton, δ7.50 is assigned to C7 –

proton, δ7.13 is assigned to C8- proton, δ6.71 is assigned to C6- proton, δ5.30 (s, b, 1H) is due to

NH- proton and δ2.29 is due to C10- proton. The spectrum agrees with the assigned structure.

4.1.3. 4-Methyl-N-(3–nitro pyridin-2-yl) benznesulphonamide 146d.

On condensation reaction of p-toluenesulphonyl chloride 144 and 2-amino-3-nitro pyridine 145d

in acetone and dry pyridine at room temperature for 24 hours, 4-methyl-N-(3-nitro pyridin-2-yl)

benzenesulphonamide146d was obtained as a yellowish needle-like solid with a melting point of

153oC- 154

oC.

SNH

H3C

OO

NO2N

1

2

3

4

5

6

7

8

9

10

8

9H3C

SO O

Cl + N

NH2

O2N-HCl

Acetone, dry pyridine, r.t

24h144 145d146d


at 3454cm-1


is assigned to Aromatic C- H, 1536cm-1

- 1333cm-1

is due to

NO2 group and 1162cm-1

is due to SO2- functional group. In the1H-NMR spectrum, the peaks at

δ8.41 (m, 7H) is due to heteroaromatic – protons, δ8.00 (s, b, 1H) is due to NH – proton, δ7.51 is

assigned to C9 – proton, δ7.13 is assigned to C4- proton, δ6.77 is assigned to C5- proton, and

δ2.29 is due to C10- proton. The spectrum agrees with the assigned structure.

H3C

S

O O

Cl+

N

NH2

NO2

SO O

NH

H3CN

NO2

- HCl

acetone, dry pyridine, r.t., 144

145c146c

24h

12

3

4

5

6

7

8

97

8

10

47

4.1.4 N-(3-Hydroxy pyridin-2-yl)-4-methyl benzenesulphonamide 146e.

On condensation reaction of p-toluenesulphonyl chloride 144 and 2-amino-3-hydroxyl pyridine

145e in acetone/DMF (in mol ratio of 2:1) and dry pyridine at room temperature for 24 hours, N-

(3-hydroxy pyridin-2-yl)-4-methyl benzenesulphonamide146e was obtained as a pale white

needle-like solid with a melting point of 105oC- 106

oC.

SNH

H3C

OO

NHO

1

2

3

45

6

7

8

9

109

8H3C

SO O

Cl + N

NH2

-HCl

Acetone, dry pyridine, r.t

24h144

HO

145e

146e


at 3474cm-1

is due to OH, 3287cm-1


is assigned to Aromatic C- H and

1164cm-1

is due to SO2- functional group. In the1H-NMR spectrum, the peaks at δ7.82 (m, 7H) is

due to heteroaromatic – protons, δ7.43 is due to NH – proton, δ7.29 is assigned to C6 – proton,

δ6.50 is assigned to C7- proton, δ5.97 is due to OH and δ2.40 is due to C10- proton. In the13

C-

NMR spectrum, peaks at δ153.10- δ112.40 are due to aromatic carbons (C1- C9) and δ21.74 is

due to aliphatic carbon (CH3). The spectrum agrees with the assigned structure.

4.1.5. 4-Methyl–N-(6-methyl pyridin-2-yl) benzenesulphonamide 146f.

On condensation reaction of p-toluenesulphonyl chloride 144 and 2-amino-6-methyl pyridine

145f in acetone and dry pyridine at room temperature for 24 hours, 4-methyl-N-(6-methyl

pyridin-2-yl) benzenesulphonamide146f was obtained as a yellowish liquid (oil).

H3C

S

O O

Cl+

N

NH2

CH3

SO O

H3CN

CH3

- HCl

acetone, dry pyridine, r.t., 144 145f

146f

24h

1

2

3

4

56

89

7

8

10

9

11

NH

48


at 3311cm-1


is assigned to Aromatic C- H and 1154cm-1

is due to SO2-

functional group. In the1H-NMR spectrum, the peaks at δ8.91 is assigned to NH –proton, δ862 is

assigned to C9- proton, δ8.09 (m, 7H) is due to heteroaromatic – protons, δ7.74 is assigned to C5

– proton, δ7.52 is assigned to C6 – proton, δ7.25 is assigned to C7- proton, δ6.83 is assigned to

C8- proton, δ2.35 is due to C10- proton and δ2.21 is due to C11- proton. The spectrum agrees with

the assigned structure.

4.1.6. 4-Methyl–N-( pyridin-4-yl) benzenesulphonamide 146g.

On condensation reaction of p-toluenesulphonyl chloride 144 and 4-amino pyridine 145g in

acetone and dry pyridine at room temperature for 24 hours, 4-methyl-N-(pyridin-4-yl)

benzenesulphonamide146g was obtained as a white solid with a melting point of 213oC- 214

oC.


at 3227cm-1


is assigned to Aromatic C- H, and 1164cm-1

is due to SO2-

functional group. In the1H-NMR spectrum, the peaks at δ8.53 is assigned to C7 – proton, δ7.87 is

assigned to C8 – proton, δ7.44 (m, 8H) is due to heteroaromatic – protons and δ2.28 is due to

C10- proton, aliphatic proton. The spectrum agrees with the assigned structure.

4.2. Antimicrobial Activity Evaluation

The obtained new compounds were screened in vitro for their antibacterial activities

against gram-positive bacteria (B. subtilis, B. cereus and S. aureus), gram-negative bacteria (P.

aeruginosa, E. coli and K. pneumoniae) and antifungal activities against fungi organisms (C.

albicansand Asp. niger), using the agar diffusion techniques.55

The choice of gram-positive and

gram-negative bacteria were because they are easily transmissible through soil, food, water,

H3C

S

O O

Cl+

SO O

H3C

- HCl

acetone, dry pyridine, r.t., 144 145g

146g

24h

1

2

34

5 68

9

7

8

10

NH

N

NH2

N

7

49

animal and human.56

Bacillus subtilis is commonly found in soil and inhibits the gut, considered

as a normal gut commensal.57

It is used in laboratory studies directed at discovering the

fundamental properties and characteristics of gram-positive spore-forming bacteria.58

Bacillus

cereus is an endemic, soil-dwelling, gram-positive, rod-shaped, beta hemolytic bacterium. Some

of its strains are harmful to humans and cause food borne illness.59

S. aureus is a bacterium that is

frequently found in the human respiratory tract and on the skin. It is a common cause of skin

infections (e.g. boils), respiratory diseases (e.g. Sinusitis) and food poisoning.60

E. coli is a

normal flora of human body which causes a lot of vancomycin-resistant Enterococci and

Methicillin-resistant Staphylococcus aureus.61

E. coli is a gram-negative, rod shaped bacterium

that is commonly found in the lower intestine of warm- blooded organisms (endotherms). It can

cause serious food poisoning in humans and are occasionally responsible for product recalls.62

K.

pneumoniae is a gram-negative, non-motile, encapsulated, lactose fermenting, facultative

anaerobic, rod shape bacterium. It is found in the normal flora of the mouth, skin and

intestines.63

P. aeruginosa is a gram negative, aerobic, coccobacillus with unipolar motility that

can cause disease such as urinary tract, burns, wounds and blood infections in animals, including

humans.60

It is found in soil, water, skin flora and most man- made environments throughout the

world.64

The choice of C. albicansand Asp. niger as fungal organisms are that they diploid

fungus that grows both as yeast and filamentous cell and a causal agent of opportunistic oral and

gential infections in humans.60

The choice of Tetracycline and Fluconazole as Clinical standards

is due to the fact that they possesses broad spectrum of antibacterial and antifungal activities

respectively.65

The results of the antibacterial and antifungal activities tests are shown in Table 1.

4.2.1. Results of Sensitivity Testing of Compounds.

Compound

Nos.

Gram-Positive Bacteria Gram-NegativeBacteria Fungi Organisms

B.Subtilis B.

Cereus

S.

Aureus

P.

Aeruginosa

E. coli K.

Pneumoniae

C.

Albicans

Asp.

Niger

146a - - - - - - - -

146b - - +++ - - - - -

146c - ++ +++ - - - ++ -

146d - - - - - - ++ -

50

146e + ++ +++ - - - ++ -

146f - - - - - - - -

146g - ++ +++ - - - - -

TCN + ++ + +++ + +++ - -

Flu - - - - - - +++ +++

TABLE 1: Results of General Sensitivity Test.

+ = Less Sensitive, ++ = Moderately Sensitive, +++ = Highly Sensitive and - = Resistance.

From the result of sensitivity testing, it was observed that compounds 146a and 146f are

not sensitive to the organisms under test. Compound 146d is not sensitive to bacteria. The

sensitive compounds 146b, 146c, 146e and 146g were only active against gram-positive bacteria.

Compounds 146c, 146d and 146e were sensitive to Candida albicans(fungi organism) only.

TCN is sensitive to bacteria only and Flu is sensitive to fungi organisms.

4.2.2. Results of Minimium Inhibitory Concentration (MIC) Testing of Compounds.

The compounds found sensitive on the tested organisms were further diluted to get the

MIC results as in Table 2.

Compound

Nos.

Gram-Positive Bacteria Gram-Negative Bacteria Fungi Organisms

B.

Subtilis

B.

Cereus

S.

Aureus

P.

Aeruginosa

E. coli K.

Pneumoniae

C.

Albicans

Asp.

Niger

146b - - 0.20 - - - - -

146c - 0.23 0.19 - - - 0.23 -

146d - - - - - - 0.30 -

146e 0.24 0.13 0.17 - - - 0.23 -

146g - 0.19 0.20 - - - - -

TCN 5.62 11.48 5.31 15.85 3.16 17.78 - -

Flu - - - - - - 24.00 27.00

TABLE 2: Results of MIC Test

51

From the point of view of B. subtilis as shown in table 2, compound 146e is the most active at

MIC value of 0.24mg/ml. From B. cereus, compounds 146e and 146g are the most active at MIC

value of 0.13mg/ml and 0.19mg/ml respectively, From S. aureus, compounds 146c and 146e are

the most active at MIC value of 0.19mg/ml and 0.17mg/ml respectively. From P. aeruginosa, E.

coli and K. pneumoniae, none of the synthesized compounds showed activity. TCN is active at

MIC values of 15.85mg/ml, 3.16mg/ml and 17.78mg/ml respectively. From C. albicans,

compounds 146c and 146e are the most active at MIC value of 0.23mg/ml and 0.23mg/ml

respectively. From Asp.niger, none of the synthesized compounds also showed activity. Flu is

active at MIC value of 27.00mg/ml.

52

CHAPTER FIVE

5.0 CONCLUSION

The synthesis of N-(heteroaryl-substituted)-p-toluenesulphonamides has been achieved

successfully. The assigned structures were supported by spectra analysis. The sulphonamides

have good antimicrobial properties against some of the tested organisms.

53

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Fig 1: IR- Spectral of Chart of 4-Methyl-N-(pyridin-2-yl) benzenesulphonamide

61

Fig 2:IR- Spectral of Chart of 4-Methyl-N-(4-methyl-2-pyridinyl) benzenesulphonamide

62

Fig 3: IR- Spectral of Chart of 4-Methyl-N-(5-nitro-2-pyridinyl) benzenesulphonamide

63

Fig 4: IR- Spectral of chart of 4-Methyl-N-(3-nitro-2-pyridinyl) benzenesulphonamide

64

Fig 5: IR- Spectral of chart of N-(3-Hydroxy-2-pyridinyl)-4-methyl benzenesulphonamide

65

Fig 6: IR- Spectral of chart of 4-Methyl-N-(6-methyl-2-pyridinyl) benzenesulphonamide

66

Fig 7: IR- Spectral of Chart of 4-Methyl-N-(pyridin-4-yl) benzenesulphonamide

67

Fig 8:1H-NMR- Spectral of Chart of 4-Methyl-N-(pyridin-2-yl) benzenesulphonamide

68

Fig 9:13

C-NMR- Spectral of Chart of 4-Methyl-N-(pyridin-2-yl) benzenesulphonamide

69

Fig 10: 1H-NMR -Spectral of chart of 4-Methyl-N-(4-methyl-2-pyridinyl)benzenesulphonamide

70

Fig 11: 1H-NMR - Spectral of Chart of 4-Methyl-N-(5-nitro-2-pyridinyl) benzenesulphonamide

71

Fig 12: 1H-NMR -Spectral of chart of 4-Methyl-N-(3-nitro-2-pyridinyl) benzenesulphonamide

72

Fig 13: 1H-NMR -Spectral of Chart of N-(3-Hydroxy-2-pyridinyl)-4-methyl

benzenesulphonamide

73

Fig 14:13

C-NMR – Spectral of Chart of N-(3-Hydroxy-2-pyridinyl)-4-methyl

benzenesulphonamide

74

Fig 15: 1H-NMR - Spectral of chart of 4-Methyl-N-(6-methyl-2-pyridinyl) benzenesulphonamide

75

Fig 16: 1H-NMR - Spectral of Chart of 4-Methyl-N-(pyridin-4-yl) benzenesulphonamide

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