studies of some heterocyclic compounds……. · heterocyclic chemistry and the pharmacological...
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Raval, Chintan C., 2012, “Studies on some Heterocyclic Compounds of
Pharmaceutical Importance”, thesis PhD, Saurashtra University
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“STUDIES OF SOME HETEROCYCLIC
COMPOUNDS OF PHARMACEUTICAL
IMPORTANCE” A THESIS
SUBMITTED TO THE
SAURASHTRA UNIVERSITY
FOR THE DEGREE OF
Doctor of Philosophy IN
THE FACULTY OF SCIENCE (CHEMISTRY)
BY
Mr. Chintan. C. Raval UNDER THE GUIDANCE
OF
Dr. A. J. Rojivadiya
Department of Chemistry
Maharshi Dayanand Science College,
Porbandar- 360575
(Gujarat-India)
Maharshi Dayanand Science College Department of Chemistry
Porbandar
(Gujarat-India)
Dr. A. J. Rojivadiya Residence:
M.Sc., Ph.D. 22, Shreejee Nagar
Maharsinh Dayanand Narsang Tekari
Science College, Porbandar- 360577
Porbandar Ph: 0286-2221011
Statement under o. Ph. D. 7 of Saurashtra University
The work included in the thesis is my own work under the supervision of
Dr. A. J. Rojivadiya and leads to some contribution in chemistry subsidized by a
number of references.
Dt. : -03-2012 (Mr. Chintan. C. Raval)
Place: Porbandar
This is to certify that the present work submitted for the Ph.D. Degree of
Saurashtra University by Mr. Chintan. C. Raval is his own work and leads to
advancement in the knowledge of chemistry. The thesis has been prepared under my
supervision.
Date : -03-2012 Dr. Atul. J. Rojivadiya
Place: Porbandar Maharshi Dayanand
Science College
Porbandar
ACKNOWLEDGEMENT
It is a moment of gratification and pride to look back at
the long traveled path, to be able to sum up some of the fine
moments, thinking of few people, some who were with me
from the beginning, some who joined me at different stages
during this voyage, whose kindheartedness, love and blessings
has brought me to this episode. I wish to thank each of them
from the bottom of my heart.
First and foremost, I would like to record my sincere
gratitude to most respectable guide Dr. Atul. J. Rojivadiya,
for his persistent support with lots of love, encouragement. I
am privileged to work under his generous guidance, because I
achieved positive thinking attitude and analyzing
capabilities, which helped me to make things simple. He
constantly encouraged me to remain focused on achieving my
goals.
I thank gratefully to Dr. P. K. Patel, for his enthusiasm,
his inspiration, and his great efforts to elucidate things
clearly and in lucid language. Throughout the entire thesis
compilation, he enriched me with his advice and innovative
ideas. His true scientific intuition has made him a constant
oasis of ideas and passion in science, which has exceptionally
inspired and enhanced my growth as a student, as a
researcher, as a human and as a scientist.
I also owe to Dr. B. M. Sharma, for his realistic approach
towards the research methodology and invariable motivation
that has persistently benefited to me throughout my research
period.
Also, I would like to express my profound gratitude to
Dr D. M. Purohit for his unvarying support, care and moral
boost that always helped me during crucial stages of research.
Words are inadequate to thank my friends and
colleagues Hardik Mehta and Dr. Dinesh Kundariya who
were always with me in good and bad phase of my research
period, helping me in all situations.
I am thankful to my friends and colleagues for their
thought provoking ideas and creating light atmosphere that
helped me to overcome difficult situations. I am heartily
thankful to my dearest friends Dhaval Manvar, Seema Joshi,
Madhvi Kundariya, Anil Patel, Suchi Gandhi, Nirav Joshi
and Kamlesh Khokhani for their valuable comments and
constant co-operation during reference work, Spectroscopic
analysis and comprehensive exchange of ideas during the
entire research path.
Dr. Dinesh Bhoot, Dr. J. M. Parmar, Dr. A. M.
Virparia, Dr. B. M. Bheshdadiya, Dr. V. A. Modhavadiya,
Dr. D. R. Bhadja, Dr. M. V. Parsania, Mr. S. S. Babariya,
Mr. R. D. Kalariya, Sanghanibhai, Bhailalbhai and
Amarbhai are greatly appreciated for their kind concern and
moral support.
I gratefully thank teaching and non-teaching staff
members of M. D. Science College , Porbandar and M. M.
Science College , Morbi for their steady support and co-
operation during my lab experiments.
I would like to express special thanks to my sister Meera
and my brother Ashish for their daily sweet punches which
ultimately encouraged me to complete my research work in
good swiftness.
Above all, I thank my Lord, for giving me the intellect to
understand the complexity of chemistry and giving me
strength to complete this research. Most specially, thank you
for sending your angels when I needed them the Most.
To all my heaven-sent angels, thank you and God bless us all.
-Chintan. C. Raval
Studies On Some Heterocyclic Compounds……
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CONTENTS Page No SYNOPSIS .. .. 04 STUDIES OF SOME HETEROCYCLIC COMPOUNDS OF PHARMACEUTICAL IMPORTANCE Introduction .. .. 13 PART-1 : STUDIES ON CHALCONES OF 2-(4-ACETYLPHENYLAMINO) PYRIDINE-3-CARBONITRILE. Introduction .. .. 27
Spectral Studies .. .. 40
Experimental .. .. 43
Data of In Vitro Evaluation of Antimicrobial screening. 46
References .. .. 48
PART-2 : CONVENTIONAL AND MICROWAVE ASSISTED SYNTHESIS AND EVALUATION STUDIES ON PYRAZOLINES. Introduction .. .. 55 Section-I Conventional and Microwave assisted Synthesis, biological evaluation of 2-(4-(4,5-dihydro-5-Aryl-1H-pyrazol-3-yl)phenylamino)pyridine-3-carbonitrile. Introduction .. .. 62
Spectral Studies .. .. 63
Experimental .. .. 66
Data of In Vitro Evaluation of Antimicrobial screening. 68
Section-II Conventional and Microwave assisted Synthesis, biological evaluation of 2-(4-(1-acetyl-4,5-dihydro-5-Aryl-1H-pyrazol-3-yl)phenylamino)pyridine-3-carbonitrile. Introduction .. .. 70
Spectral Studies .. .. 71
Experimental .. .. 74
Studies On Some Heterocyclic Compounds……
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Data of In Vitro Evaluation of Antimicrobial screening.. 76
Section-III Conventional and Microwave assisted Synthesis, biological evaluation of 2-(4-(1-phenyl-4,5-dihydro-5-Aryl-1-phenylpyrazol-3-yl)phenylamino)pyridine-3-carbonitrile. Introduction .. .. 78
Spectral Studies .. .. 79
Experimental .. .. 82
Data of In Vitro Evaluation of Antimicrobial screening. 84
References .. .. 86
PART-3 : CONVENTIONAL AND MICROWAVE ASSISTED SYNTHESIS AND EVALUATION STUDIES ON PYRIMIDINES. Introduction .. .. 90 Section-I Conventional and Microwave assisted Synthesis, biological evaluation of 2-(4-(1,2-dihydro-6-Aryl-2-thioxopyrimidin-4-yl)phenylamino)pyridine-3-carbonitrile. Introduction .. .. 101
Spectral Studies .. .. 103
Experimental .. .. 106
Data of In Vitro Evaluation of Antimicrobial screening.. 108
Section-II Conventional and Microwave assisted Synthesis, biological evaluation of 2-(4-(1,2-dihydro-2-oxo-6-Arylpyrimidin-4-yl)phenylamino)pyridine-3-carbonitrile. Introduction .. .. 110
Spectral Studies .. .. 112
Experimental .. .. 115
Data of In Vitro Evaluation of Antimicrobial screening.. 117
References .. .. 119
LIST OF NEW COMPOUNDS .. 124 PUBLICATIONS .. .. 128
Studies On Some Heterocyclic Compounds……
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“STUDIES OF SOME HETEROCYCLIC COMPOUNDS OF PHARMACEUTICAL IMPORTANCE”
A comprehensive summary of the work incorporated in the thesis with the title
“STUDIES OF SOME HETEROCYCLIC COMPOUNDS OF
PHARMACEUTICAL IMPORTANCE”
has been described as under.
PART-1 : STUDIES ON CHALCONES OF 2-(4-
ACETYLPHENYLAMINO) PYRIDINE-3-
CARBONITRILE.
PART-2 : CONVENTIONAL AND MICROWAVE ASSISTED
SYNTHESIS AND EVALUATION STUDIES ON
PYRAZOLINES.
PART-3 : CONVENTIONAL AND MICROWAVE ASSISTED
SYNTHESIS AND EVALUATION STUDIES ON
PYRIMIDINES.
Studies On Some Heterocyclic Compounds……
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PART-1 : STUDIES ON CHALCONES OF 2-(4-ACETYLPHENYLAMINO) PYRIDINE-3-CARBONITRILE
Many naturally occurring and synthetic compounds contain cyanopyridine as a
basic moiety, which posses interesting pharmacological properties, Cyanopyridine and its
derivative are well known for their versatile biological activities like antimicrobial,
antitubercular, antifungal, antiviral etc. looking to this multifold property exhibited by
cyanopyridine, we are studying here the synthesis and antimicrobial activity of some
cyanopyridine derivative. In the present study, this strategy is used for the synthesis of
this compounds in the hope that they may possess potent biological activities.
In the present study 2-chloro-3-cyano pyridine and p-amino acetophenone are
coupled together in ethanol. HCl to give 2-(4-ACETYLPHENYLAMINO)
PYRIDINE-3-CARBONITRILE
N NH
CN COCH3
2-(4-acetylphenylamino)pyridine-3-carbonitrile
The chalcones are α, β-unsaturated ketones containing the reactive ketoethylenic
group – CO – CH= CH –. Presence of α, β-unsaturated carbonyl system in chalcone
makes it biologically active.
Studies On Some Heterocyclic Compounds……
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The solution of 2-(4-Acetylphenylamino)pyridine-3-carbonitrile was treated with
various aldehydes in presence of 40% NaOH solution to give various chalcones TYPE
(I).
N NH
CNR
O
TYPE (I) R= ARYL
R= C6H5-, 4-Cl-C6H5-, 4-OH-C6H5-, 3-NO2-C6H5-……etc
PART-2 : CONVENTIONAL AND MICROWAVE ASSISTED SYNTHESIS AND
EVALUATION STUDIES ON PYRAZOLINES.
Pyrazolines have attracted attention of medicinal chemists for both with regard to
heterocyclic chemistry and the pharmacological activities associated with them. The
pharmaceutical importance of these compounds lies in the fact that they can be
effectively utilized as antibacterial, antifungal, antiviral, antiparasitic, antitubercular and
insecticidal agents.
Section-I Conventional and Microwave assisted Synthesis, biological
evaluation of 2-(4-(4,5-dihydro-5-Aryl-1H-pyrazol-3-yl)phenylamino)pyridine-3-
carbonitrile.
Considerable attention has been focused on the development and synthesis of
pyrazolines of type (II) for obtaining biologically potent molecules which have been
prepared by the condensation of chalcones of type (I) with hydrazine hydrate.
Studies On Some Heterocyclic Compounds……
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N NH
CNR
TYPE (II) R= ARYL
N NH
R= C6H5-, 4-Cl-C6H5-, 4-OH-C6H5-, 3-NO2-C6H5-……etc
Section-II Conventional and Microwave assisted Synthesis, biological
evaluation of 2-(4-(1-acetyl-4,5-dihydro-5-Aryl-1H-pyrazol-3-
yl)phenylamino)pyridine-3-carbonitrile.
The pyrazolines of type (III) have been prepared by the condensation of chalcones
of type (I) with hydrazine hydrate in acetic acid.
N NH
CNR
TYPE (III) R= ARYL
N N
COCH3
R= C6H5-, 4-Cl-C6H5-, 4-OH-C6H5-, 3-NO2-C6H5-……etc
Studies On Some Heterocyclic Compounds……
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Section-III Conventional and Microwave assisted Synthesis, biological
evaluation of 2-(4-(1-phenyl-4,5-dihydro-5-Aryl-1-phenylpyrazol-3-
yl)phenylamino)pyridine-3-carbonitrile.
The pyrazolines of type (IV) have been prepared by the condensation of chalcones
of type (I) with Phenyl hydrazine.
N NH
CN
TYPE (IV) R= ARYL
N
R
N
Ph
R= C6H5-, 4-Cl-C6H5-, 4-OH-C6H5-, 3-NO2-C6H5-……etc
Studies On Some Heterocyclic Compounds……
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PART-3 : CONVENTIONAL AND MICROWAVE ASSISTED SYNTHESIS AND
EVALUATION STUDIES ON PYRIMIDINES.
Pyrimidine is the most important member of all the diazines as this ring system
occurs widely in living organisms. Pyrimidine and its derivatives have gained
prominence bacause of their potential pharmaceutical values.
Section-I Conventional and Microwave assisted Synthesis, biological
evaluation of 2-(4-(1,2-dihydro-6-Aryl-2-thioxopyrimidin-4-
yl)phenylamino)pyridine-3-carbonitrile.
Compounds containing pyrimidine ring are widely available in nature. Many thio
pyrimidine derivatives are reported to possess different therapeutic activities. In view of
these findings, it was considered worthwhile to synthesize some new Thioxopyrimidine
to study their therapeutic activities. Thio pyrimidine derivatives of Type (VII) have been
prepared by the reaction of the chalcones of Type (I) with thiourea.
N NH
CN
TYPE (VI) R= ARYL
NHN
R
S
R= C6H5-, 4-Cl-C6H5-, 4-OH-C6H5-, 3-NO2-C6H5-……etc
Studies On Some Heterocyclic Compounds……
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Section-II Conventional and Microwave assisted Synthesis, biological
evaluation of 2-(4-(1,2-dihydro-2-oxo-6-Arylpyrimidin-4-yl)phenylamino)pyridine-
3-carbonitrile.
Oxopyrimidines and its derivatives represent one of the most active class of
compounds possessing a wide spectrum of biological activities.
In the past years considerable evidence has been accumulated to demonstrate the
efficiency of pyrimidinones. Oxopyrimidines of Type (VII) have been prepared by the
condensation of chalcones of Type (I) with urea.
N NH
CN
TYPE (VII) R= ARYL
NHN
R
O
R= C6H5-, 4-Cl-C6H5-, 4-OH-C6H5-, 3-NO2-C6H5-……etc
Studies On Some Heterocyclic Compounds……
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Biological Activity:
The newly synthesized chemical entities would be screened for various biological
activities.
Summary:
A brief summary of the entire work performed in Ph.D. would be conversed herein and
the future opportunities in the related field of work would also be discussed.
Note: All the synthesized compounds are confirmed using various analytical data
techniques like Thin layer chromatography (TLC), Infrared (IR), Proton nuclear magnetic
resonance spectroscopy (1H NMR) and Mass Spectroscopy.
Studies On Some Heterocyclic Compounds……
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INTRODUCTION:
Research in the field of pharmaceutical has its most important task in the
development of new and better drugs and their successful introduction into clinical
practice. The word 'drug' is derived from the French word 'drogue' which means a dry
herb. In general way, a drug may be defined as a substance used in the prevention,
diagnosis, treatment or cure of disease in man or other animals. The basis of
understanding in the medicinal chemistry lies in awareness of the relationships between
the chemistry of a particular compound or group of compounds and their interactions
with the body, which is known as structure activity relationship, and the mechanism by
which the compound influences the biological system, which is known as its mode of
action.
We must always continue to search for drugs which exhibit clear advantages over the
already existing respective drugs. Such advantages may be: (1) A qualitative or
quantitative improvement in activity, (2) a partial or total absence of undesirable side
effects, (3) a lower toxicity, (4) more nutritive value, (5) improved stability and (6) a
decrease in production cost.
Any drug must ideally have a broad spectrum of activity, with a rapid bactericidal action.
Some bacteria produce enzymes that can inactivate or modify antibiotics action. Some
bacteria produce enzymes that can inactivate or modify antibiotics, and insusceptibility of
a drug to such degradation or modification could result in its playing an important part in
therapy. Likewise, some bacteria possess an outer membrane that acts as a permeability
barrier to the entry of some, but not all, antibiotics. Drugs that can readily penetrate this
barrier might again be expected to be of possible clinical importance.
During the period of 1940 to 1960 a large number of important drugs have been
introduced and this period is regarded as "Golden Period" of new drug discovery. These
are some of the specific examples representing new therapeutics.
Studies On Some Heterocyclic Compounds……
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NAME OF DRUGS YEAR USAGES
Sulfa drugs 1933 First antibacterial drug
Penicillin 1940 Antibiotics
Chloroquine 1945 Antimalarial
Methyldopa 1950 Antidiabetic
Chlorthiazide 1957 Diuretic
Adrenergic betablockers 1958 Coronary Vasodilatory
Semi synthetic penicillins 1960 Antibacterial
Trimethoprim 1965 Antimicrobial
Disodium chromoglycoate 1967 Antiallergic
During the past decade, the threat of antimicrobial resistance has become increasingly
real and its global dimensions have been increasingly recognized. Antimicrobial
resistance is defined as a property of bacteria that confers the capacity to inactivate or
exclude antibiotics, or a mechanism that blocks the inhibitory or killing effects of
antibiotics, leading to survival despite exposure to antimicrobials. Some bacteria become
multi-resistant, i.e., resistant to different groups of antibiotics. Increasing reports of
outbreaks of antimicrobial resistant bacteria, such as hospital outbreaks of vancomycin
resistant enterococci, community outbreaks of antimicrobial resistant. Streptococcus
pneumoniae and human and animal outbreaks of multi-resistant. Salmonella
Typhimurium definitive type 104, have heightened the concerns of the international
public - and animal-health communities, medical and veterinary clinicians and the
general public. Another reason for increased concern is the slowing of research and
development of new antimicrobials due to the cost and time to develop new drugs as well
as a focus by pharmaceutical companies on developing products for non-infectious
disease.
Studies On Some Heterocyclic Compounds……
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AIMS AND OBJECTIVES:
In the pharmaceutical field, there has always been and will continue to be a need for new
and novel chemical entities with diverse biological activities.
Our efforts are focused on the introduction of chemical diversity in the molecular frame
work in order to synthesizing pharmacologically interesting compounds of widely
different composition.
During the course of research work, several entities have been designed, generated and
characterised using spectral studies. The details are as under.
1) To generate several derivatives like chalcones, pyrazolines, cyanopyridines,
aminopyrimidines, thiosemicarbazones, cyclohexenones, indazoles, barbitones,
imidazolinones, thiazolidinones and nitriles bearing furan nucleus.
2) To check the purity of all compounds using thin layer chromatography.
3) To characterize these products for structure elucidation using spectroscopic
techniques like IR, PMR and Mass spectral studies.
4) To evaluate these new products for better drug potential against different strains
of bacteria and fungi.
5) Selected compounds have been sent to "Tuberculosis Antimicrobial Acquisition
and coordinating facility (TAACF), Southern Research Institute, U.S.A.'' for their
in vitro antitubercular screening.
Microwave Assisted Organic Synthesis:
1.1 Introduction
Synthesis of new chemical entities is major bottleneck in drug discovery.
Conventional methods for various chemical synthesis is very well documented and
practiced1. The methods for synthesis (Heating process) of organic compounds has
continuously modified from the decade. In 1855, Robert Bunsen invented the burner
which acts as energy source for heating a reaction vessel; this was latter superseded
Studies On Some Heterocyclic Compounds……
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by isomental, oil bath or hot plate, but the drawback of heating, though method
remains the same. Microwave Assisted Organic Synthesis (MAOS), which has
developed in recent years, has been considered superior to traditional heating.
Microwave assisted organic synthesis2 (MAOS) has emerged as a new “lead” in
organic synthesis. The technique offers simple, clean, fast, efficient, and economic for
the synthesis of a large number of organic molecules. In the recent year microwave
assisted organic reaction has emerged as new tool in organic synthesis. Important
advantage of this technology include highly accelerated rate of the reaction,
Reduction in reaction time with an improvement in the yield and quality of the
product. Now day’s technique is considered as an important approach toward green
chemistry, because this technique is more environmentally friendly. This technology
is still under-used in the laboratory and has the potential to have a large impact on the
fields of screening, combinatorial chemistry, medicinal chemistry and drug
development. Conventional method of organic synthesis usually need longer heating
time, tedious apparatus setup, which result in higher cost of process and the excessive
use of solvents/ reagents lead to environmental pollution. This growth of green
chemistry holds significant potential for a reduction of the by product, a reduction in
waste production and a lowering of the energy costs. Due to its ability to couple
directly with the reaction molecule and by passing thermal conductivity leading to a
rapid rise in the temperature, microwave irradiation has been used to improve many
organic synthesis.
1.2 Microwave frequency:
Microwave heating refers the use of electromagnetic waves ranges from 0.01m to 1m
wave length of certain frequency to generate heat in the material. These microwaves
lie in the region of the electromagnetic spectrum between millimeter wave and radio
wave i.e. between I.R and radio wave. They are defined as those waves with
wavelengths between 0.01metre to 1 meter, corresponding to frequency of 30GHz to
0.3GHz.
Studies On Some Heterocyclic Compounds……
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1.3 Principle:
The basic principle behind the heating in microwave oven is due to the interaction of
charged particle of the reaction material with electro magnetic wavelength of
particular frequency. The phenomena of producing heat by electromagnetic
irradiation are ether by collision or by conduction, some time by both. All the wave
energy changes its polarity from positive to negative with each cycle of the wave.
This cause rapid orientation and reorientation of molecule, which cause heating by
collision. If the charge particles of material are free to travel through the material (e.g.
Electron in a sample of carbon), a current will induce which will travel in phase with
the field. If charge particle are bound within regions of the material, the electric field
component will cause them to move until opposing force balancing the
electric force.3-9
Studies On Some Heterocyclic Compounds……
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1.4 Heating Mechanism
In microwave oven, material may be heated with use of high frequency
electromagnetic waves. The heating arises from the interaction of electric field
component of the wave with charge particle in the material. Two basic principal
mechanisms involve in the heating of material.
1.4.1 Dipolar Polarisation
Dipolar polarisation is a process by which heat is generated in polar molecules. On
exposure to an oscillating electromagnetic field of appropriate frequency, polar
molecules try to follow the field and align themselves in phase with the field.
However, owing to inter-molecular forces, polar molecules experience inertia and are
unable to follow the field. This results in the random motion of particles, and this
random interaction generates heat. Dipolar polarisation can generate heat by either
one or both the following mechanisms:
1. Interaction between polar solvent molecules such as water, methanol and ethanol.
2. Interaction between polar solute molecules such as ammonia and formic acid.
The key requirement for dipolar polarization is that the frequency range of the
oscillating field should be appropriate to enable adequate inter -particle interaction. If
the frequency range is very high, inter-molecular forces will stop the motion of a
polar molecule before it tries to follow the field, resulting in inadequate inter-particle
interaction. On the other hand, if the frequency range is low, the polar molecule gets
sufficient time to align itself in phase with the field. Hence, no random interaction
takes place between the adjoining particles. Microwave radiation has the appropriate
frequency (0.3-30 GHz) to oscillate polar particles and enable enough inter-particle
interaction. This makes it an ideal choice for heating polar solutions.
In addition, the energy in a microwave photon (0.037 kcal/mol) is very low, relative
to the typical energy required to break a molecular bond (80-120 kcal/mol).
Therefore, microwave excitation of molecules does not affect the structure of an
organic molecule, and the interaction is purely kinetic.
Studies On Some Heterocyclic Compounds……
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1.4.1. Interfacial Polarization
Interfacial polarization is an effect, which is very difficult to treat in a simple manner,
and easily viewed as combination of the conduction and dipolar polarization effects.
This mechanism is important for system where a dielectric material is not
homogenous, but consists of conducting inclusion of one dielectric in other.
1.4.2. Conduction mechanism
The conduction mechanism generates heat through resistance to an electric current.
The oscillating electromagnetic field generates an oscillation of electrons or ions in a
conductor, resulting in an electric current. This current faces internal resistance,
which heats the conductor.
The main limitation of this method is that it is not applicable for materials that have
high conductivity, since such materials reflect most of the energy that falls on them.
Studies On Some Heterocyclic Compounds……
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1.5. Effects of solvents
Every solvent and reagent will absorb microwave energy differently. They each have
a different degree of polarity within the molecule, and therefore, will be affected
either more or less by the changing microwave field. A solvent that is more polar, for
example, will have a stronger dipole to cause more rotational movement in an effort
to align with the changing field. A compound that is less polar, however, will not be
as disturbed by the changes of the field and, therefore, will not absorb as much
microwave energy. Unfortunately, the polarity of the solvent is not the only factor in
determining the true absorbance of microwave energy, but it does provide a good
frame of reference. Most organic solvents can be broken into three different
categories: low, medium, or high absorber, as shown in Figure 6.
The low absorbers are generally hydrocarbons while the high absorbers are more
polar compounds, such as most alcohols.
Absorbance level Solvents
High
DMSO, EtOH, MeOH, Propanols,
Nitrobenzene, Formic Acid, Ethylene
Glycol
Medium
Water, DMF, NMP, Butanol,
Acetonitrile, HMPA, Methyl Ethyl
Ketone, Acetone, Nitromethane,
Dichlorobenzene, 1,2-Dichloroethane,
Acetic Acid, trifluoroacetic Acid,
Low
Chloroform, DCM, Carbon tetrachloride,
1,4-Dioxane, Ethy Acetate, Pyridine,
Triethyamine, Toluene, Benzene,
Chlorobenzene, Pentane, Nexane and
other hydrocarbons
Studies On Some Heterocyclic Compounds……
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1.6 Conventional vs. Microwave Heating.
Microwave heating is different from conventional heating in many respects. The
mechanism behind microwave Synthesis is quite different from conventional
synthesis. Points enlisted in Table 1, differ the microwave heating from
conventional heating.10-26
No CONVENTIONAL MICROWAVE
1 Reaction mixture heating proceeds
from a surface usually inside surface of
reaction vessels
Reaction mixture heating proceeds
directly inside mixture
2 The vessel should be in physical
contact with surface source that is at a
higher temperature source (e.g. mental,
oil bath, steam bath etc.)
No need of physical contact of
reaction with the higher temperature
source. While vessel is kept in
microwave cavities.
3 By thermal or electric source heating
take place.
By electromagnetic wave heating take
place.
4 Heating mechanism involve conduction Heating mechanism involve dielectric
polarization and conduction
5 Transfer of energy occur from the wall,
surface of vessel, to the mixture and
eventually to reacting species
The core mixture is heated directly
while surface (vessel wall) is source
of loss of heat
6 In conventional heating, the highest
temperature (for a open vessels) that
can be achieved is limited by boiling
point of particular mixture.
In microwave, the temperature of
mixture can be raised more than its
boiling point i.e. superheating take
place.
7 In the conventional heating all the
compound in mixture are heated
equally.
In microwave, specific component
can be heated specifically.
8 Heating rate is less Heating rate is several fold high
Studies On Some Heterocyclic Compounds……
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1.7 Application of microwave in organic synthesis.
Following reactions have been performed through microwave heating.
Sr
No
Reaction Ref No Sr No Reaction Ref No
1 Acetylation reaction 27 18 Diel’s-Alder reaction 44
2 Addition reaction 28 19 Dimerization reaction 45
3 Alkylation reaction 29 20 Elimination reaction 28
4 Alkynes metathesis 30 21 Estrification reaction 46
5 Allylation reaction 31 22 Enantioselective reaction 47
6 Amination reaction 32 23 Halogenation reaction 48
7 Aromatic nucleophillic
substitution reaction
33 24 Hydrolysis reaction 49
8 Arylation reaction 34 25 Mannich reaction 50
9 Carbonylation reaction 35 26 Oxidation reaction 51
10 Combinatorial reaction 36 27 Phosphorylation synthesis 52
11 Condensation reaction 37 28 Polymerization reaction 53
12 Coupling reaction 38 29 Rearrangement reaction 54
13 Cyanation reaction 39 30 Reduction reaction 55
14 Cyclization reaction 40 31 Ring closing synthesis 56
15 Cyclo-addition
reaction
41 32 Solvent free reaction 57
16 Deacetylation reaction 42 33 Transestrification reaction 46
17 Dehalogenation
reaction
43 34 Transformation reaction 58
Studies On Some Heterocyclic Compounds……
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References:
[1] (a) William A.S., Aleksel F.B., Ron C., Organic Synthesis: the science behind art.
Royal Society of Chemistry (Great Britain). (b) Organic Synthesis Coll vol. and
(c) Comprehensive organic Synthesis book volumes.
[2] For recent reviews on microwave-assisted organic synthesis see: (a) Kappe, C. O.
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Studies On Some Heterocyclic Compounds……
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INTRODUCTION
Heterocycles are abundant in nature and are of great significance to life because
their structural subunits exist in many natural products such as vitamins, hormones,
antibiotics etc[1]. Hence, they have attracted considerable attention in the design of
biologically active molecules [2]. A practical method for the synthesis of such compounds
is of great interest in synthetic organic chemistry.
The chemistry of chalcones generated intensive scientific studies throughout the
world, especially interesting for their biological and industrial applications. Chalcones are
colored compounds because of the presence of the chromophore and auxochromes. They
are known as benzalacetophenones or benzylidene acetophenones. Kostanecki and
Tambor gave the name Chalcone. The alternative names given to chalcones are phenyl
styryl ketones, b-phenyl acrylphenone, g-oxo-a,g-diphenyl-apropylene and a-phenyl-b-
benzoethylene.
The chalcones are α, β-unsaturated ketones containing the reactive ketoethylenic
group – CO – CH= CH –. Presence of α, β-unsaturated carbonyl system in chalcone
makes it biologically active. Some substituted chalcones and their derivatives have been
reported to possess some interesting biological properties such as antibacterial,
antifungal[3], insecticidal[4], anaesthetic[5], analgesic, ulcerogenic[6] etc. Chalcones,
considered as the precursor of flavonoids and isoflavonoids, are abundant in edible plants [7], and have also been shown to display a diverse array of pharmacological activities,
such as anti-protozoal [8], anti-inflammatory [9], anticancer [10] and antihyperglycemic
properties [11]. Consequently, the chalcone backbone could be a versatile scaffold for drug
design. A survey of the literature revealed that some natural [12,13] and synthetic chalcones [14] showed significant ALR2 inhibitory activities, and this prompted us to investigate
potential ARIs derived from chalcone-based compounds. Thus, we focused on the
compounds having a carboxylic acid moiety that was incorporated into the chalcone
backbone and synthesized these compounds.
Studies On Some Heterocyclic Compounds……
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SYNTHETIC ASPECT
A considerable variety of methods are available in literature for the synthesis of
chalcones. The most convenient method is the one, that involves the Claisen-Schimidt
condensation of equimolar quantities of an aryl methyl ketones with arylaldehyde in
presence of alcoholic alkali[15].
Chalcones possess conjugated double bonds and a completely delocalized Π-
electron system on both benzene rings. Molecules possessing such system have relatively
low redox potentials and have a greater probability of undergoing electron transfer
reactions. Chalcones are synthesized by claisen-schmidt condensation of aldehyde and
ketone by base catalyzed or acid catalyzed followed by dehydration to yield chalcones.
MECHANISM
The following mechanism has been suggested for the synthesis of chalcones.
CH3
O
ArOH-
CH2-
O
Ar
H2O
Ar'
O
H CH2-
O
Ar Ar'
O-
H
O
Ar
H2OH+
Ar'
OH
H
O
ArAr'
H
O
ArH2O
(i)
(ii)
+
+
+
Studies On Some Heterocyclic Compounds……
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REACTIVITY OF CHALCONES
The chalcones have been found to be useful for the synthesis of variety of
Heterocyclic compounds are as under.
(1) Pyrazolines[16] and their derivatives can be prepared by the condensation of
chalcones with hydrazine hydrate.
(2) Chalcones on reaction with semicarbazide hydrochloride in ethanol affords 1-
carboxamide pyrazolines[17].
(3) Chalcones on condensation with malononitrile and ammonium acetate yields 2-
amino-3-cyanopyridines[18].
(4) Chalcones on reaction with thiourea in presence of alkali/acid yields 2-
thiopyrimidines[19].
(5) Chalcones on treatment with guanidine hydrochloride in presence of alkali affords
2-aminopyrimidines[20].
(6) Cyanopyridone[21] derivatives can be prepared by the condensation of chalcone
with ethyl cyanoacetate.
(7) Chalcones on reaction with 2-aminopyridine in glacial acetic acid affords
pyridopyrimidines[22].
(8) Isoxazoles[23] can be prepared by the reaction of chalcones with hydroxylamine
hydrochloride and sodium acetate.
(9) Chalcones on treatment with urea in presence of alkali affords 2-oxo
pyrimidines[24].
(10) Chalcones react with monoethanolamine in ethanol gives 1,4-oxazipines[25].
(11) Oxirane[26] can be prepared by the reaction of chalcone with H2O2 in basic media.
(12) Chalcones on reaction with barbituric acid gave barbitone[27] derivatives.
(13) Chalcone gives imine derivatives with amine in presence of sulfuric acid as
catalyst[28].
(14) Chalcones on condensation with malononitrile in pyridine forms 2-amino-3-
cyanopyrans[29].
(15) Chalcones react with P2S5 yielded 2-isothiazolidines[30].
(16) Chalcones react with sodium nitrile in presence of glacial acetic acid in ethanol
produces 2-1H-pyrimidines[31].
Studies On Some Heterocyclic Compounds……
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(17) Chalcones with 2-amino thiophenol in acetic acid produces 1,5-thiazepines[32].
THERAPEUTIC IMPORTANCE
Chalcone derivatives have been found to possess wide range of therapeutic
activities as shown below.
1. Antiallergic[33]
2. Antiinflammatory[34,35]
3. Antiviral[36]
4. Anti HIV[37]
5. Carboxygenase inhibitor[38]
6. Antitumor[39,40]
7. Antimalarial[41]
8. Anticancer[42]
9. Antileishmanial[43]
10. Insecticidal[44,45]
11. Antiulcer[46]
12. Bactericidal[47,48]
13. Fungicidal[49-50]
13. Anthelmintics[51]
Mudalir and Joshi[52]reported insecticidal activity of some phenoxy chalcones. Ko
et al[53]. have prepared some new chalcones for potent inhibition of platelet aggregation.
Ziegler et al[54]. reported some chalcones as antiparasitic. The antimalarial activities of
chalcones have also been reported by Xue et al[55]. and Dominguez et al[56]. Seo et al[57].
have synthesized chalcones derivatives and reported them as a-glucosidase inhibitors.
Larsen and co-worker[58] and Wu et al[59]. have reported anti-plasmodial activity and
Boeck and et al[60]. have reported anti leishmanial activity of some chalcones. Analogs
containing nitro, fluorine or bromine group respectively displayed increased selectivity
against the parasites as compared with natural chalcone.
Studies On Some Heterocyclic Compounds……
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Shao-Jie Wang et al.[61] have synthesized chalcones derivatives (I) and reported
them as a Aldose Reductase Inhibitors.
R1
O
COOH
R2
R3
R1=CH3, OCH3 R3=H,CH3,OCH3,F,Cl
R2=H,OH,CH3
(I)
Recently Ni Liming et al.[62] have synthesized chalcones and screened for their
antiinflammatory and cardiovascular activity. Kumar Srinivas et al.[63]have synthesized
chalcones as a antitumor agent. Ko Horng-Huey et al.[64] have prepared chalcones as
antiinflammatory agent. Nakahara Kazuhiko et al.[65] have synthesized chalcones and
tested as carcinogen inhibitors. Antitubercular agents of chalcone derivatives have been
prepared by Lin Yuh-Meei et al.[66]
A. Nagaraj and C. Sanjeeva Reddy[67] reported Antimicrobial, Antifungal Activity
of some bis-chalcones (II).
R RO
HO OH
O
R = H, 4-OCH3, 4-Cl, 2-Cl,4-NO2, 4-Br
(II)
Studies On Some Heterocyclic Compounds……
Page 32
Furthermore, Alcaraz M. J. et al.[68] have described the role of nuclear factor-
kappa B and heme oxygenase-1 in the action of an anti-inflammatory Chalcone derivative
in RAW 264.7 cells. Nerya O. et al.[69] have prepared some new chalcones as potent
tyrosinase inhibitors (III).
O
OMe
OMe
OH
O
(III)
Dong Hwan Shon et al.[70] have synthesized and investigated the anti-
inflammatory activity of 2,4,6-tris(methoxymethoxy)chalcone derivatives. Liu Mei et
al.[71] have prepared chalcones and screened for antimalarial activity. Opletalova
Veronika et al.[72] have synthesized chalcones and tested as cardiovascular agents.
Moreover, it has been found that chalcone derivatives possesses nitric oxide
inhibitor[73,74] anti HIV[75,76]and antiproliferative[77,78] activities.
Moreover, Khatib S. et al.[79] synthesized some novel chalcones as potent
tyrosinase inhibitors (IV). Ko H. H. et al.[80] have prepared some new chalcones for
potent inhibition of platelet aggregation. Ziegler H. L. et al.[81] reported chalcones as an
antiparasitic. Go M. L. et al.[82] have described the synthesis and biological activities of
chalcones as antiplasmodial. A new class of sulfonamide chalcones (V) synthesized and
their glycosidase inhibitory activity[83] were investigated.
Studies On Some Heterocyclic Compounds……
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OH
HO
O
OH
OH
(IV)
O
S
O
O
HNCH3 R
(V)R = 3 OR 3,4-OH
N. Lall and co-workers[84] have synthesized 2’,4’,6’-trihydroxy-3’-
phenylchalcone and 4’,6’,5”-trihydroxy-6”,6”-dimethyldihydropyrano[2”,3”-2’,3’]
chalcone as an antiviral and antitubercular agents. M. L. Ferrnandiz et al.[85] have
synthesized phenylsulphonylurenyl chalcone derivatives with various patterns of
substitution and tested for their effect on nitric oxide (NO) and prostaglandin
E2(PGE2)overproduction in RAW 264.7 macrophages. Several derivatives selectively
inhibited cyclo-oxygenase-2 (COX-2) activity in human monocytes. C. C. Lin et
al.[86]have examined 1,3-diphenyl-2-propenone for its effect on proliferation in human
breast cancer cell lines, MCF-7 and MDA-MB-321.
Studies On Some Heterocyclic Compounds……
Page 34
Shah Alam Khan et al.[87] have synthesized some new chalcones containing 1, 4 -
dioxane ring system (VI) and reported antihepatotoxic activity.
R2
R3
R1
O
O
O
X
(VI)
Das B. P. et al.[88] have found that chalcones possesses larvicidal properties. Kim
Min-Young et al.[89] have synthesized chalcones and tested for their matrix
metalloproteinase inhibitor activity. Satyanarayana M. et al.[90] have synthesized chalcone
derivatives as antihyperglycemic activity (VII).
O
O
OH
NH3C
CH3
R
(VII)
Studies On Some Heterocyclic Compounds……
Page 35
Prem P. Yadav and co-workers[91] have synthesized nitrogen and sulfur containing
furanoflavonoids and thiophenylflavonoids (VIII), which have been screened for
antifungal and antibacterial activity. Meng C. Q. et al.[92] discovered some novel hetero
aryl substituted chalcones as inhibitors of TNF-alpha-induced VCAM-1 expression (IX).
X OH
O
R
X = NCH3/S
R = H/OCH3(VIII)
H3CO
H3CO
OCH3
O OCH3
OCH3
S
(IX)
Studies On Some Heterocyclic Compounds……
Page 36
Simon F. Nielsen et. al.[93]have been describes how the introduction of “cationic”
aliphatic amino groups in the Chalcone scaffold results in potent antibacterial compounds
morever Leroy Krbechek et. al.[94] describes three new, sweet dihydrochalcones and
related compounds (XI, XII), One of these, 2’,4’,6‘,3 - tetrahydroxy - 4 - n -
propoxydihydro-chalcone 4‘-/3-neohesperidoside, was found to be preapproximately
2000 times sweeter than sucrose on a weight basis.
HO
O O
OH
(X)
OHRO
OH
C
O
CH2
H2C
X
Y
OHRO
OH
C
O
CH
HC
X
Y
(XI) (XII)
Studies On Some Heterocyclic Compounds……
Page 37
Chalcones have been proved to be an important intermediate for the synthesis of
many heterocyclic compounds in organic chemistry. These facts prompted us to
synthesize some new chalcone derivatives in order to achieving better therapeutic agents
described as under.
With the biodynamic activities of chalcones and it is a good synthon for various
heterocyclic rings, the interest has been focused on the synthesis of new chalcones. With
a view to obtained compounds having better therapeutic activity, we have synthesized 2-
(4-Acetylphenylamino) pyridine-3-carbonitrile with various aromatic aldehydes in
presence of catalytic amount of alkali.
Studies On Some Heterocyclic Compounds……
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Part - 1 STUDIES ON Chalcones OF 2-(4-Acetylphenylamino) pyridine-3-carbonitrile
With the biodynamic activities of chalcones and it is a good synthon for various
heterocyclic rings, the interest has been focused on the synthesis of new chalcones. With
a view to obtained compounds having better therapeutic activity, we have synthesized
chalcones of 2-(4-Acetylphenylamino) pyridine-3-carbonitrile with various aromatic and
aliphatic aldehydes.
N NH
CNR
O
TYPE (I) R= ARYL
The constitution of the synthesized products have been characterized by using
elemental analysis, infrared and 1H-nuclear magnetic resonance spectroscopy and further
supported by mass spectroscopy.
All the compounds have been evaluated for their in vitro biological assay like
antibacterial activity towards Gram positive and Gram negative bacterial strains and
antifungal activity towards A.niger and C.albicans at a concentration of 40μg/ml. The
biological activities of synthesized compounds were compared with standard drugs.
Studies On Some Heterocyclic Compounds……
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N NH
CNR
O
N NH
CN COCH3
RCHO
40% KOH
N Cl
CN
H2N
COCH3
2-3 Drops con HCl
EtOH
TYPE (I) R= Aryl
Reaction Scheme
Studies On Some Heterocyclic Compounds……
Page 40
IR Spectral study of 2-(4-(3-(4-methoxyphenyl)acryloyl) phenylamino)pyridine-3-carbonitrile
Type Vibration Mode Frequency cm-1
References
Alkane
C-H str. (asym.) C-H str. (sym.)
C-H def. (asym.) C-H def. (sym.)
2808 2760 1498 1342
95 ,, ,, ,,
Aromatic C-H str. C=C
3101 1525
95 ,,
Azomethane N=C str. C-N str.
1593 1280
96 ,,
Nitrile N-H str. (sym.) C=N str.
3367 2222
96 ,,
N NH
O
CN
OCH3
Studies On Some Heterocyclic Compounds……
Page 41
1H NMR spectral study of 2-(4-(3-(4-methoxyphenyl)acryloyl) phenylamino)pyridine-3-carbonitrile
Signal No Signal Position
δppm
Relative No
Of Protons
Multiplicity Inference
1 3.8 3H Singlet -OCH3 (f)
2 6.7 2H Doublet -CH (h, h’)
3 7.9-7.7 2H double doublet Vin (a-b)
4 8.2 1H Singlet (broad) -NH (e)
5 8.4 1H Doublet -CH (k)
N
CN
NH
OCH3
O
a
b c
c'
d
d'
e
f
g
g'
h
h'
ij
k
Studies On Some Heterocyclic Compounds……
Page 42
Mass spectral study of 2-(4-(3-(4-methoxyphenyl)acryloyl) phenylamino)pyridine-3-carbonitrile
N
NH
O
NC
OCH3
C22
H17
N3O
2M
ol. W
t.: 3
55
Studies On Some Heterocyclic Compounds……
Page 43
EXPERIMENTAL
Synthesis of chalcones of 2-(4-ACETYLPHENYLAMINO) PYRIDINE-3-
CARBONITRILE
(A) Preparation of 2-(4-acetylphenylamino)pyridine-3-carbonitrile.
A Mixture of 2-chloro-3-cyanopyridine (0.01 M), p-aminoacetophenone (0.01 M)
and few drops of Con HCl, taken in RBF with 20 ml Ethanol and was refluxed for
16 hours on water bath. Contain was allowed to cool at room temperature for 30
minutes, the separated solid was collected and washed with cold ethanol,
crystallized from hot ethanol. Yield 80%, m.p. 163°C. (C14H13N3O; required: C
70.87%, H 4.46%, N 17.71%, found: C 70.63%, H 4.31%, N 17.65%).
(B) Preparation of 2-(4-(3-phenylacryloyl)phenylamino)pyridine-3-carbonitrile.
A Solution of Benzaldehyde (0.01 M) in minimum quantity of DMF (5 ml) was
added to the mixture of 2-(4-acetylphenylamino)pyridine-3-carbonitrile in 15ml
DMF and 40% KOH was added to make mixture alkaline, the reaction mixture
was then stirred for 24 hours at room temperature. The product was isolated by
adding mixture in cold water and crystallized it from DMF. Yield 77%, m.p.
254°C. (C21H15N3O; required: C 77.52%, H 4.65%, N 12.91%; found: C 77.39%,
H 4.53%, N 12.86%).
Similarly other substituted chalcones were prepared. The physical constants are
recorded in Table No. 1.
Studies On Some Heterocyclic Compounds……
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(C) Biological evaluation of 2-(4-(3-phenylacryloyl)phenylamino)pyridine-3-
carbonitrile
All the products have been evaluated for Antimicrobial activity as describe under.
(I) Antibacterial activity.
The purified products were screened for their antibacterial activity. The nutrient
agar broth prepared by the usual method, was inoculated aseptically with 0.5 ml of 24
hrs. old subcultures of B. subtilis, S. aureus, E. coli and P. aeruginosa in separate conical
flasks at 40-50oC and mixed well by gently shaking. About 25 ml content of the flasks
were poured and evenly spreaded in a petridish (13 cm in diameter) and allowed to set for
two hrs. The cups (10 mm in diameter) were formed by the help of borer in agar medium
and filled with 0.04 ml (40 μg) solution of sample in DMF. The plates were incubated at
37OC for 24 hrs and the inhibition of the bacterial growth were measured in millimetre
and recorded as shown in Table No. 2.
(II) Antifungal activity
A. niger and C. albicans was employed for testing antifungal activity using cup-
plate method. The culture was maintained on Sabouraud's agar slants. Sterilised
Sabouraud's agar medium was inoculated with 72 hrs. old 0.5 ml suspension of fungal
spores in a separate flask. About 25 ml of the inoculated medium was evenly spreaded in
a petridish and allowed to set for two hrs. The cups (10 mm 34 in diameter) were
punched. The plates were incubated at 30°C for 48 hrs. After the completion of
incubation period, the zone of inhibition of growth in the form of diameter in mm was
measured. Along the test solution in each petridish one cup was filled up with solvent
which acts as control. The zones of inhibition are recorded in Table No. 2.
Studies On Some Heterocyclic Compounds……
Page 45
Table No. 1: Physical Data of 2-(4-(3-phenylacryloyl)phenylamino)pyridine-3-carbonitrile.
Studies On Some Heterocyclic Compounds……
Page 46
Table No. 2: Biological Evaluation Of 2-(4-(3-phenylacryloyl)phenylamino)pyridine-3-carbonitrile.
Compounds R= Aryl Antibacterial Activity Antifungal Activity
B. subtilis s. aureus P.
aeruginosa E. coli A. niger C. albicans
1a 3-NO2-C6H4-
19 17 16 13 11 9
1b 4-Cl-C6H4- 14 13 18 19 13 10 1c C4H3O- 13 16 10 13 7 6 1d C6H5- 8 10 9 5 3 0
1e N,N-(CH3)2-C6H4-
19 11 10 14 9 8
1f 4-OCH3-C6H4-
18 15 14 14 5 2
1g 2-OH- C6H4-
21 18 16 20 4 4
1h 2-Cl- C6H4- 15 14 12 15 9 8
1i 4-OCH3-2-OH-C6H4-
12 11 14 9 5 6
1j 4-OH- C6H4-
11 9 15 11 3 5
1k 3,4-
(OCH3)2-C6H4- 18 14 14 12 7 8
1l 2-OH-C10H6 10 13 8 9 5 3 1m C8H6N- 7 9 5 8 9 11 1n C7H14- 12 9 14 10 8 5
1o 2,5-
(OCH3)2-C6H4- 12 15 11 13 7 7
1p 3,5-Cl2-2-OH-C6H4- 20 17 15 18 14 11
Sparfloxacin 25 24 25 22 - - Benzy
penicillin 17 18 16 16 - - Sparfloxacin 19 23 20 20 - - Fluconazole - - - - 22 20
Studies On Some Heterocyclic Compounds……
Page 47
ANTIBACTERIAL ACTIVITY:
From screening results, substituted schiff base 1b (R = -4-Cl-C6H4-) possesses
very good against E. coli compared with Benzyl penicillin while 1e (R = - N,N-(CH3)2-
C6H4-) and 1g (R= -2-OH- C6H4-) against B. subtilis, 1a (R= -3-NO2-C6H4-) and 1p (R= -
3,5-Cl2-2-OH-C6H4-) against E-coli and B. subtilis possesses moderate activity compared
with standard. The remaining chalcones possess modrate to poor activity against all four
bacterial species.
ANTIFUNGAL ACTIVITY:
Antifungal screening data showed that substituted chalcones 1p (R = -3,5-Cl2-2-
OH-C6H4-) and 1b (R= -4-Cl-C6H4-) against A. niger show promising activity compare
with standard drug while 1m (R = - C8H6N-) and 1p (R= 3,5-Cl2-2-OH-C6H4-) , against
C. albicans shows good activity compare with standard drug. The remaining compounds
exhibited only moderate to poor activity.
Studies On Some Heterocyclic Compounds……
Page 48
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Studies On Some Heterocyclic Compounds……
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INTRODUCTION
Pyrazolines are well known and important nitrogen containing 5-membered heterocyclic
compounds and various methods have been worked out for their synthesis. Numerous
pyrazoline derivatives have been found to possess considerable biological activities,
which stimulated the research activity in this field. They have several prominent effects,
such as antimicrobial, antimycobacterial, antifungal, antiamoebic, anti-inflammatory,
analgesic, antidepressant and anticancer activities. They also possess some potent
receptor selective biological activity like Nitric oxide synthase (NOS) inhibitor and
Cannabinoid CB1 receptor antagonists activity. 4,5-dihydro-1H- pyrazolines seem to be
the most frequently studied pyrazoline type compounds.
NH
N
As a result, a large number of such pyrazolines using different synthetic methods for their
preparation have been described in the chemistry literature. The present review provides
an insight view to pyrazolines synthesis and its biological activities.
Studies On Some Heterocyclic Compounds……
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SYNTHETIC ASPECTS
Different methods for the preparation of 2-pyrazoline derivatives documented in
literature are as follows.
N
NR R1
O
R2NHNH2
R2
R1
R
1. The most common procedure for the synthesis of 2-pyrazolines is thereaction of an
aliphatic or aromatic hydrazine with α,β-unsaturated carbonyl compounds.
2. Epoxidation of chalcones gave epoxy ketones which reacted with hydrazine and
phenyl hydrazine to give pyrazolines1.
3. A number of diarylidene cycloalkanones on reaction with hydrazine hydrate produce
pyrazolines2.
4. Dipolar cyclo addition of nitrilimines to dimethyl fumarate, fumaro nitrile and the N-
aryl maleimides yields the corresponding pyrazolines3.
5. Reaction of Et 2-(phenylazo)-3-oxobutanoates with nicotinic acid hydrazide using
glacial acetic acid gives following type of pyrazoline derivatives4.
Studies On Some Heterocyclic Compounds……
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REACTION MECHANISM
The following mechanism seems to be operable for the condensation of chalcones with
hydraz
Nucleophilic attack by hydrazine at the β-carbon of the α,β-unsaturayed carbonyl system
forms species (II), in which the -ve charge is mainly accommodated by the electro
negative oxygen atom. Proton transfer from the nitrogen to –ve oxygen produces an
intermediate enol which simultaneously ketonises to ketoamine (III). Another
intermolecular nucleophilic attack by the primary amino group of ketoamine on its
carbonyl carbon followed by proton transfer from nitrogen to oxygen leads ultimately to
carbonyl amine (IV). The later with a hydroxy group and amino group on the same
carbon lose water easily to yield the pyrazolines.
Studies On Some Heterocyclic Compounds……
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THERAPEUTIC EVALUATION
From the literature survey, it was revealed that 2-pyrazoline derivatives are better
therapeutic agents.
1. Diuretic6
2. Anticonvulsant7
3. Herbicidal8
4. Bactericidal9
5. Antiallergic10
6. Insecticidal11
7. Antiimplantation12
8. Analgesic13
9. Antitumor14
10. Antiinflammatory15
11. Leukotriene inhibitor16
12. Fungicidal17
N. Richard18 investigated pyrazolines bis phosphonate ester as novel antiinflammatory
and antiarthritic agent. Some new 1,3,5-substituted-2- pyrazolines (VI) have been
described for their antimicrobial activity.19
Studies On Some Heterocyclic Compounds……
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T. Atif and co-workers20 have patented 3-methyl-4'-(substituted phenylazo)- pyrazol-5-
ones as antibacterial agents. R. H. Udupi and A. R. Bhat21 have reported the synthesis and
biological activity of Mannich bases of certain 1,2- pyrazolines. Pyrazoline derivatives of
salicylic acid possessing antimicrobial properties have been reported22. T. M. Stavenson
et al.23 have investigated N-substituted pyrazoline type insecticides. T. Katsuhori24 have
patented pyrazoline derivatives as herbicides. Pyrazolines derivatives showing significant
antibacterial activity are described25.
CONTRIBUTION FROM OUR LABORATORY
Several pyrazolines bearing thymol moiety were evaluated for their ability as potent
antimicrobial by K. P. Roda.26 Jatin Upadhyay et al.27 have described the pyrazoline
derivatives and their use as antimicrobial agents. H. J. Vikani and co-workers28 have
prepared pyrazoline derivatives from arsanilic acid for their antimicrobial activity. Parekh
et al.29 have synthesised and reported the
antimicrobial activity of pyrazoline derivatives. Parekh et al.30 have prepared 1-acetyl-5-
aryl-3-[3-(3,4-dihydro-2-methyl- 4-one-3-quinazolinyl)-phenyl]-2-pyrazolines which
possess antimicrobial activity.
Akhil Bhatt and co-workers31 have reported pyrazoline derivatives showing antimicrobial
activity. Parekh et al.32 have synthesised acetyl pyrazoline derivatives bearing quinoline
moiety (VII) and described their antimicrobial activity.
Studies On Some Heterocyclic Compounds……
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Moreover, some pyrazoline derivatives have been studied for their antidepressant
activity33. Eggenweiler and co-workers34 have reported some pyrazoline derivatives as
inhibitors of cGMP and cAMP phosphodiesterase. Pyrazoline derivatives of anthranilic
acid (VIII) as potent antiinflammatory agents have been investigated35. Maurer et al.36
have prepared pyrazolines and reported their pesticidal activity. K. Mogilaiah and
Sudhakar37 have prepared 1,8-naphthyridinyl-2-pyrazolines and studied their antibacterial
activity.
Looking to the diversified activities exhibited and in continuation of our work on the
synthesis of biologically active compounds, the synthesis and biological screening of
pyrazoline derivatives have been described as under.
Studies On Some Heterocyclic Compounds……
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Section-I Conventional and Microwave assisted Synthesis, biological
evaluation of 2-(4-(4,5-dihydro-5-Aryl-1H-pyrazol-3-
yl)phenylamino)pyridine-3-carbonitrile.
Section-II Conventional and Microwave assisted Synthesis, biological
evaluation of 2-(4-(1-acetyl-4,5-dihydro-5-Aryl-1H-pyrazol-
3-yl)phenylamino)pyridine-3-carbonitrile.
Section-III Conventional and Microwave assisted Synthesis, biological
evaluation of 2-(4-(1-phenyl-4,5-dihydro-5-Aryl-1-
phenylpyrazol-3-yl)phenylamino)pyridine-3-carbonitrile.
Studies On Some Heterocyclic Compounds……
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Section-I
Conventional and Microwave assisted Synthesis, biological evaluation of 2-(4-(4,5-
dihydro-5-Aryl-1H-pyrazol-3-yl)phenylamino)pyridine-3-carbonitrile.
Considerable attention has been focused on the development and synthesis of pyrazolines
of type (II) for obtaining biologically potent molecules which have been prepared by the
condensation of chalcones of type (I) with hydrazine hydrate.
N NH
CNR
N NH
N NH
CNR
O
NH2NH2
EtOH
R= ArylType II
All the compounds have been evaluated for their in vitro biological assay like
antibacterial activity towards Gram positive and Gram negative bacterial strains and
antifungal activity towards A. niger and C. Albicans. The biological activities of
synthesized compounds were compared with standard drugs.
Studies On Some Heterocyclic Compounds……
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IR Spectral Study of 2-(4-(4,5-dihydro-5-(4-methoxyphenyl)-1H-pyrazol-3-yl)phenylamino)pyridine-3-carbonitrile.
Type Vibration Mode Frequency cm-1 Referance Alkane -C-H Str (asym)
-C-H Str (sym) -C-H def. (asym.) -C-H def. (sym.)
2958 2870 1417 1336
38 ,, ,, ,,
Aromatic -C-H str -C=C -C-H o.o.p. def.
3103 1550 831
,, ,, ,,
Pyrazoline C=N str C–N str
1519 1253
,, ,,
Amine N-H str 3302 39 Nitrile -C≡N 2353 ,,
N NH
CN
N NH
OCH3
Studies On Some Heterocyclic Compounds……
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1H NMR Spectral Study Of 2-(4-(4,5-dihydro-5-Phenyl-1H-pyrazol-3-yl)phenylamino)pyridine-3-carbonitrile.
Signal
No
Signal Position δppm Relative No Of
Protons
Multiplicity Inference
1 2.3 1H Triplet -CHx
2 2.5-2.6 2H Double doublet -CH2 (Ha. Hb)
3 6.8 2H Doublet -Ar CH (g, g’)
4 6.9-7.2 4H Multiplate
(overlap)
-Ar CH
(c, c’, e, j)
5 7.4 1H Singlet (broad) -NH(y)
6 8.2 1H Singlet -NH(h)
N
CN
NH
N NH
Ha, Hb
x cd
c'd'
e
f
f'g'
g
hi
j
k
y
Studies On Some Heterocyclic Compounds……
Page 65
Mass Spectral Study of 2-(4-(4,5-dihydro-5-(4-methoxyphenyl)-1H-pyrazol-3-yl)phenylamino)pyridine-3-carbonitrile.
N
NHNC
N
HN
OCH3
C 22H
19N
5OM
ol. W
t.: 3
69
Studies On Some Heterocyclic Compounds……
Page 66
EXPERIMENTAL
Conventional and Microwave assisted Synthesis, biological evaluation of 2-(4-(4,5-
dihydro-5-Aryl-1H-pyrazol-3-yl)phenylamino)pyridine-3-carbonitrile.
[A] Synthesis of 2-(4-(3-phenylacryloyl)phenylamino)pyridine-3-carbonitrile.
A Solution of Benzaldehyde (0.01 M) in minimum quantity of DMF (5 ml) was
added to the mixture of 2-(4-acetylphenylamino)pyridine-3-carbonitrile in 15ml DMF
and 40% KOH was added to make mixture alkaline, the reaction mixture was then stirred
for 24 hours at room temperature. The product was isolated by adding mixture in cold
water and crystallized it from DMF. Yield 77%, m.p. 254°C. (C21H15N3O; required: C
77.52%, H 4.65%, N 12.91%; found: C 77.39%, H 4.53%, N 12.86%).
[B] Synthesis of 2-(4-(4,5-dihydro-5-phenyl-1H-pyrazol-3-yl)phenylamino)pyridine-
3-carbonitrile.
A mixture of 2-(4-(3-phenylacryloyl)phenylamino)pyridine-3-carbonitrile (0.01
M) and hydrazine hydrate (0.05 M) in 25 ml Ethanol was refluxed for 10 hrs. The
solution was poured into crushed ice and neutralize with dilute HCl solution. Product was
isolated and crystallized from ethanol. Yield 65%, m.p. 1870C.
Similarly other 2-(4-(4,5-dihydro-5-Aryl-1H-pyrazol-3-yl)phenylamino)pyridine-
3-carbonitrile were prepared, The physical data are recorded in the Table no-3.
[C] Biological evaluation of 2-(4-(4,5-dihydro-5-Aryl-1H-pyrazol-3-
yl)phenylamino)pyridine-3-carbonitrile.
All the products have been evaluated for Antimicrobial activity as describe in
part-I. The results of the solutions are recorded in Table No. 4.
Studies On Some Heterocyclic Compounds……
Page 67
Table No. 3. Physical Data Table of 2-(4-(4,5-dihydro-5-Aryl-1H-pyrazol-3-yl)phenylamino)pyridine-3-carbonitrile.
Studies On Some Heterocyclic Compounds……
Page 68
Table No. 4. Biological evalution of 2-(4-(4,5-dihydro-5-Aryl-1H-pyrazol-3-yl)phenylamino)pyridine-3-carbonitrile.
Compounds R= Aryl Antibacterial Activity Antifungal Activity
B.
subtilis s.
aureus P.
aeruginosa E.
coli A.
niger C.
albicans
2a 3-NO2-C6H4-
16 9 11 15 13 9
2b 4-Cl-C6H4-
8 13 18 11 17 13
2c C4H3O- 15 8 9 12 9 15 2d C6H5- 11 5 6 8 10 9
2e N,N-(CH3)2-C6H4-
13 16 11 15 14 18
2f 4-OCH3-C6H4-
17 19 13 14 17 12
2g 2-OH- C6H4-
15 17 17 13 12 13
2h 2-Cl- C6H4-
15 8 11 12 10 17
2i 4-OCH3-2-OH-C6H4-
10 13 6 9 16 14
2j 4-OH- C6H4-
11 8 13 11 12 9
2k 3,4-(OCH3)2-C6H4-
17 16 12 7 9 7
2l 2-OH-C10H6
8 11 8 10 5 11
2m C8H6N- 9 13 14 6 9 14 2n C7H14- 11 9 11 15 14 14
2o 2,5-(OCH3)2-C6H4-
18 12 5 14 17 7
2p 3,5-Cl2-2-OH-C6H4-
18 9 12 16 13 18
Sparfloxacin 25 24 25 22 - - Benzy
penicillin 17 18 16 16 - -
Ampicillin 19 23 20 20 - - Fluconazole - - - - 22 20
Studies On Some Heterocyclic Compounds……
Page 69
ANTIBACTERIAL ACTIVITY:
From screening results, substituted pyrazoline 2p (R = -3,5-Cl2-2-OH-C6H4-) and
2o (R= 2,5-(OCH3)2-C6H4-) possesses very good activity against B. subtilis compared
with Benzyl penicillin while 2b (R = 4-Cl-C6H4-) against P. aeruginosa, The remaining
pyrazoline derivatives possess moderate to poor activity against all four bacterial species.
ANTIFUNGAL ACTIVITY:
Antifungal screening data showed that substituted pyrazoline 2e (R = N,N-
(CH3)2-C6H4-) and 2p (R= 3,5-Cl2-2-OH-C6H4-) against C.albicans, While 2b (R= 4-Cl-
C6H4-) and 2o (R = 2,5-(OCH3)2-C6H4-) against A.niger, show highly promising activity
compare with standard drug. While remaining compounds exhibited moderate to poor
activity against both bacterial species.
Studies On Some Heterocyclic Compounds……
Page 70
SECTION-II
Conventional and Microwave assisted Synthesis, biological evaluation of 2-(4-(1-
acetyl-4,5-dihydro-5-Aryl-1H-pyrazol-3-yl)phenylamino)pyridine-3-carbonitrile.
Looking to the interesting properties of pyrazolines, with an intension to
synthesizing better therapeutic agents, pyrazoline derivatives of Type-III has been
synthesized.
The constitution of the synthesized products have been characterized by using elemental
analysis, Infrared and 1H-nuclear magnetic resonance spectroscopy and further supported
by mass spectroscopy.
All the compounds have been evaluated for their in vitro biological assay
like antibacterial activity towards gram positive and gram negative bacterial
strains and antifungal activity towards A.niger and C.Albicans. The biological
activities of synthesized compounds were compared with standard drugs.
N
CN
NH
O
R
R= Aryl
N
CN
NH
N
R
2-(4-((3-phenylacryloyl)phenylamino)pyridine-3-carbonitrile
N
COCH3
2-(4-((3-arylacryloyl)phenylamino)pyridine-3-carbonitrile
AcOH, NH2NH2
Type-III
Studies On Some Heterocyclic Compounds……
Page 71
IR Spectral Study Of 2-(4-(1-acetyl-4,5-dihydro-5-(3,4-dimethoxyphenyl)-1H-pyrazol-3-yl)phenylamino)pyridine-3-carbonitrile.
Type Vibration Mode Frequency cm-1 Reference
Alkane -C-H str. (asym.)
-C-H str. (sym.)
-C-H def. (asym.)
-C-H def. (sym.)
2932
2860
1458
1367
38
,,
,,
,,
Aromatic -C=C str.
-C-H
1518
839
,,
,,
Pyrazoline -C=O str.
-C=N str
-C-N str.
1664
1606
1182
,,
,,
,,
Amine -N-H str 3310 39
Nitrile -C≡N 2210 ,,
N NH
CN
N N
OCH3
OCH3
COCH3
Studies On Some Heterocyclic Compounds……
Page 72
1H NMR Spectral Study Of 2-(4-(1-acetyl-4,5-dihydro-5-phenyl-1H-pyrazol-3-yl)phenylamino)pyridine-3-carbonitrile.
Signal No Signal Position δppm
Relative No Of Protons
Multiplicity Inference
1 2.1 3H Singlet -COCH3 (g) 2 3.3-3.5 2H Double doublet -CH (a, b) 3 5.6 1H Doublet -CH (c) 4 6.8 2H Double
Doublet -CH (i, i’)
5 8.1 1H Doublet -CH (m) 6 8.4 1H Singlet (broad) -NH (j)
N
CN
NH
N N
COCH3
a, b
c d
d'
e
e'f
g
h
h'
i'
i
jk
l
m
Studies On Some Heterocyclic Compounds……
Page 73
Mass Spectral Study Of 2-(4-(1-acetyl-4,5-dihydro-5-(3,4-dimethoxyphenyl)-1H-pyrazol-3-yl)phenylamino)pyridine-3-carbonitrile.
N
NHNC
N
N
OCH3H3CO
H3COC
C25
H23
N5O
3M
ol. W
t.: 4
41
Studies On Some Heterocyclic Compounds……
Page 74
EXPERIMENTAL
Conventional and Microwave assisted Synthesis, biological evaluation of 2-(4-(1-
acetyl-4,5-dihydro-5-Aryl-1H-pyrazol-3-yl)phenylamino)pyridine-3-carbonitrile.
[A] Synthesis of 2-(4-(3-phenylacryloyl)phenylamino)pyridine-3-carbonitrile.
A Solution of Benzaldehyde (0.01 M) in minimum quantity of DMF (5 ml) was
added to the mixture of 2-(4-acetylphenylamino)pyridine-3-carbonitrile in 15ml DMF
and 40% KOH was added to make mixture alkaline, the reaction mixture was then stirred
for 24 hours at room temperature. The product was isolated by adding mixture in cold
water and crystallized it from DMF. Yield 77%, m.p. 254°C. (C21H15N3O; required: C
77.52%, H 4.65%, N 12.91%; found: C 77.39%, H 4.53%, N 12.86%).
[B] Synthesis of 2-(4-(1-acetyl-4,5-dihydro-5-phenyl-1H-pyrazol-3-
yl)phenylamino)pyridine-3-carbonitrile.
A mixture of 2-(4-(3-phenylacryloyl)phenylamino)pyridine-3-carbonitrile (0.01
M) and hydrazine hydrate (0.05 M) in 15 ml glac acetic acid was refluxed for 8 hrs. The
solution was poured into crushed ice and product was isolated and crystallized from
ethanol. Yield 70%, m.p. 2100C.
Similarly other 2-(4-(1-acetyl-4,5-dihydro-5-pheyl-1H-pyrazol-3-
yl)phenylamino)pyridine-3-carbonitrile were prepared, The physical data are recorded in
the Table No. 5.
[C] Biological evalution of 2-(4-(1-acetyl-4,5-dihydro-5-Aryl-1H-pyrazol-3-
yl)phenylamino)pyridine-3-carbonitrile.
All the products have been evaluated for Antimicrobial activity as describe in
Part-I, The zone of inhibition of test solutions are recorded in Table No. 6.
Studies On Some Heterocyclic Compounds……
Page 75
Table No. 5 Past Physical Data of 2-(4-(1-acetyl-4,5-dihydro-5-Aryl-1H-pyrazol-3-yl)phenylamino)pyridine-3-carbonitrile.
Studies On Some Heterocyclic Compounds……
Page 76
Table No. 6 Biological activity of 2-(4-(1-acetyl-4,5-dihydro-5-Aryl-1H-pyrazol-3-yl)phenylamino)pyridine-3-carbonitrile.
Compounds R= Aryl Antibacterial Activity Antifungal Activity
B. subtilis
s. aureus
P. aeruginosa E. coli A.
niger C.
albicans 3a 3-NO2-C6H4- 12 15 20 14 14 18 3b 4-Cl-C6H4- 16 17 18 19 11 19 3c C4H3O- 13 11 10 13 10 7 3d C6H5- 9 5 8 6 9 5
3e N,N-(CH3)2-C6H4-
15 10 16 10 15 11
3f 4-OCH3-C6H4- 17 15 11 18 12 7 3g 2-OH- C6H4- 15 11 18 19 9 13 3h 2-Cl- C6H4- 11 18 10 12 5 11
3i 4-OCH3-2-OH-C6H4-
12 16 11 13 16 13
3j 4-OH- C6H4- 13 9 11 16 13 11
3k 3,4-(OCH3)2-C6H4-
18 15 19 17 18 12
3l 2-OH-C10H6 11 16 10 8 11 16 3m C8H6N- 9 11 10 13 9 5 3n C7H14- 12 9 12 11 6 10
3o 2,5-(OCH3)2-C6H4-
17 11 16 18 15 11
3p 3,5-Cl2-2-OH-C6H4-
21 17 17 18 18 13
Sparfloxacin 25 24 25 22 - - Benzy
penicillin 17 18 16 16 - -
Ampicillin 19 23 20 20 - - Fluconazole - - - - 22 20
Studies On Some Heterocyclic Compounds……
Page 77
ANTIBACTERIAL ACTIVITY:
From screening results, substituted acetyl pyrazoline 3p (R = -3,5-Cl2-2-OH-
C6H4-) and 3k (R= 3,4-(OCH3)2-C6H4-) possesses very good activity against B. subtilis
compared with Benzyl penicillin while 3a (R = 3-NO2-C6H4-) and 3k (R = 3,4-(OCH3)2-
C6H4-) against P. aeruginosa, 3b (R= 4-Cl-C6H4-), 3g (R= 2-OH- C6H4-) and 3p (R= -
3,5-Cl2-2-OH-C6H4-) possesses good activity against E.coli. The remaining acetyl
pyrazoline derivatives possess modrate to poor activity against all four bacterial species.
ANTIFUNGAL ACTIVITY:
Antifungal screening data showed that substituted acetyl pyrazoline 3b (R = 4-Cl-
C6H4-) against C.albicans, While 3k (R= 3,4-(OCH3)2-C6H4-) and 3p (R = 3,5-Cl2-2-OH-
C6H4-) against A.niger, show highly promising activity compare with standard drug.
While remaining compounds exhibited moderate to poor activity against both bacterial
species.
Studies On Some Heterocyclic Compounds……
Page 78
SECTION-III
Conventional and Microwave assisted Synthesis, biological evaluation of 2-(4-(1-
phenyl-4,5-dihydro-5-Aryl-1-phenylpyrazol-3-yl)phenylamino)pyridine-3-
carbonitrile.
With a view of getting better therapeutic agents and considering the association of
various biological activities the preparation of pyrazolines of type-IV have been under
taken. The constitution of the synthesized products have been characterized by using
elemental analysis, Infrared, 1H-NMR and further supported by mass spectroscopy.
All the compounds have been evaluated for their in vitro biological assay like
antibacterial activity towards gram positive and gram negative bacterial strains and
antifungal activity towards A.niger and C.Albicans. The biological activities of
synthesized compounds were compared with standard
drugs.
N
CN
NH
O
R
R= Aryl
N
CN
NH
N
R
N
Ph
2-(4-((3-arylacryloyl)phenylamino)pyridine-3-carbonitrile
Type-IV
2-(4-(1-phenyl-4,5-dihydro-5-Aryl-1-phenylpyrazol-3-yl)phenylamino)pyridine-3-carbonitrile
PhNHNH2
Studies On Some Heterocyclic Compounds……
Page 79
IR spectral Study Of 2-(4-(5-(3,5-dichloro-2-hydroxyphenyl)-4,5-dihydro-1-phenyl-1H-pyrazol-3-yl)phenylamino)pyridine-3-carbonitrile.
Type Vibration Mode Frequency cm-1 Reference
Alkane C-H str. (asym.) C-H str. (sym.) C-H def. (asym.) C-H def. (sym.)
2907 2848 1429 1340
38 ,, ,, ,,
Aromatic C-H str. C=C str. -C-Cl str
3103 1462 752
,, ,, ,,
Pyrazoline C=N str. N-Ph
1585 1508
,,
Amine -N-H str 3331 39
Nitrile -C≡N 2218 ,,
N
CN
NH
N OH
Cl
Cl
N
Studies On Some Heterocyclic Compounds……
Page 80
1H NMR Spectral Study Of 2-(4-(4,5-dihydro-5-(4-methoxyphenyl)-1-phenyl-1H-pyrazol-3-yl)phenylamino)pyridine-3-carbonitrile.
Signal No Signal Position
δppm
Relative No
Of Protons
Multiplicity Inference
1 2.6 1H Double Doublet -CHa
2 2.4 1H Double Doublet -CHb
3 3.3 3H Singlet -CH3 (m)
4 5.3 1H double doublet -CH (x)
5 6.4 2H Doublet -CH (h,h’)
6 6.5 2H Doublet -CH (b,b’)
7 7.7 2H Doublet -CH (g,g’)
8 8.2 1H Singlet (broad) -NH
N NH
CN
N N
OCH3
x
Ha, Hb
a
a'
b
b'
c
c'
e
e'
f
g
g'
h
h'
i
j
k
l
m
Studies On Some Heterocyclic Compounds……
Page 81
Mass Spectral Study Of 2-(4-(5-(3,5-dichloro-2-hydroxyphenyl)-4,5-dihydro-1-phenyl-1H-pyrazol-3-yl)phenylamino)pyridine-3-carbonitrile.
N
NHNC
N
N
Cl
HO Cl
C 27H
1 9C
l 2N5O
Mol
. Wt.:
500
.38
Studies On Some Heterocyclic Compounds……
Page 82
EXPERIMENTAL [A] Synthesis of 2-(4-(3-phenylacryloyl)phenylamino)pyridine-3-carbonitrile.
A Solution of Benzaldehyde (0.01 M) in minimum quantity of DMF (5 ml) was
added to the mixture of 2-(4-acetylphenylamino)pyridine-3-carbonitrile in 15ml DMF
and 40% KOH was added to make mixture alkaline, the reaction mixture was then stirred
for 24 hours at room temperature. The product was isolated by adding mixture in cold
water and crystallized it from DMF. Yield 77%, m.p. 254°C. (C21H15N3O; required: C
77.52%, H 4.65%, N 12.91%; found: C 77.39%, H 4.53%, N 12.86%).
[B] Synthesis of 2-(4-(1-phenyl-4,5-dihydro-5-phenyl-1H-pyrazol-3-
yl)phenylamino)pyridine-3-carbonitrile.
A mixture of 2-(4-(3-phenylacryloyl)phenylamino)pyridine-3-carbonitrile (0.01
M) and Phenyl hydrazine (0.01 M) in 25 ml Ethanol was refluxed for 10 hrs. The solution
was poured into crushed ice and neutralize with dilute HCl solution. Product was isolated
and crystallized from ethanol. Yield 70%, m.p. 2540C.
Similarly other 2-(4-(1-phenyl-4,5-dihydro-5-Aryl-1H-pyrazol-3-
yl)phenylamino)pyridine-3-carbonitrile were prepared, The physical data are recorded in
the Table No-7.
[C] Biological evalution of 2-(4-(1-phenyl-4,5-dihydro-5-Aryl-1H-pyrazol-3-
yl)phenylamino)pyridine-3-carbonitrile.
All the products have been evaluated for Antimicrobial activity as describe in
Part-I. The zones of inhibition of test solutions are recorded in Table No. 8.
Studies On Some Heterocyclic Compounds……
Page 83
Table No. 7 Physical Data of 2-(4-(1-phenyl-4,5-dihydro-5-Aryl-1-phenylpyrazol-3-yl)phenylamino)pyridine-3-carbonitrile.
Studies On Some Heterocyclic Compounds……
Page 84
Table No. 8 Biological Activity of 2-(4-(1-phenyl-4,5-dihydro-5-Aryl-1-phenylpyrazol-3-yl)phenylamino)pyridine-3-carbonitrile.
Compounds R= Aryl Antibacterial Activity Antifungal Activity
B. subtilis
s. aureus
P. aeruginosa
E. coli
A. niger
C. albicans
4a 3-NO2-C6H4- 17 12 16 13 12 9 4b 4-Cl-C6H4- 19 15 11 18 11 15 4c C4H3O- 12 15 11 12 6 9 4d C6H5- 5 8 11 9 8 5
4e N,N-(CH3)2-C6H4-
15 11 17 12 15 11
4f 4-OCH3-C6H4-
17 13 12 17 10 14
4g 2-OH- C6H4- 19 18 11 18 16 12 4h 2-Cl- C6H4- 12 17 11 12 17 11
4i 4-OCH3-2-OH-C6H4-
11 14 9 10 10 16
4j 4-OH- C6H4- 8 15 11 9 10 17
4k 3,4-(OCH3)2-C6H4-
19 11 10 13 8 11
4l 2-OH-C10H6 7 14 9 11 9 5 4m C8H6N- 6 12 7 12 12 6 4n C7H14- 12 6 16 10 10 13
4o 2,5-(OCH3)2-C6H4-
12 15 11 10 12 10
4p 3,5-Cl2-2-OH-C6H4-
16 12 18 19 9 16
Sparfloxacin 25 24 25 22 - - Benzyl
penicillin 17 18 16 16 - -
Ampicillin 19 23 20 20 - - Fluconazole - - - - 22 20
Studies On Some Heterocyclic Compounds……
Page 85
ANTIBACTERIAL ACTIVITY:
From screening results, substituted phenyl pyrazoline 4b (R = -4-Cl-C6H4-), 4g (R= 2-OH- C6H4-) and 4k (R= 3,4-(OCH3)2-C6H4-) possesses very good activity against B. subtilis compared with Benzyl penicillin while 4e (R = N,N-(CH3)2-C6H4-) and 4p (R = 3,5-Cl2-2-OH-C6H4-) against P. aeruginosa, 4b (R= 4-Cl-C6H4-), 4g (R= 2-OH- C6H4-) and 4p (R= 3,5-Cl2-2-OH-C6H4-) possesses very good activity against E.coli. The remaining phenyl pyrazoline derivatives possess moderate to poor activity against all four bacterial species.
ANTIFUNGAL ACTIVITY:
Antifungal screening data showed that substituted phenyl pyrazoline 4j (R = -4-
OH- C6H4-) against C.albicans and 4h (R = -2-Cl- C6H4-) against A.niger, show highly
promising activity compare with standard drug. While remaining compounds exhibited
moderate to poor activity against both bacterial species.
Studies On Some Heterocyclic Compounds……
Page 86
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Studies On Some Heterocyclic Compounds……
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Int. Appl. WO 03 58, 887 (2002); Chem. Abstr., 139, 117441z (2003).
37. K. Mogilaiah and G. Raman Sudhakar; Indian J. Chem., 42B, 636-40 (2003).
38. V. M. Parikh; “Absorption spectroscopy of organic molecules” Addition-Wesley
Pub. Co. London, 243-258 (1978). A. Hand book of spectroscopic data by B. D.
Mishtry; 1st ed. ABD Press jaipur 11-36 (2000).
39. A. R. Kartizky and R. Alans Jones;J. Chem. Soc., 2942 (1960). Introduction of Infra
red and Raman spectroscopy by Norman B. Colthup, Lowrence H. Daly and Stephan
E. Wiberluy. Academic Press (1975).
Studies On Some Heterocyclic Compounds……
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INTRODUCTION
Heterocycles are abundant in nature and are of great significance to life because
their structural subunits exist in many natural products such as vitamins, hormones,
antibiotics etc. Hence, they have attracted considerable attention in the design of
biologically active molecules. Oxopyrimidines & Thiopyrimidines and its derivatives
represent one of the most active classes of compounds possessing a wide spectrum of
biological activities. Pyrimidine derivatives which occurs in natural products like nucleic
acid, vitamin-B and having remarkable pharmaceutical importance because of their broad
spectrum of biological activities. Several analogs of nucleic acids like fluorouracil which
has been used in cancer treatment. Pyrimidines are among those molecules that make life
possible as being some of the building blocks of DNA and RNA.
Pyrimidine is considered to be a resonance hybrid of the charged and uncharged
cannonical structures, its resonance energy has been found to be less than benzene or
pyridine. The naturally occuring pyrimidine derivatives was first isolated by Gabrial and
Colman in 1870, and its structure was confirmed in 1953 as 5-β-D-gluco-pyranoside of
divicine.
Some oxo pyrimidines of physiologically as well as therapeutically importance are as
under: e.g., Blasticidin, Zidovudine.
Studies On Some Heterocyclic Compounds……
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SYNTHETIC ASPECT
Different methods for the synthesis of pyrimidinones have been cited in the
literature [1]
.
An efficient and robust solid-phase synthesis of 6-substituted-2,5,6,8-tetrahydro-3H-
imidazo[1,2-a]pyrimidin-7-one (II), 3-substituted-1,3,4,6,7,8-exahydropyrimido[1,2-
a]pyrimidin-2-ones (III) using Baylis Hillman reagent[2]
.
Studies On Some Heterocyclic Compounds……
Page 92
Oliver Kappe et al.[3]
have synthesized dihydropyrimidine-5-carboxylicacid (IV) in two
steps by multicomponent condensation of benzyl or allyl β-ketoesters with aldehyde and
urea, followed by suitable benzyl or allyl deprotection strategies.
The condensation of the azaenolates derived from readily available ketimines with
fluorinated nitrile offers an efficient and straightforward entry to new fluorinated 1,3-
vinylogous amides. These versatile compounds in turn react with triphosgene to yield
new fluorinated pyrimidin-2(1H)-ones (V) in high yield[4]
.
Fikret karci et al.[5]
have synthesized 4-amino-1H-benzo[4,5]imidazo[1,2-a]
pyrimidin-2-one by the reaction of 2-aminobenzimidazole with ethylcyanoacetate.
Studies On Some Heterocyclic Compounds……
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There are many other methods of pyrimidine ring synthesis which are of more limited
scope. The reaction of 1,3-dicarbonyl compound or an equivalent reagent with
formamide provides a route of several pyrimidine which are unsubstituted at the 2-
position.
Biginelli[6]
investigated that condensation of aromatic aldehyde with β-ketoester and urea
yield the pyrimidine derivatives (VI).
Studies On Some Heterocyclic Compounds……
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REACTION MECHANISM
The reaction mechanism for the formation of pyrimidine derivatives described as under.
THERAPEUTIC IMPORTANCE
It is revealed from the literature survey that pyrimidine derivatives have been
found to possessing biological activities mentioned as under.
1. Anti HIV[7,8]
2. Antiviral[9]
3. Antimicrobial[10]
4. Herbicidal[11-17]
5. Antagonists[18-22]
6. Antitumor[23]
7. Antiinflammatory and anticonvulsant[24,25]
8. Carcinostatic[26]
9. Antimalarial[27]
Studies On Some Heterocyclic Compounds……
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10. Antithyroid[28]
Sanjay Batra et al.[29]
have synthesized several 1-(2-cyano-3-aryl-allyl)-3-urea by the
reaction between allylamines generated from Baylis-Hilman acetates and substituted
isocyanates and isothiocyanate. Further, their cyclization in the presence of a base led to
the formation of 5-arylmethyl-4-imino-3-aryl-3,4-dihydro-1H-pyrimidin-2-ones (VII) and
were tested for their antibacterial activity.
2-(Arylcarbonylmethyl)thio-6-alpha-naphthylmethyld derivatives of dihydro
alkoxybenzyloxopyrimidines[30]
(DABO) were newly found to exhibit activity against
both HIV-1 and HIV-2. These compounds were evaluated for their in vitro anti-HIV
activity in MT-4 cells. The IC(50) values for anti-HIV-1 and HIV-2 were found
moderately active.
(±)-1-(anti-3-Hydroxy-cyclopentyl)-3-(4-methoxy-phenyl)-7-phenylamino-3,4-
dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one (RO4383596) is a potent and selective
inhibitor of the pro-angiogenic receptor tyrosine kinases KDR, FGFR, and PDGFR[31]
.
This agent has an excellent pharmacokinetic profile and is highly efficacious in rodent
models of angiogenesis upon oral administration.
Relationship between the topological indices and anti-HIV activity of
dihydro(alkylthio)(napthylmethyl) oxopyrimidines (5-DABO) has been investigated by
Lather V. and Madau A. K.[32]
The use of models based upon these topological indices
resulted in prediction of anti-HIV activity with an accuracy ranging from 86% to 89%.
Studies On Some Heterocyclic Compounds……
Page 96
Herve Ganeste and co-workers[33]
synthesized substituted 1H-pyrimidin-2-one (VIII) with
selective dopamine D3-receptor antagonists activity.
2-Alkylamino-6-[1-(2,6-difluorophenyl)alkyl]-3,4-dihydro-5-alkylpyrimidin-(3H)
-ones (F (2)-NH-DABOs) 4,5 belonging to dihydro-alkoxy-benzyl-oxopyrimidine
(DABO)[34]
and bearing different alkyl and arylamino side chains at the C (2)-position of
the pyrimidine ring were designed as active against wild type (wt) Human
Immunodeficiency virus type 1 (HIV-1) and some relevant HIV-1 mutants.
Studies On Some Heterocyclic Compounds……
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Thirty six allyl substituted oxopyrimidine analogues[35]
such as barbituric acid
(BA), barbiturates, uracil, thymine, and related derivatives including 13 new compounds
were synthesized and their pharmacologic effects ([hypnotic activity, anticonvulsant
activity against pentylentetrazol (PTZ)-induced seizures, and LD(50)]) and interactions
with the barbiturates were evaluated in mice and rats.
Bruce M. A. and co-workers[36]
have prepared the dihydropyrimidinones (IX) as
NPY antagonists. Sidler and Larsen[37]
have reported pyrimidinone derivatives (X), useful
as an α-adrenergic receptor antagonists.
Pyrimidinone derivatives[38]
(XI) have been found to be calcium channel blocker.
Barbuliene M. M. et al.[4O]
have synthesized pyrimidinones as antiinflammatory agent.
Amuti Kofies et al.[41]
have suggested pyrimidinones (XII) and (XIII) as herbicidal and
plant growth regulators.
Studies On Some Heterocyclic Compounds……
Page 98
Swaminathan R. et al.[42]
have synthesized P38 MAP Kinase inhibitors based on 3,4-
dihydropyrimido[4,5-d]pyrimidin-2-ones (XIV) .
Cano Soldado P. et al.[43]
have described pyrimidine derivatives as nucleoside inhibitors
of HIV-1. Gompel M. et al.[44]
have reported new family of protein kinase inhibitors
isolated from the ascidian aplidium meridianum. Junmei Wang et al.[45]
have prepared
hierarchical database screenings for HIV-1 Reverse Transcriptase (XV).
Studies On Some Heterocyclic Compounds……
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S. S. Sangapure[46]
have tested the antimicrobial activity of benzofuro[3,2-d]pyrimidine
derivatives (IX). El Sayed[47]
have synthesized alkylated substituted mercapto pyrimidine
derivatives (X) and studied their anticancer and antineoplastic activity. H. Y. Moustafa[48]
have reported some pyrimidine derivatives and studied their biological activities.
Shimizu T. et al.[49]
have described N3-substituted uridine and related Pyrimidine
nucleosides as antinociceptive effects in mice. Sanmartin C. et al.[50]
have prepared new
symmetrical derivatives as cytotoxic agents and apoptosis inducers. Agarwal A. et al.[51]
have synthesized 2,4,6-trisubstituted pyrimidine derivatives as pregnancy
Studies On Some Heterocyclic Compounds……
Page 100
interceptiveagents. Shigeta S. et al.[52]
have been synthesized 5-alkyl-2-thiopyrimidine
nucleoside analogues and examined for antiviral activities against Herps Simplex virus
(HSV), Varicella-Zoster virus (SZV) and Human Cytomegalo virus (HCMV).
Thus, diverse biological activities have been encountered in compounds containing
oxopyrimidine ring system. To further assess the potential of such type of compounds,
study of oxopyrimidines has been carried out.
Section-I Conventional and Microwave assisted Synthesis, biological
evaluation of 2-(4-(1,2-dihydro-6-Aryl-2-thioxopyrimidin-4-
yl)phenylamino)pyridine-3-carbonitrile.
Section-II Conventional and Microwave assisted Synthesis, biological
evaluation of 2-(4-(1,2-dihydro-2-oxo-6-Arylpyrimidin-4-
yl)phenylamino)pyridine-3-carbonitrile.
Studies On Some Heterocyclic Compounds……
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Section-I Conventional and Microwave assisted Synthesis, biological evaluation of 2-(4-(1,2-
dihydro-6-Aryl-2-thioxopyrimidin-4-yl)phenylamino)pyridine-3-carbonitrile.
Thioxopyrimidines represent one of the most active classes of compounds possessing a
wide spectrum of biological activities, such as significant in vitro activity against viruses
including polio viruses, diuretic, antitubercular spermidical etc. These valid observation
led us to synthesize 2-(4-(1,2-dihydro-6-Aryl-2-thioxopyrimidin-4-
yl)phenylamino)pyridine-3-carbonitrile of Type (V) by cyclocondensation of chalcones
of Type (I) and Thiourea in presence of KOH as catalyst.
The constitution of the synthesized products have been characterized by using
elemental analysis, infrared and 1H-nuclear magnetic resonance spectroscopy and further
supported by mass spectroscopy.
All the compounds have been evaluated for their in vitro biological assay like
antibacterial activity towards Gram positive and Gram negative bacterial strains and
antifungal activity towards A. niger and C. Albican. The biological activities of
synthesized compounds were compared with standard drugs.
Studies On Some Heterocyclic Compounds……
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Reaction Scheme
N NH
CNR
O
KOH
EtOHThiourea
N NH
CNR
N NH
S
R= ArylType-V
Studies On Some Heterocyclic Compounds……
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IR Spectral Study Of 2-(4-(6-(4-chlorophenyl)-1,2-dihydro-2-thioxopyrimidin-4-yl)phenylamino)pyridine-3-carbonitrile.
Type Vibration Mode Frequency cm-1 Reference
Alkane C-H str. (asym.)
C-H str. (sym.)
C-H def. (asym.)
C-H def. (sym.)
2918
2860
1417
1253
49
,,
,,
,,
Aromatic C-H str.
C=C
3198
1521
,,
,,
Thiopyrimidine C=S str.
N-H str.
1589
3302
,,
,,
Halide C-Cl str. 771 50
Nitrile -C≡N 2322 ,,
N
CN
NH
N NH
S
Cl
Studies On Some Heterocyclic Compounds……
Page 104
1H NMR Spectral Study Of 2-(4-(1,2-dihydro-6-(3,4-dimethoxyphenyl)-2-thioxopyrimidin-4-yl)phenylamino)pyridine-3-carbonitrile.
Signal No. Signal Position δppm
Relative No Of Protons
Multiplicity Inference
1 3.8 6H Singlet (overlapped)
-CH3 (g, f)
2 5.2 1H Singlet -CH (a) 3 6.6 3H Double doublet -CH (i, i’, e) 4 6.8 2H Singlet -CH (c, d) 5 7.8 1H Singlet -NH (b) 6 7.9 2H Double doublet -CH (h, h’) 7 8.2 1H Singlet -NH (j)
N
CN
NH
N NH
S
OCH3
OCH3
a
b
c
d
e f
gh
h'
i'
i
jk
l
m
Studies On Some Heterocyclic Compounds……
Page 105
Mass Spectral Study Of 2-(4-(6-(4-chlorophenyl)-1,2-dihydro-2-thioxopyrimidin-4-yl)phenylamino)pyridine-3-carbonitrile.
N
NC NH
N
HN
S
Cl
C2 2
H1 4
ClN
5SM
ol. W
t.: 4
15.5
Studies On Some Heterocyclic Compounds……
Page 106
EXPERIMENTAL
[A] Synthesis of 2-(4-(3-phenylacryloyl)phenylamino)pyridine-3-carbonitrile.
A Solution of Benzaldehyde (0.01 M) in minimum quantity of DMF (5 ml) was
added to the mixture of 2-(4-acetylphenylamino)pyridine-3-carbonitrile in 15ml DMF
and 40% KOH was added to make mixture alkaline, the reaction mixture was then stirred
for 24 hours at room temperature. The product was isolated by adding mixture in cold
water and crystallized it from DMF. Yield 77%, m.p. 254°C. (C21H15N3O; required: C
77.52%, H 4.65%, N 12.91%; found: C 77.39%, H 4.53%, N 12.86%).
[B] Synthesis of 2-(4-(1,2-dihydro-6-phenyl-2-thioxopyrimidin-4-
yl)phenylamino)pyridine-3-carbonitrile.
A mixture of 2-(4-(3-phenylacryloyl)phenylamino)pyridine-3-carbonitrile (0.01
mol) and Thiourea (0.01 mol) in ethanol (20 ml) was refluxed on water bath in presence
of alcoholic KOH for 10 hrs. The excess solvent was distilled off and the residue was
neutralized with 10% HCl, the separated solid was filtered out and crystallized from
ethanol. Yield 70 %, m.p. 268OC.
Similarly, other 2-(4-(1,2-dihydro-6-Aryl-2-thioxopyrimidin-4-
yl)phenylamino)pyridine-3-carbonitrile were prepared. The physical data are recorded in
Table No. 9.
[C] Biological Evaluation Of 2-(4-(1,2-dihydro-6-Aryl-2-thioxopyrimidin-4-
yl)phenylamino)pyridine-3-carbonitrile.
Antimicrobial testing were carried out as described in Part-I. The zones of
inhibition of test solutions are recorded in Table No. 10.
Studies On Some Heterocyclic Compounds……
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Table No. 9 Physical Data of 2-(4-(1,2-dihydro-6-Aryl-2-thioxopyrimidin-4-yl)phenylamino)pyridine-3-carbonitrile.
Studies On Some Heterocyclic Compounds……
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Table No. 10 Biological Activity of 2-(4-(1,2-dihydro-6-Aryl-2-thioxopyrimidin-4-yl)phenylamino)pyridine-3-carbonitrile.
Compounds R= Aryl Antibacterial Activity Antifungal Activity
B. subtilis
s. aureus
P. aeruginosa E. coli A.
niger C.
albicans
5a 3-NO2-C6H4-
19 14 16 12 19 14
5b 4-Cl-C6H4- 16 14 12 19 17 19 5c C4H3O- 10 8 12 9 12 15 5d C6H5- 9 10 11 8 9 7
5e N,N-
(CH3)2-C6H4-
13 15 11 10 12 8
5f 4-OCH3-C6H4-
18 16 12 16 11 14
5g 2-OH- C6H4-
20 17 16 19 6 9
5h 2-Cl- C6H4-
16 12 18 10 11 12
5i 4-OCH3-2-OH-C6H4-
13 11 15 9 16 12
5j 4-OH- C6H4-
9 10 13 10 19 11
5k 3,4-
(OCH3)2-C6H4-
19 15 18 12 16 20
5l 2-OH-C10H6
9 12 7 8 17 12
5m C8H6N- 7 9 6 8 8 5 5n C7H14- 11 9 10 7 9 12
5o 2,5-
(OCH3)2-C6H4-
12 15 12 10 14 17
5p 3,5-Cl2-2-OH-C6H4-
20 16 14 18 15 19
Sparfloxacin 25 24 25 22 - - Benzy
penicillin 17 18 16 16 - -
Ampicillin 19 23 20 20 - - Fluconazole - - - - 22 20
Studies On Some Heterocyclic Compounds……
Page 109
ANTIBACTERIAL ACTIVITY:
From screening results, substituted acetyl Thiopyrimidine 5g (R = -2-OH- C6H4-)
and 5p (R= 3,5-Cl2-2-OH-C6H4-) possesses very good activity against B. subtilis
compared with Benzyl penicillin while 5b (R = 4-Cl-C6H4-) and 5g (R= -2-OH- C6H4-)
against E.coli, The remaining Thiopyrimidine derivatives possess moderate to poor
activity against all four bacterial species.
ANTIFUNGAL ACTIVITY:
Antifungal screening data showed that substituted Thiopyrimidine 5b (R = 4-Cl-
C6H4-) and 5k (R= 3,4-(OCH3)2-C6H4-) against C.albicans, While 5a (R= 3-NO2-C6H4-)
and 5j (R= 4-OH- C6H4-) against A.niger, show highly promising activity compare with
standard drug. While remaining compounds exhibited moderate to poor activity against
both bacterial species.
Studies On Some Heterocyclic Compounds……
Page 110
SECTION-II Conventional and Microwave assisted Synthesis, biological evaluation of 2-(4-(1,2-dihydro-2-oxo-6-Arylpyrimidin-4-yl)phenylamino)pyridine-3-carbonitrile. In the past years considerable evidence has been accumulated to demonstrate the
efficiency of pyrimidinones. 2-(4-(1,2-dihydro-2-oxo-6-Arylpyrimidin-4-
yl)phenylamino)pyridine-3-carbonitrile of Type (VI) have been prepared by the
condensation of 2-(4-(3-arylacryloyl)phenylamino)pyridine-3-carbonitrile of Type (I)
with urea in presence of basic catalyst as shown under.
The constitution of the synthesized products have been characterized by using
elemental analysis, infrared and 1H-nuclear magnetic resonance spectroscopy and further
supported by mass spectroscopy.
All the compounds have been evaluated for their in vitro biological assay like
antibacterial activity towards Gram positive and Gram negative bacterial strains and
antifungal activity towards A. niger and C. Albicans. The biological activities of
synthesized compounds were compared with standard drugs.
Studies On Some Heterocyclic Compounds……
Page 111
REACTION SCHEME
N NH
CNR
O
KOH
EtOH
N NH
CNR
N NH
OUrea
R= ArylType-VI
Studies On Some Heterocyclic Compounds……
Page 112
IR Spectral Study Of 2-(4-(1,2,5,6-tetrahydro-6-(4-hydroxyphenyl)-2-oxopyrimidin-4-yl)phenylamino)pyridine-3-carbonitrile.
Type Vibration Mode Frequency cm-1 Reference
Alkane C-H str. (asym.)
C-H str. (sym.)
C-H def. (asym.)
C-H def. (sym.)
2898
2760
1408
1361
49
,,
,,
,,
Aromatic C-H str.
C=C
3103
1525
,,
,,
Oxopyrimidine C=O str.
C=N str.
C–N str.
N-H str.
1658
1588
1172
3337
,,
50
,,
,,
Nitrile -C≡N 2253 ,,
N
CN
NH
N NH
O
OH
Studies On Some Heterocyclic Compounds……
Page 113
1H NMR Spectral Study Of 2-(4-(1,2-dihydro-6-(4-methoxyphenyl)-2-oxopyrimidin-4-yl)phenylamino)pyridine-3-carbonitrile.
Signal No
Signal Position δppm Relative No Of Protons
Multiplicity Inference
1 3.3 3H Singlet -OCH3 (c) 2 5.1 1H Singlet -Ar-H (a) 3 6.8 2H Double
Doublet -CH (g,g’)
4 7.0 1H Triplet -CH (j) 5 8.3 2H Double
Doublet -CH (i)
6 8.4 1H Singlet (broad) -NH (h) 7 8.8 1H Singlet -NH (b)
N
CN
NH
N NH
O
OCH3
a
b
c
d
d'
e
e'
f
f'
g
g'
hi
j
k
Studies On Some Heterocyclic Compounds……
Page 114
Mass Spectral Study Of 2-(4-(1,2,5,6-tetrahydro-6-(4-hydroxyphenyl)-2-oxopyrimidin-4-yl)phenylamino)pyridine-3-carbonitrile.
N
NC NH
N
HN
O
OH
C 22H
15N
5O2
Mol
. Wt.:
381
Studies On Some Heterocyclic Compounds……
Page 115
EXPERIMENTAL
Conventional and Microwave assisted Synthesis, biological evaluation of 2-(4-(1,2-
dihydro-2-oxo-6-Arylpyrimidin-4-yl)phenylamino)pyridine-3-carbonitrile.
[A] Synthesis of 2-(4-(3-phenylacryloyl)phenylamino)pyridine-3-carbonitrile.
A Solution of Benzaldehyde (0.01 M) in minimum quantity of DMF (5 ml) was
added to the mixture of 2-(4-acetylphenylamino)pyridine-3-carbonitrile in 15ml DMF
and 40% KOH was added to make mixture alkaline, the reaction mixture was then stirred
for 24 hours at room temperature. The product was isolated by adding mixture in cold
water and crystallized it from DMF. Yield 77%, m.p. 254°C. (C21H15N3O; required: C
77.52%, H 4.65%, N 12.91%; found: C 77.39%, H 4.53%, N 12.86%).
[B] Synthesis of 2-(4-(1,2-dihydro-2-oxo-6-phenylpyrimidin-4-yl)phenylamino) pyridine-3-carbonitrile.
A mixture of -(4-(3-phenylacryloyl)phenylamino)pyridine-3-carbonitrile (0.01 mol)
and urea (0.01 mol) in ethanol (20 ml) was refluxed on water bath in presence of
alcoholic KOH for 12 hrs. The excess solvent was distilled off and the residue was
neutralized with 10% HCl, the separated solid was filtered out and crystallized from
methanol. Yield 71 %, m.p. 2190C.
Similarly, other 2-(4-(1,2-dihydro-2-oxo-6-Arylpyrimidin-4-
yl)phenylamino)pyridine-3-carbonitrile were prepared. The physical data are recorded in
Table no. 11.
[C] Biological evaluation of 2-(4-(1,2-dihydro-2-oxo-6-Arylpyrimidin-4-
yl)phenylamino)pyridine-3-carbonitrile
Antimicrobial testing were carried out as described in Part-I. The zones of
inhibition of test solutions are recorded in Table No. 12
Studies On Some Heterocyclic Compounds……
Page 116
Table No. 11 Physical Data of 2-(4-(1,2-dihydro-2-oxo-6-Arylpyrimidin-4-yl)phenylamino)pyridine-3-carbonitrile.
Studies On Some Heterocyclic Compounds……
Page 117
Table No. 12 Biological Activity Of 2-(4-(1,2-dihydro-2-oxo-6-Arylpyrimidin-4-yl)phenylamino)pyridine-3-carbonitrile.
Compounds R= Aryl Antibacterial Activity Antifungal Activity
B. subtilis s. aureus
P. aeruginos
a E. coli A.
niger C.
albicans
6a 3-NO2-C6H4-
20 16 12 17 14 9
6b 4-Cl-C6H4- 16 12 19 15 11 15 6c C4H3O- 13 16 10 13 7 4 6d C6H5- 8 10 9 5 9 10
6e N,N-(CH3)2-C6H4-
18 13 9 16 17 13
6f 4-OCH3-C6H4-
19 14 18 14 12 17
6g 2-OH- C6H4-
19 12 18 15 11 6
6h 2-Cl- C6H4- 14 10 9 13 8 12
6i 4-OCH3-2-OH-C6H4-
15 12 17 10 10 12
6j 4-OH- C6H4-
12 9 16 12 17 10
6k 3,4-
(OCH3)2-C6H4-
20 12 17 13 12 10
6l 2-OH-C10H6 11 9 13 6 10 5 6m C8H6N- 9 6 12 10 11 7 6n C7H14- 12 7 12 10 9 4
6o 2,5-
(OCH3)2-C6H4-
16 11 18 17 14 10
6p 3,5-Cl2-2-OH-C6H4-
20 17 18 14 11 17
Sparfloxacin 25 24 25 22 - - Benzy
penicillin 17 18 16 16 - -
Ampicillin 19 23 20 20 - - Fluconazole - - - - 22 20
Studies On Some Heterocyclic Compounds……
Page 118
ANTIBACTERIAL ACTIVITY:
From screening results, substituted acetyl Oxopyrimidine 6a (R = -3-NO2-C6H4-),
6p (R= 3,5-Cl2-2-OH-C6H4-) and 6k (R= 3,4-(OCH3)2-C6H4-) possesses very good
activity against B. subtilis compared with Benzyl penicillin while 6b (R = 4-Cl-C6H4-)
against P. aeruginosa, The remaining Oxopyrimidine derivatives possess moderate to
poor activity against all four bacterial species.
ANTIFUNGAL ACTIVITY:
Antifungal screening data showed that substituted Oxopyrimidine 6f (R = 4-
OCH3-C6H4-) and 6p (R= 3,5-Cl2-2-OH-C6H4-) against C.albicans, While 6e (R= N,N-
(CH3)2-C6H4-) and 6j (R = 4-OH- C6H4-) against A.niger, show highly promising activity
compare with standard drug. While remaining compounds exhibited moderate to poor
activity against both bacterial species.
Studies On Some Heterocyclic Compounds……
Page 119
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N
CN
NH
R
O
N
CN
NH
R
N NH
R R
3-NO2-C6H4-
3-NO2-C6H4- 4-Cl-C6H4-
4-Cl-C6H4-
C4H3O-
C4H3O- C6H5-
C6H5-
N,N-(CH3)2-C6H4-
N,N-(CH3)2-C6H4- 4-OCH3-C6H4-
4-OCH3-C6H4-
2-OH- C6H4-
2-OH- C6H4- 2-Cl- C6H4-
2-Cl- C6H4-
4-OCH3-2-OH-C6H4-
4-OCH3-2-OH-C6H4- 4-OH- C6H4-
4-OH- C6H4-
3,4-(OCH3)2-C6H4-
3,4-(OCH3)2-C6H4- 2-OH-C10H6
2-OH-C10H6
C8H6N-
C8H6N- C7H14-
C7H14-
2,5-(OCH3)2-C6H4-
2,5-(OCH3)2-C6H4- 3,5-Cl2-2-OH-C6H4-
3,5-Cl2-2-OH-C6H4-
Studies On Some Heterocyclic Compounds……
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N
CN
NH
R
N N
COCH3
N
CN
NH
R
N N
Ph
R R
3-NO2-C6H4-
3-NO2-C6H4- 4-Cl-C6H4-
4-Cl-C6H4-
C4H3O-
C4H3O- C6H5-
C6H5-
N,N-(CH3)2-C6H4-
N,N-(CH3)2-C6H4- 4-OCH3-C6H4-
4-OCH3-C6H4-
2-OH- C6H4-
2-OH- C6H4- 2-Cl- C6H4-
2-Cl- C6H4-
4-OCH3-2-OH-C6H4-
4-OCH3-2-OH-C6H4- 4-OH- C6H4-
4-OH- C6H4-
3,4-(OCH3)2-C6H4-
3,4-(OCH3)2-C6H4- 2-OH-C10H6
2-OH-C10H6
C8H6N-
C8H6N- C7H14-
C7H14-
2,5-(OCH3)2-C6H4-
2,5-(OCH3)2-C6H4- 3,5-Cl2-2-OH-C6H4-
3,5-Cl2-2-OH-C6H4-
Studies On Some Heterocyclic Compounds……
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N
CN
NH
R
N NH
O
N
CN
NH
R
N NH
S
R R
3-NO2-C6H4-
3-NO2-C6H4- 4-Cl-C6H4-
4-Cl-C6H4-
C4H3O-
C4H3O- C6H5-
C6H5-
N,N-(CH3)2-C6H4-
N,N-(CH3)2-C6H4- 4-OCH3-C6H4-
4-OCH3-C6H4-
2-OH- C6H4-
2-OH- C6H4- 2-Cl- C6H4-
2-Cl- C6H4-
4-OCH3-2-OH-C6H4-
4-OCH3-2-OH-C6H4- 4-OH- C6H4-
4-OH- C6H4-
3,4-(OCH3)2-C6H4-
3,4-(OCH3)2-C6H4- 2-OH-C10H6
2-OH-C10H6
C8H6N-
C8H6N- C7H14-
C7H14-
2,5-(OCH3)2-C6H4-
2,5-(OCH3)2-C6H4- 3,5-Cl2-2-OH-C6H4-
3,5-Cl2-2-OH-C6H4-
Studies On Some Heterocyclic Compounds……
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1) Chintan. C. Raval*., P. K. Patel., A. j. Rojiwadiya.; Asian J. Biochem and
Pharma Research., Vol-1, Issue 2, 391-394 (2012).
E-mail:
Under Communication
Synthesis Of Substituted Pyrimidine Derivatives and Evaluation of their
Antimicrobial Activity Chintan. C. Raval*, B. M. Sharma, Hardik Mehta, A. J. Rojiwadiya
M. D. Science College, Porbandar and M. M. Science College, Morbi, Gujarat (India). [email protected].
Abstract:
Keto group of cyano pyridine moiety have been treated with various aromatic
aldehydes to give corresponding chalcones. The Chalcones have been reacted with urea
and thiourea to get corresponding novel oxopyrimidines and thiopyrimidines, the
structure of all newly synthesized compounds were confirmed by spectral analysis. The
synthesized compounds were evaluated for their antimicrobial activity. All the
synthesized pyrimidine compounds have show good to moderate antimicrobial activity.