Studies Of Some Heterocyclic Compounds……. · heterocyclic chemistry and the pharmacological activities associated with them. The pharmaceutical importance of these compounds lies

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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

Dedicated

To

My parents

…for their immortal support and encouragement

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……

Page 1

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




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




Page 2

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




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




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




References .. .. 119

LIST OF NEW COMPOUNDS .. 124 PUBLICATIONS .. .. 128


Page 3

SYNOPSIS


Page 4

“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.


Page 5

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.


Page 6

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.


Page 7

N NH

CNR

TYPE (II) R= ARYL

N NH


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



Page 8

Section-III Conventional and Microwave assisted Synthesis, biological

evaluation of 2-(4-(1-phenyl-4,5-dihydro-5-Aryl-1-phenylpyrazol-3-


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



Page 9

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.


evaluation of 2-(4-(1,2-dihydro-6-Aryl-2-thioxopyrimidin-4-


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



Page 10


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



Page 11

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.


Page 12

Introduction


Page 13

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.


Page 14

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.


Page 15

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


Page 16

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.


Page 17

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


Page 18

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.


Page 19

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.


Page 20

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


Page 21

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


Page 22

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


Page 23

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

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(2004) Angew.Chem.Int.Ed., 43, 6250. (b) Kappe, C. O., Dallinger, D. (2006)

Nat. Drug. Disc. Rev., 5, 51. (c) Nagariya A.K., Meena.A.K., Kiran, Yadav A.K.,

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[5] Johansson, H. (2001) Am. Lab. 33, 10, 28-32.

[6] Bradley, D. (2001) Modern Drug Discovery 4, 32-36.

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[8] Wathey, B.; Tierney, J.; Lidrom, P.; Westman, (2002) J. Drug Discovery Today,

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[9] Dzieraba, C. D.; Combs, A. P. (2002) Annual reports in medicinal chemistry,

academic press, 37, 247-256.

[10] In; http://www.milestonesci.com.

[11] In; http://www.maos.net.

[12] In; http://www.cem.com.

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Page 26

Part-I Studies On Chalcones


Page 27

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.


Page 28

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)

+

+

+


Page 29

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].


Page 30

(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.


Page 31

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)


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.


Page 33

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.


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)


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)


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)


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.


Page 38

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.


Page 39

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


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


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


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


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.


Page 44

(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.


Page 45

Table No. 1: Physical Data of 2-(4-(3-phenylacryloyl)phenylamino)pyridine-3-carbonitrile.


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


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.


Page 48

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Page 54

Part-II

Studies On

Pyrazoline Derivatives


Page 55

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.


Page 56

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.


Page 57

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.


Page 58

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


Page 59

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.


Page 60

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.


Page 61


evaluation of 2-(4-(4,5-dihydro-5-Aryl-1H-pyrazol-3-



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.


Page 62

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



antifungal activity towards A. niger and C. Albicans. The biological activities of

synthesized compounds were compared with standard drugs.


Page 63

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


Page 64

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


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


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


Page 66

EXPERIMENTAL


dihydro-5-Aryl-1H-pyrazol-3-yl)phenylamino)pyridine-3-carbonitrile.

[A] Synthesis of 2-(4-(3-phenylacryloyl)phenylamino)pyridine-3-carbonitrile.


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-


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.


Page 67

Table No. 3. Physical Data Table of 2-(4-(4,5-dihydro-5-Aryl-1H-pyrazol-3-yl)phenylamino)pyridine-3-carbonitrile.


Page 68

Table No. 4. Biological evalution of 2-(4-(4,5-dihydro-5-Aryl-1H-pyrazol-3-yl)phenylamino)pyridine-3-carbonitrile.


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


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


penicillin 17 18 16 16 - -

Ampicillin 19 23 20 20 - - Fluconazole - - - - 22 20


Page 69


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 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.


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


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


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


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


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


Page 74

EXPERIMENTAL


acetyl-4,5-dihydro-5-Aryl-1H-pyrazol-3-yl)phenylamino)pyridine-3-carbonitrile.







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-



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-



Part-I, The zone of inhibition of test solutions are recorded in Table No. 6.


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.


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.


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


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


penicillin 17 18 16 16 - -



Page 77


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 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.


Page 78

SECTION-III


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.


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


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.


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


N

CN

NH

N OH

Cl

Cl

N


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


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


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


Page 82

EXPERIMENTAL [A] Synthesis of 2-(4-(3-phenylacryloyl)phenylamino)pyridine-3-carbonitrile.






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-



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-



Part-I. The zones of inhibition of test solutions are recorded in Table No. 8.


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.


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.


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


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 - -



Page 85


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 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.


Page 86

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Page 87

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Page 89

Part-III

Studies On

Pyrimidines derivatives


Page 90

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.


Page 91

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]

.


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.


Page 93

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).


Page 94

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]


Page 95

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%.


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.


Page 97

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.


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).


Page 99

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


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.


evaluation of 2-(4-(1,2-dihydro-6-Aryl-2-thioxopyrimidin-4-



evaluation of 2-(4-(1,2-dihydro-2-oxo-6-Arylpyrimidin-4-



Page 101

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.






antifungal activity towards A. niger and C. Albican. The biological activities of



Page 102

Reaction Scheme

N NH

CNR

O

KOH

EtOHThiourea

N NH

CNR

N NH

S

R= ArylType-V


Page 103

IR Spectral Study Of 2-(4-(6-(4-chlorophenyl)-1,2-dihydro-2-thioxopyrimidin-4-yl)phenylamino)pyridine-3-carbonitrile.


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


N

CN

NH

N NH

S

Cl


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


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


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


Page 106

EXPERIMENTAL







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-



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-


Antimicrobial testing were carried out as described in Part-I. The zones of

inhibition of test solutions are recorded in Table No. 10.


Page 107

Table No. 9 Physical Data of 2-(4-(1,2-dihydro-6-Aryl-2-thioxopyrimidin-4-yl)phenylamino)pyridine-3-carbonitrile.


Page 108

Table No. 10 Biological Activity of 2-(4-(1,2-dihydro-6-Aryl-2-thioxopyrimidin-4-yl)phenylamino)pyridine-3-carbonitrile.


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


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


penicillin 17 18 16 16 - -



Page 109


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 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.


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.






antifungal activity towards A. niger and C. Albicans. The biological activities of



Page 111

REACTION SCHEME

N NH

CNR

O

KOH

EtOH

N NH

CNR

N NH

OUrea

R= ArylType-VI


Page 112

IR Spectral Study Of 2-(4-(1,2,5,6-tetrahydro-6-(4-hydroxyphenyl)-2-oxopyrimidin-4-yl)phenylamino)pyridine-3-carbonitrile.


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

,,

,,


N

CN

NH

N NH

O

OH


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


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


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


Page 115

EXPERIMENTAL


dihydro-2-oxo-6-Arylpyrimidin-4-yl)phenylamino)pyridine-3-carbonitrile.







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


Page 116

Table No. 11 Physical Data of 2-(4-(1,2-dihydro-2-oxo-6-Arylpyrimidin-4-yl)phenylamino)pyridine-3-carbonitrile.


Page 117

Table No. 12 Biological Activity Of 2-(4-(1,2-dihydro-2-oxo-6-Arylpyrimidin-4-yl)phenylamino)pyridine-3-carbonitrile.


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


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


penicillin 17 18 16 16 - -



Page 118


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 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.


Page 119

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Page 123

List Of

New Compounds


Page 124

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-


Page 125

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-


Page 126

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-


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Publications


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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).

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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.

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