Sanghani HG Thesis Chemistry

Saurashtra University
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Sanghani, Harshad G., 2004, Studies on Heterocyclic Compounds, PhD, Saurashtra University
thesis
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STUDIES ON HETEROCYCLIC COMPOUNDS

A THESIS SUBMITTED TO THE SAURASHTRA UNIVERSITY FOR THE DEGREE OF

Doctor of Philosophy
IN THE FACULTY OF SCIENCE (CHEMISTRY) BY
Sangani Harshad G.
UNDER THE GUIDANCE OF
Dr. A. R. Parikh
DEPARTMENT OF CHEMISTRY SAURASHTRA UNIVERSITY RAJKOT - 360 005. INDIA 2004
Ph. D. Thesis
Chemistry
Ph. D. Thesis
2004
Harshad G. Sangani
N N
CH3 N N O
Harshad G. Sangani
DEPARTMENT OF CHEMISTRY SAURASHTRA UNIVERSITY RAJKOT - 360 005. GUJARAT (INDIA) 2004
Gram : UNIVERSITY Fax : 0281-2577633
Phone : (R) 2577392 (O) 2578512
SAURASHTRA UNIVERSITY
University Road, RAJKOT - 360 005. Dr. A. R. PARIKH
M.Sc.; Ph. D., F. I.C. Residence :
Rtd. Professor & Head, Department of Chemistry
No.
'RASDHARA' 32-B, University Karmachari Co. Society, University Road, RAJKOT - 360 005. GUJARAT (INDIA) Dt.
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. R. Parikh and leads to some contribution in chemistry subsidised by a number of references.
Date :
- 06 - 2004
(Harshad G. Sangani)
Place : Rajkot
This is to certify that the present work submitted for the Ph. D. Degree of Saurashtra University by Harshad G. Sangani is his own work and leads to the advancement in the knowledge of chemistry. The thesis has been prepared under my supervision. Date : - 06 - 2004 Dr. A. R. PARIKH Rtd. Professor and Head, Department of Chemistry Saurashtra University RAJKOT
Place : Rajkot
ACKNOWLEDGEMENTS
"Oum Shree Ganeshay Namah " Hats off to the Omnipresent, Omniscient and Almighty God, the glorious rapturous dedication from within my heart, to the Omnipotent Lord fountain
and continuous source of inspirations! I offer salutations to him and my head bows with Shree Krishna.
My head bows with fullest devotion, reverence, heartfelt obeisance, deep sense of respect and admiration, to my most esteemed mentor, my co-traveler and guide Dr. A. R. Parikh, Rtd. Professor and Head, Department of Chemistry, Saurashtra University, Rajkot, who held the torch of excellent guidance high and lighted up the darkness, with perpetual affectionate encouragement and occasional constructive needed, towards the goal of my academic journey. I also owe to, from the deepest corner of heart, deepest sense of gratitude and indebtedness to Dr. (Mrs.) H. H. Parekh, Professor and Head, Department of Chemistry, Saurashtra University, Rajkot, as I have been constantly benefited with her lofty research methodology and the motivation as well as his highly punctual, affectionate, yet noncompromising nature which always inspired me in heading rapidly towards my goal and helped me achieving the aim of my present task very speedily. I wish to thank Dr. N. A. Chauhan, for his constant guidance and moral support during the course of my research work. Who in this world can entirely and adequately thank the parents who have given us everything that we possess in this life? The life itself is their gift to us, so I am at loss of words in which to own my most esteemed father Shri Gopalbhai and My loving mother Smt. Kanchanben and most venerated late grand father Devajibhai, grand mother Nathiben. Through the stress and strain of this study, my younger brother Mahendra, has encouraged me to reach my destination. criticism when
As with the completion of this task, I find myself in difficult position on attempting to express my deep indebtedness to Dr. Ranjan Khunt,Dr. Neela Datta and Dr. Fatema Bharmal. I wish to thank Kanji for his most willing co-operation and comprehensive exchange of ideas during the course of my research work. I offer my heart full gratitude to Ravindra, Ashok, Siddharth, Dinesh, Snehal, Hitarth, Ashish and all my Seniors for their support and much fruitful discussion at various stages. I am most thankful to all my Juniors for their valuable co-operation and help during the course of my work. I feel lucky and very proud to have intimate friends like Ashok, Jayesh, Prakash, Dinesh, Prashant, Sunil, Suresh, Siddique, Kalpesh, Jagadish, Maulin and Manoj who have been always participating with my problems and disappointments and rebuilt my confidence at appropriate stages. I am thankful to Mr. Harshad Joshi and Mrs. Namrata for their kind support and providing chemicals and glasswares on time. I am thankful to Mr. Devendra Goswami for his co-operation in magnifying the presentation of my work in the form of thesis. I Gratefully acknowledge the most willing help and co-operation shown by AlembicBaroda for providing facilities for spectral studies and library work, CDRI Lucknow, CIL, Chandigarh for spectral studies and Tuberculosis Antimicrobial activity. Finally, I express my grateful acknowledgment to Department of Chemistry, Saurashtra University for providing me the excellent laboratory facilities and kind furtherance for accomplishing this work. Acquisition Co-ordinating Facility, Alabama, U. S. A. for kind co-operation extended by them for antitubercular
Harshad G. Sangani
CONTENTS Page No. SYNOPSIS .. .. .. 01
STUDIES ON HETEROCYCLIC COMPOUNDS Introduction [A] STUDIES ON PYRAZOLES Introduction PART - I Introduction : .. STUDIES ON CHALCONES .. .. .. 21 .. .. 15 .. .. .. 12
Section - I : Synthesis and biological evaluation of 1-Aryl3-[1'N,3'-diphenyl-4'-pyrazolyl]-2-propene-1-ones Introduction and Spectral studies.. Experimental .. .. .. .. .. .. .. .. .. 27 34 38 40
Graphical data of In Vitro Evaluation of Antimicrobial screening In Vitro Evaluation of Antitubercular Activity PART - II Introduction : STUDIES ON CYANOPYRIDINES .. ..
..
41
Section - I : Synthesis and biological evaluation of 1'N,3'-Diphenyl4'-pyrazolyl-[2-amino-3-cyano-6-aryl-4-pyridyl]-pyrazoles Introduction and Spectral studies.. Experimental .. .. .. .. .. .. .. 46 51 53
Graphical data of In Vitro Evaluation of Antimicrobial screening PART - III Introduction : STUDIES ON CYANOPYRANS .. ..
..
55
Section - I : Synthesis and biological evaluation of 1'N,3'Diphenyl-4'-[2-amino-3-cyano-6-aryl-4-dihydropyranyl]-pyrazoles Introduction and Spectral studies.. Experimental .. .. .. .. .. .. .. 59 64 66
Graphical data of In Vitro Evaluation of Antimicrobial screening PART - IV Introduction : STUDIES ON PYRAZOLINES .. ..
..
68
Section - I : Synthesis and biological evaluation of 3-Aryl -5-[1'N, 3'-diphenyl-4'-pyrazolyl]-pyrazolines
Introduction and Spectral studies.. Experimental
.. ..
.. .. ..
.. .. .. ..
76 82 84 86
Graphical data of In Vitro Evaluation of Antimicrobial screening In Vitro Evaluation of Antitubercular Activity
Section - II : Synthesis and biological evaluation of 1N-phenyl3-aryl-5-[1'N, 3'-diphenyl-4'-pyrazolyl]-pyrazolines Introduction and Spectral studies.. Experimental .. .. .. .. .. .. .. 87 92 94
Graphical data of In Vitro Evaluation of Antimicrobial screening PART - V Introduction : STUDIES ON PYRIMIDINONES .. ..
..
96
Section - I : Synthesis and biological evaluation of 6-Aryl-[1'N-3'-diphenyl4'-pyrzolyl]-1,2,3,4-tetrahydropyrimidin-2-ones Introduction and Spectral studies.. Experimental .. .. .. .. .. .. .. 102 107 109
Graphical data of In Vitro Evaluation of Antimicrobial screening Section - II : Synthesis and biological evaluation of 5-Alkyl6-alkyl/aryl-4-[1'N, 3'- dipheyl-4'-pyrazolyl]1,2,3,4-tetrahydropyrimidine-2-ones Introduction and Spectral studies.. Experimental .. .. .. ..
.. .. ..
111 116 118
Graphical data of In Vitro Evaluation of Antimicrobial screening PART - VI Introduction : STUDIES ON BARBITONES .. ..
..
120
Section - I : Synthesis and biological evaluation of 5-[1'-Aryl-3'(1"N, 3"-diphenyl-4"-pyrazolyl)-prop-2'-enylidine]barbituric acids Introduction and Spectral studies.. Experimental .. .. .. .. .. .. .. 125 130 132
Graphical data of In Vitro Evaluation of Antimicrobial screening PART - VII Introduction : STUDIES ON IMIDAZOLINONES .. ..
..
134
Section - I : Synthesis and biological evaluation of 1N-Aryl2-alkyl/aryl-4-[1'N, 3'-diphenyl-4'-pyrazolylmethino]imidazolin-5-ones
Introduction and Spectral studies.. Experimental
.. ..
.. ..
.. .. ..
141 147 149
Graphical data of In Vitro Evaluation of Antimicrobial screening PART - VIII Introduction : STUDIES ON 4-THIAZOLIDINONES .. ..
..
151
Section - I : Synthesis and biological evaluation of 2-Arylimino 3N-aryl-5-[1'N, 3'-diphenyl-4'-pyrazolylmethino]4-thiazolidinones Introduction and Spectral studies.. Experimental .. .. .. .. .. .. .. 157 163 166
Graphical data of In Vitro Evaluation of Antimicrobial screening PART - IX Introduction : STUDIES ON NITRILES .. [1'N, 3'-diphenyl-4'-pyrazolyl]-acetonitriles Introduction and Spectral studies.. Experimental .. .. .. .. ..
..
168
Section - I : Synthesis and biological evaluation of -Arylamino.. .. .. 172 177 179
Graphical data of In Vitro Evaluation of Antimicrobial screening
[B] STUDIES ON MICROWAVE INDUCED PYRAZOLINES SYNTHESIS Introduction PART - I Introduction Section-I : : .. .. .. 181 STUDIES ON PYRAZOLINES BY CONVENTIONAL AND MICROWAVE INDUSED SYNTHESIS .. .. .. 184 Synthesis and biological evaluation of 1N-Acetyl3-aryl-5-[1'N, 3'-diphenyl-4'-pyrazolyl]-pyrazolines (Conventional method) Introduction and Spectral studies.. Experimental .. .. .. .. .. .. .. 185 190 192
Graphical data of In Vitro Evaluation of Antimicrobial screening Section - II : Microwave indnced an expeditius synthesis of
[1'N, 3'-diphenyl-4'-pyrazolyl]-pyrazolines (conventional method) Introduction and Spectral studies.. Experimental REFERENCES LIST OF NEW COMPOUNDS .. .. .. .. .. .. .. .. .. .. .. 194 195 197 235
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SYNOPSIS
The work incorporated in the thesis with the title STUDIES ON HETEROCYCLIC COMPOUNDS has been described as under.
[A] [B]
STUDIES ON PYRAZOLES STUDIES ON MICROWAVE INDUCED PYRAZOLINE SYNTHESIS
[A]
STUDIES ON PYRAZOLES Pyrazole nucleus represent one of the most important class of compounds
possesing wide range of therapeutic activities such as antimicrobial, atitubercular, hypnotic, anthelminetic, amoebicidal, anticonvulsant, CNS depressant, antitumor and antithyroid. Pyrazole derivatives are also used as insecticidal and herbicidal. Considering the increasing importance of pyrazole nucleus, we have undertaken the synthesis of some novel chalcone, pyrimidinone, cyanopyridine, cyanopyran, imidazolinone, barbitone, thiazolidinone, acetonitrile and pyrazoline bearing 1N,3-diphenyl pyrazole nucleus.
PART - I
: STUDIES ON CHALCONES
Chalcones are phenylstyryl ketone containing reactive ethylinic group (-CO-CH=CH-). Chalcone derivatives represent various biological activities such as antibacterial, analgesic, anthelmintic, antiinflammatory, antitubercular, antifungal, antimicrobial etc. These valid observation led us to synthesise some novel chalcone derivatives, which have been described as under.
SECTION - I : Synthesis and biological evaluation of 1-Aryl-3-(1N,3diphenyl-4-pyrazolyl)-2-propene-1-ones
N N R O
Type ( I )
R = Aryl
The chalcone derivatives of type (I) have been prepared by the condensation of 1N,3-diphenyl-4-formyl-pyrazole with different aryl ketones in presence of 40% NaOH.
PART - II : STUDIES ON CYANOPYRIDINES Cyanopyridine derivatives have attracted considerable attention in view of their great therapeutic importance as anticonvulsant, antifungal,antibacterial, antidiabetic and hypertensive agents. To approach these goal, preparation of some novel cyanopyridine has been undertaken as under.
SECTION - I : Synthesis and biological evaluation of 1N,3-Diphenyl -4[2-amino-3-cyano-6-aryl-4-pyridyl]-pyrazoles
N N R N N H2N
Type (II)
R = Aryl
The cyanopyridne derivatives of type (II) have been prepared by the reaction of type (I) with malononitrile and ammonium acetate.
PART - III
: STUDIES ON CYANOPYRANS
Pyran derivatives represants one of the modest classes of compounds possessing wide range of therapeutic activities such as antimicrobial,antifungal, antiviral, antifilarial and antisecretory. In view of these facts, it was contemplated to synthesise some new pyrans, which have been described as under.
SECTION - I : Synthesis and biological evaluation of 1N,3-Diphenyl-4[2-amino-3-cyano-6-aryl-4-dihydropyranyl]-pyrazoles
N N R O N H2N
Type(III)
R=Aryl
The cyanopyran derivatives of type (III) have been prepared by the reaction of type (I) with malononitrile in pyridine.
PART - IV
: STUDIES ON PYRAZOLINES
Pyrazoline derivatives are endowed with different therapeutic activities such as antibacterial, analgesic, anthelmintic, antiinflammatory, antitubercular etc. These valid observation led us to synthesise some novel pyrazoline derivatives bearing 1N,3-diphenyl pyrazole moiety, which have been described as under.
SECTION - I : Synthesis and biological evaluation of 3-Aryl-5-(1N,3diphenyl-4-pyrazolyl)-pyrazolines
N N
R HN N
Type(IV)
R=Aryl
The pyrazoline derivatives of type (IV) have been prepared by the reaction of type (I) with hydrazine hydrate.
SECTION - II : Synthesis and biological evaluation of 1N-Phenyl-3-aryl-5(1N,3-diphenyl-4-pyrazolyl)-pyrazolines
N N
R N N
Type(V)
R=Aryl
The pyrazoline derivatives of type (V) have been prepared by the reaction of type (I) with phenyl hydrazine in presence of basic catalyst like pyridine.
6 PART - V : STUDIES ON PYRIMIDINONES
Pyrimidinone nucleus possess remarkable pharmaceutical importance and biological activity, some of the pyrimidinones, which occur as natural product, like nucleic acids and vitamin B and can be used as therapeutic agent for the treatment of AIDS and antitumor agents, keeping in association of pyrmidinones with varied biological activity, it was thought worthwile to synthesise new pyrimidinone as under. SECTION - I : Synthesis and biological evaluation of 6-Aryl-4-(1N,3diphenyl-4-pyrazolyl)-1,2,3,4-tetrahydropyrimidin-2-ones
N N R HN NH O
Type (VI )
R = Aryl
The pyrimidinone derivatives of type (VI) have been prepared by the reaction of type (I) with urea in presence of acidic catalyst like HCl. SECTION - II : Synthesis and biological evaluation of 5-Alkyl- 6-alkyl/ aryl-4-(1N,3-diphenyl-4-pyrazolyl)-1,2,3,4tetrahydropyrimidin-2-ones
N N R1 R2 HN NH O
Type (VII)
R 1 = Alkyl
R 2 = Alkyl/Aryl
7 The pyrimidinone derivatives of type (VII) have been prepared by the reaction of 1N,3-diphenyl-4-formyl-pyrazole, urea with different 1,3-diketones in presence of acidic catalyst like HCl in methanol.
PART - VI
: STUDIES ON BARBITONES
Barbitone derivatives have been found to be biological activities viz. anticonvulsant, hypnotic, sedative and antiinflammatory. Promoted by above facts, some new barbitones have been prepared as under.
SECTION - I : Synthesis and biological evaluation of 5-[1-Aryl-3-(1N,3 -diphenyl-4-pyrazolyl)-prop-2-enylidine]-barbituric acids
N N R O
O HN NH O
Type (VIII)
R = Aryl
The barbitone derivatives of type (VIII) have been prepared by the reaction of type (I) with barbituric acid in glacial acetic acid.
PART - VII
: STUDIES ON IMIDAZOLINONES
Imidazolidinone derivatives have been found to be potent drug in pharmaceutical and possess a wide range of biological activities such as anticonvulsant, sedative, hypnotic, antiinflammatory, antihistamine and antithyroid. In order to develop medicinally important compounds, we have synthesised some new imidazolinones shown as under.
8 SECTION - I : Synthesis and biological evaluation of 1N-Aryl-2-alkyl/ aryl-4-(1N,3-diphenyl-4-pyrazolylmethino)-imidazolin5-ones
N N
N N R2
Type (IX)
R 1=Aryl
R 2 = Alkyl / Aryl
R1
The imidazolinone derivatives of type (IX) have been prepared by the reaction of azalactone with different aryl amine in pyridine. PART - VIII : STUDIES ON 4-THIAZOLIDINONES Compounds bearing thiazolidinone nucleus show wide range of biological
activity such as antimicrobial, CNS depressant, antiinflammatory, antitubercular, sedative, anticonvulsant, analgesic and antihypertensive. By considering these valid observations, we have synthesised some new thiazolidinones which have been described as under. SECTION - I : Synthesis and biological evaluation of 2-Arylimino- 3N-aryl -5-(1N,3-diphenyl-4-pyrazolylmethino)- 4- thiazolidinones
N N
S N N R
Type (X) R
R = Aryl
The thiazolidinone derivatives of type (X) have been undertaken by the condensation of 1N,3-diphenyl-4-formyl-pyrazole with different thiazolidinones in glacial acetic acid.
PART - IX
: STUDIES ON NITRILES
Recently substituted nitrile derivatives have drawn considerable attention due to their good pharmacological activities like cardiovascular, sedative, antifungal and antibacterial. By considering these valid observations, we have synthesised some new nitriles which have been described as under.
SECTION - I : Synthesis and biological evaluation of -Arylamino-(1N,3 -diphenyl-4-pyrazolyl)-acetonitriles
N N NH R
Type ( XI )
R = Aryl
The nitriles of type (XI) have been prepared by the condensation of 1N,3-diphenyl-4-formyl-pyrazole with different aromatic amines by the presence of potassium cyanide and glacial acetic acid at 0-5 0C.
10
[B] STUDIES ON MICROWAVE INDUCED PYRAZOLINES SYNTHESIS In the recent year, MORE (Microwave Induced Organic Reaction Enhancement) technique has become very popular due to substantial reduction in reaction time, operational time, operational simplisity and formation of clear reaction products. Keeping this in view, we investigated the synthesis of the pyrazolines using microwave irradiation and also by conventional method.
PART - I
: STUDIES ON PYRAZOLINES BY CONVENTIONAL AND MICROWAVE INDUCED SYNTHESIS
Pyrazoline derivatives are endowed with different therapeutic activity such as antibacterial, analgesic, anthelmintic, antiinflammatory, antitubercular etc. This valid observation led us to synthesise some novel pyrazolines bearing pyrazole which have been described as under. moiety,
SECTION - I : Synthesis and biological evaluation of 1N-Acetyl-3-aryl-5(1N,3-diphenyl-4-pyrazolyl)-pyrazolines by conventional method
N N
R H3C O N N
Type (XII)
R = Aryl
The pyrazoline derivatives of type (XII) have been prepared by the reaction of type (I) with hydrazine hydrate and glacial acetic acid.
11 SECTION - II : Synthesis and biological evaluation of 1N-Acetyl-3-aryl-5(1N,3-diphenyl-4-pyrazolyl)-pyrazolines by microwave method
N N
R H3C O N N
Type (XIII)
R = Aryl
The pyrazoline derivatives of type (XIII) have been prepared by the reaction of type (I) with hydrazine hydrate and glacial acetic acid under microwave irradiation in few minutes.
The constitution of the synthesised product have been characterised using elemental analysis, infra red and 1H nuclear magnetic resonance spectroscopy and further supported by mass spectrometry. Purity of all the compounds have been checked by thin layer chromatography.
in vitro studies on multiple biological activities. (I) All the compounds have been evaluated for their in vitro biological assay like antitubercular activity towards a strain of Mycobacterium tuberculosis H37Rv at a concentration of 6.25 g/ml using Rifampin as standard drug, which have been tested by Tuberculosis Antimicrobial Acquisition Coordinating Facility (TAACF), alabama, U.S.A.
12 (II) All the compounds have been also evaluated for their antibacterial activity towards Gram positive and Gram negative bacterial strains and antifungal activity towards Aspergillus niger at a concentration of 40g/ml. The biological activity of the synthesised compounds have been compared with standard drugs.
13
SYNOPSIS of the Thesis to be submitted to the Saurashtra
University for the degree of Doctor of Philosophy in Chemistry.

Faculty Subject Title : : : Science Chemistry STUDIES ON HETEROCYCLIC COMPOUNDS Name of the Candidate Registration number Date of Registra tion Name of the Guide : : : : HARSHAD G. SANGANI 2605 9 th August 2001
Dr. A. R. Parikh
Rtd- Professor & Head, Department of Chemistry, Saurashtra University, RAJKOT - 360 005.
Submitted to
Saurashtra University
Place of Work Chemical Research Laboratory Department of Chemistry Saurashtra University Rajkot - 360 005. (GUJARAT STATE - INDIA)
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12
INTRODUCTION
H eterocyclic chemistry has seen unparalled progress owing to their wide

natural occurance, specific chemical reactivity and broad spectrum utility. Heterocyclic compounds have great applicability in pharmaceutics because they have specific chemical reactivity and provides false synthons in biosynthetic process or block the normal functioning of biological receptors. The inhibition of amide resonance resulting into more susceptibility of -lactam to nucleophile is considered at least in part responsible for antibacterial property, apparently by acetylating transpeptidase and thus inhibiting bacterial cell wall biosynthesis. Most of the alkaloids which are nitrogenous bases occuring in plants and many antibiotics including penicillin and streptomycin have also heterocyclic ring system. Many natural pigments such as indigo, haemoglobin and anthocyanin are heterocycles. Most of the sugars are their derivatives including Vitamin C for intance, exist largely in the form of five membered. Vitamin B 6 (Pyridoxine) is a derivative of pyrimidine essential in aminoacid metabolism. Important drugs, poisons and medicines (both natural and synthetic) such as sulphathiazole, pyrenthrin, rotenmone, strychnine, reserpine, certain of the antihistaminics, the ergot alkaloids caeffine, cocaine, barbiturates, etc. are heterocyclic compounds. Heterocyclic compounds have great biological significance because : 1. 2. They have a specific chemical reactivity. They resemble essential metabolism and can also provide false synthons in biosynthetic process.
13 3. 4. They fit receptors and block their normal working. They provide convenient building blockers to which biologically active substituents can be attached. The interesting biological activities of heterocycles have stimulated considerable research work in recent years including to the synthetic utility. Heterocyclic compounds can be synthesised by cyclisation reactions (accompanied by elemination of small molecules), addition reactions (adduct formation), ring transformation reactions or replacement involving groups. Formation of heterocycle from acyclic compounds alters the reactivity. Piperidine is reactive than ethyl propylamine due to the reduction in steric incumbrance of the nitrogen lone pair. AIMS AND OBJECTIVES In the pharmaceutical field, there is a need for new and novel chemical inhibitors of biological functions. Our efforts are focused on the introduction of chemical diversity in the molecular frame work in order to synthesising pharmacologically interesting heterocyclic compounds of widely different composition. During the course of research work looking to the applications of heterocyclic compounds, several entities have been designed, generated and characterised using spectral studies. The aims and objectives of the work carried out are as under. 1. To s y n t h e s i s e p h a r m a c o l o g i c a l l y a c t i v e e n t i t i e s l i k e c h a l c o n e s , cyanopyridines, cyanopyrans, pyrazolines, pyrimidinones, barbitones, imidazolinones, thiazolidinones and nitriles bearing 1N, 3-diphenyl pyrazole nucleus.
14 2. 3. 4. To characterise these products for structural elucidation using spectroscopic techniques like IR, PMR and Mass spectral studies. To check the purity of all compounds using thin layer chromatography. To evaluate these new products for better drug potential against different strains of bacteria, fungi and for antitubercular activity. The research work is presented as studies on [A] Pyrazoles and [B] Microwave induced pyrazolines synthesis. I n a p r o g r a m m e d re s e a rc h d i re c t e d t o w a r d s t h e c o n s t r u c t i o n o f therapeutically active new heterocycles bearing 1 N, 3-diphenyl pyrazole nucleus has been investigated in following parts. [A] : STUDIES ON PYRAZOLES PART - I PART - II PART - III PART - IV PART - V PART - VI PART - VII PART - VIII PART - IX : STUDIES ON CHALCONES : STUDIES ON CYANOPYRIDINES : STUDIES ON CYANOPYRANS : STUDIES ON PYRAZOLINES : STUDIES ON PYRIMIDINONES : STUDIES ON BARBITONES : STUDIES ON IMIDAZOLINONES : STUDIES ON THIAZOLIDINONES : STUDIES ON NITRILES
[B] : STUDIES ON MICROWAVE INDUCED PYRAZOLINES PART - I : SYNTHESIS AND BIOLOGICAL EVALUATION OF PYRAZOLINES (MICROWAVE IRRADIATION AND CONVENTIONAL METHOD)
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[ A ] STUDIES ON PYRAZOLES
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Pyrazoles...
15
INTRODUCTION
The pyrazole ring system (I) consists of a doubly unsaturated five membered
ring containing two adjacent nitrogen atoms. Knorr 1,2 first synthesised a compound containing this system in 1883 by a reaction of ethylacetoacetate with phenylhydrazine which yield 1-phenyl-3-methyl-5-pyrazolone (II).
CH3 CH CH N N H CH O N C6H5 N
(I)
(II)
Knorr 3 introduced the name pyrazole for these compounds to donate that the nucleus was derived from pyrrole by replacement of carbon by nitrogen; since many durgs and dyes contain the pyrazole nucleus, the class has been widely studied and the field continuous to be active today even though antipyrine and related medicine no longer in common use. Pyrazolone dyes are especially important in colour photography. SYNTHETIC ASPECT Various methods for the preparation of pyrazoles have been cited in literature. 1. The reaction of hyrazine or its derivatives such as alkyl or aryl hydrazines, semicarbazine or aminoguanidine with 1,3-dicarbonyl compounds.
CH3
CH3COCH2COCH3
C6H5NH.NH2 H3C N Ph
Pyrazoles... 2. 3.
16
The reaction of hydrazines with , -unsaturated carbonyl compounds. The reaction of aliphatic diazo compounds such as diazomethane or diazoester with acetylene or olefins.
THERAPEUTIC IMPORTANCE Much research has been carried out with the aim to finding therapeutic values of pyrazole moiety since their discovery. A large number of substituted pyrazole derivatives are prepared and tested for variety of biological activities. 1. Antitumor 4 2. 3. 4. 5. 6. 7. 8. 9. Anticancer 5 Antiviral 6 Herbicidal 7-10 AntiHIV 11 Antiinflammatory 12-13 Insecticidal 14 p-38 Kinase inhibitors 15-18 Antiepilectic 19
10. Nemeticidal 20 Havaldar Freddy et. al. 21 synthesised 4,5-dihydro-3-phenyl-1H-pyrazole and reported their biological activity. Carbau Romuald and co-worker 22 have prepared pyrazole derivatives useful as reverse transcriptase inhibitors for the treatment of HIV infection.
Cl
Cl
Me OH N S N Me
(III)
Pyrazoles... 17 Someya Shinzo and co-worker 23 have synthesised pyrazole derivatives and repor ted their herbicidal activity. Gehring Reinhold et. al. 24 have synthesised 5-Amino-4-cyano-1-aryl-pyrazoles and shown them as plant growth inhibitors. Nakamura Katsyya and co-workers 25,26 have prepared 1,5-diphenyl pyrazoles as Cox-II inhibitors.
R1 MeO2S N R2 N
(IV) Jansen Karte et. al. 27 have synthesised pyrazole derivatives as pesticides.
Cl N F 3C N SO2CF3 Cl COOH
(V) Feid-Allah Hassan 2 8 have prepared pyrazoles and repor ted their antidiabetic and antibacterial activity. Ejima Akio et. al. 29 have synthesise pyrazole derivatives as antitumor agents.
Cl Cl N N N Me N N F
(VI) Banks Bernard et. al. 30 have synthesised pyrazole derivatives (VII) and tested for their antiparasitic activity.
Pyrazoles...
CH2 Cl
18
F 3C
N N Cl N
(VII) Schindler Ursula et. al. 31 synthesised new pyrazole derivatives (VIII) as cardiovascular agents.
R3 R2 R4-(CH2)n N N R'a
(VIII)
R'
Pier Giovanni Baraldi et. al. 32 synthesised pyrazole derivatives as antileukemic agents. Thomas Alan Crowell et. al. 33 prepared new pyrazoles as selective 3 adrenergic agonists. Kevin M. Moore et. al. 34 prepared pyrazoles as human dopamine-D4-receptors. Grazid Mamolo et. al. 35 have newly synthesised pyrazole derivatives tested for antimicrobial activity. R. V. Huang and co-worker 36 have prepared some 1,2,4-triaryl-4-alkyl-pyrazoles as estrogen receptor. C. Vittoria and co-worker37 have prepared some pyrazoles as adinosine receptor antagonists. Recently,Atkinson R. N. et. al. 38 have synthesised pyrazoles as sodium channel blocker (IX). Murakanli Hiroshi et. al. 39 have synthesised pyrazoles as antifouling agent. Gellibert Francoise et. al. 40 have synthesised pyrazole derivatives as TGF-13 inhibitors.
Pyrazoles...
F 3C CONH Cl N N N
19
(IX) Laborde Edgardo et. al. 41 have found that pyrazoles possess glycine transporter-2 inhibitor activity. Andrew Thurkaub et. al. 42 have synthesised high affinity C 5a receptor modulator pyrazoles. Nagaaki Sato et. al. 43 have prepared pyrazoles as neuropeptide T 5 receptor antagonists. G. M. B. Hi Yamanouch Pharma Co. 44 has prepared pyrazoles as glycine transporter protein inhibitor (X).
N N F COOC2H5 N
(X) Jacques Dumas and co-workers 45 have prepared pyrazole derivatives as rafkinase and angiogenesis inhibitor agents. David L. S. et. al. 46 have synthesised pyrazoles as activators of the nitrile oxide receptor and soluble guanglate cyclase agent. T Van Herk et. al. 47 have synthesised pyrazoles as nicotinic acid receptor (XI). Barber Christopher et. al. 48 have synthesised pyrazole derivatives as phosphidiesterase inhibitors. Nishimura Tsoshihiro et. al. 49 have synthesised p y r a z o l e s a s i n h i b i t o r s o f h u m a n S G LT 2 ( S o d i u m d e p e n d e n t g l u c o s e transporter-2).
COOH R2 N R1 N H
(XI)
Pyrazoles...
20
Recently, it is found that pyrazole derivatives possesses a number of biological activities such as fungicidal 50,51 , herbicidal 52-55 , cardiovascular 56 , antiinflammatory 57-59 , Cox-II inhibitor 60 , antimicrobial 61 , anticancer 62-64 , protein kinase inhibitor 65-68 , antibacterial 69,70 , antiviral 71 , antiparasitic 72 , HIV reverse transcriptase inhibitor 73,74 and 5-H T 20 receptors 75-77 . Literature survey reveals that the compounds bearing pyrazole moiety in general passage potential drug activity. Looking to the diversified biological activity, it appeared of interest to synthesise some chalcones, cyanopyridines, cyanopyrans, pyrazolines, pyrimidinones, barbitones, imidazolinones, thiazolidinones and nitriles bearing pyrazole moiety, in order to achieving compounds having better therapeutic importance. These study are described in following parts. [A] : STUDIES ON PYRAZOLES PART - I PART - II PART - III PART - IV PART - V PART - VI PART - VII PART - VIII PART - IX : STUDIES ON CHALCONES : STUDIES ON CYANOPYRIDINES : STUDIES ON CYANOPYRANS : STUDIES ON PYRAZOLINES : STUDIES ON PYRIMIDINONES : STUDIES ON BARBITONES : STUDIES ON IMIDAZOLINONES : STUDIES ON THIAZOLIDINONES : STUDIES ON NITRILES
MMMMMMMMMMMMMMMMM M
PART-I STUDIES ON CHALCONES
M MMMMMMMMMM
Chalcones...
21
INTRODUCTION
T he
chemistry of chalcones have generated intensive scientific studies
throughout the world, specially interesting are their biological and industrial applications. Chalcones are coloured compounds because of the presence of the chromophore, auxochromes. They are known as benzalacetophenones or benzylidene acetophenones. Kostanecki and Tambor 78 gave the name "chalcone". Chalcones are characterised by their possession of a structure in which two aromatic rings A and B are linked by an aliphatic three carbon chain.
O
A
(I)
The alternative names given to chalcones are phenyl styryl ketones, benzalacetophenone, -phenyl acrylphenone, -oxo-,-diphenyl--propylene and -phenyl--benzoethylene. SYNTHETIC ASPECT A considerable variety of methods are available for the synthesis of chalcones. The most convenient method is one that involves the Claisen-Schmidt condensation of equimolar quantities of an ary methyl ketones with arylaldehyde in presence of alcoholic alkali 79 .
Chalcones...
22
Several condensing agents used are alkali of different strength 80,81 , hydrogen chloride 82,83 , phosphorous oxychloride 84 , piperidine 85 , anhydrous aluminium chloride 86 , boron trifluoride 87 , aq. solution of borax 88 , amino acids 89 and perchloric acid 90 etc. MECHANISM Chalcone formation proceeds through Aldol type of condensation and the process is catalysed by the presence of alkali 91 . Following are the steps of the reaction mechanism.
(i) CH COR 3 O (ii) R' C H O (iii) R' C+ H + CH CO R 2 + OH O R' C+ H O R' C CH C R 2 H O OH R' C CH C R + OH 2 H O CH COR + H O 2 2
(iv)
O R' C CH C R + H O 2 2 H O OH R' C CH C R 2 H O
(v)
R' CH = CH C R + H O 2 O
The intermediate Aldol type of products formed readily undergoes dehydration even under mild condition, particularly when R and R' are aryl groups. REACTIVITY OF CHALCONES The chalcones have been found to be useful for the synthesis of variety of heterocyclic compounds are as under. a. Pyrazolines 92 and its derivatives can be prepared by the condensation of chalcones with hydrazine hydrate and acetic acid.
Chalcones... b. c. d. e. f. g. h. i. j. k. l. m. n. o. p. q.
23
Chalcones on condensation with malononitrile and ammonium acetate yields 2-amino-3-cyano pyridines 93 . Isoxazoles 94 can be prepared by the treatment of chalcones with hydroxylamine hydrochloride and sodium acetate. Chalcone on condensation with malononitrile in pyridine forms 2-amino3-cyanopyrans 95 . C h a l c o n e s o n t re a t m e n t w i t h u r e a i n p re s e n c e o f a l k a l i a f f o r d s 2-oxopyrimidines 96 . Chalcones on reaction with thiourea in presence of alkali/acid yields 2-thienopyrimidines 97 . Chalcones on treatment with guanidine hydrochloride in presence of alkali affords 2-amino pyrimidines 98 . Chalcones reacts with P 2 S 5 yielding 2-isothiazolines 99 . Chalcones with sodium nitrile in presence of glacial acetic acid in ethanol produces 2-1H-pyrimidines 100 . Chalcones with monoethanolamine in ethanol gives 1,4-oxazipines 101 . Chalcones with 2-amino thiophenol in acetic acid produces 1,5-thiazepines 102 . Chalcones on reaction with semicarbazide hydrochloride in ethanol affords 1-carboxamide pyrazolines 103 . Chalcones on reaction with 2-aminopyrimidine in glacial acetic acid affords pyrido pyrimidines 104 . Oxiran 105 can be prepared by the reaction of chalcone with H 2 O 2 in basic media. Cyanopyridone 106 derivatives can be prepared by the condensation of chalcone with ethylcyanoacetate. Chalcones on reaction with barbituric acid gave barbitone 107 derivatives. Chalcones gives imine derivatives with amine in presence of sufuric acid as catalyst 108 .
Chalcones... THERAPEUTIC INTEREST
24
Chalcones are potential biocides, some naturally occuring antibiotics and aminochalcones probably owe their biological activity to the presence of ,-unsaturated carbonyl group. 1. Insecticidal 109,110 2. 3. 4. 5. 6. 7. 8. 9. Antiulcer 111 Antiinflammatory 112,113 Bactericidal 114,115 Fungicidal 116,117 Antiviral 118 Anthelmintics 119 Antiallergic 120
Carboxygenase inhibitor 121 10. Antitumor 122,123 11. Antimalarial 124 12. Anticancer 125 13. Antileishmanial 126 Moreover, synthesis and antibacterial activity of substituted chalcone derivatives have been reported by Modi et. al. 127 and Attia A 128 , V. Mudalir et. al. 129 have prepared phenoxychalcones and observed their insecticidal activity. Kammei et. al. 130 have synthesised chalcone derivatives having antitumor activity. De Vincenzo et. al. 131 and Han et. al. 132 have reported chalcone derivatives for their antiinflammatory activity. Aldose reductase inhibitor activity of chalcone derivatives have been reported by Okuyama et. al. 133 . They are also associated with antitumor and antifungal activity as reported by Tsotitus and co-worker 134 . Antifeedant activity of chalcones have been observed by Sarma and Sreenivasulu 135 .
Chalcones...
25
Ezio Bombardelli et. al. 136 have demonstrated that chalcone possess a valuable antiproliferation activity both on sensitivie cancereous cell and on cell which are resistant to common chemotherapeutic drugs. Some of the chalcones have been patented for their use for treatment of glaucoma 137 and showed antifungal 1 3 8 , 1 3 9 aldose reductase inhibitor 1 4 0 , anticancer 1 4 1 and antimicrobial 142,143 activities. Recently, Ni Liming et. al. 144 have synthesised chalcones and screened for their antiinflammatory and cardiovascular activity (II). Kumar Srinivas et. al. 145 have synthesised chalcones as a antitumor agent.Ko Horng-Huey et. al. 146 have prepared chalcones as antiinflammatory agent. Nakahara Kazuhiko et. al. 147 have synthesised chalcones as carcinogen inhibitors. Antitubercular agents of chalcone derivatives have been prepared by Lin Yuh-Meei et. al. 148 .
O OCH3
HOOC
CH3 S
(II) Das B. P. et. al. 149 have found that chalcones possesses lar vicidal properties. Kim Min-Young et. al. 150 have synthesised chalcones and tested for their matrix metalloproteinase inhibitor activity (III).
O
R 1-5
R 6-10
(III)
R 1-10 = H,OH,OMe,Cl
Chalcones...
26
Liu Mei et. al. 151 have prepared antimalarial chalcones. Opletalova Veronika et. al. 152 have synthesised chalcones and screened as cardiovascular agents. Moreover, it has been found that chalcone derivatives possesses nitric oxide inhibitor (IV) 153,154 , anti-HIV 155,156 and antiproliferative 157,158 (V) activities.
O OMe O R1 O
R 3-6
Me2N O R2 R7
(IV)
OMe
(V)
R 1- R 7 = H, OH, OMe
Chalcone bearing a very good synthon, variety of novel heterocycles with good pharmacological profile can be designed. These valid observation led us to explore chalcone chemistry by synthesising several derivatives like cyano pyrans, cyanopyridines, pyrazolines, pyrimidinones and barbitones bearing different heterocyclic ring systems for medicinal value, in order to achieving better therapeutic agents, this study described as under. SECTION - I : SYNTHESIS AND BIOLOGICAL EVALUATION OF 1A RY L - 3 - [ 1 ' N , 3 ' -D I P H E N Y L - 4 ' -P Y R A Z O LY L ] - 2 PROPENE-1-ONES
27 SECTION - I SYNTHESIS AND BIOLOGICAL EVALUATION OF 1-ARYL-3-[1'N, 3'DIPHENYL-4'-PYRAZOLYL]-2-PROPENE-1-ONES Recently much interest has been focoused on the synthesis and biodynamic activities of chalcones and it is a good synthon for various heterocyclic rings. With a view to obtained compounds having better therapeutic activity, we have synthesised 1-Aryl-3-(1'N,3'-diphenyl-4'-pyrazolyl)-2-propene-1-ones by the condensation of 1N,3-Diphenyl-4-formyl-pyrazole with various aromatic ketones.
O N N CHO R N R CH3 N O
40% NaOH
Type - (I)
R = Aryl
The constitution of the synthesised products have been characterised by using elemental analyses, infrared and 1 H nuclear magnetic resonance spectroscopy and mass spectrometry also. In mass spectrometry the m/z value indicate the molecular weight, i.e. when R=p-Anisyl, molecular weight=380, m/z=381 (m+1) All the compounds have been also evaluated for their antibacterial activity towards Gram positive and Gram negative bacterial strains and antifungal activity towards Aspergillus niger at a concentration of 40g/ml. The biological activity of the synthesised compounds have been compared with standard drugs. Some compounds have been found to have good and equivalent activity as compared to the known antibiotics recorded on Page No.38. Moreover, some selected compounds have been evaluated for their in vitro biological assay towards a strain of Mycobacterium tuberculosis H 37 Rv at a concentration of 6.25 g/ml using Rifampin as a standard drug which have been tested at Tuberculosis Antimicrobial Acquisition Co-ordinating Facility (TAACF), Alabama, U. S. A.
28 REACTION SCHEME
NH2 N H
O CH3 Methanol gla. CH 3COOH
N N H CH3 DMF POCl 3
N N CHO R-COCH3 40%NaOH
N N O R
Type - (I)
R = Aryl
29
IR SPECTRAL STUDY OF 1-p-ANISYL-3-[1'N,3'-DIPHENYL-4'-PYRAZOLYL]-2-PROPENE-1-ONE
120.0 %T
O
100.0
N N
80.0 2835.2 2929.7 3130.3 3413.8
CH3
910.3 60.0 833.2 505. 956.6 1112.9 979.8 599.8 1062.7 806.2 1305.7 692.4 1336.6 752.2 1031.8 1361.7 1535.2 1658.7 1413.7 1446.5 1166.9 1596.9 1257.5 1502.4 1218.9 500.0 1/cm
(KBr disc)
40.0
20.0
0.0 3250.0 2000.0 1750.0 1500.0 1250.0 1000.0 750.0 chalcone4-ome

I Instrument : SHIMADZU-FT-IR 8400-Spectrophotometer; Frequency range : 4000-400 cm Vibration mode C-H str. (sym.) CH def. (asym.) CH def. (asym.) Aromatic C-H str. C=C str. CH i.p.def. unsaturated Ketone Ether Pyrazole moiety -CH=CH str. C-O-C str. (asym) C-O-C str. (sym) C=N str. 1502 1218 1031 1596 1644-1618 1260-1220 1075-1020 1610-1590 " 671 " " -C=O str. Frequency in cm Observed 2929 1446 1353 3060 1507 1112 1658 -1 Ref. 670 '' '' 670 '' " 673 -1
Type Alkane
Reported 2975-2950 1470-1435 1385-1370 3090-3030 1520-1480 1125-1090 1700-1640
30
PMR SPECTRAL STUDY OF 1-(p-ANISYL)-3-[1'N,3'-DIPHENYL-4'-PYRAZOLYL]-2PROPENE-1-ONE
c d e f i a j g' h' g O CH3 h k O N b a N a a a
Internal Standard : TMS; Solvent : CDCl ; Instrument : BRUKER Spectrometer (300 MHz) 3 Signal Signal Position No. ( ppm) 1 2 3 4 5 6 7 8 9 3.88 6.92-6.97 7.3-7.4 7.4-7.5 7.7-7.73 7.75-7.8 7.9 7.94-8.0 8.33 Relative No. of Protons 3H 2H 2H 5H 2H 2H 1H 2H 1H Multiplicity singlet doublet doublet multiplate doublet doublet doublet doublet singlet Inference Ar-OCH CHhh' CHjk CHa CHbf CHce CHd CHgg' CHi 3 J Value In Hz J=8.9 J=8.9 -
31 EXPANDED AROMATIC RIGION
c d e f i a j g' h' g O CH3 h k O N b a N a a a
O N N
CH3
m/z = 381 (m+1)
SB- 1
+
o
+
N N
+
o N N m/z = 220 N N m/z = 273
+
CH2 o
H2N
NH m/z = 107 m/z = 245
H3C O
+
o m/z = 135 BASE PEAK O N N H3C O N N
CH3
+
o
m/z = 233 O m/z = 381 (M

+
1)
+
o O
m/z = 115
H3C O H3C
+
o
+
o
H3C
m/z = 135 BASE PEAK
+
o HN O m/z = 165 N H O m/z = 128
H3C O CH3
m/z = 178
32
33 ANTIMICROBIAL ACTIVITY Cup-Plate 159 Staphylococcus aureus Bacillus Megaterium Gram negative bacteria : Proteus Vulgaris Escherichia Coli Fungi Concentration Solvent Standard drugs : : : : Aspergillus niger 40g Dimethyl formamide Ampicillin, Amoxicillin, Norfloxacin, Penicillin, Greseofulvin
Method Gram positive bacteria
: :
The antimicrobial activity was compared with standard drug viz Ampicillin, Amoxicillin, Norfloxacin, Penicillin and antifungal activity was compared with viz Greseofulvin. The inhibition zones measured in mm. ANTITUBERCULAR ACTIVITY The antitubercular evaluation of the compounds was carried out at Tuberculosis Antimicrobial Acquisition Co-ordinating Facility (TAACF) U.S.A. Method Bacteria : : BACTEC 460 Radiometric system. Mycobacterium Tuberculosis H 37 Rv 6.25 g/mg. Rifampin.
Concentration : Standard drug :
34 EXPERIMENTAL SYNTHESIS AND BIOLOGICAL EVALUATION OF 1-ARYL-3-[1'N-3'DIPHENYL-4'-PYRAZOLYL]-2-PROPENE-1-ONES [A] Synthesis of N-Phenylamino- -methyl-phenyl azomethine A mixture of phenylhydrazine (1.08g, 0.01M) and acetophenone (1.20g, 0.01M) in absolute ethanol was refluxed in waterbath for 4 hrs. in presence of 1 ml glacial acetic acid. Product obtained after cooling was crystallised from absolute ethanol. Yield, 1.8 g (90%), m.p.64 o C. (C 14 H 14 N 2 ; Requires : C, 80.00 ; H, 6.66; N,13.37%; found; C, 79.92; H, 6.60; N,13.30%). [B] Synthesis of 1N,3-Diphenyl-4-formyl pyrazole N-Phenylamino--methyl-phenyl azomethine (0.84 g, 0.004 M) was added in a mixture of Vilsmeier-Haack reagent (prepared by dropwise addition of 1.2ml POCl 3 in ice cooled 10 ml DMF) and refluxed for 6 hrs. The reaction mixture was poured into crushed ice followed by neutralization using sodium bicarbonate. Crude product was isolated and crystallized from methanol. (87%), m.p. 125 o C. (C Yield, 2.16 g H N O; Requires ; C, 77.42; H, 4.84; N, 11.29%; 16 12 2 found : C, 77.38; H, 4.80; N, 11.23%). [C] Synthesis of 1-(p-Anisyl)-3-[1'N,3'-diphenyl-4'-pyrazolyl]-2-propene1-one To a well stirred solution of 1,N-3-Diphenyl-4-formyl pyrazole (2.48 g, 0.01 M) and p-methoxyacetophenone (1.5 g, 0.01 M) in ethanol (25 ml), 40% NaOH added till the solution become basic. The reaction mixture was stirred for 24 hrs. The contents were poured into ice, acidified, filtered and crystallized from ethanol. Yield, 3.57 g (94%), m.p.102 o C. (C 25 H 20 N 2 O 2 ; Requires : C, 78.95; H, 5.26; N, 7.36%; found : C,78.92; H, 5.20; N, 7.32%). TLC solvent system Acetone : Benzene (1:9). Similarly other substituted chalcones have been prepared. The physical data are recorded in Table No. 1.
35 [D] Antimicrobial and antitubercular activity of 1-Aryl-3-[1'N,3'diphenyl-4'-pyrazolyl]-2-propene-1-ones All the compounds have been evaluated for antimicrobial and antitubercular activity as described under. (a) Antimicrobial activity It was carried out buy cup-plate diffusion method which has been described as under. (I) Antibacterial activity The purified products were screened for their antimicrobial activity. The nutrient agar, both prepared by the usual method, was inoculated aseptically with 0.5 ml of 24 hrs. old subcultures of B. megaterium, S. aureus, E. coli and P valgaris in separate conical flasks at 40-50 oC and mixed well by gentle . shaking. About 25 ml content of the flask were poured and evenly spreaded in a petridish. (13 cm in diameter) and allowed to set for 2 hrs. The cups (10 mm in diameter) were formed by the help of borar in agar medium and filled with 0.04 ml (40 g) solution of sample in DMF. The plates were incubated at 37 o C for 24 hrs. and the control was also maintained with 0.04 mole of DMF in a similar manner and the zones of inhibition of bacterial growth were measured in millimeter and are recorded in Graphical Chart No. 1. (II) Antifungal activity A. niger was employed for testing antifungal activity using cup-plate method. The culture was maintained on Sabouraud's agar slants. Sterilised
36 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 plates were incubated at 30 o C for 48 hrs. After the completion of incubation period, the zones of inhibition of growth in the form of diameter in mm was measured. Along the test solution in each petridish one cup was filled with solvent which act as control. The zone of inhibition are recorded in Graphical Chart No. 1. (b) Antitubercular activity The antitubercular evaluation of compounds was carried out at Tuberculosis Antimicrobial Acquisition Co-ordinating Facility (TAACF), U.S.A. Primary screening of the compounds for antitubercular activity have been conducted at 6.25 g/ml towards Mycobacterium Tuberculosis H 37 Rv in BACTEC 12B medium using the BACTEC 460 radiometric system. The compounds demonstrating atleast >90% inhibition in the primary screen have been retested at lower concentration towards Mycobacterium Tuberculosis H 37 Rv to determine the actual minimum inhibitory concentration (MIC) in the BACTEC 460. The antitubercular activity data have been compared with standard drug Rifampin at 0.25 g/ml concentration and it showed the 98% inhibition. The antitubercular activity data are showed in Table No. 1a.
TABLE NO. 1 : Sr. No. 1

1a 1b 1c 1d 1e 1f 1g 1h 1i 1j 1k 1l 1m
PHYSICAL CONSTANTS OF 1-ARYL-3-[1'N,3'-DIPHENYL-4'-PYRAZOLYL-2-PROPENE]-1-ONES Molecular Formula 3

H N O 24 18 2 C H N OBr 24 17 2 C H N OCl 24 17 2 C H N OF 24 17 2 C H N O 25 20 2 C H N O 25 20 2 2 C H N O 24 18 2 2 C H N O 24 18 2 2 C H N O 24 19 3 C H N O 24 17 3 3 C H N O3 24 17 3 C H N O 22 16 2 2 C H N OS 22 16 2 C
R 2
C H 6 5 4-Br-C H 6 4 4-Cl-C H 6 4 4-F-C H 6 4 4-CH -C H 3 6 4 4-OCH -C H 3 6 4 2-OH-C H 6 4 4-OH-C H 6 4 4-NH -C H 2 6 4 3-NO -C H 2 6 4 4-NO -C H 2 6 4 2-C H O4 3 2-C H S4 3
Molecular Weight 4
350 429 384.5 368 364 380 366 366 365 395 395 340 356
M.P. o C 5
111 150 105 144 120 102 229 251 215 168 103d 160 178
Rf * Value 6
0.53 0.56 0.58 0.54 0.50 0.45 0.60 0.61 0.52 0.57 0.51 0.55 0.61
Yield % 7
92 94 88 86 90 94 78 75 95 90 92 70 76
% of Nitrogen Found Calcd. 9 8

7.99 6.53 7.28 7.60 7.69 7.36 7.65 7.65 11.50 10.63 10.63 8.23 7.86 7.94 6.56 7.23 7.58 7.67 7.32 7.63 7.62 11.43 10.67 10.64 8.25 7.83
*TLC Solvent System : Acetone : Benzene (1 : 9).
37
GRAPHICAL CHART NO. 1 :
ANTIMICROBIAL ACTIVITY OF 1-ARYL-3-[1N,3-DIPHENYL-4-PYRAZOLYL]2-PROPENE-1-ONES
30
ZONE OF INHIBITION IN mm
25
20
15
10
0 1a B.mega s.aureus E.coli P.vulgaris A.niger 14 17 20 13 15 1b 11 12 17 19 12 1c 17 15 18 15 17 1d 11 20 13 17 13 1e 23 15 11 16 16 1f 13 11 12 16 18 1g 14 13 15 17 15 1h 12 16 22 14 19 1i 15 14 15 18 20 1j 13 16 11 15 20 1k 19 19 14 17 18 1l 20 12 18 12 21 1m 11 21 19 11 13
Ampici Amoxy Norflox Penicill Grese llin cillin acin in ofulvin 23 22 21 15 0 22 23 21 18 0 24 17 23 17 0 25 24 19 20 0 0 0 0 0 25
38
COMPARATIVE STUDY OF ANTIMICROBIAL ACTIVITY WITH KNOWN ANTIBIOTICS [A] PART-I Section - I : Antimicrobial activity of 1-Aryl-3-[1'N,3'-diphenyl-4'-pyrazolyl]-2-propene-1-ones
Antibacterial activity Zone of inhibition in m.m. B. mega

1e (23) 1l (20)
Antifungal activity Zone of inhibition in m.m. E. coli

1a (20) 1h (22) 1m (19)
S. aureus
1d (20) 1k (19) 1m (21)
P vulgaris .
1b (19) 1i (18)
A. niger
1i (20) 1j (20) 1l (21)
Ampicillin Amoxicillin Norfloxacin Penicillin Greseofulvin
23 22 24 25 -
22 23 17 24 -
21 21 23 19 -
15 18 17 20 -
25
39
40
TABLE NO. 1a : DATA OF IN VITRO EVALUATION OF ANTITUBERCULAR ACTIVITY
N N O R
R = Aryl
Dr. A. R. Parikh Saurashtra University
TAACF, Southern Research Institute Primary Assay Summary Report Sample Corp ID ID 4-OH-C H 6 4 Sau.uni Sau. uni. Sau.uni Sau.uni Sau.uni Alamar Alamar Alamar Alamar Alamar Alamar Alamar Alamar Alamar Alamar Alamar Alamar Alamar 162336 SHI-8 Where,R= Supplier Assay MTb H MIC
% Inhib 92 58 56 52 44 41 33 20 18 14 14 5 0
comment
MIC Rifampin = 0.025mg/ml @98% inhibition
Strain g/ml 37 Rv >6.25
162341 SHI-13 2-C H S4 3 162337 SHI-9 4-NH -C H 2 6 4
H37Rv >6.25 H H H H H H H H H H H 37 37 37 37 37 37 37 37 37 37 37 Rv >6.25 Rv >6.25 Rv >6.25 Rv >6.25 Rv >6.25 Rv >6.25 Rv >6.25 Rv >6.25 Rv >6.25 Rv >6.25 Rv >6.25
"
'' '' '' '' '' '' '' '' '' '' "
162340 SHI-12 2-C H O4 3 162335 SHI-7 162334 SHI-6 2-OH-C H 6 4
4-OCH -C H - Sau.uni 3 6 4 Sau.uni Sau.uni Sau.uni Sau.uni Sau.uni Sau.uni Sau.uni
162338 SHI-10 3-NO -C H 2 6 4 162330 SHI-2 162332 SHI-4 162331 SHI-3 4-Br-C H 6 4 4-F-C H 6 4 4-Cl-C H 6 4
162339 SHI-11 4-NO -C H 2 6 4 162333 SHI-5 162329 SHI-1 4-CH -C H 3 6 4 C H 6 5
NIAID/ Southern Research institute/ GWL Hansen's Center/ Colorado state university proprietary information.
MMMMMMMMMMMMMMMMM M
PART-II STUDIES ON CYANOPYRIDINES
M MMMMMMMMMM
Cyanopyridines...
41
INTRODUCTION
P yridine, nucleus has been extensively explored for their applications in

the field of medicine, agriculture and industrial chemistr y. Pyridine-3carboxamide occurs as a component of the structure of the important coenzymes NADP+(I), one of the B 2 complex of vitamins, occurs in red blood corpuscles and participates in biochemical redox reaction. Pyridoxol (Vitamin B 6 ) (II), occurs in yeast and wheatgerm is an important food additive.
-
O O P O
O P O
OH
O OR O N N N H3C NH2 N HO CH2OH CH2OH
O
+
OH N
OH
(II)
O H2N
(I) R = PO(OH)
The availability of 3-cyanopyridine, nicotinamide and nicotinic acid make possible their use as synthetic intermediates. SYNTHETIC ASPECT Different method for preparation of 3-cyano-pyridines are available in literature 160-166 . The well known method is :
Cyanopyridines... 1.
42
Sakurai and Midorikaw 167,168 have reported that malononitrile reacts with ,-unsaturated ketones to give 2-amino-3-cyano-4,6-disubstituted pyridines (III).
R O R R' CH2(CN)2 R' N N
(III)
NH2
MECHANISM The reaction proceeds through conjugated addition of active methylene compounds to the ,-unsaturated system as shown below.
O R CH CH R' CH3COONH4 CH R CH2 R' R CH2(CN)2 N N NH N CH CH CH R' N NH2
CH
NH2 N R N -2H R' R N CH CH
NH2 N CH R' N R CH CH
NH NH CH R'
THERAPEUTIC IMPORTANCE Cyanopyridine have attracted considerable attention as they appeared of interest to possess antibacterial, anticholestermic, antifungal, antihypertensive and antidiabetic activities. Thiele Kurt et. al. 169 have studied the analgesic activity of substituted 3-cyanopyridines. N. Latif and co-workers 170 have repor ted the antibacterial and antifungal activity of 2-amino-3-cyano-4,6d i s u b s t i t u t e d p y r i d i n e s . M . B e r n a r d a n d c o - w o r k e r 1 7 1 re p o r t e d t h e anticonvulsant activity of 3-cyanopyridines. D. G. Bhatt et. al. 172 have prepared 3-cyanopyridines as an immunosuppressive agent. U. Teu and co-worker 173 have shown cyanopyridine as agrochemical fungicides.
Cyanopyridines...
43
Hammana Abou and co-worker 174 have studied anticancer and anti HIV activity of 3-cyanopyridines. Abdallah Navine et. al. 175 have prepared cyanopyridine derivatives which showed analgesic and antiinflammatory activity. Manna Fedele and co-worker 176 have reported the antiinflammatory activity of 3-cyanopyridines. H. Yoshida et. al. 177 have studied the antihistamic and antiallergic activity of 3-cyanopyridine derivatives. Abd El-Galil and cow o r k e r 1 7 8 h a v e p re p a re d 3 - c y a n o p y r i d i n e s ( I V ) a n d s t u d i e d t h e i r pharmacological activity. Gadaginamath and co-worker 179 have synthesised various cyanopyridyl derivatives (V) and documented their variety of biological activities.
Ar N Ar N
H3CO O CH3
N H2N N N NH2
H2N
CH3 N R
(IV)
(V)
J. A. Vann Allan et. al. 180 have prepared fused heterocylic 3-cyanopyridine (VI). Abu and co-worker 181 have prepared novel fused cyanopyridines (VII) for the treatment and preparation of systemic fungal infection.
C6H5 N N N CH3 N N NH2
NH2
H2N
(VI)
(VII)
S. V. Roman et. al. 182 have synthesised 2-amino-3-cyanopyridines and reported their biological activity. El-Taweel and co-worker 183 have prepared cyanopyridine derivatives and showed their significant biological activity. A. R.
Cyanopyridines...
44
Parikh et. al. 184 have synthesised 3-cyanopyridine derivatives as antimicrobial agent. Hussan M. & co-worker 185 have prepared 3-cyanopyridines and reported their pharmacological activity. Pyachenko U. D. and co-worker 186 have synthesised some cyanopyridines which are useful in the treatment of retroviral disease. Streightoff 187 and Seydal 188 have studied the bacteriostatic effect of some substituted 3-cyanopyridines. Francis and co-worker 189 have studied the effect of some substituted pyridines on the growth of the walker carcinosarcome-256 in tissue culture. Barton et. al. 190 have reported fungicidal and insecticidal properties. W. Hoefling and co-worker 191 have studied 3- and 4-cyanopyridines as tuberculosis arresting agents. K. Kadlec and Hanslian 192 showed that 2-Methyl-3-nitro-4-methoxyethyl5-cyano-6-chloro pyridines caused occupational eczema in Vitamin B 6 factory workers. Rigterink and Raymond 193 have studied the pesticidal activity of 3cyanopyridines. M. R. Pavia and co-worker 194 have prepared N-substituted 2aminopyridines which possess anticonvulsant proper ty. 3-cyanopyridines reported by L. Castedo et. al. 195 showed a minimum inhibitory concentration of 1.56 g/ml against S. aureus. W. Von Benbenburg and co-worker 196 have synthesised 2-amino-3,6disubstituted pyridines as antiepileptic agents. V. Scott and E. Joseph 197,198 have prepared 2-amino-3-cyanopyridine derivatives which were found to be useful as antipsoriasis pharmaceuticals. J . J . B a l d w i n 1 9 9 - 2 0 1 h a v e p r e p a re d c y a n o p y r i d i n e s ex h i b i t i n g antihyper tensive activity.
Cyanopyridines... CONTRIBUTION FROM OUR LABORATORY
45
A. R. Parikh, H. H. Parekh et. al. have synthesised cyanopyridines with versatile biological activities 202-209 like anticancer and antitubarcular. Moreover, Murtus et. al.210 synthesised 2-formyl pyridine thiosemicarbazone a s a c a rc i n o s t a t i c a g e n t . A d r i a n o A f o n s o e t . a l . 2 1 1 h a v e f o u n d t h a t cyanopyridines are Fernesyl protein transferase inhibitors. Hussain et. al. 212 have synthesised cyanopyridines as a antimicrobial agent. Wu Wenxue et. al. 213 have synthesised cyanopyridines as histamine H 3 antagonists. Saudi Manal N. S. et. al. 214 have found that cyanopyridines have fasciolicidal property. Harada Hironori et. al. 215 have prepared cyanopyridines and screened for their large conductance calcium activated potassium channel opener activity. Thus, diverse biological activities have been encountered in compounds containing cyanopyridine ring system. To further assess the potential of such type of compounds, study of cyanopyridines have been carried out as under. SECTION - I : SYNTHESIS AND BIOLOGICAL EVALUATION OF 1'N,3'-DIPHENYL-4'-[2-AMINO-3-CYANO-6-ARYL-4PYRIDYL]-PYRAZOLES
46 SECTION - I SYNTHESIS AND BIOLOGICAL EVALUATION OF 1'N,3'-DIPHENYL4'-[2-AMINO-3-CYANO-6-ARYL-4-PYRIDYL] PYRAZOLES In the past years, considerable evidence has been accumulated to demonstrate the efficience of cyanopyridines. To further assess the potential of such a class of compounds cyanopyridine derivatives of type (II) have been synthesised by the condensation of malononitrile and ammonium acetate with 1-Aryl-3-[1'N,3'-diphenyl-4'-pyrazolyl]-2-propene-1-ones.
N N N
N N
CH2(CN)2 CH3COONH4
O R R N NH2
Type (II)
R = Aryl
The constitution of the synthesised products have been characterised by using elemental analyses, infrared and 1 H nuclear magnetic resonance spectroscopy and mass spectrometry also. In mass spectrometry the m/z value indicate the molecular weight, i.e. when R=2-Hydroxyphenyl, molecular weight=429, m/z=428 (m-1) . All the compounds have been also evaluated for their antibacterial activity towards Gram positive and Gram negative bacterial strains and antifungal activity towards Aspergillus niger at a concentration of 40g/ml. The biological activity of the synthesised compounds have been compared with standard drugs. Some compounds have been found to have good and equivalent activity as compared to the known antibiotics recorded on Page No. 53.
47
I R S P E C T R A L S T U DY O F 1 ' N , 3 ' -D I P H E N Y L - 4 ' - [ 2 -A M I N O - 3 - C YA N O 6-(p-FLUOROPHENYL)-4-PYRIDYL]-PYRAZOLE
100.0 %T 90.0 80.0 70.0 60.0 50.0 40.0 30.0 2854.5 2916.2 3058.9 2218.0 3355.9
N N N
NH2 N
875.6 914.2
F
509.2
956.6 829.3 1292.2 1018.3 1342.4 1415.7 1064.6 1446.5 1589.2 1114.8 1531.4 1153.3 1500.5 1226.6 613.3 690.5 759.9
3250.0 2000.0 1750.0 1500.0 1250.0 1000.0 750.0 4-F cyanopyridine

I Instrument : SHIMADZU-FT-IR 8400-Spectrophotometer; Frequency range : 4000-400 cm Vibration mode C-H str. (sym.) CH str. (asym.) CH str. (asym.) Aromatic C-H str. C=C str. CH o.o.p.ben. Pyrazole moiety Pyridine ring C=N str. C-N str. N-H str. (-NH ) 2 C=N str. C=N str. C-F str. Ether C-O-C str. (sym.) C-O-C str (asym.) Frequency in cm Observed 2916 2854 1446 3058 1500 829 1589 1226 3355 2218 1531 759 1292 1064 -1 -1
500.0 1/cm
(KBr disc)
Type Alkane
Reported 2975-2950 2962-2853 1470-1435 3090-3030 1500-1480 835-810 1650-1600 1220-1020 3350-3250 2240-2120 1650-1600 800-750 1275-1200 1075-1020
Ref. 671 '' '' " '' " 673 " " " " " 671 "
48
P M R S P E C T R A L S T U DY O F 1 ' N , 3 ' -D I P H E N Y L - 4 ' - [ 2 -A M I N O - 3 - C YA N O 6-p-ANISYL-4-PYRIDYL]-PYRAZOLE
a e f g h a d N N i j N a a N a
NH2 k
b' b c' c O CH3
Internal Standard : TMS; Solvent : CDCl ; Instrument : BRUKER Spectrometer (300 MHz) 3 Signal Signal Position No. ( ppm) 1 2 3 4 5 6 7 8 3.83 6.85 7.20 7.35 7.50 7.75 7.82 8.53 Relative No. of Protons 3H 2H 2H 2H 6H 3H 2H 1H Multiplicity singlet doublet doublet multiplet multiplet multiplet doublet singlet Inference Ar-OCH CHcc' CHdh CHeg CHa+CHj CHf+CHk CHbb' CHi 3 J Value In Hz J=8.4 J=8.4 -
a e f g h a d N N i j N a a N a
NH2 k
b' b c' c O CH3
NH2 N
m/z = 428 (m-1)
HO
H3C SB- 9 H N H N
+
o
+ +
NH2
+
o
N m/z = 115
H2N
N m/z = 238
HN
OH N m/z = 107 N H m/z = 400
+
o
N m/z = 267 OH
H2N
N H OH N
NH2 N
+
o
+
N H N m/z = 217 N m/z = 222 N CH3 N HO NH m/z = 251 N H
+
N HN H2N N m/z = 148
m/z = 428 (M - 1) OH
OH HN N H N m/z = 356 CH3
+ +
N N
+
+
o
NH
H2N
N H
H3C OH m/z = 384
HN N H
NH2
N m/z = 208 H3C N m/z = 326
m/z = 175
50
51 EXPERIMENTAL SYNTHESIS AND BIOLOGICAL EVALUATION OF 1'N,3'-DIPHENYL4'-[2-AMINO-3-CYANO-6-ARYL-4-PYRIDYL] PYRAZOLES [A] Synthesis of N-Phenylamino- -methyl-phenyl azomethine See [A] Part-I, Section-I (A). [B] Synthesis of 1 N,3-Diphenyl-4-formyl pyrazole See [A] Part-I, Section-I (B). [C] Synthesis of 1-(p-Anisyl)-3-[1'N,3'-diphenyl-4'-pyrazolyl]-2-propene1-one See [A] Part-I, Section-I (C). [D] Synthesis of 1'N,3'-Diphenyl-4'-[2-amino-3-cyano-6-p-anisyl4-pyridyl]-pyrazole A mixture of 1-(p-Anisyl)-3-[1'N,3'-diphenyl-4'-pyrazolyl]-2-propene-1-one (3.8 g 0.01 M), malononitrile (0.66 g, 0.01 M) and ammonium acetate (6.61 g, 0.08 M) dissolved in methanol was refluxed for 12 hrs. The reaction product was poured into ice, kept overnight, isolated and crystallized from ethanol. Yield, 4.2g, (95%), m.p. 167 C. (C 28 H 21 N 5 O ; Requires : C,75.85; H, 4.74; N, 15.79; found : C,75.80; H, 4.70; N, 15.72%). TLC solvent system Acetone : Benzene (2:8). Similarly other cyanopyridines have been synthesised. The physical data are recorded in Table No. 2 [E] Antimicrobial activity of 1'N,3'-Diphenyl-4'-[2-amino-3-cyano-6aryl-4-pyridyl]-pyrazoles Antimicrobial testing was carried out as described in [A] Part-I, Section-I (D). The zone of inhibition of the test solutions are recorded in Graphical Chart No. 2.
o

2a 2b 2c 2d 2e 2f 2g 2h 2i 2j 2k 2l 2m
P H Y S I CA L C O N S TA N T S O F 1 ' N , 3 ' -D I P H E N Y L - 4 ' - [ 2 -A M I N O - 3 - CYA N O - 6 -ARY L - 4 -P Y R I DY L A ] -4-PYRAZOLES Molecular Formula 3

H N 27 19 5 C H N Br 27 18 5 C H N Cl 27 18 5 C H N F 27 18 5 C H N 28 21 5 C H N O 28 21 5 C H N O 27 19 5 C H N O 27 19 5 C H N 27 20 6 C H N O 27 18 6 2 C H N O2 27 18 6 C H N O 25 17 5 C H N S 25 17 5 C
R 2
Molecular Weight 4
413 492 447.5 431 427 443 429 429 428 458 458 403 419
M.P. o C 5
148 178 104 201 103 167 210 198 186 192 230 218 178
Rf * Value 6
0.53 0.48 0.63 0.70 0.44 0.39 0.49 0.55 0.65 0.57 0.70 0.68 0.63
Yield % 7
93 81 94 73 78 95 85 87 97 91 86 88 92

16.94 14.22 15.64 16.23 16.38 15.79 16.31 16.31 16.61 18.33 18.33 17.36 16.69 16.89 14.20 15.61 16.18 16.40 15.72 16.33 16.30 19.58 18.31 18.30 17.32 16.67
52
ANTIMICROBIAL ACTIVITY OF 1N,3- DIPHENYL-4-[2-AMINO-3-CYANO-6-ARYL4-PYRIDYL]-PYRAZOLES
30
25
20
15
10
53
COMPARATIVE STUDY OF ANTIMICROBIAL ACTIVITY WITH KNOWN ANTIBIOTICS [A] PART-II Section - I : Antimicrobial activity of 1'N,3'-Diphenyl-4'-[2-amino-3-cyano-6-aryl-4-pyridyl]-pyrazoles

2e (20) 2l (22)

2j (21) 2l (17)
S. aureus
2b (20) 2k (19)
P vulgaris .
2g (20)
A. niger
2g (23) 2l (21)
23 22 24 25 -
22 23 17 24 -
21 21 23 19 -
15 18 17 20 -
25
54
MMMMMMMMMMMMMMMMM M
PART-III STUDIES ON CYANOPYRANS
M MMMMMMMMMM
Cyanopyrans...
55
INTRODUCTION
T he chemistry of pyran with different functional group exhibit wide range

of applications in the field of pharmaceuticals, dyes, insecticides and sweet smelling substances. Pyran ring system is also present in large number of natural coloured compounds in Vitamin E, hemorrhagic compound in cloves, in fish poisions, in certain alkaloids and other substances. Pyran is a doubly unsaturated six membered ring system with a single oxygen as hetero atom. The two double bonds may be conjugated as or 1,2pyran or isolated as in or 1,4-pyran.
O
- or 1,4-pyran
(I)
- or 1,2-pyran
A degree of stabilisation of the pyran nucleus is achieved by substituting phenyl group in the 2 or 4 and preferably also in the 6 position. SYNTHETIC ASPECT Various methods for the preparation of pyran derivatives have been cited in the literature 216-225 . 1. Reaction between (A) with CH 2 (CN) 2 led to corresponding 2-amino-3cyano-4H-pyrans (B) 226 .
O R N R1 N CH2(CN)2 O O H2N O R
R1
(A)
(II)
(B)
Cyanopyrans... MECHANISM :
56
The reaction of malononitrile with ,-unsaturated system leads to the formation of cyano 4H-pyran via Michael addition.
O CH R CH R' R CH2(CN)2 N CH CH CH2 R' R N O N CH CH CH R' N OH
NH2 N R O R' N R
NH O R'
THERAPEUTIC IMPORTANCE Literature survey revealed that various pyrans have resulted in many potential drugs and are known to possess a broad biological spectrum such as, 1. Anti HIV 227,228 2. 3. 4. 5. 6. 7. 8. 9. Antifungal229-231 Antiallergic 232 Analgesic 233 Antagonist 234,235 Antitumor 236 CNS active agent 237 Cytotoxic 238
Inhibitors of cell proliferation 239 10. Gastric acid secretion inhibitor 240 11. Antimicrobial 241 12. Hypolipidemic 242 13. Antipyretic 243 14. Antiinvasive 244
Cyanopyrans...
57
Moreover, Fathy F. Abdel-Latif et. al. 245 have reported the synthesis of 2-amino-3-cyanopyran derivatives and studied their biological activity. Piao Minz, Zhu et. al. 246 have prepared biologically active 2-amino pyran derivatives. Sharanin Y. U. A. et. al. 247 have suggested new 2-amino-3-cyano-4Hpyran derivatives (III).
Me O N O R O NH2
(III) Zwaagstra Mariel 248 have newly synthesised pyran derivatives and tested for antiashamatic activity. Boyer Frederick et. al. 249 have prepared some new2-amino-3-cyano-4H-pyran and reported anti HIV agent and antiviral activity. Some of the pyran derivatives have been patented for their use as antihypertensive 250 , antiestogens 251 , antagonist 252,253 , antitumor 254 and antiviral 255 activities. Synthesis and biological activity of pyran ring system have been reported by O'Brien et. al. 256 .
N N N
NH2
(IV) Synthesis and anticancer activity of pyran (V) containing flourine have been reported by Mohamed S. Abd et. al. 257 4H-pyran of type (VI) were prepared to enhance the anticancer and anti HIV activity.
Cyanopyrans...
F
58
NH2 O HOOC N N X
NH2
N H3C N S R
(V)
Cl
(VI)
El-Subbagh and co-worker 258 have synthesised cyanopyran derivatives and showed their antiviral activity. Corbou Romuld et. al. 259 have synthesised cyanopyran derivatives (VII) which have significant pharmacological activity.
OMe N N OMe O N NH2
(VII) CONTRIBUTION FROM OUR LABORATORY Parikh A. R. et. al. 260 have synthesised cyanopyrans bearing 2-chloro-6bromoquinoline nucleus as a potential antimicrobial and anticancer agents. With a view to get better therapeutic agent, it was contemplated to synthesise pyran derivatives to enhance the overall activity of resulting compounds which have been described as under. SECTION - I : SYNTHESIS AND BIOLOGICAL EVALUATION OF 1'N,3'-DIPHENYL-4'-[2-AMINO-3-CYANO-6-ARYL-4DIHYDROPYRANYL]-PYRAZOLES
59 SECTION - I SYNTHESIS AND BIOLOGICAL EVALUATION OF 1'N,3'-DIPHENYL4'-[2-AMINO-3-CYANO-6-ARYL-4-DIHYDROPYRANYL]-PYRAZOLES 3-Cyano-4,6-disubstituted 4H-pyrans are endowed with a variety of phar macodynamic activities such as anticonvulsant, antiinflammatory, antihypertensive, antitumor etc. Looking to the interesting proper ties of cyanopyrans, it was considered worthwhile to synthesis some new 2-amino-3cyano-4H-pyrans bearing 1N,3-diphenyl pyrazole nucleus of type (III), for obtaining biologically potent molecules by reacting chalcones of type (I) with malononitrile as shown below.
N N
N
Piperidine CH2(CN)2 O R
N H2N O R
Type (III)
R = Aryl
The constitution of the synthesised products have been characterised by using elemental analyses, infrared and 1 H nuclear magnetic resonance spectroscopy and mass spectrometry also. In mass spectrometry the m/z value indicate the molecular weight, i.e. when R=2-Furyl, molecular weight=406, m/z=406 (m). All the compounds have been also evaluated for their antibacterial activity towards Gram positive and Gram negative bacterial strains and antifungal activity towards Aspergillus niger at a concentration of 40g/ml. The biological activity of the synthesised compounds have been compared with standard drugs. Some compounds have been found to have good and equivalent activity as compared to the known antibiotics recorded on Page No. 66.
60
I R S P E C T R A L S T U DY O F 1 ' N , 3 ' -D I P H E N Y L - 4 ' - [ 2 -A M I N O - 3 - C YA N O 6-(p-FLUOROPHENYL)-4-DIHYDROPYRANYL]-PYRAZOLE
90.0 %T 80.0 2854.5 2916.2 3060.8 3355.9 2216.1 912.3 962.4 997.1 1307.6 1064.6 837.0 1411.8 1159.1 1448.4
F
464. 513.0 588.2
70.0
60.0
N N
1535.2 1595.0 1502.4 1232.4
694.3 759.9
50.0
N H2N O
40.0 3250.0 2000.0 1750.0 1500.0 1250.0 1000.0 750.0 Cyano pyran4 F
I Instrument : SHIMADZU-FT-IR 8400-Spectrophotometer; Frequency range : 4000-400 cm Vibration mode C-H str. (sym.) CH str. (asym.) Aromatic C-H str. C=C str. C-H o.o.p. (def.) Pyrazole moiety Pyran ring C=N str. C-N str. N-H str. (-NH ) 2 C=N str. C=N str. Fluorine Ether C-F str. C-O-C str. (sym.) C-O-C str. (asym.) Frequency in cm Observed 2916 1448 3060 1502 837 1596 1232 3355 2216 1535 759 1232 1064 -1 Ref. 675 " 671 " " 673 " 670 " " 671 " " -1
500.0 1/cm
(KBr disc)
Type Alkane
Reported 2975-2950 1470-1435 3090-3030 1520-1480 835-810 1640-1590 1220-1020 3350-3250 2240-2120 1650-1600 800-750 1275-1200 1075-1020
61
PMR SPECTRAL STUDY OF 1'N,3'-DIPHENYL-4'-[2-AMINO-3-CYANO-6-p-TOLYL4-DIHYDROPYRANYL]-PYRAZOLE
b a g h i j f N N k l e m o' d n o CH3 c
N H2N
n'
Internal Standard : TMS; Solvent : CDCl ; Instrument : BRUKER Spectrometer (300 MHz) 3 Signal Signal Position No. ( ppm) 1 2 3 4 5 6 7 8 9 2.30 5.40 6.71-6.73 7.1-7.12 7.25 7.3-7.43 7.47-7.52 7.75-7.79 8.33 Relative No. of Protons 3H 1H 2H 2H 1H 4H 2H 4H 1H Multiplicity singlet singlet doublet doublet singlet multiplet triplet multiplet singlet Inference Ar-CH l CHoo' CHnn' CHm CHa,b,d,e CHc,h CHf,g,i,j CHk -NH 2 not observed CH 3 J Value In Hz J=8.4 J=8.4 -
b a g h i j f N N k l e m o' d n o CH3 c
N H2N
n'
N N
O N H2N O
m/z = 406 (m)
H2N SB- 10 N CH3
+
o H3C
+
o O H2N O
O NH
+
o N N N H2N O O m/z = 178
+
o
m/z = 242 m/z = 189 O m/z = 299
+
O o O CH3 m/z = 279 NH N
+
o O
m/z = 273
+
o N HN O m/z = 258 N NH2 N NH2 O O N N N N O
+
o
+
O N H m/z = 201 NH o
m/z = 406 (M)
m/z = 373
+
o
+
o H N
H2N N O N N
N N
+
o N
+
o N O O m/z = 391 O m/z = 148 NH NH2
m/z = 331
+
o m/z = 107
H2N
m/z = 120
63
64 EXPERIMENTAL SYNTHESIS AND BIOLOGICAL EVALUATION OF 1'N,3'-DIPHENYL4'-[2-AMINO-3-CYANO-6-ARYL-4-DIHYDROPYRANYL]-PYRAZOLES [A] Synthesis of N-Phenylamino- -methyl-phenyl azomethine See [A] Part-I, Section-I (A). [B] Synthesis of 1N,3-Diphenyl-4-formyl pyrazole See [A] Part-I, Section-I (B). [C] Synthesis of 1-(p-Anisyl)-3-[1'N,3'-diphenyl-4'-pyrazolyl]-2-propene1-one See [A] Part-I, Section-I (C). [D] Synthesis of 1'N,3'-Diphenyl-4'-[2-amino-3-cyano-6-p-anisyl4-dihydropyranyl]-pyrazole A mixture of 1-(p-Anisyl)-3-[1'N,3'-diphenyl-4'-pyrazolyl]-2-propene-1-one (3.8 g, 0.01 M), malononitrile (0.66 g, 0.01 M) dissolved in pyridine (20 ml) was heated under reflux for 12 hrs. The product was isolated and crystallized from absolute ethanol. Yield, 3.89g (88%), m.p. 119 oC. (C 28 H 22 N 4 O ; Requires ; C,78.14; H, 5.12; N, 13.01%; found : C,78.11; H,5.07; N,12.98%). TLC solvent system Ethyl acetate : Hexane (3:7). Similarly other cyanopyrans have been prepared. The physical constants are recorded in Table No. 3. [E] Antimicrobial activity of 1'N,3'-Diphenyl-4'-[2-amino-3-cyano-6aryl-4-dihydropyranyl]-pyrazoles Antimicrobial activity was carried out as described in [A] Part-I, Section-I (D). The zone of inhibitions of the test solution are recorded in Graphical Chart No. 3.

3a 3b 3c 3d 3e 3f 3g 3h 3i 3j 3k 3l 3m
P H Y S I CA L C O N S TA N T S OF DIHYDROPYRANYL]-PYRAZOLES Molecular Formula 3

H N O 27 20 4 C H N OBr 27 19 4 C H N OCl 27 19 4 C H N OF 27 19 4 C H N O 28 22 4 C H N O 28 22 4 2 C H N O 27 20 4 2 C H N O 27 20 4 2 C H N O 27 21 5 C H N O 27 19 5 3 C H N O 27 19 5 3 C H N O 25 18 4 2 C H N OS 25 18 4 C
1 ' N , 3 ' -D I P H E N Y L - 4 ' - [ 2 -A M I N O - 3 - C YA N O - 6 -A R Y L - 4 M.P. o C 5

114 186 140 210 119 208 218 148 98 177 213 220 190
R 2
Molecular Weight 4
416 495 450.5 434 430 446 432 432 431 461 461 406 422
Rf * Value 6
0.46 0.58 0.64 0.71 0.63 0.60 0.56 0.49 0.61 0.58 0.50 0.63 0.43
Yield % 7
78 81 91 92 88 80 85 82 80 83 90 90 81

13.45 11.31 12.43 12.90 13.01 12.55 12.96 12.96 16.23 15.18 15.18 13.78 13.26 13.41 11.30 12.44 12.93 12.98 12.53 12.94 12.97 16.21 15.15 15.19 13.79 13.27
*TLC Solvent System : Ethyl acetate : Hexane (3 : 7).
65
ANTIMICROBIAL ACTIVITY OF 1N,3- DIPHENYL-4-[2-AMINO-3-CYANO-6-ARYL4-DIHYDROPYRANYL]-PYRAZOLES
30
25
20
15
10
66
COMPARATIVE STUDY OF ANTIMICROBIAL ACTIVITY WITH KNOWN ANTIBIOTICS [A] PART-III Section - I : Antimicrobial activity of 1'N,3'-Diphenyl-4'-[2-amino-3-cyano-6-aryl-4-dihydropyranyl]-pyrazoles

3f (22) 3k (23)

3c (21) 3d (20) 3j (19)
S. aureus
3e (19) 3i (20)
P vulgaris .
3b (20) 3j (19)
A. niger
3d (24) 3l (22)
23 22 24 25 -
22 23 17 24 -
21 21 23 19 -
15 18 17 20 -
25
67
MMMMMMMMMMMMMMMMM M
PART-IV STUDIES ON PYRAZOLINES
M MMMMMMMMMM
Pyrazolines...
68
INTRODUCTION
A mongst
nitrogen containing five membered heterocycles, pyrazolines
have proved to be the most useful frame work for biological activities, pyrazolines have attracted attention of medicinal chemistr y for both with regard to heterocyclic chemistry and the pharmacological activities associated with them. In 1967 Jarobe, reviewed the chemistry of pyrazolines, which have been studied extensively for their biodynamic behaviour 261 and industrial applications 262 .
N H
(I) SYNTHETIC ASPECT : Different methods for the preparation of 2-pyrazoline derivatives documented in literature are as follows. 1. 2-pyrazolines can be constructed by the cyclocondensation of chalcones with hydrazine hydrate 263 .
O R R1 R1
NH2.NH2.H 2O
R N H
2. 3. 4.
2-pyrazolines can also be prepared by the condensation of chalcone dibromide with hydrazines 264 . 2-pyrazolines can be synthesised by the cycloaddition of diazomethane to substituted chalcone 265 . Dipolar cycloaddition of nitrilimines of dimethyl fumarate, fumaronitrile and the N-aryl maleimides yields the corresponding pyrazolines 266 .
Pyrazolines... 5.
69
Epoxidation of chalcones have epoxy ketones which reacted with hydrazine and phenyl hydrazine to give pyrazolines 267 .
Furthermore, B. Gyassi et. al. 268 investigated the one pot synthesis of some pyrazolines in dry media under microwave irradiation. S. Paul et. al. 269 and Dandia Anshu et. al. 270 have also described the microwave assisted synthesis of 2-pyrazolines. MECHANISM : The following mechanism seems to be operable for the condensation of chalcones with hydrazine hydrate 271 .
O R R2 R1 (I) NH2-NH R
+ -
CH
R1 ( i ) proton transfer ( ii ) ketonisation NH R2
R O N
R1
H2N (II)
H2N (III) intermolecular Nucleophillic attack
:
N H
R2
R N N
R1
-H2O
R HO N
R1
R2 (V)
R2 (IV)
Nucleophilic attack by hydrazine at the -carbon of the ,-unsaturated carbonyl system forms species (II), in which the -ve charge is mainly accomodated by the electronegative oxygen atom. Proton transfer from the nitrogen to -ve oxygen produces an intermediate enol which simultaneously ketonises to ketoamine (III). Another intramolecular nucleophilic attack by the primary amino group of ketoamine on its carbonyl carbon followed by proton transfer from nitrogen to oxygen leads ultimately to
Pyrazolines...
70
carbonyl amine (IV). The later with a hydroxy group and amino group on the same carbon lose water molecule to yield the pyrazolines. THERAPEUTIC IMPORTANCE From the literature survey, it was revealed that 2-pyrazolines are better therapeutic agents. 1. Analgesic 272,273 2. 3. 4. 5. 6. 7. 8. 9. Bactericidal 274,275 Cardiovascular 276 Diuretic 277 Fungicidal 278 Herbicidal 279 Hypoglycemic 280 Insecticidal 281
Tranquilizer 282 10. Antiallergic 283 11. Anticonvulsant 284,285 12. Antidiabetic 286 13. Antiimplantation 287 14. Antiinflammatory 288 15. Antitumor 289 16. Antineoplastic 290 17. Antimicrobial 291 S. S. Sonarc et. al. 292 have synthesised-3-(2-Acetoxy-4-methoxyphenyl)5-(substitutedphenyl)-pyrazolines (I) and tested their antimicrobial activity. H. H. Parekh et. al. 293 have also synthesised some new pyrazolines as an antimicrobial agent.
Pyrazolines...
H3CO OAC
71
R2 R1
N R
(I) G. N. Mishirika et. al. 294 have also prepared 2-pyrazolines of salicylic acid (II) possessing antimicrobial properties.
R COOH
OH N N R
(II)
Tuntawy Atif and co-worker 295 have patented 3-methyl-4'-(substituted phenylazo)-pyrazol-5-ones as antibacterial agent. M o re o v e r, F. M a n n a a n d c o - w o r k e r 2 9 6 h a v e d e s c r i b e d 1 -A c e t y l 5-(2'-bromophenyl)-4,5-dihydro-3-(2'-hydroxyphenyl)-1H-pyrazolines (III) and its derivatives which acts as potent antiinflammatory, analgesic and antipyratic agents.
(H3C)2-N OH R
N H3COC
R1 N
(III) Udupi R. H. and Bhat A. R. 297 have reported the synthesis and biological activity of Mannich bases of cer tain 1,2-pyrazolines. Nugent Richard 298 investigated pyrazolines bis phosphonate ester as novel antiinflammatory and antiarthritic agent.
Pyrazolines...
72
Fuche Rainer et. al. 299 have prepared some new 1H-pyrazoline (IV) derivatives and reported them as pesticides.
O Cl N N N N H CF3 R N N NH
(IV)
(V)
Furthermore, Tsuboi et. al. 300 have synthesised some new phenylcarbonyl pyrazolines (V) as an insecticides and at 40% concentration shows 100% mortality of spodopetra litura larve after seven drops. Moreover, T. M. Stivenen et. al. 301 have also investigated N-substituted pyrazoline type insecticides. Tanka Katsohori 302 have patented pyrazoline derivatives as herbicides and Johannes et. al. 303 as insecticides. Moritaz Z. and Hadol 304 to investigated a semi emperial molecular orbital study on the reaction of aminopyrazolinyl azodye with singlet molecular oxygen. Shivnanda M. K. and co-worker 305 have prepared pyrazolines and reported their antibacterial activity. E. Palska et. al. 306 have prepared 3,5-diphenyl-2pyrazolines (VI) and cited their antidepressant activity.
N R1 NH
R2 OMe
OMe
(VI)
R1 = H, Cl, Br, Me. MeO R2 = H, Cl
Pyrazolines...
73
B. Shivarama Holla et. al. 307,308 have synthesised pyrazolines as antibacterial agent. Hiremath Sp. et. al. 309 have synthesised pyrazolines as analgesic, antiinflammatory and antimicrobial agent. Malhotra V. et. al. 310 have synthesised new pyrazolines as a cardiovascular agent (VII).
Ph N N R1 R2 NH S
(VII)
R1, R2 = Aryl
Almstead J. et. al. 311 have prepared pyrazolines as vascularization agent. Guniz Kucukguzel et. al. 312 have synthesised pyrazolines as a antimicrobial and anticonvulsant agents. Gulhan T. Z. and co-workers 313 have prepared pyrazolines as a hypotensive agent. Shalabh Sharma et. al. 314 have synthesised pyrazolines and tested their antiinflammatory activity (VIII).
N N NH S N NH N R CH3
S O N H N O N COCH3 H N O OCH3
(VIII)
(IX)
Ashok Kumar et. al. 315 have synthesised pyrazolines as anticonvulsant agents (IX). Maurer Fritz et. al. 316 have synthesised pyrazoles and screened for their pesticidal activity.
Pyrazolines...
74
CONTRIBUTION FROM OUR LABORATORY Parekh et. al. 317 have prepared 1-Acetyl-5-aryl-3-[3,-(3,4-dihydro-2methyl-4-one-3-quinazolinyl)-phenyl]-2-pyrazolines which possess antimicrobial activity. Several pyrazolines bearing thymol moiety were evaluated for their ability as potent antimicrobial by Hansa Parekh et. al. 318 Parekh and coworkers 319 have prepared pyrazolines from arsanilic acid for their antimicrobial activity. Parekh et. al. 320,321 have synthesised and reported the antimicrobial activity of pyrazolines. Parikh et. al. 322 have synthesised some antimicrobial pyrazolines. Parekh et. al. 323 have synthesised phenyl pyrazolines bearing quinoline (X) moiety and described their antimicrobial activity.
R
N N Ph N CH3
(X)
Parikh et. al. 324 have synthesised and tested the antimicrobial activity of p-(2',5'-Dibromobenzenesulphonamido)-phenyl-5-aryl-1H/acetyl/phenyl2-pyrazolines.
Br R
SO 2 NH Br N N
R1
(XI)
R = Aryl, R1 = COCH3, Ph
Pyrazolines...
75
Recently, A. R. Parikh, H. H. Parekh and co-worker have synthesised newer pyrazolines with variety of biological activity, described as under. 5-Aryl-1H-3-(6'-methoxy--naphthyl)-2-pyrazolines 325 . Preparation and antimicrobial 326 activity of 3-[3'-(p-Chlorophenyl sulphonamidophenyl)-5-aryl-1H/acetyl pyrazolines. Synthesis of some novel pyrazolines 327 as biological potent agents. Antimicrobial activity of some newly synthesised pyrazolines 328 derivatives. Pyrazolines 329 as a antimicrobial agents. Antimicrobial activity of pyrazolines 330 . In view of therapeutic activities shown by pyrazolines, it was contemplated to synthesise some new pyrazolines in search of agents possessing higher biological activity with least side effect have been described as under. SECTION - I : SYNTHESIS AND BIOLOGICAL EVALUATION OF 3 -A RY L - 5 - [ 1 ' N , 3 ' - D I P H E N Y L - 4 ' -P Y R A Z O LY L ] PYRAZOLINES SECTION - II : SYNTHESIS AND BIOLOGICAL EVALUATION OF 1'N -PH ENY L - 3-ARY L - 5 - [ 1'N, 3'-DI PH EN YL4'-PYRAZOLYL]-PYRAZOLINES
v v
v v v v
76 SECTION - I SYNTHESIS AND BIOLOGICAL EVALUATION OF 3-ARYL-5-[1'N,3'DIPHENYL-4'-PYRAZOLYL]-PYRAZOLINES Pyrazolines are endowed with valid antimicrobial activites. Looking at their versatile therapeutic importance and with an aim to getting better drug, it was considered worthwhile to synthesise some new pyrazolines bearing 1N,3-diphenyl pyrazole nucleus. The preparation of 3-Aryl-5-[1'N,3'-diphenyl-4'-pyrazolyl]pyrazolines (IV) have been undertaken by cyclocondensation of type (I) with hydrazine hydrate.
N N
NH2NH2H2O
HN
R N
O R
Type (IV)
R = Aryl
The constitution of the synthesised products have been characterised using elemental analysis, infrared and 1 H nuclear magnetic resonance spectroscopy and mass spectrometry also. In mass spectrometry the m/z value indicate the m o l e c u l a r w e i g h t , i . e . w h e n R = p -A n i s y l , m o l e c u l a r w e i g h t = 3 9 4 , m/z=394 (m). All the compounds have been also evaluated for their antibacterial activity towards Gram positive and Gram negative bacterial strains and antifungal activity towards Aspergillus niger at a concentration of 40g/ml. The biological activity of the synthesised compounds have been compared with standard drugs. Some compounds have been found to have good and equivalent activity as compared to the known antibiotics recorded on Page No. 84.
77 Moreover, some selected compounds have been evaluated for their in vitro biological assay towards a strain of Mycobacterium tuberculosis H 37 Rv at a concentration of 6.25 g/ml using Rifampin as a standard drug which have been tested at Tuberculosis Antimicrobial Acquisition Co-ordinating Facility (TAACF), Alabama, U. S. A.
78
IR SPECTRAL STUDY OF 3-(p -TOLYL)-5-[1'N,3'-DIPHENYL-4'-PYRAZOLYL]PYRAZOLINE
90.0 %T 80.0 70.0 60.0 50.0 40.0 30.0 20.0 3250.0 2000.0 1750.0 1500.0 1250.0 1000.0 750.0 4- Meo S P
I Instrument : SHIMADZU-FT-IR 8400-Spectrophotometer; Frequency range : 4000-400 cm Vibration mode C-H str. (sym.) CH str. (asym.) C-H def. (asym.) Aromatic C-H str. C=C str. C-H i.p. def. C-H. o.o.p. def. Pyrazole moiety Pyrazoline ring C=N str. C-N str. C-N str. N-H str. C=N str. -C-H-(CH )str. 2 Frequency in cm Observed 2922 1446 1353 3064 1510 1002 835 1598 1172 1112 3315 1548 2839 -1 -1
N N
420. 2839.0 509.2 2922.0 3064.7 3315.4 906.5 1548.7 1407.9 1299.9 958.6 1002.9 711.7 611.4 835.1 690.5 756.0 545.8
HN
CH3
1353.9 1446.51253.6 1112.9 1598.9 1172.6 1510.2 1232.4
500.0 1/cm
(KBr disc)
Type Alkane
Reported 2975-2950 1470-1435 1390-1350 3090-3030 1585-1480 1125-1000 835-810 1640-1600 1230-1020 1230-1020 3320-3140 1650-1550 2850-1790
Ref. 670 " " 671 " " " 673 " 672 " " "
79
PMR SPECTRAL STUDY OF 3-(p-ANISYL)-5-[1'N,3'-DIPHENYL-4'-PYRAZOLYL]PYRAZOLINE
a e f g h a d N N l i HN N b c a Hj Hk a a
b'
c' OCH3
Internal Standard : TMS; Solvent : CDCl ; Instrument : BRUKER Spectrometer (300 MHz) 3 Signal Signal Position No. ( ppm) 1 2 3 4 5 6 7 8 9 10 11 3.01-3.09 3.42-3.5 3.83 5.1-5.22 6.89-6.94 7.27-7.31 7.41-7.5 7.6-7.64 7.70-7.74 7.8-7.88 8.05 Relative No. of Protons 1H 1H 3H 1H 2H 1H 5H 2H 3H 1H 1H Multiplicity multiplet multiplet singlet multiplet doublet multiplet multiplet doublet doublet multiplet singlet Inference CHk CHj Ar-OCH 3 CHl CHcc' CHf CHa CHbb' CH d,e,g CHh CHi J Value In Hz
J=8.8
J=8.8
-NH not observed
a e f g h a d N N l i HN N b c a Hj Hk a a
b'
c' OCH3
N N
CH3 HN N O
m/z = 394
SB- 2 HO N N N N N N
N HN m/z = 365 N
+
o m/z = 272
+
NH o
CH2
+
o m/z = 260
+
CH3 o
m/z = 246
+
o NH N N m/z = 233 m/z = 340 H2N N O N CH3 CH3
+
o
+
o m/z = 394 (M) H3C NH NH N N N
+
o
m/z = 221 m/z = 175
H3C
+
NH2 H3C o
+ +
o O N o H3C
+
CH3 o
NH
m/z = 190 N NH m/z = 149 H3C CH3 m/z = 165 N m/z = 378 OH NH2 HN m/z = 204
+
o
CH
81
82 EXPERIMENTAL SYNTHESIS AND BIOLOGICAL EVALUATION OF 3-ARYL-5-[1'N,3'DIPHENYL-4'-PYRAZOLYL]-PYRAZOLINES [A] Synthesis of N-Phenylamino- -methyl-phenyl azomethine See [A] Part-I, Section-I (A). [B] Synthesis of 1N,3-Diphenyl-4-formyl pyrazole See [A] Part-I, Section-I (B). [C] Synthesis of 1-(p-Anisyl)-3-[1'N,3'-diphenyl-4'-pyrazolyl]-2-propene1-one See [A] Part-I, Section-I (C). [D] Synthesis of 3-(p-Anisyl)-5-[1'N,3'-diphenyl-4'-pyrazolyl]-pyrazoline A mixture of 1-(p-Anisyl)-3-[1'N,3'-diphenyl-4'-pyrazolyl]-2-propene-1-one (3.8 g, 0.01 M), hydrazine hydrate (2 g, 0.04 M) in 30 ml methanol was refluxed for 12 hrs. The product obtained was filtered, washed with hot methanol and crystallised from dioxan. Yield, 3.2 g (81%), m.p. 155 oC. (C 25H 22 N 4 O; Requires : C, 76.14; H, 5.58; N, 14.20%; found : C, 76.10; H, 5.53; N, 14.17%). TLC solvent system Acetone : Benzene (1:9). Similarly other pyrazolines have been undertaken. The physical data are recorded in Table No. 4. [E] Antimicrobial activity of 3-Aryl-5-[1'N,3'-diphenyl-4'-pyrazolyl]pyrazolines Antimicrobial testing was carried out as described in [A] Part - I, Section - I (D). The zone of inhibition of the test solutions are reported in Graphical Chart No. 4. The antitubercular screening of the compounds of type (IV) was carried out by TAACF, the Souther n Research Institute, U.S.A. as described in [A] Part - I, Section - I(E), and the percentage of inhibition data of the compounds are recorded in Table No.4a.

4a 4b 4c 4d 4e 4f 4g 4h 4i 4j 4k 4l 4m
PHYSICAL CONSTANTS OF 3-ARYL-5-[1'N,3'-DIPHENYL-4'-PYRAZOLYL]-PYRAZOLINES. Molecular Formula 3

H N 24 20 4 C H N Br 24 19 4 C H N Cl 24 19 4 C H N F 24 19 4 C H N 25 22 4 C H N O 25 22 4 C H N O 24 20 4 C H N O 24 20 4 C H N 24 21 5 C H N O 24 19 5 2 C H N O 24 19 5 2 C H N O 22 18 4 C H N S 22 18 4 C
R 2
Molecular Weight 4
364 443 398.5 382 378 394 380 380 379 409 409 354 370
M.P. o C 5
140 198 198 86 210 155 >230 208 148 130 166 79 97
Rf * Value 6
0.72 0.57 0.63 0.66 0.58 0.54 0.43 0.48 0.59 0.69 0.49 0.80 0.57
Yield % 7
70 73 80 85 72 81 77 73 90 75 69 82 80

15.37 12.64 14.05 14.65 14.80 14.20 14.73 14.73 18.46 17.10 17.10 15.81 15.12 15.36 12.60 14.03 14.61 14.76 14.17 14.69 14.71 18.43 17.12 17.13 15.83 15.10
83
ANTIMICROBIAL ACTIVITY OF 3-ARYL-5-[1N,3-DIPHENYL-4-PYRAZOLYL]PYRAZOLINES
30
25
20
15
10
84
COMPARATIVE STUDY OF ANTIMICROBIAL ACTIVITY WITH KNOWN ANTIBIOTICS [A] PART-IV Section - I : Antimicrobial activity of 3-Aryl-5-[1'N,3'-diphenyl-4'-pyrazolyl]-pyrazolines

4b (20) 4f (21) 4j (22) Ampicillin Amoxicillin Norfloxacin Penicillin Greseofulvin 23 22 24 25 -

4a (20) 4e (21) 4j (21) 21 21 23 19 -
S. aureus
4d (22) 4e (20) 4h (23) 22 23 17 24 -
P vulgaris .
4e (20) 4b (18) 4m (18) 15 18 17 20 -
A. niger
4d (21) 4j (20) 4k (23) 25
85
86
TABLE NO. 4a: DATA OF IN VITRO EVALUATION OF ANTITUBERCULAR ACTIVITY
N N
HN
R N
R = Aryl
TAACF, Southern Research Institute Primary Assay Summary Report Sample Corp ID ID Sau.uni Sau.uni Sau.uni Sau. uni. Sau.uni Sau.uni Sau.uni Sau.uni Sau.uni Alamar Alamar Alamar Alamar Alamar Alamar Alamar Alamar Alamar Alamar Alamar Alamar Alamar Where,R= Supplier Assay MTb H H H MIC Dr. A. R. Parikh Saurashtra University % Inhib 57 56 53 53 45 40 39 39 35 33 32 23 16 '' '' '' '' '' ''
MIC Rifampin = 0.025mg/ml @98% inhibition
comment
Strain g/ml 37 37 37 Rv >6.25 Rv >6.25 Rv >6.25
162358 SHI-30 4-F-C H 6 4 162361 SHI-33 2-OH-C H 6 4 162356 SHI-28 4-Br-C H 6 4 162367 SHI-39 2-C H S 4 3 162362 SHI-34 4-OH-C H 6 4
'' ''
H37Rv >6.25 H H H H H H H H H 37 37 37 37 37 37 37 37 37 Rv >6.25 Rv >6.25 Rv >6.25 Rv >6.25 Rv >6.25 Rv >6.25 Rv >6.25 Rv >6.25 Rv >6.25
" '' ''
162363 SHI-35 4-NH -C H 2 6 4 162355 SHI-27 C H 6 5
162364 SHI-36 3-NO -C H 2 6 4 162365 SHI-37 4-NO -C H 2 6 4
162360 SHI-32 4-OCH -C H - Sau.uni 3 6 4 162359 SHI-31 4-CH -C H 3 6 4 162366 SHI-38 2-C H O4 3 162357 SHI-29 4-Cl-C H 6 4 Sau.uni Sau.uni Sau.uni
NIAID/ Southern Research institute/ GWL Hansen's Center/ Colorado state university proprietary information.
87 SECTION - II SYNTHESIS AND BIOLOGICAL EVALUATION OF 1N-PHENYL-3-ARYL5-[1'N,3'-DIPHENYL-4'-PYRAZOLYL]-PYRAZOLINES Looking to the interesting therapeutic activities of pyrazolines, it was considered worthwhile to synthesise compounds bearing 1N,3-diphenyl pyrazole moiety linked to the pyrazoline nucleus. Pyrazolyl pyrazoline of type (V) have been prepared by the action of 1-Aryl-3-(1'N,3'-diphenyl-4'-pyrazolyl)-2-propene1-ones with phenylhydrazine in presence of piperidine.
N N
Piperidine C6H5.NH.NH 2
N N
N O R
R N
Type (V)
R = Aryl
The constitution of the synthesised products have been characterised using elemental analyses, infrared and 1 H nuclear magnetic resonance spectroscopy and mass spectrometry also. In mass spectrometry the m/z value indicate the molecular weight, i.e. when R=4-methoxyphenyl, molecular weight=470, m/z=470 (m). All the compounds have been also evaluated for their antibacterial activity towards Gram positive and Gram negative bacterial strains and antifungal activity towards Aspergillus niger at a concentration of 40g/ml. The biological activity of the compounds have been found to have good and equivalent activity as compared to the known antibiotics recorded on Page No. 94.
88
I R S P E C T R A L S T U DY O F 1 N -P H E N Y L - 3 - ( p -A N I S Y L ) - 5 - [ 1 ' N , 3 ' -D I P H E N Y L 4'-PYRAZOLYL]-PYRAZOLINE
100.0 %T 90.0 80.0 70.0 60.0 50.0 40.0

N
2044.4 2339.5 2842.9 3109.0 2922.0 3064.7 3317.3

N
906.5 1109.0 958.6 1299.9 1002.9 1548.7 1406.0 1033.8 1174.6 1055.0 1253.6 1353.9 1230.5 1444.6 1598.9 1510.2
418. 461. 503. 543.9
605.6 642.3
30.0
CH3 N
20.0
711.7 835.1 688.5 756.0 500.0 1/cm

-1 (KBr disc)
3250.0 2000.0 1750.0 1500.0 1250.0 1000.0 750.0 Phenyl pyrazoline,4-OCH3

I Instrument : SHIMADZU-FT-IR 8400-Spectrophotometer; Frequency range : 4000-400 cm Vibration mode C-H str. (sym.) CH str. (asym.) C-H str. (sym.) Aromatic C-H str. C=C str. C-H i.p. def. C-H. o.o.p. def. Pyrazole moiety Pyrazoline ring C=N C-N C-N str. C=N str. -C-H-(CH ) str. 2 Frequency in cm Observed 2922 1444 1353 3064 1510 1002 835 1598 1174 1109 1548 2842 -1
Type Alkane
Reported 2975-2950 1470-1435 1390-1350 3090-3030 1585-1480 1125-1000 835-810 1640-1600 1230-1020 1230-1020 1650-1550 2850-2790
Ref. 670 " " 671 " " " 673 " 673 " "
89
PMR SPECTRAL STUDY OF 1 N -P H E N Y L - 3 -(p -A N I S Y L ) - 5 - [ 1 ' N , 3 ' -D I P H E N Y L 4'-PYRAZOLYL]-PYRAZOLINE
k f g h i j e N N p o a a b a a N n Hq Hr m l
c'
d' CH3 O
N c d
Internal Standard : TMS; Solvent : CDCl ; Instrument : BRUKER Spectrometer (300 MHz) 3 Signal Signal Position No. ( ppm) 1 2 3 4 5 6 7 8 9 10 11 12 13 3.17-3.25 3.77-3.87 3.83 5.44-5.50 6.76-6.81 6.89-6.92 7.0-7.1 7.16-7.25 7.34-7.4 7.42-7.45 7.49-7.54 7.62-7.68 7.78-7.83 Relative No. of Protons 1H 1H 3H 1H 1H 2H 2H 3H 2H 1H 2H 4H 3H Multiplicity quartet triplet singlet quartet triplet doublet doublet multiplet triplet doublet triplet triplet triplet Inference CHl CHr Ar-OCH 3 CHp CHb CHdd' CHfh CHe,g,i CHk,m CHl CH j,n CHa CHcc'+CHo J Value In Hz J=8.7 J=8.7
k f g h i j e N N p o a a b a a N n Hq Hr m l
c'
d' CH3 O
N c d
N N
CH3 N N O
m/z = 470
SB- 4 N N N N
+
o N N N CH3 N m/z = 336 m/z = 378 OH N
+
o
H N
+
o
+
NH o N H
O H3C m/z = 322
m/z = 365
+
HO CH3 N HO o N m/z = 251 N N
H N
+
o NH NH
m/z = 231
+
N N N N m/z = 245 CH2 CH3 O m/z = 470 o
H3C
+
o N N O m/z = 267 CH3
+
N o N
+
N N m/z = 202 NH2 o
+ +
o N o
+
o N H N
N m/z = 365 N
m/z = 221
m/z = 212
N m/z = 349
91
92 EXPERIMENTAL SYNTHESIS AND BIOLOGICAL EVALUATION OF 1N-PHENYL-3-ARYL5-[1'N,3'-DIPHENYL-4'-PYRAZOLYL]-PYRAZOLINES [A] Synthesis of N-Phenylamino- -methyl-phenyl azomethine See [A] Part-I, Section-I (A). [B] Synthesis of 1N,3-Diphenyl-4-formyl pyrazole See [A] Part-I, Section-I (B). [C] Synthesis of 1-(p-Anisyl)-3-[1'N,3'-diphenyl-4'-pyrazolyl]-2-propene1-one See [A] Part-I, Section-I (C). [D] Synthesis of 1N-phenyl-3-(p-Anisyl)-5-[1'N,3'-diphenyl-4'-pyrazolyl]pyrazoline A mixture of 1-(p-Anisyl)-3-[1'N,3'-diphenyl-4'-pyrazolyl]-2-propene-1-one (3.8 g, 0.01 M), phenylhydrazine (1.08 g, 0.01 M) in 25 ml methanol was reflux for 12 hrs. in presence of basic catalyst piperidine. The reaction product was poured into ice, crude product was isolated, cr ystallized from dioxan. Yield, 3.8 g (81%), m.p. 176 o C. (C 31 H 26 N 4 O; Requires : C, 79.15; H, 5.53; N, 11.91%; found : C, 79.10; H, 5.48; N, 11.88%). TLC solvent system Acetone : Benzene (2:8). Similarly other pyrazolines were prepared. The physical data are recorded in Table No. 5. [E] Antimicrobial activity of 1N-Phenyl-3-aryl-5-[1'N,3'-diphenyl-4'pyrazolyl]-pyrazolines Antimicrobial testing was carried out as described in [A] Part - I, Section I (D). The zone of inhibition of the test solutions are recorded in Graphical Chart No. 5.

5a 5b 5c 5d 5e 5f 5g 5h 5i 5j 5k 5l 5m
P H Y S I CA L C O N S TA N T S PYRAZOLINES Molecular Formula 3

H N 30 24 4 C H N Br 30 23 4 C H N Cl 30 23 4 C H N F 30 23 4 C H N 31 26 4 C H N O 31 26 4 C H N O 30 24 4 C H N O 30 24 4 C H N 30 25 5 C H N O 30 23 5 2 C H N O 30 23 5 2 C H N O 28 22 4 C H N S 28 22 4 C
OF
1 N -P H E N Y L - 3 -A RY L - 5 - [ 1 ' N , 3 ' -D I P H E N Y L - 4 ' -P Y R A Z O LY L ] M.P. o C 5

156 146 124 218 115 176 193 208 217 196 179 110 124
R 2
Molecular Weight 4
440 519 474.5 458 454 470 456 456 455 485 485 430 446
Rf * Value 6
0.70 0.63 0.59 0.53 0.49 0.53 0.57 0.65 0.69 0.49 0.59 0.68 0.63
Yield % 7
76 80 81 70 77 81 84 78 82 79 79 80 81

12.72 10.79 11.80 12.22 12.33 11.91 12.27 12.27 15.37 14.42 14.42 13.01 12.55 12.70 10.77 11.77 12.20 12.30 11.88 12.29 12.28 15.33 14.40 14.43 13.03 12.53
*TLC Solvent System :
5a, 5b, 5e, 5f, 5i, 5j, 5k Acetone : Benzene (2 : 8). 5c, 5d, 5g, 5h, 5l, 5m : Ethyl acetate : Hexane : (4 : 6).
93
ANTIMICROBIAL ACTIVITY OF 1N-PHENYL-3-ARYL-5-[1N,3-DIPHENYL4-PYRAZOLYL]-PYRAZOLINES
30
25
20
15
10
94
COMPARATIVE STUDY OF ANTIMICROBIAL ACTIVITY WITH KNOWN ANTIBIOTICS [A] PART-IV Section - II : Antimicrobial activity of 1N-Phenyl-3-aryl-5-[1'N,3'-diphenyl-4'-pyrazolyl]-pyrazolines

5d (20) 5l (22)

5b (20) 5d (20) 5i (21)
S. aureus
5a (20) 5d (21) 5f (19) 5j (19)
P vulgaris .
5c (19) 5f (20) 5g (19)
A. niger
5d (22) 5h (23) 5l (23)
23 22 24 25 -
22 23 17 24 -
21 21 23 19 -
15 18 17 20 -
25
95
MMMMMMMMMMMMMMMMM M
PART-V STUDIES ON PYRIMIDINONES
M MMMMMMMMMM
Pyrimidinones...
96
INTRODUCTION
P yrimidine derivatives occur in natural products331 like nucleic acids and

Vitamin - B have remarkable pharmaceutical impor tance becuse of their biological activities 332-336 . Several analogs of nucleic acids have been used as compounds that interfere with the synthesis and functioning of nucleic acids, and example is fluorouracil which has been used in cancer treatment. Pyrimidines are among those molecules that make life possible as being same of the building blocks of DNA and RNA. Some pyrimidines of physiologically as well as phar macologically importance are as under: e.g. cytosine, beclmethrin (I), blasticidin (II).
NH2 HOH2C N N O CH3 N N O O O NH2 NH COOH NH CH3 NH2
(I)
(II)
Synthetic pyrimidinone derivatives contribute much to the searchable literature of pyrimidinone derivatives, in huge libraries owing to their wide applicability in different fields. SYNTHETIC ASPECT Different methods for the synthesis of pyrimidinones have been cited in the literature 337 . 1. Bigi and co-worker 338 have synthesised as shown below under solvent free condition.
Pyrimidinones...
Ph H5C2OOC O H3C H2N O NH2 Ph-CHO,HCl H5C2OOC N H H N O
97
H3C
(III)
MECHANISM The reaction of ,-unsaturated system with urea leds to the formation of 4-oxopyrimidine by 1,2 and 1,4-michael addition.
R R'
+
O H 1, 4-Michael addition
+
H2N O
NH2
1, 2-Michael addition
R CH HN
CH2
R' C O NH2
R CH
CH C N C O -H2O
R' OH H
C O
H2N
R CH HN
CH2
OH C N R' H -H2O
R HN N O
R'
C O
R HN O NH
R'
Pyrimidinones... THERAPEUTIC IMPORTANCE
98
Pyrimidinone derivatives have proven to be of great impor tance in exhibiting and enhancing the biological activities such as, 1. Antitumor 339 2. 3. 4. 5. 6. 7. 8. 9. Carcinostatic 340 Antiinflammatory and anticonvulsant 341,342 Antimalarial 343 Antithyroid 344 Anthelmintic 345 Anti HIV 346,347 Antilishmenial 348 Antiviral 349
10. Antimicrobial 350 11. Herbicidal 351-357 12. Antagonists 358-362 Moreover, Azaryan et. al. 363 have synthesised pyrimidine diones as antitumor agent. Krivongov and co-worker 364 have synthesised pyrimidinone derivatives possessing immunotropic and antiinflammatory activity. Omer M. T. and co-worker 365 have prepared some new pyrimidinone derivatives showed moderate activity against the growth of Bacillus subtilis, Staphylococus aureus and Aspergillus niger. Amuti Kofies et. al. 366 have suggested that pyrimidinones (V & VI) as herbicidal and plant growth regulators.
H N N R4 O F Cl CH3 CH3 O F 3C N N O O CH
R3
(V)
R 3 = Alkyl, R 4 = H, Halogen
(VI)
Pyrimidinones...
99
K. Mogilaiah 367 have prepared spiropyrimidinones as antibacterial. Drewes and Wilhelm 368 have synthesised pyrimidinones as herbicidal agents. Timothy and co-worker 369 have suggested imidazolyl pyrimidinones as antiviral. Nagamatsu et. al. 370 have prepared some new triazolo [3,4-c] pyrimidinone as Xanthin oxidase inhibitors. Andree Roland et. al. 371 have prepared oxazolyl uracil as herbicidal and insecticidal. Yari M. M. and coworker 372 have investigated the pyrimidinone derivatives which possess calcium antagonist activity. Bruce M. A. and co-worker 373 prepared the dihydropyrimidinones (VII) as NPY antagonists.
R2 NH O HN R1OOC R N N H O O N H Me NH N H2N
COOMe
Me
(VII)
R = Alkyl, R 1 = Alkyl R 2 = Ph, Methoxyphenyl
Sidler and Larsen 374 have reported pyrimidinone derivatives (VIII), useful as an -adrenergic receptor antagonists.
F F F F
O H3COOC H3COOC NH N H OCH3 O OCH3 N H (CH2)3 N O NH N
(VIII)
Pyrimidinones... 100 Mona Mahram and co-worker 375 have synthesied pyrimidine derivatives as potent antimicrobial and antitumor agents. Saxen a A . K. an d co- wor ker 3 7 6 h a v e p re p a re d 2 , 6 - d i s u b s t i t u t e d pyrimidinones as CNS agent (IX).
O R
R = Alkyl
N N R1
R2
R 1 = Alkyl/Aryl R 2 = Alkyl/Aryl
(IX)
Pyrimidinone derivatives 377,378 have found to be calcium channel blocker (X). Barbuliene M. M. et. al.379 have synthesised pyrimidinones as antiinflammatory agent.
O Ar COOEt HN O N H Me O HN N H CO2R
Me
(X)
Recently, Amjad Ali et. al. 380 have synthesised new fused pyrimidinones as antimicrobial agents. Abd El-Galil et. al. 381 have synthesised pyrimidinone as androgenic anabolic and antiinflammatory agents. Martin Bolli et. al. 382 have synthesised pyrimidines as endothelin receptor antagonists. Patricia F. F. et. al. 383 have synthesised and screened for their leukocyte functions inhibitor activity. Dumas Jacques et. al. 384 have synthesised pyrimidinones and tested their hyderproliferative disorder activity. Adenosine receptor antagonists pyrimidinones have been prepared by Tsutsumi Hideo et. al. 385
Pyrimidinones... 101 Thus, diverse biological activities have been encountered in compounds containing pyrimidinone ring system. To further assess the potential of such type of compounds, study of pyrimidinones have been carried out as under. SECTION - I : SYNTHESIS AND BIOLOGICAL EVALUATION OF 6-ARYL-4-[1'N,3'-DIPHENYL-4'-PYRAZOLYL]-1,2,3,4TETRAHYDROPYRIMIDIN-2-ONES SECTION - II : SYNTHESIS AND BIOLOGICAL EVALUATION OF 5 -A L KY L - 6 -A L KY L / A RY L - 4 - [ 1 ' N , 3 ' -D I P H E N Y L 4'-PYRAZOLYL]-1,2,3,4-TETRAHYDROPYRIMIDIN2-ONES
102 SECTION - I SYNTHESIS AND BIOLOGICAL EVALUATION OF 6-ARYL-4-[1'N,3'DIPHENYL-4'-PYRAZOLYL]-1,2,3,4-TETRAHYDROPYRIMIDIN-2-ONES Looking to the interesting pharmacological and agricultural activity of pyrimidinone ring system, It was considered worthwile to synthesis compounds bearing 1N,3-diphenyl-pyrazole nucleus linked to the pyrimidinone nucleus. Pyrimidinone of type (VI) have been prepared by the condensation of 1-Aryl3-[1'N,3'-diphenyl-4'-pyrazolyl]-2-propene-1-one with urea in presence of catalytic amount of conc. HCl as shown under.
N N
H2N
N N
NH2
+
H N
MeOH, H
O NH
O R R
Type (VI)
R = Aryl
The constitution of the synthesised products have been characterised by using elemental analyses, infrared and 1 H nuclear magnetic resonance spectroscopy and mass spectrometry also. In mass spectrometry the m/z value indicate the molecular weight, i.e. when R=p-Tolyl, molecular weight=406, m/z=405 (m-1). All the compounds have been also evaluated for their antibacterial activity towards Gram positive and Gram negative bacterial strains and antifungal activity towards Aspergillus niger at a concentration of 40g/ml. The biological activity of the synthesised compounds have been compored with standerd drugs. Some compounds have been found to have good and equivalent activity as compared to the known antibiotics recorded on Page No. 109.
103
IR SPECTRAL STUDY OF 6-(p-TOLYL)-4-[1'N,3'-DIPHENYL-4'-PYRAZOLYL]-1,2,3,4TETRAHYDROPYRIMIDIN-2-ONE
100.0 %T 90.0 80.0 70.0 60.0 50.0 40.0 2852.5 2922.0 3066.6 3244.0
N N
H N
NH
810.0 920.0
CH3
511.1
958.6 1317.3 981.7 1355.9 692.4 1026.1 1539.1 1411.8 756.0 1234.4 1448.4 1502.4 1596.9 1652.9 1110.9 617.2
3250.0 2000.0 1750.0 1500.0 1250.0 1000.0 750.0 M 2-AT Urea

-1
500.0 1/cm
(KBr disc)
Instrument : SHIMADZU-FT-IR 8400-Spectrophotometer; Frequency range : 4000-400 cm Vibration mode C-H str. (sym.) C-H str. (asym.) C-H def. (sym.) Aromatic C-H str. C=C str. Frequency in cm Observed 2852 1448 1355 3066 1502 1110 C-H i.p.def. Pyrazole moiety Pyrimidinone ring C=N str. C-N str. N-H str. C=O str. 1026 1596 1234 3244 1653 -1
Type Alkane
Reported 2880-2860 1470-1435 1390-1350 3090-3030 1520-1480 1125-1090 1070-1000 1640-1600 1230-1020 3220-3140 1690-1630
Ref. 670 " " 671 " " " 673 " 672 "
104
PMR SPECTRAL STUDY OF 6-(p-TOLYL)-4-[1'N,3'-DIPHENYL-4'-PYRAZOLYL]-1,2,3,4TETRAHYDROPYRIMIDIN-2-ONE
e f g h i k NH j O b c b' H3C c' N H a a N d a N a a
Internal Standard : TMS; Solvent : CDCl ; Instrument : BRUKER Spectrometer (300 MHz) 3 Signal Signal Position No. ( ppm) 1 2 3 4 5 6 7 8 2.38 6.58 7.22-7.29 7.34-7.39 7.48-7.58 7.66-7.70 7.88-7.71 9.08 Relative No. of Protons 3H 1H 3H 2H 7H 2H 2H 1H Multiplicity singlet singlet multiplet triplet multiplet multiplet doublet singlet Inference Ar-CH CHk CHcc' + CHj CH d,h CHa+CH e,g CH i,f CH bb' NH -NH not observed J=8.5 J=8.5 J Value In Hz
e f g h i k NH j O b c b' H3C c' N H a a N d a N a a
H N
NH
m/z = 406 (m-1)
CH3
NH SB- 7
+
o N N N N m/z = 221
+
o O N H
+
o
+
o NH CH3 m/z = 189 H2C N m/z = 119 N
+
o CH3
HN NH N m/z = 313 O NH O m/z = 329
+
o N N m/z = 258 N CH3 N N m/z = 211 CH3 CH2 N N
+
o
+
o HN NH O N N m/z = 273 m/z = 406 (M - 1)
+
o N N BASE PEAK m/z = 300
+
CH3 o
N NH
+
o H2N N NH m/z = 203 N O N CH2 N N m/z = 233 m/z = 245 m/z = 107 NH
+ +
o N N
+
H3C o
CH3 o
m/z = 258
106
107 EXPERIMENTAL SYNTHESIS AND BIOLOGICAL EVALUATION OF 6-ARYL-4-[1'N,3'DIPHENYL-4'-PYRAZOLYL]-1,2,3,4-TETRAHYDROPYRIMIDIN-2-ONES [A] Synthesis of N-Phenylamino- -methyl-phenyl azomethine See [A] Part-I, Section-I (A). [B] Synthesis of 1N,3-Diphenyl-4-formyl pyrazole See [A] Part-I, Section-I (B). [C] Synthesis of 1-(p-Tolyl)-3-[1'N,3'-diphenyl-4'-pyrazolyl]-2-propene1-one See [A] Part-I, Section-I (C). [D] Synthesis of 6-(p-Tolyl)-4-[1'N,3'-diphenyl-4'-pyrazolyl]-1,2,3,4tetrahydropyrimidin-2-one A mixture of 1-p-Tolyl-3-(1'N,3'-diphenyl-4'-pyrazolyl)-2-propene-1-one (3.64 g, 0.01 M) and urea (0.60 g, 0.01 M) was refluxed at 90 o C for 14 hrs in presence of acid catalyst like HCl in methanol. The reaction product was poured into ice, crude product was isolated, crystallized from dioxan. Yield, 2.7 g (66%), m.p. 188 o C. (C 26 H 22 N 4 O; Requires : C, 76.85, H, 5.42; N, 13.78%; found : C, 76.81; H, 5.38; N, 13.72%). TLC solvent system Acetone : Benzene (2:8). Similarly other pyrimidinones were prepared. The physical data are recorded in Table No. 6. [E] Antimicrobial activity of 6-Aryl-4-[1'N,3'-diphenyl-4'-pyrazolyl]1,2,3,4-tetrahdropyrimidin-2-ones Antimicrobial testing was carried out as described in [A] Part-I, Section-I (D). The zone of inhibition of the test solutions are recorded in Graphical Chart No. 6.

6a 6b 6c 6d 6e 6f 6g 6h 6i 6j 6k 6l 6m
PHYSICAL CONSTANTS OF 6-ARYL-4-[1'N,3'-DIPHENYL-4'-PYRAZOLYL]-1,2,3,4-TETRAHYDRO PYRIMIDIN-2-ONES Molecular Formula 3

H N O 25 20 4 C H N OBr 25 19 4 C H N OCl 25 19 4 C H N OF 25 19 4 C H N O 26 22 4 C H N O 26 22 4 2 C H N O 25 20 4 C H N O 25 20 4 C H N O 25 21 5 C H N O 25 19 5 3 C H N O 25 19 5 3 C H N O 23 18 4 2 C H N OS 23 18 4 C
R 2
Molecular Weight 4
392 471 426.5 410 406 422 408 408 407 437 437 382 398
M.P. o C 5
110 193 211 217 188 186 221 208 189 168 196 194 115
Rf * Value 6
0.68 0.57 0.71 0.69 0.52 0.55 0.63 0.71 0.49 0.62 0.73 0.55 0.58
Yield % 7
70 68 58 71 66 61 72 67 60 73 65 66 74

14.28 11.89 13.12 13.65 13.78 13.26 13.72 13.72 17.19 16.01 16.01 14.65 14.06 14.27 11.83 13.10 13.60 13.72 13.23 13.76 13.70 17.18 16.00 15.99 14.62 14.02
6a-6d, 6i-6k : Acetone : Benzene (2 : 8). 6e-6h, 6l, 6m : Ethyl acetate : Haxene : (4 : 6).
108
ANTIMICROBIAL ACTIVITY OF 6-ARYL-4-[1N,3- DIPHENYL-4-PYRAZOLYL]1,2,3,4- TETRAHYDROPYRIMIDIN-2-ONES
30
25
20
15
10
109
COMPARATIVE STUDY OF ANTIMICROBIAL ACTIVITY WITH KNOWN ANTIBIOTICS [A] PART-V Section - I : Antimicrobial activity of 6-Aryl-4-[1'N,3'-diphenyl-4'-pyrazolyl]-1,2,3,4-tetrahydropyrimidin-2-ones

6a (22) 6f (23)

6b (20) 6f (20) 6h (20) 6k (20)
S. aureus
6j (20) 6m (22)
P vulgaris .
6c (19) 6i (19) 6j (20)
A. niger
6i (23) 6l (24)
23 22 24 25 -
22 23 17 24 -
21 21 23 19 -
15 18 17 20 -
25
110
111 SECTION - II SYNTHESIS AND BIOLOGICAL EVALUATION OF 5-ALKYL-6-ALKYL/ ARYL-4-(1'N,3'-DIPHENYL-4'-PYRAZOLYL)-1,2,3,4-TETRAHYDRO PYRIMIDIN-2-ONES With a view to synthesising the compounds having better therapeutic activity the pyrimidinones of type (VII) have been prepared by the condensation of 1N,3-diphenyl-4-formyl pyrazole, urea and different 1,3-diketones in presence of HCl as catalyst as given below.
N N
N N H N
+
O
CHO R2
H2N MeOH, H
NH2
+
O NH
R2 R1
R1
Type (VII) R 1 = Alkyl/Aryl ,R 2 = Alkyl
The constitution of synthesised products have been characterised by using elemental analyses, infrared and 1 H nuclear magnetic resonance spectroscopy and mass spectrometry also. In mass spectrometry the m/z value indicate the m o l e c u l a r w e i g h t , i . e . w h e n R 1 = C a r b e t h ox y, R 2 = m e t h y l , m o l e c u l a r weight=402, m/z=403 (m+1). All the compounds have been also evaluated for their antibacterial activity towards Gram positive and Gram negative bacterial strains and antifungal activity towards Aspergillus niger at a concentration of 40g/ml. The biological activity of the synthesised compounds have been compared with standard drugs. Some compounds have been found to have good and equivalent activity as compared to the known antibiotics recorded on Page No. 118.
112
IR SPECTRAL STUDY OF 6-METHYL-5-CARBMETHOXY-4-[1'N,3'-DIPHENYL4'-PYRAZOLYL]-1,2,3,4-TETRAHYDROPYRIMIDIN-2-ONE
100.0
N
N H N
%T 80.0
H3COOC H3C
O NH
896.8 923.8
60.0 3057.0 2950.9 3224.8 3103.3 3361.7 20.0
493. 449. 516.9 574.7
40.0
960.5 779.2 1359.7 1016.4 804.3 619.1 1539.1 1379.0 1060.8 1409.9 684.7 715.5 1598.9 1315.4 1429.2 1191.9 752.2 1452.3 1213.1 1500.5 1099.3 1641.3 1234.4 1695.3
0.0
3250.0 2000.0 1750.0 1500.0 1250.0 1000.0 M MAA Urea

I
750.0
-1
500.0 1/cm
(KBr disc)
Instrument : SHIMADZU-FT-IR 8400-Spectrophotometer; Frequency range : 4000-400 cm Vibration mode C-H str. (sym.) C-H str. (asym.) C-H def. (sym.) Aromatic C-H str. C=C str. C-H i.p. def. C-H o.o.p. def. Pyrazole moiety Pyrimidinone ring Ester Ether C=N str. C-N str. N-H str. Ring C=O str. C=O str. C-O-C str (sym.) C-O-C str. (asym.) Frequency in cm Observed 2950 1452 1379 3057 1500 1099 804 1598 1213 3361 1641 1695 1234 1060 -1
Type Alkane
Reported 2975-2950 1470-1435 1390-1350 3090-3030 1585-1480 1125-1000 835-810 1640-1600 1230-1020 3320-3140 1690-1630 1745-1680 1275-1200 1075-1020
Ref. 670 " " 673 " " " 672 " 670 " " " "
113
PMR SPECTRAL STUDY OF 5-CARBETHOXY-6-METHYL-4-[1'N,3'-DIPHENYL4'-PYRAZOLYL]-1,2,3,4-TETRAHYDROPYRIMIDIN-2-ONE
a a b b b b b N N c d H N a O NH H3C e a a
H3CH2COOC g f
Internal Standard : TMS; Solvent : CDCl ; Instrument : BRUKER Spectrometer (300 MHz) 3 Signal Signal Position No. ( ppm) 1 2 3 4 5 6 7 1.19-1.25 2.32 4.13-4.25 5.88 7.25-7.65 8.23 8.53 Relative No. of Protons 3H 3H 2H 1H 10H 1H 1H Multiplicity triplet singlet multiplet singlet multiplet singlet singlet -CHg -CHe -CHf CHd CH a,b CHc -NHh Inference
-NH not observed
a a b b b b b N N c d H N a O NH H3C e a a
H3CH2COOC g f
N N H N O NH H3C
H3 CH2COOC
m/z = 403 (m+1)
SB- 8 N
+
o N
+
N o
+
o
+
N o H N N O H3C O H3C O N NH2 O H3C
N N N O H3C O H3C O H3C m/z = 297
+
o NH
H3C O
H3C
m/z = 274 m/z = 231
NH
N N HO m/z = 357
m/z = 373
NH O
H3C
+
NH o O N N N H N O N N
+
o
O N H3C H m/z = 183 CH3 O
NH O m/z = 329 O NH
NH
CH3
+
o H3C
N H N
O m/z = 403 (M
+
H3C 1) N N
+
o
m/z = 388
H N
+
o NH N
m/z = 221
+
o N O H N
+
o
+
O OH o
+
o
+
o
m/z = 115
m/z = 314 N
N HN NH m/z = 115 HN NH m/z = 128 N m/z = 257
NH m/z = 107
NH2
115
CH3
116 EXPERIMENTAL SYNTHESIS AND BIOLOGICAL EVALUATION OF 5-ALKYL-6-ALKYL/ ARYL-4-[1'N,3'-DIPHENYL-4'-PYRAZOLYL]-1,2,3,4-TETRAHYDRO PYRIMIDIN-2-ONES [A] Synthesis of N-Phenylamino- -methyl-phenyl azomethine See [A] Part-I, Section-I (A). [B] Synthesis of 1N,3-Diphenyl-4-formyl pyrazole See [A] Part-I, Section-I (B). [C] Synthesis of 5-Carbethoxy-6-methyl-4-[1'N,3'-diphenyl-4'-pyrazolyl]1,2,3,4-tetrahydropyrimidin-2-one A mixture of 1N,3-Diphenyl-4-formyl-pyrazole (2.48 g, 0.01 M), ethyl aceto acetate (1.3 g, 0.01 M) and urea (0.60 g, 0.01 M) was refluxed for 12 hrs. in presence of acid catalyst like HCl in methanol. The reaction product was poured into ice, crude product was isolated and crystallized from DMF. Yield, 2.95 g (73%), m.p. 160 o C. (C 23 H 22 O 3 N 4 ; Requires : C, 68.87; H, 5.47; N, 13.92%; found : C, 68.84; H, 5.42; N, 13.89%). TLC solvent system Acetone : Benzene (3:7). Similarly other pyrimidinones have been prepared. The physical data are recorded in Table No. 7. [D] Antimicrobial activity of 5-Alkyl-6-alkyl/aryl-4-[1'N,3'-diphenyl-4'pyrazolyl]-1,2,3,4-tetrahydropyrimidin-2-ones Antimicrobial testing was carried out as described in [A] Part-I, Section-I (D). The zone for inhibition of the test solutions are recorded in Graphical Chart No. 7.

7a 7b 7c 7d 7e 7f 7g 7h 7i 7j 7k 7l 7m
P H Y S I CA L C O N S TA N T S O F 5 -A L KY L - 6 -A L KY L / A RY L - 4 - [ 1 ' N , 3 ' -D I P H E N Y L - 4 ' -P Y R A Z O LY L ] 1,2,3,4-TETRAHYDROPYRIMIDIN-2-ONES R2 3

-CH -NH -CH -CH -NH 3 2 3 3
R1 2
-COCH 3 -COOC H 2 5 -COOCH 3 -COOC H 2 5 -CN -COOC H 2 5 -COOC H 2 5 -COOC H 2 5 -COOC H 2 5 -COOC H 2 5 -COOC H 2 5 -COOC H 2 5 -COOC H 2 5
Molecular Formula 4
H O N 22 20 2 4 C H O N 22 21 3 5 C H O N 22 20 3 4 C H O N 23 22 3 4 C H ON 20 16 6 C H O N 28 24 3 4 C H O N Br 28 23 3 4 C H O N Cl 28 23 3 4 C H O N F 28 23 3 4 C H O N 29 26 3 4 C H O N 29 26 4 4 C H O N 28 26 4 4 C H O N 28 26 4 4 C
Molecular Weight 5
372 403 388 402 356 464 543 498.5 482 478 494 480 480
M.P. o C 6
178 195 195 160 178 123 193 211 179 223 115 79 210
Rf * Value 7
0.56 0.65 0.70 0.57 0.50 0.68 0.58 0.70 0.49 0.59 0.66 0.58 0.60
Yield % 8
80 81 76 73 70 81 68 74 60 63 65 75 68

15.05 17.36 14.42 13.92 23.60 12.06 10.31 11.23 11.61 11.71 11.33 11.66 11.66 15.01 17.33 14.39 13.89 23.62 12.03 10.34 11.25 11.60 11.69 11.30 11.65 11.68
2 C H 6 5 4-Br-C N 6 4 4-Cl-C H46 4-F-C H 6 4 4-CH -C H 3 6 4 4-OCH -C H 3 6 4 2-OH-C H 6 4 4-OH-C H 6 4
7a-7f : Acetone : Benzene (3 : 7). 7g-7m : Ethyl acetate : Hexane (5 : 5).
117
ANTIMICROBIAL ACTIVITY OF 5-ALKYL- 6-ALKYL/ARYL-4-[1N,3-DIPHENYL4- PYRAZOLYL]-1,2,3,4-TETRAHYDROPYRIMIDIN-2-ONES
30 25
20 15 10
5 0 7a 17 18 22 17 19 7b 20 17 19 21 17 7c 16 22 22 18 23 7d 15 18 17 20 18 7e 21 20 21 18 24 7f 18 16 18 19 16 7g 11 20 14 15 19 7h 16 11 15 13 15 7i 12 17 18 16 20 7j 17 12 14 11 20 7k 13 16 19 17 11 7l 18 13 12 15 13 7m 14 13 18 18 12 7n 19 14 17 16 20 Ampici Amoxy Norflo Penicil Grese llin cillin xacin lin ofulvin 23 22 21 15 0 22 23 21 18 0 24 17 23 17 0 25 24 19 20 0 0 0 0 0 25
B.mega s.aureus E.coli P.vulgaris A.niger
118
COMPARATIVE STUDY OF ANTIMICROBIAL ACTIVITY WITH KNOWN ANTIBIOTICS [A] PART-V Section II : Antimicrobial activity of 5 -A l ky l - 6 - a l k y l / a r y l - 4 - [ 1 ' N , 3 ' - d i p h e n y l - 4 ' - p y r a z o l y l ] 1,2,3,4-tetrahydropyrimidin-2-ones Antibacterial activity Zone of inhibition in m.m. B. mega
7b (20) 7e (21)

7a (22) 7c (22) 7e (21) 21 21 23 19 -
S. aureus
7c (22) 7e (20) 7g (20)
P vulgaris .
7b (21) 7d (20) 7f (19) 15 18 17 20 -
A. niger
7c (23) 7e (24)
23 22 24 25 -
22 23 17 24 -
25
119
MMMMMMMMMMMMMMMMM M
PART-VI STUDIES ON BARBITONES
M MMMMMMMMMM
Barbitones... 120
INTRODUCTION
B arbitones, which belongs to an important group of nitrogen containing

heterocyclic compounds have been extensively explored for their application in the field of medicine. Most important is the effect of barbiturates on CNS. Barbituric aicd derivatives constitute an important class of compounds possessing diverse type of biological properties including hyphotic, sedative, anticonvulsant, cardiovascular etc. Barbituric acid usually represented as the trione (I, R 1 =R 2 =H) was first made about 1864 and it has no hypnotic properties. The origin of the name is lost, although there are several plausible explanations associated with St. Barbara's feast day, a favourite Munchen Kellnerin rejoicing in that given name, and even the barba which is a beard of the business end of a key.
O R2 R1 O N H NH O
(I)
SYNTHETIC ASPECT D i f f e re n t m e t h o d s a re u s e d f o r t h e p re p a r a t i o n o f b a r b i t o n e s i n literature 386,387 1. Cao-Yan Weu et. al. 388 have prepared barbitones by reaction of different aldehydes with barbituric acid in basic media.
Barbitones... 121
Ar O R - CHO O HN O NH O HN O NH O
OH
2.
M. R. Mahmoud et. al. 389 have synthesised barbituric acid derivatives from chalcone.
R O O gla. acetic acid HN R' O O NH HN NH O R'
3.
Ogus Funda et. al. 390 have prepared barbitones by the reaction of acetone and barbituric aicd.
THERAPEUTIC IMPORTANCE The first hyphotic barbiturate, 5,5-diethyl barbituric acid (barbital, Veronal ; I; R 1 R 2 =Et) was made in 1904, was introduced into medicine in 1905, and is still used sometimes; the second was 5-ethyl-5-phenylbarbituric acid (phenobarbital, Luminal, I; R 1 =Et, R 2 =Ph), also prepared in 1904 but used as a long acting CNS depressant only from 1912 until the present day. Several thousand active barbiturates were made subsequently but scarcely a dozen are still used to any extent. Among these are pentobarbital (Nembutal; I; R 1 =C 2 H 5 , R 2 =CHMePr), amobarbital (Amytal ; I; R 1 =C 2 H , R 2 =CH 2 CH 2 CHMe 2 ), 5 secobarbital (Seconal; I; R 1 =CH 2 CH=CH 2 , R 2 =CHMePr), hexobarbital (Sombulex/Evipal; II), thiopental (Pentothal ; III). The whole subject is well reviewed 391-393 .
Barbitones... 122
O CHMePr Me O N CH3 NH Et O O N H
H N S
O N N CH3 CH3
(II)
(III)
(IV)
T h e ' p s e u d o - b a r b i t u r a t e ' , 2 - m e t h y l - 3 - o - t o l y l q u i n a z o l i n- 4 ( 3 H ) - o n e (methaqualone, Revonal; IV) has an ever winder spectrum of activities that do the barbiturates proper; it appears to be quite widely used as a sedative, hyphotic, anticonvulsant, antispasmodic and local anaesthetic agent 394 . Some barbituric acid derivatives used as sedative and hyphotic is carbubarb 395 , which is used as veternar y anaesthetics. Some isoxazolo pyrimidines have been studied because of their potential as pesticidal 396,397 activity. Some barbiturates showing cardiovascular 398-400 and analgesics and antiinflammatory activities 401 have been reported. Ulf Wellmar et. al. 402 have synthesised some uracil derivatives and screened for antiviral activity 403,404 . Raymond et. al. 405 have synthesised some barbiturates (V), which showed anticancer activity. Mahmoud et. al. 406 synthesised barbituric acid derivatives and reported their antimicrobial activity.
CH3 O O
HN N H
(V)
Barbitones... 123 Some isoxazolopyrimidines have been extensively studied and reported as antagonist 407 and antitumor 408 activity. Wolf-Gang et. al. 409 have reported 5-(3-Benzylthiazolidin-2-ylidene)-1,3-dimethyl hexahydropyrimidin-2,4,6-trione having agricultural activity. Andre Roland et. al. 410 demonstrated some barbituric acid derivatives used as herbicidal and insecticides. Omar M. T. 411 has synthesised barbitone derivatives, showing antimicrobial activity. Sakai et. al. 412 have synthesised new barbitones which were assessed for bone and cartilage disease. Ambrogio Oliva et. al. 413 have synthesised barbitones possessing antimetastatic and antitumor activity. Weber W et. al. 414 have synthesised barbitones as main metabolite (VI). Frank Grams et. al. 415 have synthesised barbitones and found to be metalloprotease inhibitors. R T Pardasani et. al. 416 have synthesised new barbitones for antibacterial agents. (VII).
H N O N H O O CH3 NH (CH2)2 COOH R1 O NH O O
CH2
(VI) (VII)
N H
L evesque D. L. et. al. 417 have synthesised barbitones as uridine phosphoralase inhibitors. Wyzlic I. M. et. al. 418 have synthesised and tested barbitones as anticonvulsant agent. Shivanyuk A. N. and co-worker 419 have prepared barbitones as Porphyrin Melamine Calixarene receptor. Gursu Esin et. al. 420 have prepared barbitone as biological activity agent. Bosies Elmar and co-worker 421 have prepared barbitones as metalloproteinase inhibitor (VIII).
Barbitones... 124
O Ph N O O N CH2CH2OH Et Ph R3 O N R1 O HN O O N S N R2
H N O N H
(VIII)
(IX)
R 1 , R 2 = H, Halo, R 3 = CH 3 , Et, Ph
Abdel Hamide S. G. et. al. 422 have prepared barbitone as anticonvulsant agent (IX). Li Laizhong et. al. 423 have synthesised barbitones and screened for their anticonvulsant activity. Recently, Geppert Dangmar et. al. 424 have synthesised barbitones and tested their metalloproteinase inhibitory activity. These observations led us to explore barbitone chemistry by synthesising its derivatives in order to achieve better therapeutic agents. It has been described as under. SECTION - I : SYNTHESIS AND BIOLOGICAL EVALUATION OF 5-[1'-ARYL-3'-(1''N,3''-DIPHENYL-4''-PYRAZOLYL)PROP-2'-ENYLIDINE]-BARBITURIC ACIDS
125 SECTION - I SYNTHESIS AND BIOLOGICAL EVALUATION OF 5-[1'-ARYL-3'-(1''N,3''DIPHENYL-4''-PYRAZOLYL)-PROP-2'-ENYLIDINE]-BARBITURIC ACIDS Barbiturates have received considerable attention in the field of medicinal chemistry due to wide range of pharmaceutical activities exhibited by them. Prompted by these facts, the preparation of barbitone of type (VIII) was carried out by the reaction of chalcone of type (I) with barbituric acid in glacial acetic acid.
N N N Barbituric acid gl. acetic acid O
N R O HN R O NH O
Type (VIII)
R = Aryl
The constitution of the synthesised products have been characterised by using elemental analyses, infrared and 1 H nuclear magnetic resonance spectroscopy and mass spectrometry also. In mass spectrometry the m/z value indicate the molecular weight, i.e. when R=4-Bromophenyl, molecular weight=539, m/z=541 (m+2). All the compounds have been also evaluated for their antibacterial activity towards Gram positive and Gram negative bacterial strains and antifungal activity towards Aspergillus niger at a concentration of 40g/ml. The biological activity of the synthesised compounds have been compared with standard drugs. Some compounds have been found to have good and equivalent activity as compared to the known antibiotics recorded on Page No. 132.
126
IR SPECTRAL STUDY OF 5-[1'-(p-ANISYL)-3'-(1"N,3"-DIPHENYL-4"-PYRAZOLYL)PROP-2'-ENYLIDINE]-BARBITURIC ACID
100.0
N O CH3
%T 80.0
O HN O NH
60.0 2850.6 40.0 3055.0 3209.3 20.0 1666.4 1598.9
920.0 952.8 983.6
661.5 727.1 682.8
754.1 509.2 596.0 1016.4 792.7 617.2
0.0
I
1315.4 1112.9 1525.6 1691.4 1425.3 1203.5 1566.1 1500.5 1355.9 1739.7 1398.3 1222.8 3250.0 2000.0 1750.0 1500.0 1250.0 1000.0 750.0 4-meo barbi
-1
500.0 1/cm
(KBr disc)
Instrument : SHIMADZU-FT-IR 8400-Spectrophotometer; Frequency range : 4000-400 cm Vibration mode C-H str. (sym.) C=C str. C-H i.p. def. C-H o.o.p. def. Pyrazole moiety Barbitone ring C=N C-N N-H str. -C=O str. -C=O str. C-H str. (sym.) C-H def. Frequency in cm Observed 3055 1525 1016 830 1598 1203 3209 1739 1691 2850 1425 -1
Type Aromatic
Reported 3090-3030 1585-1480 1125-1000 835-810 1640-1600 1230-1020 3350-3200 1750-1680 1750-1680 2950-2850 1470-1435
Ref. 671 " " " 673 " 670 " " " "
127
PMR SPECTRAL STUDY OF 5-[1'-(p-ANISYL)-3'-(1"N,3"-DIPHENYL-4"-PYRAZOLYL)PROP-2'-ENYLIDINE]-BARBITURIC ACID
a a
a a c b c' O CH3
e f
d N
a k
i g h
j O HN O NH
b' O
Internal Standard : TMS; Solvent : CDCl ; Instrument : BRUKER Spectrometer (300 MHz) 3 Signal Signal Position No. ( ppm) 1 2 3 4 5 6 7 8 9 3.86 6.92-6.96 7.31-7.39 7.43-7.52 7.69-7.72 7.77-7.81 7.85-7.91 7.94-7.96 8.34 Relative No. of Protons 3H 2H 2H 5H 2H 2H 1H 2H 1H Multiplicity singlet doublet doublet multiplet doublet doublet doublet doublet singlet Inference Ar-OCH CHcc' CH jk CHa CH d,h CH e,g CHf CH bb' CHi 3 J Value In Hz J=8.9 J=8.9 -
Both -NH not observed
a a
a a c b c' O CH3
e f
d N
a k
i g h
j O HN O NH
b' O
N N
Br
O HN O NH
m/z = 541 (m+2)
+
O SB- 22 N N O H N o N HN O N NH H3C O HN m/z = 348 Br Br Br m/z = 319 O CH3
+
H N o
+
o
m/z = 452
+
o
+
o N N O N H N O NH m/z = 290 NH Br
m/z = 215
+
o N N m/z = 258
N O N
+
BASE PEAK m/z = 541 (M
+
NH2 2) Br NH m/z = 107
N HN CH3
+
o
N HN
+
o O N
+
o N N N m/z = 277 Br m/z = 245 CH2 N
+
o
N O
129
m/z = 277
m/z = 221
130 EXPERIMENTAL SYNTHESIS AND BIOLOGICAL EVALUATION OF 5-[1'-ARYL-3'-(1''N,3''DIPHENYL-4''-PYRAZOLYL)-PROP-2'-ENYLIDINE]-BARBITURIC ACIDS [A] Synthesis of N-Phenylamino- -methyl-phenyl azomethine See [A] Part-I, Section-I (A). [B] Synthesis of 1N,3-Diphenyl-4-formyl pyrazole See [A] Part-I, Section-I (B). [C] Synthesis of 1-(p-Anisyl)-3-[1'N,3'-diphenyl-4'-pyrazolyl]-2-propene1-one See [A] Part-I, Section-I (C). [D] Synthesis of 5-[1'-(p-Anisyl)-3'-[1''N,3"-diphenyl-4"-pyrazolyl]-prop2-enylidine]-barbituric acid A mixture of 1-(p-Anisyl)-3-[1'N,3'-diphenyl-4'-pyrazolyl]-2-propene-1-one (3.8 g, 0.01 M), barbituric acid (1.28 g, 0.01 M) in glacial acetic acid was refluxed for 12 hrs. in oil bath. The contents were poured into ice and product was H N O , 29 22 4 4 Requires: C, 71.02; H, 4.49; N, 11.42%; found : C, 71.05; H, 4.46; N, 11.40%). TLC solvent system Acetone : Benzene (4:6). Similarly other barbitones have been prepared. The physical data are recorded in Table No. 8. [E] Antimicrobial activity of 5-[1'-Aryl-3'-(1"N,3"-diphenyl-4"-pyrazolyl)prop-2'-enylidine]-barbituric acids Antimicrobial testing was carried out as described in [A] Part-I, Section-I (D). The zone for inhibition of the test solutions are recorded in Graphical Chart No. 8. isolated, crystallized from DMF. Yield, 3.1 g (63%), m.p. 223 o C. (C

8a 8b 8c 8d 8e 8f 8g 8h 8i 8j 8k 8l 8m
PHYSICAL CONSTANTS OF 5-[1'-ARYL-3'-(1"N,3"-DIPHENYL-4"-PYRAZOLYL)-PROP-2'-ENYLIDINE]BARBITURIC ACIDS Molecular Formula 3

H N O 28 20 4 3 C H N O Br 28 19 4 3 C H N O Cl 28 19 4 3 C H N O F 28 19 4 3 C H N O 29 22 4 3 C H N O 29 22 4 4 C H N O 28 20 4 4 C H N O 28 20 4 4 C H N O 28 21 5 3 C H N O 28 19 5 3 C H N O 28 19 5 3 C H N O 26 18 4 4 C H N O S 26 18 4 3 Acetone : Benzene (4 : 6). C
R 2
Molecular Weight 4
460 539 494.5 478 474 490 476 476 475 505 505 450 466
M.P. o C 5
118 178 210 133 198 223 143 178 205 196 192 137 133
Rf * Value 6
0.70 0.58 0.60 0.54 0.63 0.70 0.58 0.65 0.57 0.67 0.55 0.69 0.53
Yield % 7
59 68 63 58 70 63 54 71 65 59 68 63 59

12.17 10.39 11.32 11.71 11.81 11.42 11.76 11.76 14.73 13.85 13.85 12.44 12.01 12.13 10.36 11.30 11.68 11.80 11.40 11.73 11.74 14.78 13.81 13.81 12.41 12.04
131
ANTIMICROBIAL ACTIVITY OF 5-[1-ARYL-3-(1N,3 -DIPHENYL-4-PYRAZOLYL)PROP-2-ENYLIDINE]-BARBITURIC ACIDS
30
25
20
15
10
132
COMPARATIVE STUDY OF ANTIMICROBIAL ACTIVITY WITH KNOWN ANTIBIOTICS [A] PART-VI Section - I : Antimicrobial activity of 5-[1'-Aryl-3'-(1"N,3"-diphenyl-4"-pyrazolyl)-prop-2'-enylidine]-barbituric acids Antibacterial activity Zone of inhibition in m.m. B. mega
8c (21) 8k (22)

8d (20) 8l (21)
S. aureus
8e (22) 8i (23)
P vulgaris .
8c (19) 8j (20)
A. niger
8c (24) 8g (23) 8k (24)
23 22 24 25 -
22 23 17 24 -
21 21 23 19 -
15 18 17 20 -
25
133
MMMMMMMMMMMMMMMMM M
PART-VII STUDIES ON IMIDAZOLINONES
M MMMMMMMMMM
Imidazolinones... 134
INTRODUCTION
T he five membered heterocyclic ring system 5-oxo-imidazolines have two

nitrogen atom at 1- and 3-positions and a carbonyl group at 5-position.
N O N H
(I) The discovery of the 2-substituted-5-imidazolines dates back to the year 1888, when A. W. Hoffman 425 for the first time discovered 5-oxo-imidazoline by heating N'-diacetylethylene diamine in a stream of dry hydrogen chloride. Moreover, some compounds were prepared by A. Ladenburg 426 by the fusion of two equivalents of sodium acetate with one equivalent of ethylene diamine dihydrochloride. SYNTHETIC ASPECT Various methods have been reported for the synthesis of imidazolinones in literature 427 . Aminolysis of oxazolone with amine leads to the formation of imidazolinones which has been reported in literature 428 . 1. A. Saxena et. al. 429 have synthesised new imidazolinones (II).
O Ar Cl N O O dry pyridine N Cl N NH2 NH Ar O O
NH
(II)
Imidazolinones... 135 2. 3. Allimony et. al. 430 have synthesised (II) new imidazolinone derivatives by conventional method. Feng-Jun-Cai et. al. 431 have synthesised 5-imidazolinone derivatives by microwaves irradiation. MECHANISM Azalactone reacts with variety of compounds such as water, alcohols, amines and hydrogen halides. Amides of -acylamino acryclic acids obtained from the condensation of azalactone and primary amine can be converted to imidazolinones as shown in equation (III).
R O N R O HN R'-NH2 X (b) NH O R' POCl 3 X (c) N R O
O X (a)
N R'
R' - NH2, Dry C 5H5N / Abs. C 2H5OH, K 2CO3
(III) The ring closer can be effected under a variety of conditions. Substituted anilides have been converted to imidazolinone derivatives by the action of POCl 3 . THERAPEUTIC IMPORTANCE Naphazoline hydrochloride, xylometazoline hydrochloride etc. are various imidazolinone derivatives which have been used as adrenergic stimulants and t o l a z o l i n e a n d p h e n o t o l a m i n e a s a d re n e r g i c b l o c k i n g a g e n t s . Va r i o u s imidazolinones are known to exhibit a broad spectrum of biological activities such as,
Imidazolinones... 136 1. 2. 3. 4. 5. 6. 7. 8. 9. Antitubercular 432 Potent CNS depressant 433,434 Insecticidal 435 Antiviral 436 Hypertensive 437 Antiinflammatory 438-440 Glucagon antagonists 441 Antimicrobial 442
Thrombin inhibitor 443 10. Anticonvulsant 444,445 11. Sedative and hypnotics 446 12. Bactericidal 447,448 13. Fungicidal 449,450 14. Antiparkinsonian 451,452 15. Anthelmintic 453 16. Antihistaminic 454 17. Anticancer 455,456 18. Antidiabatic 457 K. K. Awasthi et. al. 458 (IV) have synthesised some new imidazolinone derivatives and reported their antimicrobial activity.
R O S N N NH H3C CH3
NH
(IV) Farmshow Christopher Geoffrey et. al. 459 and Pilkington et. al. 460 have synthesised and studied antifungal activity of imidazolinones. L. Joseph Peter
Imidazolinones... 137 and co-worker 461 have prepared substituted imidazolinones which inhibited the abnormal cell growth in human body. Stefama Lauter and Co-worker 462 have isolated imidazoline from different methods and tested for the treatment of cytokine release. Imidazoline derivatives have been prepared by DecleraArthur and co-worker 463 showing anti-HIV activity. Ding, Ming-Wu et. al. 464 have prepared novel imidazolines and reported their antifungal activity. Kolhe Vishnu et. al. 465 have reported anti-AIDS, antibacterial and fungicidal activity of 5-oxo-imidazolines. B. R. Shah and co-worker 466 have prepared some new imidazolines and reported anticancer and anti HIV activity. U. Akyoshi et. al. 467 have prepared some new imidazolinone derivatives (V) and reported their herbicidal activity. Agrochemical activity of imidazolinones have been reported by Bascou and co-workers 468 .
N H3C
N NH
O H N
CH3
CH3
(V)
CH3
Rama Sharma and co-workers 469 have reported antimicrobial activity of 5-oxo-imidazolines (VI).
R2 H N N N N N
R1 N
(VI)
R3
Imidazolinones... 138 CONTRIBUTION FROM OUR LABORATORY Parikh et. al. 470 have synthesised imidazolinones bearing thiazole as moderately active bactericidal and fungicidal. H. H. Parekh et. al. 471 have elaborated better activity for some imidazolinones with activated benzylidene group at 5-position. Recently, Dr. H. H. Parekh et. al. 472 suggested imidazolinones as a antitubercular, anticancer (VII).
H3C O NH S O CH3 NH N N Ar
(VII) H. H. Parekh and co-worker have synthesised imidazolinone derivatives having isoniazide 473 and s-triazine 474 moiety. Imidazolinones bearing aminobenzylamino 475 , chloramphenicol 476 and phthalazine 477 moiety at 1position have been demonstrated as a antimicrobial agents by A. R. Parikh and co-workers (VIII). General structure for above references are under.
Z O R N N X Y OH
(VIII)
X = NH 2 / Aryl-CO-NH/Aryl- ;
CH2OH
Imidazolinones... 139
O HN NH N
;
N N N
NH C 2H5
;
HN N N
NH
O N N CH3
Y = CH 3 / C 6 H 5 , Z = H, R = Aryl
A. R. Parikh et. al. have synthesised imidazolinones bearing phthalazine 478, 2-base of chloramphenicol 479 moiety at one position which were evaluated for their antimicrobial activity. Parikh et. al. 480 have reported 4-(4'-Arylidine-2'phenyl-5'-oxo-imidazolin-1-yl) benzophenones which were screened for their antimicrobial activity. Biplabde et. al. 481 have reported some new 5-oxoimidazoline as antimicrobial agents. Imidazolinones have been reported to possess antioxidant activity. Moreover, A. R. Parikh, H. H. Parekh and co-workers have synthesised the newer 5-oxo-imidazolines with different variety of activities described as under. 1-p-(4'-Acetamidobenzenesulphonamido) phenyl-2-phenyl-4-substituted benzal-5-oxoimidazolines 482 . Synthesis of biologically active 5-oxo-imidazolines 483-485 . Preparation and antimicrobial activity of 1-N-Aryl-2-methyl-4'-(8-hydroxy quinolin-7'-yl)-methine-5-oxoimidazolines 486 . Synthesis of some 5-imidazolinones as novel bioactive compounds derived from benzimidazole 487 . Synthesis and biological screening of 2-Chloro-8-methylquinolin-3-yl-N(2'-phenyl-4'-arylidine-5'-oxo-imidazolin-1'-yl)-azomethines 488 .
v v
Imidazolinones... 140 Moreover Yoneda Naoto et. al. 489 have synthesised imidazolinones as antihypertensive agent. R. C. Dage et. al. 490 have synthesised cardiotonic imidazolones. Armando Rossello et. al. 491 have synthesised imidazolones as antifungal agent. Cooper A. B. and co-workers 492 have found that imidazolones are inhibitors of farnesyl proteing transferase. Machii Daisuke et. al. 493 have synthesised new imidazolones as a telomerase inhibitors and antitumor agents. Jean M. R. et. al. 494 have synthesised imidazolones and tested as antileishmanial agent. Chafiq Hamdouchi et. al. 495 have synthesised imidazolinones and screened for their potent and broad spectrum activity. Irene M. L. et al. 496 have synthesised imidazolinones and tested as antireteroviral activity (IX).
CH3 H3C O N O NH2
N H
Cl
Cl
(IX) Xu Zhi-Feng et. al. 497 have synthesised imidazolinones as biological agent. With a view to getting better therapeutic agent, it was contemplated to synthesise imidazolinones to enhance the overall activity of resulting compounds which have been described as under. SECTION - I : SYNTHESIS AND BIOLOGICAL EVALUATION OF 1N-ARYL-2-ALKYL/ARYL-4-[1'N,3'-DIPHENYL-4'PYRAZOLYLMETHINO]-IMIDAZOLIN-5-ONES
141 SECTION - I SYNTHESIS AND BIOLOGICAL EVALUATION OF 1N-ARYL-2-ALKYL/ ARYL-4-[1'N,3'-DIPHENYL-4'-PYRAZOLYLMETHINO]-IMIDAZOLIN-5ONES Imidazolinones represent one of the most active classe of compounds having a wide spectrum of biological activities with an aim to getting better therapeutic agent. The preparation of 5-oxo-imidazolines of type (IX) have been undertaken by the condensation of azalactone with different aromatic amines as shown in reaction scheme.
N N N
R1-NH2 Pyridine
N O R2 R2 O N N O
Type (IX) R 1 = Aryl R 2 = Alkyl/Aryl
R1
The constitution of the synthesised products have been characterised by using elemental analyses, infrared and 1 H nuclear magnetic resonance spectroscopy and further supported by mass spectrometry. In mass spectrometry the m/z value indicate the molecular weight, i.e. when R=4-nitrophenyl, molecular weight=511, m/z=510 (m-1). All the compounds have been also evaluated for their antibacterial activity towards Gram positive and Gram negative bacterial strains and antifungal activity towards Aspergillus niger at a concentration of 40 g/ml. The biological activity of the synthesised compounds have been compared with standard drugs. Some compounds have been found to have good and equivalent activity as compared to the known antibiotics recorded on Page No. 149.
142 REACTION SCHEME
N N CHO
R2
NH CO
COOH
(CH3CO)2O CH3COONa
N N
N O R2 R1-NH2 Pyridine
N N
N N R2 R1
Type (IX)
R 1 = Aryl R 2 = Alkyl/Aryl
143
IR SPECTRAL STUDY OF 1N-(o-CHLOROPHENYL)-2-PHENYL-4-[1'N,3'-DIPHENYL4'-PYRAZOLYLMETHINO]-IMIDAZOLIN-5-ONE
100.0 %T 90.0 80.0 70.0 60.0 3267.2 50.0 40.0 30.0 20.0 2923.9 3057.0
Cl
N N
N N
808.1 900.7 956.6 773.4 983.6 1022.2 1361.7 617.2 1060.8 1718.5 756.0 1444.6 1201.6 1286.4 692.4 1105.1 1639.4 1539.1 1253.6 1596.9 1477.4 1504.4 750.0
-1
3250.0 2000.0 1750.0 1500.0 1250.0 1000.0 IMIDA 3,4-DI CHLORO
500.0 1/cm
(KBr disc)
Instrument : SHIMADZU-FT-IR 8400-Spectrophotometer; Frequency range : 4000-400 cm Vibration mode C-H str. C=C str. C-H i.p. def. C-H o.o.p. def. Pyrazole moiety Imidazolinone ring C=N str. C-N str. C=O str. C=N str. C-N str. C=C str. Chlorine C-Cl str. Frequency in cm Observed 3057 1504 1060 808 1596 1201 1718 1639 1253 2923 750 -1
Type Aromatic
Reported 3090-3030 1585-1480 1125-1000 835-810 1650-1580 1220-1020 1760-1655 1650-1580 1260-1220 2950-2850 800-750
Ref. 673 " " " 672 " 670 " " " "
144
PMR SPECTRAL STUDY OF 1 N -P H E N Y L - 2 - M E T H Y L - 4 - [ 1 ' N , 3 ' -D I P H E N Y L - 4 ' PYRAZOLYLMETHINO]-IMIDAZOLIN-5-ONE
a a c d e f b N N l N N H3C k j i g h m a a a
Internal Standard : TMS; Solvent : CDCl ; Instrument : BRUKER Spectrometer (300 MHz) 3 Signal Signal Position No. ( ppm) 1 2 3 4 5 6 2.26 7.17-7.22 7.25 7.35-7.59 7.67-7.70 7.91-7.99 Relative No. of Protons 3H 1H 1H 10H 2H 3H Multiplicity singlet triplet singlet multiplet multiplet multiplet -CH Inference
CHd CHm CH a,e,c,h,j,i CH g,k CH b,f,l
a a c d e f b N N l N N H3C k j i g h m a a a
O N N N N
m/z = 510 (m-1)
+
SB- 11 o
+ +
N N o m/z = 107 NH NH2 o N O N N NH2 m/z = 209 m/z = 473 O m/z = 115 HN NH H3C
+
o
+
o
N N
N N N H m/z = 347
+
o
O O N
+
H2N m/z = 459 N NH O N N O N
+ -
NH
+
o
H N N N O m/z = 363 N H
+
o
N m/z = 511 (M - 1)
m/z = 317
+
O N
+
o
-
+ + +
N o N m/z = 301 N N N H N N o
+
o NH H N O H N
N HN
m/z = 193
+
o N
N O
-
NH
N O
HN m/z = 149 N H N H m/z = 165
H3C m/z = 279 m/z = 235
146
147 EXPERIMENTAL SYNTHESIS AND BIOLOGICAL EVALUATION OF 1N-ARYL-2-ALKYL/ ARYL-4-[1'N,3'-DIPHENYL-4'-PYRAZOLYLMETHINO]-IMIDAZOLIN-5ONES [A] Synthesis of 1N,3-Diphenyl-4-formyl-pyrazole See [A] Part-I, Section-I (B). [B] Synthesis of 2-Methyl-4-[1'N,3'-diphenyl-4'-pyrazolylmethino]oxazolin-5-one A mixture of 1N,3-Diphenyl-4-formyl pyrazole (6.2 g, 0.025 M), acetic anhydride (7.6 g, 0.075 M) and sodium acetate (2.0 g) was heated on a waterbath for 4 hrs. Resulting mass was poured into ice cold water, filtered and crystallised from DMF. Yield, 65% (2.1 g), m.p. 194 o C. [C] S y n t h e s i s of 1 N -P h e n y l - 2 - m e t h y l - 4 - [ 1 ' N , 3 ' - d i p h e n y l -
4'-pyrazolylmethino]-imidazolin-5-one A mixture of 2-Methyl-4-[1'N,3'-diphenyl-4'-pyrazolyl-methino]-oxazolin5-one (3.27 g, 0.01 M) and aniline (0.93 g, 0.01 M) in dry pyridine (20 ml) was refluxed for 12 hrs. in oil bath. Resulting mass was poured into crushed ice and neutralised with HCl, filtered and crystallised from dioxan. Yield, 2.8 g, (69%), mp. 123 o C. (C 20 H 20 N 4 O ; Requires : C, 59.41; H, 4.95; N, 13.85%; found : C, 59.40; H, 4.90; N, 13.80%). TLC solvent system Acetone : Benzene (4:6). Similarly other imidazolin-5-one have been prepared. The physical constants are recorded in Table No. 9. [D] Antimicrobial activity of 1N-Aryl-2-alkyl/aryl-4-[1'N,3'-diphenyl-4'pyrazolylmethino]-imidazolin-5-ones Antimicrobial activity was carried out as described in [A] Part-I, Section-I (D). The zone of inhibition of the test solutions are recorded in Graphical Chart No. 9.

9a 9b 9c 9d 9e 9f 9g 9h 9i 9j 9k 9l 9m
P H Y S I CA L C O N S TA N T S O F 1 N -A RY L - 2 -A L KY L / A RY L - 4 - [ 1 ' N , 3 ' -D I P H E N Y L - 4 ' -P Y R A Z O LY L METHINO]-IMIDAZOLIN-5-ONES R2 3

-CH -CH -CH 3 3
R1 2
C H 6 5 4-Cl-C H 6 4 4-NO -C H 2 6 4 C H 6 5 2-CH -C H 3 6 4 4-CH -C H 3 6 4 2-OCH -C H 3 6 4 4-OCH -C H 3 6 4 4-F-C H 6 4 2-Cl-C H 6 4 2-NO -C H 2 6 4 3-NO -C H 2 6 4 4-NO -C H 2 6 4
Molecular Formula 4
H ON 20 20 4 C H ON Cl 26 19 4 C H O N 26 19 3 5 C H ON 31 22 4 C H ON 32 24 4 C H ON 32 24 4 C H O N 32 24 2 4 C H O N 32 24 2 4 C H ON F 31 21 4 C H ON Cl 31 21 4 C H O N 31 21 3 5 C H O N 31 21 3 5 C H O N 31 21 3 5 C
Molecular Weight 5
404 438.5 449 446 480 480 496 496 484 500 511 511 511
M.P. o C 6
123 163 196 213 185 173 210 196 178 183 193 211 218
Rf * Value 7
0.68 0.55 0.71 0.63 0.57 0.65 0.54 0.64 0.55 0.70 0.58 0.71 0.63
Yield % 8
69 67 68 65 61 75 68 60 63 73 68 66 71

13.85 12.77 15.58 12.01 11.66 11.66 11.28 11.28 11.56 11.18 13.69 13.69 13.69 13.83 12.70 15.53 12.03 11.62 11.63 11.23 11.24 11.51 11.13 13.71 13.63 13.65
3 -C H 6 5 -C H 6 5 -C H 6 5 -C H 6 5 -C H 6 5 -C H 6 5 -C H 6 5 -C H 6 5 -C H 6 5 -C H 6 5
9a, 9b, 9c, 9f, 9g, 9k, 9j : Acetone : Benzene (4 : 6). 9d, 9e, 9h, 9i, 9l, 9m : Hexane : Ethyl acetate : (4 : 6).
148
GRAPHICAL CHART NO. 9 : ANTIMICROBIAL ACTIVITY OF 1N-ARYL-2-ALKYL/ARYL-4-[1N,3-DIPHENYL4-PYRAZOLYLMETHINO]-IMIDAZOLIN-5-ONES
30
25
20
15
10
149
COMPARATIVE STUDY OF ANTIMICROBIAL ACTIVITY WITH KNOWN ANTIBIOTICS [A] PART-VII Section - I : Antimicrobial activity of 1N-Aryl-2-alkyl/aryl-4-[1'N,3'-dipheyl-4'-pyrazolylmethino]-imidazolin5-ones Antibacterial activity Zone of inhibition in m.m. B. mega
9c (20) 9j (21)

9d (23) 9m (20)
S. aureus
9e (22) 9i (20)
P vulgaris .
9g (19) 9k (20)
A. niger
9c (23) 9g (23) 9m (22)
23 22 24 25 -
22 23 17 24 -
21 21 23 19 -
15 18 17 20 -
25
150
MMMMMMMMMMMMMMMMM M
PART-VIII STUDIES ON THIAZOLIDINONES
M MMMMMMMMMM
Thiazolidinones... 151
INTRODUCTION
T hiazolidinones,
which belong to an important group of heterocyclic
compounds have been extensively explored for their applications in the field of medicine. Thiazolidinones, with a carbonyl group at position 2 (I), 4 (II) or 5 (II) have been subjected of extensive study in the recent past. Numerous reports have appeared in the literature which highlight their chemistry and use.
H N O
O NH S
O S
H N
(I)
(II)
(III)
4-Thiazolidinones are derivatives of thiazolidine with carbonyl group at 4position (II). Substituent in the 2, 3 and 5 positions may be varied, but the greatest different in structure and properties is exerted by the groups attached to carbon atom at the 2-position and to nitrogen atom at the 3-position. The cyclic structure was assigned after recognisation of mercaptoacetic acid as a primary product of hydrolysis of 3-phenyl-2-phenylimino-4-thiazolidinones 498 . SYNTHETIC ASPECT Several method for the preparation of 4-thiazolidinones are narrated in literature 499-507 1. R. Nath and K. Shanker 508 have prepared 4-thiazolidinone by cyclization of N-aryl-N'-(2'-pyridyl)-thiocarbamide with chloroacetic acid.
O
NH N S NH R
Cl.CH2COOH N
N S N R
(IV)
Thiazolidinones... 152 2. I. D. Shah and J. P. Trivedi 509 synthesised thiazolidinones from 4-aryl thiosemicarbazones by condensing them with chloroacetic acid, -bromopropionic and -bromophenyl acetic acid.
R NH R' S NH N R'' R-CH-COOH Br O N N N R'' S
(V)
R' R' = H, Ph, CH3, R'' = Aryl
3.
M. Seeda et. al. 510 have synthesised some new thiazolidinones.

Ph NH Ph S NH2 N ClCH2COOH HN O Ph N S R N SO2 Ar O SO2Cl R = Aryl S Ar.CHO HN O Ph N S
Ar
(VI) MECHANISM
R = Aryl
The reaction of 4-thiazolidinones proceeds by the attacks of the chloroacetic acid upon the C=S group, the tautomerism takes place with removal of HCl followed by removal of water and subsequent cyclization.
OH Cl NH R S NH R R SH HOOC N R N S O R' O R'-CHO R R N S -H2O N R NH N R -HCl O S N R HN R
Thiazolidinones... 153 THERAPEUTIC IMPORTANCE Much research has been carried out with the aim to finding therapeutic values of thiazolidinone moiety since their discovery. The thiazolidinones, substituted at 2- and 3-position are reported to exhibit a wide variety of biological activities. 1. 2. 3. 4. 5. 6. 7. 8. 9. Anthelmintics511,512 Cardiovascular 513 Mosquito repellent 514 Antiviral 515 Hypnotic516-518 Antifungal519-521 Antitumor 522 Antiulcer 523,524
Local anaesthetic 525 10. Antimicrobial 526,527 11. Antibacterial 528,529 12. Antitubercular 530,531 13. Anti HIV and anticancer 532 14. Antidiabetic 533 15. Insecticidal 534 16. Herbicidal 535 Hassan et. al. 536 have prepared 2-imino-4-thiazolidinones which have been found to possess antimicrobial activity. K. Mogilaiah and co-workers 537,538 isolated some 4-thiazolidinone derivatives and tested their antibacterial activity. G. S. Godaginamath et. al. 539 also prepred thiazolidinone derivatives as antimicrobial agent. R. S. Lodhi and co-worker 540 have been synthesised and studied antimicrobial, antiinflammatory and analgesic proper ty of 4-thiazolidinone and arylidene derivatives (VIII).
Thiazolidinones... 154
R1 S
NH N N O
(VII)
Z R1 = (un) substituted aryl Z = H2 Z = CH2R2 R1,R2 = Substituted aryl
Pawar and co-worker 541 reported synthesis and in vitro antibacterial activity of some 4-thiazolidinone derivatives. Goel et al. 542 have synthesised thiazolidinone derivatives and compared their antiinflammatory activity, ulcerogenic liability, cardiovascular and CNS effects. In other study, some thiazolidinones have been found to be promising antibacterial agent 543,544 . Siddique, Mohammed et. al. 545 have prepared substituted thiazolidinones and reported their antinbacterial, antifungal, antithyroid and amoebicidal properties (IX).
R2 R5 O N R1 S S R4 R3
(VIII)
R1 = OH; R2, R4, R5 = H; R3 = Me
CONTRIBUTION FROM OUR LABORATORY Parikh et. al. have used diphenylsulphone 546,547 , substituted aryl 548558, arsenoic acid559, 2-aryl-1,3,4-thiadiazole560, 2-benzyl-1,3,4thiadiazol561,562, picolinylamino563, s-triazine564, benzoylamino acetamido 565 , sulphonamidobenzoylamino 566 , phthalazin-1-yl-amino 567 , moieties at 3-position (X) of 4-thiazolidinone ring. They have prepared
Thiazolidinones... 155 t h i a z o l i d i n o n e w i t h s u b s t i t u t e d a r y l , s u b s t i t u t e d h y d r ox y a r y l , , ' dichloroethylaminophenyl, 8-hydroxyquinolinyl moiety at 2-position (R) of 4thiazolidinone ring system. H. H. Parekh and co-workers have synthesised 4-thiazolidinones having dapson 568-573 , s-triazine 574-577 , acridin 578,579 , thymoloxyacetamido 580 , 6-hydroxypyridine 581,582 moiety at 3-position (X) of 4-thiazolidinone ring system. Parikh A. R. et. al. 583 have reported bactericidal and fungicidal activity of 4-thiazolidinones, Parekh & co-worker 584 have synthesised 2-Aryl-3-pacetamidophenoxyacetamido-5H/methyl-4-thiazolidinones which showed antitubercular activity. General structure for above references are as under.
Z X N R S
Y O N
X=
SO 2
;
S NH
CONH
N N NH Aryl N
NH
Aryl
OCH2CONH
Y = H, CH , CH COOH 3 2 Z = H, CH , C H 3 6 5 R = Aryl
Thiazolidinones... 156 Akama Tsutoma et. al. 585 have synthesised thiazolidinones as a Telomerase inhibitors. S. Guniz Kucukguzel et. al. 586 have synthesised thiazolidinone as antimicrobial and anticancer agent. S. K. Srivastava et. al. 587 have prepared new thiazolidinone as antibacterial, antifungal, analgesic and diuretic agents. Recently, Fujiwara Norio et. al. 588 have synthesised thiazolidinones as antiinflammatory agent. Pfahl Magnus et. al. 589 have synthesised thiazolidinones and tested their phosphatase inhibitory and anticancer activity. Jag Mohan et . al. 590 have prepared antimicrobial thiazolidinones (X).
R H N S N H O O
(IX)
R = H, alkyl
Govindarajan R. et. al.591 have synthesised thiazolidinones as antitubercular, antifungal and antibacterial agent. Dinh T. T. H et. al. 592 have prepared antibacterial and antifungal thiazolidinones. Takagi Masae and co-worker 593 have synthesised thiazolidinones and screened for their antiinflammatory activity. Ma Tonghui et. al. 594 have synthesised thiazolidinones as CFTR (cystic fibrosis transmembrane conductance regulator) inhibitor. These valid observations led us to explore thiazolidinone chemistry by synthesising its derivatives bearing pyrazole moiety of medicinal value in order to achieve better therapeutic agents. It has been described in the following section. SECTION - I : SYNTHESIS AND BIOLOGICAL EVALUATION OF 2 -A RY L I M I N O - 3 N - A R Y L - 5 - [ 1 ' N , 3 ' -D I P H E N Y L 4'-PYRAZOLYLMETHINO]-4-THIAZOLIDINONES
157 SECTION - I SYNTHESIS AND BIOLOGICAL EVALUATION OF 2-ARYLIMINO-3NA R Y L - 5 - [ 1 ' N , 3 ' - D I P H E N Y L - 4 ' - P Y R A Z O LY L M E T H I N O ] 4-THIAZOLIDINONES With a view to getting better therapeutic agents and considering the association of various biological activities of thiazolidinone heterocycles, the preparation of arylidenes of type (X) have been undertaken by the condensation of 1N,3-Diphenyl-4-formyl pyrazole with different 2-Arylimino-3N-aryl-5H-4thiazolidinones.
Type (X)
R = Aryl
The constitution of the synthesised products have been characterised by using elemental analyses, infrared and 1 H nuclear magnetic resonance spectroscopy and mass spectrometry also. In mass spectrometry the m/z value indicate the molecular weight, i.e. when R=p-Tolyl, molecular weight=526, m/ z=527 (m+1). All the compounds have been also evaluated for their antibacterial activity towards Gram positive and Gram negative bacterial strains and antifungal activity towards Aspergillus niger at a concentration of 40g/ml. The biological activity of the synthesised compounds have been compared with standard drugs. Some compounds have been found to have good and equivalent activity as compared to the known antibiotics recorded on Page No. 166.
158 REACTION SCHEME

R NH2
C S S EtOH
H2N
NH R S
NH R
ClCH2COOH gla. CH3COOH CH3COONa N R N S O (I) R
N N N R
+
CHO O
N S
gla. CH3COOH CH3COONa
N N
Type (X)
R = Aryl
159
IR SPECTRAL STUDY OF 2-p-TOLYLIMINO-3N-(p-TOLYL)-5-[1'N,3'-DIPHENYL4'-PYRAZOLYLMETHINO]-4-THIAZOLIDINONE
100.0 %T 80.0 2852.5 2920.0 3024.2 3057.0

N N
457. 570.9 671.2 867.9 736.8 509.2 542.0 954.7 817.8 887.2 651.9 617.2 688.5 758.0
60.0
1415.7 1706.9 1535.2 1598.9 1502.4

CH3
40.0
O
1018.3 1269.1 1442.7 1051.1 1211.2 1109.0 1143.7
20.0
H3C
1633.6
1365.5 500.0 1/cm

(KBr disc)
0.0
3250.0 2000.0 1750.0 1500.0 1250.0 1000.0 750.0 P T Arylidine

I Instrument : SHIMADZU-FT-IR 8400-Spectrophotometer; Frequency range : 4000-400 cm Vibration mode C-H str. (sym.) C-H str. (asym.) C-H i.p. def. C-H o.o.p. def. C-H str. C=C str. C-H i.p. def. C-H o.o.p. def. C=N str. C-N str. C=O str. C-S-C str. C-O-C str. (sym.) C-O-C str. (asym.) C-N str. C=N str. Frequency in cm Observed 2920 2852 1442 1365 3020 1502 1109 817 1598 1211 1706 617 1018 1269 1143 1633 -1 -1
Type Alkane
Reported 2975-2950 2880-2860 1470-1435 1395-1370 3090-3030 1585-1480 1125-1000 835-810 1640-1600 1230-1020 1760-1655 700-600 1075-1020 1275-1200 1220-1020 1640-1590
Ref. 670 " " " 672 " " " 671 " 675 " " " " "
Aromatic
Pyrazole moiety Thiazolidinone ring
160
PMR SPECTRAL STUDY OF 2-p-TOLYLIMINO-3N-(p-TOLYL)-5-[1'N,3'-DIPHENYL4'-PYRAZOLYLMETHINO]-4-THIAZOLIDINONE
f g e j h i k O b a N H3C b' S c a' N d l j j j j
c'
d'
CH3
Internal Standard : TMS; Solvent : DMSO.d + CDCl ; Instrument : BRUKER Spectrometer (300 MHz) 6 3 Signal Signal Position No. ( ppm) 1 2 3 4 5 6 7 8 9 10 11 2.35 2.41 6.84-6.87 7.15-7.18 7.33 7.35 7.45-7.53 7.64-7.67 7.72 7.8-7.85 8.28 Relative No. of Protons 3H 3H 2H 2H 4H 1H 5H 2H 1H 2H 1H Multiplicity singlet singlet doublet doublet singlet doublet multiplet doublet singlet triplet singlet Inference Ar-CH 3 Ar-CH 3 CHaa' CHbb' CH c,c'd,d' Chg CHj CH f,h CHl CH e,i CHk J Value In Hz J=8.7 J=8.7 -
f g e j h i k O b a N H3C b' S c a' N d l j j j j
c'
d'
CH3
N H3C
m/z = 527 (m+1)
CH3
SB- 6
+
o N N
+
o N N
+
o
O N NH
HN N m/z = 276 H2N m/z = 221
m/z = 460
H3C
HN
NH
+
O H N N o
H3C
+
o N N m/z = 244 N
O N
N N m/z = 165
S
+
+
1) o
m/z = 527 (M
NH
NH H3C
SH
+
o N
NH
+
o
H3C m/z = 258 NH m/z = 107
+
NH2 o H3C m/z = 120 N m/z = 470
162
163 EXPERIMENTAL SYNTHESIS AND BIOLOGICAL EVALUATION OF 2-ARYLIMINO3 N - A R Y L - 5 - [ 1 ' N , 3 ' - D I P H E N Y L - 4 ' - P Y R A Z O LY L M E T H I N O ] 4-THIAZOLIDINONES [A] Synthesis of N-Phenylamino- -methyl-phenyl azomethine See [A] Part-I, Section-I (A). [B] Synthesis of 1N,3-Diphenyl-4-formyl pyrazole See [A] Part-I, Section-I (B). [C] Synthesis of Bis-p-tolylthiourea 595 A mixture of p-toludine (2.14 g, 0.02 M) and carbondisulphide (0.76 g, 0.01 M) in absolute ethanol was heated at 40 oC in waterbath for 12 hrs. The product solidified on completion of reaction, the excess of the solvent was removed by distillation. The crude product was treated with dil. HCl, isolated and cr ystallised from rectified spirit. Yield, 4.1 g (80%), m.p. 154 o C. (C 15 H 16 N 2 S; Requires C, 70.31; H, 6.25; N, 10.93%; found : C, 70.32; H, 6.27; N, 10.95%). [D] Synthesis of 2-p-Tolylimino-3-(p-tolyl)-5H-4-thiazolidinone 596 A mixture of Bis-p-tolylthiourea (2.54 g, 0.01 M), chloroaceticacid (0.95 g, 0.01 M) and sodium acetate (1.23 g, 0.015 M) in glacial acetic acid (30 ml) was refluxed in oil bath for 10 hrs. The reaction product was poured into ice, kept overnight, crude product was isolated, crystallised from glacial acetic acid. Yield, 2.35 gm (80%), m.p. 145 o C. (C 17 H 16 N 2 OS; Requires C, 68.91; H, 5.40; N, 9.45%; found : C, 68.92; H, 5.44; N, 9.47%).
164 [E] Synthesis of 2-p-Tolylimino-3N-(p-tolyl)-5-[1'N,3'-diphenyl-4'pyrazolylmethino]-4-thiazolidinone A m i x t u re o f 1 N , 3 -D i p h e n y l - 4 - f o r m y l p y r a z o l e ( 2 . 4 8 g , 0 . 0 1 M ) , 2-p-tolylimino-3-(p-tolyl)-5H-4-thiazolidinone (2.96 g, 0.01 M) and fused sodium acetate (0.9 g, 0.01 M) in glacial acetic acid was refluxed for 8 hrs. The solid thus obtained was filtered, washed, dried and crystallized from DMF. Yield, 3.7 g (71%) , m.p. 210 o C. (C 33 H 26 N 4 OS ; Requires : C, 75.29; H, 4.94; N, 10.64%; found : C,75.32; H, 4.90; N, 10.67%). TLC solvent system, Acetone : Benzene (2:8). Similarly other arylidines or thiazolidinones were prepared. The physical data are recorded in Table No. 10. [F] Antimicrobial activity of 2-Arylimino-3N-aryl-5-[1'N,3'-diphenyl-4'pyrazolylmethino]-4-thiazolidinones Antimicrobial testing was carried out as described in [A] Part-I, Section-I (D). The zone of inhibition of the test solutions are recorded in Graphical Chart No. 10.
TABLE NO. 10 Sr. No. 1

10a 10b 10c 10d 10e 10f 10g 10h 10i 10j 10k 10l 10m
P H Y S I CA L C O N S TA N T S OF 2 -A RY L I M I N O - 3 N -A RY L - 5 - [ 1 ' N , 3 ' -D I P H E N Y L 4'-PYRAZOLYLMETHINO]-4-THIAZOLIDINONES Molecular Formula 3

C H N OS 31 22 4 C H N OSCl 31 20 4 2 C H N OSCl 31 20 4 2 C H N OSF 31 20 4 2 C H N OS 33 26 4 C H N OS 33 26 4 C H N OS 33 26 4 C H N O S 33 26 4 3 C H N O S 33 26 4 3 C H N O S 33 22 4 5 C H N O S 31 20 6 5 C H N O S 31 20 6 5 C H N O S 31 20 6 5
R 2
C H 6 5 2-Cl-C H 6 4 4-Cl-C H 6 4 4-F-C H 6 4 2-CH -C H 3 6 4 3-CH -C H 3 6 4 4-CH3-C H 6 4 2-OCH -C H 3 6 4 4-OCH -C H 3 6 4 4-COOH-C H 6 4 2-NO -C H 2 6 4 3-NO -C H 2 6 4 4-NO -C H 2 6 4
Molecular Weight 4
498 567 567 534 526 526 526 558 558 586 588 588 588
M.P. o C 5
193 196 188 192 186 143 210 219 188 185 180 173 195
Rf * Value 6
0.58 0.56 0.65 0.54 0.61 0.63 0.49 0.65 0.70 0.70 0.52 0.51 0.63
Yield % 7
83 73 64 62 68 70 71 69 63 75 65 64 63

11.24 10.51 10.51 10.49 10.64 10.64 10.64 10.03 10.03 9.55 14.28 14.28 14.28 11.23 10.50 10.48 10.53 10.65 10.63 10.67 10.01 10.07 9.53 14.29 14.25 14.30
165
ANTIMICROBIAL ACTIVITY OF 2-ARYLIMINO- 3N-ARYL-5-[1N,3-DIPHENYL4-PYRAZOLYLMETHINO]- 4- THIAZOLIDINONES
30
25
20
15
10
166
COMPARATIVE STUDY OF ANTIMICROBIAL ACTIVITY WITH KNOWN ANTIBIOTICS [A] PART-VIII S e c t i o n - I : A n t i m i c r o b i a l a c t i v i t y o f 2 -Ar y l i m i n o - 3 N - a r y l - 5 - [ 1 ' N , 3 ' - d i p h e n y l - 4 ' - p y r a z o l y l m e t h i n o ] - 4 thiazolidinones Antibacterial activity Zone of inhibition in m.m. B. mega
10d (22) 10j (20) 10l (21) Ampicillin Amoxicillin Norfloxacin Penicillin Greseofulvin 23 22 24 25 22 23 17 24 -

10d (20) 10h (21) 10k (19) 21 21 23 19 -
S. aureus
10b (22) 10h (22)
P vulgaris .
10b (19) 10d (20) 10m (18) 15 18 17 20 -
A. niger
10b (21) 10f (20)
25
167
MMMMMMMMMMMMMMMMM M
PART-IX STUDIES ON ACETONITRILES
M MMMMMMMMMM
Nitriles... 168
INTRODUCTION
N itriles are reported to possess various therapeutic activities, but due to

their high toxicity, they have low therapeutic importance. The term 'Nitrile' was first introduced by Febung 597 in 1844. The first synthesis of nitrile has been reported by Wohler and Liebig 598 in 1832 and Poleuze 599 in 1834. They are very much useful as intermediates for various products such as acrylonitrile for plastic, synthetic rubber and fibers, phthalonitrile for dye stuff. SYNTHETIC ASPECT D. Mowry 600 reviewed various methods of preparation of nitriles. Few recent methods are as mentioned below. 1. 2. 3. 4. From halides using NaCN; Al 2 O 3 601 From alkylhalides using KCN tetra alkyl ammonium salt 602 and water in trace. The pyrolysis of schiff's base 603 Mohanakrishna A. K. and co-worker 604 have synthesised nitrile derivatives of type (I) is as under.
S S S N S
(I)
Nitriles... 169 MECHANISM : The mechanism of nitrile is shown as under.

R H O R O H
-
CN
:
CN
H R1 R1-NH2 CN H -H2O H R OH
HN R
CN
THERAPEUTIC EVALUATION 1. 2. 3. 4. 5. 6. 7. 8. They shows various therapeutic activities, which are described as under. Antihypertensive 605 Central Nervous System agent 606 Antimicrobial 607 Antihypoxic 608 Antiinflammatory 609,630 Antiarrythemic 610 Pesticidal 611,631,632 Fungicidal 612
Cardenolide nitrile showed moderate biological activity in rats 613 . Nitriles, with fused pyridine ring were reported as elcer inhibitor 614 . Kobayashi Shigco et. al. 615 have synthesised new derivatives of nitriles. M. C. Dougal 616 have synthesised nitriles and studied their pharmacological activities. Lai Hio Kiong and co-workers 617 have reported nitriles (II) showing fungicidal activity.
Nitriles... 170
N R N (CH2)n R'
(II)
R = cycloalkyl, alkyl, alkenyl R' = Substituted aryl, alkyl and haloalkenyl
Volmajer Juliya et. al. 618 synthesised some new nitriles and reported them as anticonvulsant agent. Shibata Yasushi and co-workers 619 have synthesised nitrile derivatives associated with insecticides. Nosyrava et. al. 620 have prepared novel nitriles which have been shown to possess muscle relaxant activity. Yagihara and co-workers 621 have prepared nitriles which possess antimicrobial and antiinflammatory activity. Parlo Sanna et. al. 622 have synthesised nitriles and screened for their antitubercular activity (III). Iwanowicz E. J. et. al. 623 have prepared nitriles and found to preventing and treating IMPDH-associated disorders, such as transplant rejection and autoimmune disease.
N N N
CH3 S N
N H2N N NH2
(III)
(IV)
Collin Xavier and co-workers 624 have synthesised antifungal acetonitriles. Bhatnagar Neerja et. al. 625 have synthesised nitriles as inhibitors of Cathepsin K. Bernard M. et. al. 626 have synthesised nitriles as thromboxane receptor antagonists. Alwal K. S. et. al. 627 have prepared nitriles as inhibitors of mitochondrial F 1 F 0 ATpase. Recently, Mura Kami Hiroshi et. al. 628 have synthesised some new nitriles and screened for their pesticidal and marin antifouling activity (V).
Nitriles... 171
X BO R N H3C N N Y
(V) CONTRIBUTION FROM OUR LABORATORY F. M. Bharmal, D. J. Kaneria and H. H. Parekh 629 have synthesised newer acetonitriles bearing quinoline moiety and tested as antimicrobial agents (VI).
R HN
N N CH3 Cl
(VI)
R = Aryl
Looking to the interesting properties of nitriles, we have synthesised some new nitriles, which have been described as under. SECTION - I : SYNTHESIS AND BIOLOGICAL EVALUATION OF -ARYLAMINO-[1'N,3'-DIPHENYL-4'-PYRAZOLYL]ACETONITRILES
172 SECTION - I SYNTHESIS AND BIOLOGICAL EVALUATION OF -ARYLAMINO[1'N,3'-DIPHENYL-4'-PYRAZOLYL]-ACETONITRILES In view of therapeutic activities of nitriles, it was contemplated to synthesise some new nitriles in search of agents possessing higher biological activity. Nitriles of type (XI) have been synthesised by the reaction of 1N,3-Diphenyl-4-formylpyrazole with different aromatic amines by the presence of potassium cyanide and glacial acetic acid at 0-5 oC.
o
N N CHO
R-NH2, KCN, 0-5 C gl. CH 3COOH
N N R NH
Type (XI)
R = Aryl
The constitution of the synthesised products have been characterised by using elemental analyses, infrared and 1 H nuclear magnetic resonance spectroscopy and mass spectrometry also. In mass spectrometry the m/z value indicate the molecular weight, i.e. when R=p-Tolyl, molecular weight=364, m/z=365 (m+1). All the compounds have been also evaluated for their antibacterial activity towards Gram positive and Gram negative bacterial strains and antifungal activity towards Aspergillus niger at a concentration of 40g/ml. The biological activity of the synthesised compounds have been compared with standard drugs. Some compounds have been found to have good and equivalent activity as compared to the known antibiotics recorded on Page No. 179.
173
IR SPECTRAL STUDY OF -(p-TOLYLAMINO)-[1'N,3'-DIPHENYL-4'-PYRAZOYL]ACETONITRILE
100.0 %T 90.0 80.0 2916.2 3122.5 3024.2 70.0 60.0

N NH
2229.6 2854.5 457.
1616.2
N
50.0 3355.9 40.0

N CH3
812.0 1365.5 1596.9 914.2 1409.9 686.6 958.6 1452.3 597.9 1280.6 702.0 1500.5 1122.5 759.9 1215.1 1058.8 617.2 1521.7
3250.0 2000.0 1750.0 1500.0 1250.0 1000.0 750.0 P T Nitrile

I Instrument : SHIMADZU-FT-IR 8400-Spectrophotometer; Frequency range : 4000-400 cm Type Alkane Vibration mode C-H str. (sym.) C-H str. (asym.) C-H def. (asym.) C-H def. (sym.) Aromatic C-H str. C=C str. C-H i.p. def. C-H o.o.p. def. Pyrazole moiety Nitrile C=N str. C-N str. C=N str. N-H str. (sym.) Frequency in cm Observed 2916 2854 1409 1365 3045 1521 1122 812 1596 1058 2229 3355 -1 -1
500.0 1/cm
(KBr disc) Ref. 670 " " " 672 " " " 673 " 674 "
Reported 2975-2950 2850-2740 1470-1435 1390-1370 3090-3030 1520-1480 1125-1090 835-810 1640-1590 1120-1020 2240-2220 3350-3200
174
PMR SPECTRAL STUDY OF -(p-TOLYLAMINO)-[1'N,3'-DIPHENYL-4'-PYRAZOLYL]ACETONITRILE
d c i j k h N N l m g NH n a' b' CH3 a b f e
Internal Standard : TMS; Solvent : CDCl ; Instrument : BRUKER Spectrometer (300 MHz) 3 Signal Signal Position No. ( ppm) 1 2 3 4 5 6 7 8 9 2.3 5.39 6.7-6.73 7.09-7.2 7.32-7.37 7.39-7.47 7.49-7.52 7.7-7.79 8.32 Relative No. of Protons 3H 1H 2H 2H 1H 3H 2H 4H 1H Multiplicity singlet singlet doublet doublet multiplet multiplet triplet doublet singlet Inference Ar-CH CHn 3 J Value In Hz J=8.4 J=8.4 -
CH bb' CH aa' CHj CH e,f,d CH c,g CH h,i,k,l CHm
-NH not observed
d c i j k h N N l m g NH n a b a' b' CH3 f e
N N NH
CH3
m/z = 365 (m+1)
SB- 5 N N
+
o N N
+
o
+
NH m/z = 107 NH2 o
N BASE PEAK m/z = 258 H3C NH m/z = 338
CH3
+
o
+
o N N H3C
N N
NH CH3 m/z = 149 N
NH
CH3 m/z = 365 (M m/z = 231

+
1)
+
o
+
H3C CH3 o H3C
H3C CH3 NH
+
o
N N
m/z = 221 m/z = 120
176
m/z = 149
177 EXPERIMENTAL SYNTHESIS AND BIOLOGICAL EVALUATION OF -ARYLAMINO[1'N,3'-DIPHENYL-4'-PYRAZOLYL]-ACETONITRILES [A] Synthesis of N-Phenylamino- -methyl-phenyl azomethine See [A] Part-I, Section-I (A). [B] Synthesis of 1N,-3-Diphenyl-4-formyl pyrazole See [A] Part-I, Section-I (B). [C] Synthesis of -(p-Tolylamino)-[1'N,3'-diphenyl-4'-pyrazolyl]acetonitrile 1N,3-Diphenyl-4-formyl-pyrazole (2.48 g, 0.01 M) dissolved in ethanol (25 ml) was added to potassium cyanide (0.64 g, 0.01 M) disolved in water (5 ml) followed by glacial acetic acid (5 ml). The contents were then stirred for 5 minutes to form cyanohydrin at 0 o C. p-Toludine (1.07 g, 0.01 M) dissolved in methanol was added to the reaction mixture, contents were kept at room temperature for 24 hrs. and poured into ice. The solid product was crystallized from ethanol. Yield, 2.5 gm (69% ), m.p. 174 o C. (C 24 H 20 N 4 ; Requires : C, 79.12; H, 5.49; N, 15.37%; found : C, 79.10; H, 5.46; N, 15.34%). TLC solvent system Acetone : Benzene (3:7). Similarly other nitriles were prepared. The physical data are recorded in Table No. 11. [D] Antimicrobial activity of -Arylamino-[1'N,3'-diphenyl-4'-pyrazolyl]acetonitriles Antimicrobial testing was carried out as described in [A] Part-I, Section-I (D). The zone of inhibition of the test solutions are recorded in Graphical Chart No. 11.

11a 11b 11c 11d 11e 11f 11g 11h 11i 11j 11k 11l 11m
P H Y S I CA L C O N S TA N T S ACETONITRILES Molecular Formula 3

H N 23 18 4 C H N 24 20 4 C H N 24 20 4 C H N 25 22 4 C H ON 24 20 4 C H ON 24 20 4 C H N Cl 23 17 4 C H N Cl 23 17 4 C H N Cl 23 16 4 2 C H N Cl 23 16 4 2 C H O N 23 17 2 5 C H O N 23 17 2 5 C H O NS 23 17 2 C
OF
-A RY L A M I N O - [ 1 ' N , 3 ' -D I P H E N Y L - 4 ' -P Y R A Z O LY L ] M.P. o C 5

118 179 174 211 186 178 210 >230 205 196 188 192 209
R 2
C H 6 5 3-CH -C H 3 6 4 4-CH -C H 3 6 4 2,3-(CH ) -C H 32 6 3 2-OCH -C H 3 6 4 4-OCH -C H 3 6 4 3-Cl-C H 6 4 4-Cl-C H 6 4 2,5-(Cl) -C H 2 6 3 2,6-(Cl) -C H 2 6 3 2-NO -C H 2 6 4 3-NO -C H 2 6 4 4-NO -C H 2 6 4
Molecular Weight 4
350 364 364 378 380 380.0 384.5 384.5 419 419 395 395 395
Rf * Value 6
0.58 0.63 0.49 0.64 0.50 0.65 0.52 0.66 0.54 0.68 0.56 0.70 0.58
Yield % 7
81 77 69 65 68 77 69 73 75 78 80 61 65

15.99 15.37 15.37 14.80 14.73 14.73 14.56 14.56 13.86 13.86 17.71 17.71 17.71 15.94 15.36 15.34 14.73 14.74 14.71 14.57 14.54 13.84 13.83 17.69 17.68 17.72
178
GRAPHICAL CHART NO. 11 : ANTIMICROBIAL ACTIVITY OF -ARYLAMINO-[1N,3 -DIPHENYL-4-PYRAZOLYL]ACETONITRILES
30
25
20
15
10
179
COMPARATIVE STUDY OF ANTIMICROBIAL ACTIVITY WITH KNOWN ANTIBIOTICS [A] PART-IX Section - I : Antimicrobial activity of -Arylamino-[1'N,3'-diphenyl-4'-pyrazolyl]-acetonitriles

11g (22) 11i (23)

11d (20) 11h (20) 11l (21)
S. aureus
11c (21) 11f (22) 11i (20) 11m (20)
P vulgaris .
11g (18) 11k (19)
A. niger
11c (23) 11g (24) 11k (23)
23 22 24 25 -
22 23 17 24 -
21 21 23 19 -
15 18 17 20 -
25
180
MMMMMMMMMMMMMMMMM M
[ B ]
STUDIES ON MICROWAVE INDUCED PYRAZOLINES SYNTHESIS
M MMMMMMMMMM
Microwave induced pyrazolines... 181
INTRODUCTION
T he microwave region of the electromagnetic spectrum lies between 1 cm

to 1 m and in order to avoid interfering with radar and telecommunication activities which operate within this region, most domestic and commercial microwave instruments operate at 2.45 GHz. The heating effect utilized in microwave assisted organic transformations is due in the main, to dielectric polarisation, although conduction losses can be important particularly at higer temperatures whilst the polarisability of a molecule (determined by the Debye equation) is the sum of a number of contributions, only dipolar and interfacial polarisation are impor tant to heating effects associated with microwave irradiation. When a molecule is irradiated with microwaves it rotates to align itself with the applied field. The frequency of a molecular rotation is similar to the frequency of microwave radiation and consequently the molecule continually attempts to realign itself with the changing field and energy is absorbed. It is particularly convenient that qualitertively, the larger the dielectric constant, the great the coupling with microwaves. Thus solvents such as water, methanol, DMF, ethyl acetate, acetone, chloroform, aceticacid and dichloromethane are all heated when irradiated with microwaves. Solvents such as hexane, toluene, diethylether, CCl 4 do not couple and therefore do not heat with microwave irradiation, although it is ofcourse possible to use mixtures comprising microwave active/microwave inactive solvents. POWER SOURCES The development of electron tubes including those for the most microwave range, has been a mature field. Today it is feasible to generate almost any desired power level for microwave frequencies of practical interest limited only by costs.
Microwave induced pyrazolines... 182 Power Sources in the millimeter wave rang are mostly in the category of extended interaction Klystrons or narrow band backward wave oscillators. They are quite expensive and suffer from low life and efficiency. The most dramatic evolution of a microwave power is that of the cooker magnetron for microwave ovens. These tubes generate well over 100 watt 2450 MHz into a matched load and exhibit a tube efficiency on the order of 70%. It is feasible to utilize a number of such tubes to generate large total power eq. 25 or 50 KW. APPLICATION IN ORGANIC SYNTHESIS The first application of microwave oven in organic synthesis began very recently in the first experiments, Gedye and then Giguere, provided evidence for dramatic accelerations in some classical organic reactions and these were described to temperature and pressure effects, when performed in closed teflon vessels. Since solvents were used in these experiments, some problems with safe operation appeared and explosion of solvent free reactions to solve these problems and to facillitate the scale up of preparative runs. Three types of solvent free procedures can be coupled with microwave activation. 1. Reaction between heat reactants, needing at least one polar molecule, as liquid-liquid or liquid solid systems. In this later case, reactions presumbly occur at the interface due to absorption of the liquid reactant at the surface of the solid one. 2. 3. Reaction between supported reagents on solid mineral supports in << dry media >> by impregnation of compounds on alumina, silicas or clays. Phase Transfer Catalysis (PTC) conditions in the absence of organic solvent, i.e. when a liquid reagent acts both as a reactant and an organic phase. This last methodology can be improved under sonochemical activation.
Microwave induced pyrazolines... 183 Microwave constitutes very original procedure for heating materials, clearly different from the classical ways. Their main advantages derive from the almost instantaneous "in core" heating of materials, in an homogeneous and selective manner. Especially those with poor neat conduction properties. This technique proves to be exellent in case where traditional heating has a fow efficiency because of poor heat transmission and hence local overheating is a major inconvenience. The main interests can thus be listed as the rapid transfer of energy into the bulk of the reaction mixture, without inertia since only the product is heated and the case of utilization. Furthermore, as the depth of penetration in materials in of the same order of magnitude as the wavelength, microwaves interact with substance of apprecialble thickness (about 10 cm). Sucessfully leading to the path way from non traditional approach to the experimental setup of organic reactions, the concept of "Microwave Induced Organic Reaction Enhancement" (MORE) chemistry has been utilized for rapid and efficient synthesis of pyrazolines which is described as under. PART - I : STUDIES ON PYRAZOLINES BY CONVENTIONAL AND MICROWAVE INDUCED SYNTHESIS
MMMMMMMMMMMMMMMMM M
PART-I
STUDIES ON PYRAZOLINES BY CONVENTIONAL & MICROWAVE INDUCED PYRAZOLINES SYNTHESIS
M MMMMMMMMMM
184 INTRODUCTION The use of domestic microwave oven in this regard is now a well established procedure in MORE 633 (Microwave Induced Organic Reaction Enhancement). It has been reported that the rate of variety of organic reaction such DielsAlder 634,635 , Claisan reaction 636,637 , oxidation 638-640 , reduction 641 , diacetylation 642,643 , deacetylation 644 , esterification 645 , hydrolysis of esters 646,647 , Doener condensation 648 , Knoevenagel condensation 649 could be enhanced by microwave irradiation. Recent days, domestic microwave oven is useful to prepare isoflavons 650 , for mazans 651 , chalcones 652 , quinazolinones 653 , benzofurans 654 and pyrazolines 655-658 . The name reaction such as Biginelli 659 , Prins 660 , C a n n i z z a r o 6 6 1 a n d c r o s s C a n n i z z a r o 6 6 2 , M i c h a e l a d d i t i o n 6 6 3 , Fr i e s migration 664, Wolfkishner reduction 665 , Gould Jacobs reaction 666 , Backmann reaction 667 , Tendem-Fries 668 , Aldol 669 can also be performed by domestic microwave oven. As a part of ongoing research towards the non traditional approach to the experimental setup of organic reaction, the concept of microwave enhanced reaction has been utilized for rapid and efficient synthesis of 1-N-Acetyl-3-aryl5-[1'N,3'-diphenyl-4'-pyrazolyl]-pyrazolines. LG domestic microwave oven is used as a microwave irradiation source and compared in terms of yield and reaction period and have been cited in Table No. 12a. SECTION - I : SYNTHESIS AND BIOLOGICAL EVALUATION OF 1 N -A C E T Y L - 3 -A RY L - 5 - [ 1 ' N , 3 ' -D I P H E N Y L - 4 ' PYRAZOLYL]-PYRAZOLINES SECTION - II : M I C R O WAV E INDUCED AN EXPEDITIOUS
S Y N T H E S I S O F 1 N -A C E T Y L - 3 -A RY L - 5 - [ 1 ' N , 3 ' DIPHENYL-4'-PYRAZOLYL]-PYRAZOLINES
185 SECTION - I SYNTHESIS AND BIOLOGICAL EVALUATION OF 1N-ACETYL-3-ARYL5-[1'N,3'-DIPHENYL-4'-PYRAZOLYL]-PYRAZOLINES Pyrazolines are endowed with valid antimicrobial activities. Looking at their versatile therapeutic importance and with an aim to getting better drug, it was considered worthwhile to synthesise some new pyrazolines. The preparation of 1N-Acetyl-3-aryl-5-[1'N,3'-diphenyl-4'-pyrazolyl] pyrazolines (XII) have been undertaken by cyclocondensation of chalcone of type (I) with hydrazine hydrate in glacial acetic acid.
N N N
NH2.NH2.H2O
N
COCH3
gl. HOAC
R O R
Type (XII)
R = Aryl
The constitution of the synthesised products have been characterised using elemental analyses, infrared and 1 H nuclear magnetic resonance spectroscopy and mass spectrometry also. In mass spectrometry the m/z value indicate the molecular weight, i.e. when R=p-Anisyl, molecular weight=436, m/z=437 (m+1). All the compounds have been also evaluated for their antibacterial activity towards Gram positive and Gram negative bacterial strains and antifungal activity towards Aspergillus niger at a concentration of 40 g/ml. The biological activity of the synthesised compounds have been compared with standard drugs. Some compounds have been found to have good and equivalent activity as compared to the known antibiotics recorded on Page No. 194.
186
I R S P E C T R A L S T U DY O F 1 N -AC E T Y L - 3 - ( p -T O LY L ) - 5 - [ 1 ' N , 3 ' -D I P H E N Y L 4'-PYRAZOLYL]-PYRAZOLINE
100.0 %T 80.0
N N
COCH3 N N
420. 461. 904.6 794.6 864.1
60.0 2837.1 40.0 2929.7 3193.9 3402.2

H3C
518.8 547.7 588.2
20.0
0.0
833.2 617.2 1062.7 960.5 1542.9 1298.0 1020.3 1176.5 692.4 1332.7 1228.6 1112.9 1504.4 754.1 1359.7 1255.6 1602.7 1421.4 1654.8 3250.0 2000.0 1750.0 1500.0 1250.0 1000.0 750.0 4- Me AP 500.0 1/cm
-1 (KBr disc) Ref. 670 " " 671 " " " 673 " 671 " "
I Instrument : SHIMADZU-FT-IR 8400-Spectrophotometer; Frequency range : 4000-400 cm Type Alkane Vibration mode C-H str. (asym.) C-H str. (sym.) C-H def. (asym.) Aromatic C-H str. C=C str. C-H i.p. def. C-H o.o.p. def. Pyrazole moiety Pyrazoline ring C=N str. C-N str. C=O str. C=N str. C-C str. (-CH ) 2 Frequency in cm Observed 2929 1421 1359 3060 1504 1112 794 1602 1228 1654 1062 2837 -1
Reported 2975-2950 1470-1435 1390-1350 3090-3030 1520-1480 1125-1000 835-800 1640-1600 1230-1020 1705-1650 1125-1000 2850-2790
187
P M R S P E C T R A L S T U DY O F 1 N -AC E T Y L - 3 - p -A N I S Y L - 5 - [ 1 ' N , 3 ' -D I P H E N Y L 4'-PYRAZOLYL]-PYRAZOLINE
e f g h i l Hj Hk c b c' b' H3CO N N N d a N a a a COCH3 a
Internal Standard : TMS; Solvent : CDCl ; Instrument : BRUKER Spectrometer (300 MHz) 3 Signal Signal Position No. ( ppm) 1 2 3 4 5 6 7 8 9 10 11 2.44 3.03-3.1 3.55-3.64 3.83 5.85-5.9 6.88-6.91 7.22-7.26 7.27-7.46 7.59-7.62 7.64-7.69 7.76-7.79 Relative No. of Protons 3H 1H 1H 3H 1H 2H 1H 5H 2H 2H 3H Multiplicity singlet quartet quartet singlet quartet doublet multiplet multiplet doublet doublet triplet Inference -COCH 3 CHj CHk Ar-OCH 3 CHl CH bb' CHf CHa CH cc' CHeg CH d,h,i J Value In Hz J=8.9 J=8.9 -
e f g h i l Hj Hk c b c' b' H3CO N N N d a N a a a COCH3 a
COCH3 N N O CH3
N N
m/z = 437 (m+1)
+
o SB- 3
+
o NH
+
o CH3
N N CH3 HN O N m/z = 394
N m/z = 149 CH3 m/z = 378 N
OH
+
o N N
+
o N N m/z = 245 BASE PEAK m/z = 221 N N
CH2
+
o
+
H3C N N O m/z = 218 O m/z = 437 (M
+
CH3 o O H3C N N O
CH3 m/z = 115
1) NH
+
o
OH o
+ +
o N N CH3 O N
N H3C O
N m/z = 205 N
m/z = 305
+
o HN CH3 m/z = 107 NH NH2 N m/z = 175
+
o
m/z = 260
CH3 O
189
190 EXPERIMENTAL SYNTHESIS AND BIOLOGICAL EVALUATION OF 1N-ACETYL-3-ARYL5-[1'N,3'-DIPHENYL-4'-PYRAZOLYL]-PYRAZOLINES [A] Synthesis of N-Phenylaminophenyl- -methyl-phenyl azomethine See [A] Part-I, Section-I (A). [B] Synthesis of 1N,3-Diphenyl-4-formyl pyrazole See [A] Part-I, Section-I (B). [C] Synthesis of 1-(p-Anisyl)-3-[1',N,3-diphenyl-4'-pyrazolyl]-2-propene-1-one See [A] Part-I, Section-I (C). [D] Synthesis of 1N-Acetyl-3-(p-Anisyl)-5-[1'N,3'-diphenyl-4'-pyrazolyl]pyrazoline A mixture of 1-(p-Anisyl)-3-[1'N,3'-diphenyl-4'-pyrazol]-2-propene-1-one (3.8 g, 0.01 M), hydrazine hydrate (2 g, 0.04 M) in and 30 ml. glacial acetic acid was refluxed for 12 hrs. The solution was poured into crushed ice. Product was isolated and cr ystallised from DMF - Methanol. Yield, 3.4 g (78%), m.p. 180 o C. (C 27 H 24 N 4 S 2 ; Requires C, 74.31; H, 5.50; N, 12.84%; found : C, 74.26; H, 5.44; N, 12.76%). TLC solvent system Ethyl acetate : Hexane (4:6). Similarly, other pyrazolines were prepared The physical data are recorded in Table No. 12. Antimicrobial testing was carried out described in [A] Part - I, Section (D). The zone of inhibition of test solutions are recorded in Graphical Chart No. 12.

12a 12b 12c 12d 12e 12f 12g 12h 12i 12j 12k 12l 12m
P H Y S I CA L C O N S TA N T S O F 1 N -AC E T Y L - 3 -A RY L - 5 - [ 1 ' N , 3 ' -D I P H E N Y L - 4 ' -P Y R A Z O LY L ] PYRAZOLINES Molecular Formula 3

H N O 26 22 4 C H N OBr 26 21 4 C H N OCl 26 21 4 C H N OF 26 21 4 C H N O 27 24 4 C H N O 27 24 4 2 C H N O 26 22 4 2 C H N O 26 22 4 2 C H N O 26 23 5 C H N O 26 21 5 3 C H N O 26 21 5 3 C H N O 24 20 4 2 C H N OS 24 20 4 C
R 2
Molecular Weight 4
406 485 440.5 424 420 436 422 422 421 451 451 396 412
M.P. o C 5
204 196 178 208 149 180 183 210 173 186 113 98 114
Rf * Value 6
0.56 0.49 0.63 0.57 0.50 0.65 0.58 0.70 0.68 0.59 0.71 0.63 0.75
Yield % 7
94 80 83 77 82 78 80 75 79 75 74 80 71

13.78 11.54 12.71 13.20 13.32 12.84 13.26 13.26 16.62 15.51 15.51 14.13 13.58 13.73 11.53 12.70 13.17 13.30 12.80 13.21 13.23 16.64 15.53 15.49 14.11 13.57
12a, 12b, 12c, 12d, 12h, 12j : Acetone : Benzene (2 : 8). 12e, 12f, 12g, 12i, 12k, 12l, 12m : Ethyl acetate : Hexane : (4 : 6).
191
ANTIMICROBIAL ACTIVITY OF 1N-ACETYL-3-ARYL-5- [1N,3-DIPHENYL4-PYRAZOLYL]-PYRAZOLINES
30
25
20
15
10
192
COMPARATIVE STUDY OF ANTIMICROBIAL ACTIVITY WITH KNOWN ANTIBIOTICS [B] PART-I Section - I : Antimicrobial activity of 1N-Acetyl-3-aryl-5-[1'N,3'-diphenyl-4'-pyrazolyl]-pyrazolines

12b (22) 12j (23) 12k (23)

12d (23) 12i (20)
S. aureus
12c (20) 12g (21) 12k (22)
P vulgaris .
12e (19) 12g (20)
A. niger
12c (23) 12l (21)
23 22 24 25 -
22 23 17 24 -
21 21 23 19 -
15 18 17 20 -
25
193
194 SECTION - II M I C R O WAV E I N D U C E D A N E X P E D I T I O U S S Y N T H E S I S O F 1 N - A C E T Y L - 3 - A R Y L - 5 - [ 1 ' N , 3 ' - D I P H E N Y L - 4 ' - P Y R A Z O LY L ] PYRAZOLINES As a part of our programme directed towards non traditional approach to the experiment setup of organic reactions, the concept of "Microwave Induced Organic Reaction Enhancement" chemistry has been utilised for rapid and efficient synthesis of some 1N-Acetyl-3-aryl-5-[1'N,3'-diphenyl-4'-pyrazolyl] pyrazolines (XII) by the condensation of chalcone of type (I) and hydrazine hydrate in glacial acetic acid.
N N
r, 4-6 min
N N N N COCH3
NH2.NH2.H2O gl. CH 3COOH

R O
Type (XIII) R = Aryl
The constitution of the synthesised products have been characterised using elemental analyses, infrared and 1 H nuclear magnetic resonance spectroscopy and mass spectrometry also. In mass spectrometry the m/z value indicate the molecular weight, i.e. when R=p-Anisyl, molecular weight=436, m/z=437 (m+1). All the compounds have been also evaluated for their antibacterial activity towards Gram positive and Gram negative bacterial strains and antifungal activity towards Aspergillus niger at a concentration of 40 g/ml. The biological activity of the synthesised compounds have been compared with standard drugs. Some compounds have been found to have good and equivalent activity as compared to the known antibiotics recorded on Page No. 194. The spectral and antimicrobial activity of the product obtained by microwave method are found to be identical. The yields of the products obtained by both the methods have been compared. (Recorded in table No. 12.)
195 EXPERIMENTAL SYNTHESIS AND BIOLOGICAL EVALUATION OF 1N-ACETYL-3-ARYL5-[1'N,3'-DIPHENYL-4'-PYRAZOLYL]-PYRAZOLINES [A] Synthesis of N-Phenylaminophenyl- -methyl-phenyl azomethine See [A] Part-I, Section-I (A). [B] Synthesis of 1N,3-Diphenyl-4-formyl pyrazole See [A] Part-I, Section-I (B). [C] Synthesis of 1-(p-Anisyl)-3-[1',N,3-diphenyl-4'-pyrazolyl]-2-propene-1-one See [A] Part-I, Section-I (C). [D] Synthesis of 1N-Acetyl-3-(p-Anisyl)-5-[1'N,3'-diphenyl-4'-pyrazolyl]pyrazoline A mixture of 1-(p-Anisyl)-3-[1'N,3'-diphenyl-4'-pyrazolyl]-2-propene-1-one (3.8 g, 0.01 M), hydrazine hydrate (2 g, 0.04 M) and glacial acetic acid (1-3 ml) was irridiated longer than 1 min. at a time to avoid boiling of solvent. After the completion of reaction the reaction mixture was cooled and poured into cold water. The product was isolated and crystallized from DMF - Methanol. Yield, 3.4 g (78%), m.p. 180 o C. (C 27 H 24 N 4 S 2 ; Requires C, 74.31; H, 5.50; N, 12.84%; found : C, 74.26; H, 5.44; N, 12.76%). TLC solvent system Ethyl acetate : Hexane (4:6). Similarly, other pyrazolines were prepared The physical data are recorded in Table No. 12. Antimicrobial testing was carried out described in [A] Part - I, Section (D). The zone of inhibition of test solutions are recorded in Graphical Chart No. 12.
196
TABLE NO. 12a : COMPARISION OF CONVENTIONAL METHOD AND MICROWAVE ENHANCED SYNTHESIS OF PYRAZOLINES Comp. No. R Thermal Reaction Yield Period (hr.) %
10 12 11 10 11 12 10 12 11 12 12 10 10 78 76 77 69 74 72 73 70 69 70 68 72 66
Microwave Reaction Yield Period (min.) %

4 6 6 6 5 5 5 6 4 4 5 6 4 84 80 83 77 82 78 80 75 79 75 74 80 71
M.P. o C
12a 12b 12c 12d 12e 12f 12g 12h 12i 12j 12k 12l 12m
204 196 178 208 149 180 183 210 173 186 113 98 114
MMMMMMMMMMMMMMMMM M
Chemical Abstract
J. Het. Chem.
J. O. C
REFERENCES
M MMMMMMMMMM
197
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MMMMMMMMMMMMMMMMM M
AL CHEMIC T ABSTRAC
( 11) VOL., 139 Sec., 28 ( 2003)
LIST OF NEW COMPOUNDS
M MMMMMMMMMM
N N O R
N
N N NH2 N R N N
R O H2N
R
T T T T T T T T T T T T T C H 6 5 4-Br-C H 6 4 4-Cl-C H 6 4 4-F-C H 6 4 4-CH -C H 3 6 4 4-OCH -C H 3 6 4 2-OH-C H 6 4 4-OH-C H 6 4 4-NH -C H 2 6 4 3-NO -C H 2 6 4 4-NO -C H 2 6 4 2-C H O4 3 2-C H S4 3 T T T T T T T T T T T T T
R
R
235
N N
N N
N
N H N
O NH
HN
R N
R N
R
R
T T T T T T T T T T T T T C H 6 5 4-Br-C H 6 4 4-Cl-C H 6 4 4-F-C H 6 4 4-CH -C H 3 6 4 4-OCH -C H 3 6 4 2-OH-C H 6 4 4-OH-C H 6 4 4-NH -C H 2 6 4 3-NO -C H 2 6 4 4-NO -C H 2 6 4 2-C H O4 3 2-C H S4 3 T T T T T T T T T T T T T
R
R
236
N N H N O N
N N R O R1 R2 O NH HN NH O
N N R2 R1
R1
-COCH 3 -COOC H 2 5 -COOCH 3 -COOC H 2 5 -CN -COOC H 2 5 -COOC H 2 5 -COOC H 2 5 -COOC H 2 5 -COOC H 2 5 -COOC H 2 5 -COOC H 2 5 -COOC H 2 5
R2
-CH -NH -CH -CH -NH 3 2 3 3
R
R1
C H 6 5 4-Cl-C H 6 4 4-NO -C H 2 6 4 C H 6 5 2-CH -C H 3 6 4 4-CH -C H 3 6 4 2-OCH -C H 3 6 4 4-OCH -C H 3 6 4 4-F-C H 6 4 2-Cl-C H 6 4 2-NO -C H 2 6 4 3-NO -C H 2 6 4 4-NO -C H 2 6 4
R2
-CH -CH -CH 3 3
T T T T T T T T T T
2 C H 6 5 4-Br-C H 6 4 4-Cl-C H 6 4 4-F-C H 6 4 4-CH -C H 3 6 4 4-OCH -C H 3 6 4 2-OH-C H 6 4 4-OH-C H 6 4
3 C H 6 5 C H 6 5 C H 6 5 C H 6 5 C H 6 5 C H 6 5 C H 6 5 C H 6 5 C H 6 5 C H 6 5
237
N N N R NH
N N N N COCH 3
S N N R
R
T T T T T T T T T T T T T C H 6 5 2-Cl-C H 6 4 4-Cl-C H 6 4 4-F-C H 6 4 2-CH -C H 3 6 4 3-CH -C H 3 6 4 4-CH -C H 3 6 4 2-OCH -C H 3 6 4 4-OCH -C H 3 6 4 4-COOH-C H 6 4 2-NO -C H 2 6 4 3-NO -C H 2 6 4 4-NO -C H 2 6 4 T T T T T T T T T T T T T
R
C H 6 5 3-CH -C H 3 6 4 4-CH -C H 3 6 4 2,3-(CH ) -C H 32 6 3 2-OCH -C H 3 6 4 4-OCH -C H 3 6 4 3-Cl-C H 6 4 4-Cl-C H 6 4 2,5-(Cl) -C H 2 6 3 2,6-(Cl) -C H 2 6 3 2-NO -C H 2 6 4 3-NO -C H 2 6 4 4-NO -C H 2 6 4 T T T T T T T T T T T T T
R
238
T : Compound selected by TAACF, USA.

Sanghani HG Thesis Chemistry

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Saurashtra University

Re Accredited Grade B by NAAC (CGPA 2.93)

Saurashtra University Theses Service http://etheses.saurashtrauniversity.edu repository@sauuni.ernet.in

STUDIES ON HETEROCYCLIC COMPOUNDS

STUDIES ON HETEROCYCLIC COMPOUNDS

Gram : UNIVERSITY Fax : 0281-2577633

Phone : (R) 2577392 (O) 2578512

Rtd. Professor & Head, Department of Chemistry

CONTENTS Page No. SYNOPSIS .. .. .. 01

Section - I : Synthesis and biological evaluation of 3-Aryl -5-[1'N, 3'-diphenyl-4'-pyrazolyl]-pyrazolines

Introduction and Spectral studies.. Experimental

111 116 118

Section - I : Synthesis and biological evaluation of 1N-Aryl2-alkyl/aryl-4-[1'N, 3'-diphenyl-4'-pyrazolylmethino]imidazolin-5-ones

Introduction and Spectral studies.. Experimental

141 147 149

Section - I : Synthesis and biological evaluation of -Arylamino.. .. .. 172 177 179

Graphical data of In Vitro Evaluation of Antimicrobial screening

STUDIES ON PYRAZOLES STUDIES ON MICROWAVE INDUCED PYRAZOLINE SYNTHESIS

SECTION - I : Synthesis and biological evaluation of 1-Aryl-3-(1N,3diphenyl-4-pyrazolyl)-2-propene-1-ones

SECTION - I : Synthesis and biological evaluation of 1N,3-Diphenyl -4[2-amino-3-cyano-6-aryl-4-pyridyl]-pyrazoles

SECTION - I : Synthesis and biological evaluation of 1N,3-Diphenyl-4[2-amino-3-cyano-6-aryl-4-dihydropyranyl]-pyrazoles

SECTION - I : Synthesis and biological evaluation of 3-Aryl-5-(1N,3diphenyl-4-pyrazolyl)-pyrazolines

SECTION - II : Synthesis and biological evaluation of 1N-Phenyl-3-aryl-5(1N,3-diphenyl-4-pyrazolyl)-pyrazolines

6 PART - V : STUDIES ON PYRIMIDINONES

SECTION - I : Synthesis and biological evaluation of 5-[1-Aryl-3-(1N,3 -diphenyl-4-pyrazolyl)-prop-2-enylidine]-barbituric acids

8 SECTION - I : Synthesis and biological evaluation of 1N-Aryl-2-alkyl/ aryl-4-(1N,3-diphenyl-4-pyrazolylmethino)-imidazolin5-ones

SECTION - I : Synthesis and biological evaluation of -Arylamino-(1N,3 -diphenyl-4-pyrazolyl)-acetonitriles

: STUDIES ON PYRAZOLINES BY CONVENTIONAL AND MICROWAVE INDUCED SYNTHESIS

SECTION - I : Synthesis and biological evaluation of 1N-Acetyl-3-aryl-5(1N,3-diphenyl-4-pyrazolyl)-pyrazolines by conventional method

11 SECTION - II : Synthesis and biological evaluation of 1N-Acetyl-3-aryl-5(1N,3-diphenyl-4-pyrazolyl)-pyrazolines by microwave method

SYNOPSIS of the Thesis to be submitted to the Saurashtra

University for the degree of Doctor of Philosophy in Chemistry.

STUDIES ON HETEROCYCLIC COMPOUNDS

H eterocyclic chemistry has seen unparalled progress owing to their wide

PART-I STUDIES ON CHALCONES

chemistry of chalcones have generated intensive scientific studies

Chalcones... THERAPEUTIC INTEREST

O CH3 Methanol gla. CH 3COOH

N N H CH3 DMF POCl 3

N N CHO R-COCH3 40%NaOH

80.0 2835.2 2929.7 3130.3 3413.8

0.0 3250.0 2000.0 1750.0 1500.0 1250.0 1000.0 750.0 chalcone4-ome

Reported 2975-2950 1470-1435 1385-1370 3090-3030 1520-1480 1125-1090 1700-1640

c d e f i a j g' h' g O CH3 h k O N b a N a a a

31 EXPANDED AROMATIC RIGION

c d e f i a j g' h' g O CH3 h k O N b a N a a a

m/z = 381 (m+1)

NH m/z = 107 m/z = 245

m/z = 233 O m/z = 381 (M

m/z = 135 BASE PEAK

Method Gram positive bacteria

Concentration : Standard drug :

TABLE NO. 1 : Sr. No. 1

PHYSICAL CONSTANTS OF 1-ARYL-3-[1'N,3'-DIPHENYL-4'-PYRAZOLYL-2-PROPENE]-1-ONES Molecular Formula 3

% of Nitrogen Found Calcd. 9 8

*TLC Solvent System : Acetone : Benzene (1 : 9).

GRAPHICAL CHART NO. 1 :

ANTIMICROBIAL ACTIVITY OF 1-ARYL-3-[1N,3-DIPHENYL-4-PYRAZOLYL]2-PROPENE-1-ONES

0 1a B.mega s.aureus E.coli P.vulgaris A.niger 14 17 20 13 15 1b 11 12 17 19 12 1c 17 15 18 15 17 1d 11 20 13 17 13 1e 23 15 11 16 16 1f 13 11 12 16 18 1g 14 13 15 17 15 1h 12 16 22 14 19 1i 15 14 15 18 20 1j 13 16 11 15 20 1k 19 19 14 17 18 1l 20 12 18 12 21 1m 11 21 19 11 13

Ampici Amoxy Norflox Penicill Grese llin cillin acin in ofulvin 23 22 21 15 0 22 23 21 18 0 24 17 23 17 0 25 24 19 20 0 0 0 0 0 25

Antibacterial activity Zone of inhibition in m.m. B. mega

Antifungal activity Zone of inhibition in m.m. E. coli