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STUDIES ON CHEMICALENTITIES OF THERAPEUTIC
INTERESTA THESIS
SUBMITTED TO THE
SAURASHTRA UNIVERSITY
FOR THE DEGREE OF
Doctor of PhilosophyIN
THE FACULTY OF SCIENCE (CHEMISTRY)
BY
Dinesh J. Paghdar
UNDER THE GUIDANCE
OF
Dr. H. S. Joshi
DEPARTMENT OF CHEMISTRY
SAURASHTRA UNIVERSITY
RAJKOT - 360 005.
INDIA
2005
P X
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Gram : UNIVERSITY Phone : (R) 2584221Fax : 0281-2577633 (O) 2578512
SAURASHTRA UNIVERSITYUniversity Road.Rajkot - 360 005.
Dr. H. S. Joshi Residence :M.Sc., Ph.D.F.I.C.S. B-1,Amidhara AppartmentAssociate Professor, 2- Jalaram Plot,Department of Chemistry University Road,
Rajkot - 360 005.No. GUJARAT (INDIA)
Dt. -06-2005.
Statement under O. Ph. D. 7 of Saurashtra University
The work included in the thesis is my own work under the supervision of
Dr. H. S. Joshi and leads to some contribution in chemistry subsidised by a number of
references.
Dt. : -06-2005 (Dinesh J. Paghdar)Place : Rajkot.
This is to certify that the present work submitted for the Ph.D. Degree
of Saurashtra University by Dinesh J. Paghdar is his own work and leads to advance-
ment in the knowledge of chemistry. The thesis has been prepared under my supervi-
sion.
Date : -06-2005 Dr. H. S. Joshi Place: Rajkot. Associate Professor
Department of ChemistrySaurashtra UniversityRajkot - 360 005.
Dedicated toMy Family
ACKNOWLEDGEMENTS“ Shree Ganeshay Namah “
Hats off to the Omnipresent, Omniscient and Almighty God, the gloriousfountain and continuous source of inspirations! I offer salutations to himand my head bows with rapturous dedication from within my heart, to theOmnipotent Lord “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. H. S. JOSHI. Associate Professor, Department ofChemistry, Saurashtra University, Rajkot, who held the torch of excellentguidance high and lighted up the darkness, with perpetual affectionateencouragement and occasional constructive criticism when needed, towardsthe goal of my academic journey.
I also owe to, from the deepest corner of heart, deepest sense of gratitudeand indebtedness to Dr. (Mrs.) H. H. Parekh, Professor and Head, Departmentof Chemistry, Saurashtra University, Rajkot, as I have been constantlybenefited with her lofty research methodology and the motivation as well ashis highly punctual, affectionate, yet noncompromising nature which alwaysinspired me in heading rapidly towards my goal and helped me achieving theaim of my present task very speedily.
I wish to thank Dr. R. C. Khunt, for her constant guidance and moralsupport during the course of my research work.
Who in this world can entirely and adequately thank the parents whohave given us everything that we possess in this life? The life it self is theirgift to us, so I am at loss of words in which to own my most esteemed fatherShri Jayntibhai and My loving mother Late Smt. Chaturaben and mostvenerated grand father Laxmanbhai, grand mother Jeeviben. Through the stressand strain of this study, my younger brother Vimal, has encouraged me toreach my destination.P X
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As with the completion of this task, I find myself in difficult positionon attempting to express my deep indebtedness to Praful Chovatia . I wish tothank Zalavadia Paresh for his most willing co-operation and comprehensiveexchange of ideas during the course of my research work.
I offer my heart full gratitude to Purohit Dushyant, Manavar Dinesh,Kachhadia pankaj, Rokad Sunil, Ladani Mahesh, Joshi Mayur, Akabarijignesh, Arun Mishra, Gothalia vrajlal, Dhaduk , Khunt Rupesh, Dr.Kachhadia, Dr.Tapan, Dr.Vyas Dipen, Dr.Mayur, Dr. Nagaji, Dr. K.Bhimani,Dr. Harshad and my research colleagues for their support and much fruitfuldiscussion at various stages. I am most thankful to all my Juniors for theirvaluable co-operation and help during the course of my work.
I am thankful to Mr. Harshad Joshi and Mrs. Namrata for their kindsupport and providing chemicals and glasswares on time his co-operation inmagnifying the presentation of my work in the form of thesis.
I Gratefully acknowledge the most willing help and co-operation shownby CDRI Lucknow, CIL, Chandigarh for spectral studies and TuberculosisAntimicrobial Acquisition Co-ordinating Facility, Alabama, U. S. A. for kindco-operation extended by them for antitubercular activity.
Finally, I express my grateful acknowledgment to Department ofChemistry, Saurashtra University for providing me the excellent laboratoryfacilities , jounior research fellowship and kind furtherance for accomplishingthis work.
DINESH J. PAGHDAR
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CONTENTS
.
SYNOPSIS . . . . . . 01
STUDIES ON CHEMICAL ENTITIES OF THERAPEUTICS INTEREST
Introduction . . . . . . 10
PART - I : STUDIES ON PYRAZOLINES
Introduction . . . . . . 16
Section - I : Synthesis and biological screening of (2E)1-[4-(methylsulfonyl)phenyl]-
3-aryl-2-propene-1-ones
Introduction and Spectral studies... . . . . 27
Experimental . . . . . . 33
Graphical data of In Vitro Evaluation of Antitubercular Activity . . 38
In Vitro Evaluation of Antimicrobial screening . . . . 39
Section - II : Synthesis and biological screening of 1-Acetyl-3-[4-methylsulfonyl)phenyl]-
5-aryl-4,5-dihydro-1H-pyrazoles
Introduction and Spectral studies... . . . . 40
Experimental . . . . . . 44
Graphical data of In In Vitro Evaluation of Antitubercular Activity . . 46
In Vitro Evaluation of Antimicrobial screening . . . . 47
Section - III : Synthesis and biological screening of 3-[4-(Methylsulfonyl)phenyl]-
5-aryl-4,5-dihydro-1H-pyrazoles
Introduction and Spectral studies... . . . . 48
Experimental . . . . . . 52
Graphical data of In Vitro Evaluation of Antimicrobial screening . . 54
Reference . . . . . . 55
PART - II : STUDIES ON CYANOPYRIDINES
Introduction . . . . . . 65
Section - I : Synthesis and biological screening of 2-Methoxy-6-[4-(methylsulfonyl)
phenyl]-4-arylnicotinonitriles
Introduction and Spectral studies... . . . . 69
Page No
Experimental . . . . . . 73
Graphical data of In Vitro Evaluation of Antimicrobial screening . . 75
Reference . . . . . . 76
PART - III : STUDIES ON CYNOPYRIDONES
Introduction . . . . . . 79
Section - I : Synthesis and biological screening of 6-[4-(Methylsulfonyl)phenyl]-2-oxo-
4-aryl-1,2dihydropyridine-3-carbonitriles
Introduction and Spectral studies... . . . . 83
Experimental . . . . . . 87
Graphical data of In Vitro Evaluation of Antitubercular Activity . . 89
In Vitro Evaluation of Antimicrobial screening . . . . 90
Reference . . . . . . 91
PART - IV : STUDIES ON CYANOPYRAN
Introduction . . . . . . 94
Section - I : Synthesis and biological screening of 2-Amino-6-[4-(methylsulfonyl)phenyl]-
4-aryl-4H-pyran-3-carbonitriles
Introduction and Spectral studies... . . . . 99
Experimental . . . . . . 103
Graphical data of In Vitro Evaluation of Antitubercular Activity . . 105
In Vitro Evaluation of Antimicrobial screening . . . . 106
Reference . . . . . . 107
PART - V : STUDIES ON PYRIMIDINES
Introduction . . . . . . 111
Section - I : Synthesis and biological screening of 4-[4-(Methylsulfonyl)phenyl]-6-aryl
pyrimidin-2(1H)-ones
Introduction and Spectral studies... . . . . 120
Experimental . . . . . . 124
Graphical data of In Vitro Evaluation of Antitubercular Activity . . 126
In Vitro Evaluation of Antimicrobial screening . . . . 127
Section - II : Synthesis and biological screening of 4-[4-(Methylsulfonyl)phenyl]-6-aryl
pyrimidin-2(1H)-thiones
Introduction and Spectral studies... . . . . 128
Experimental . . . . . . 132
Graphical data of In Vitro Evaluation of Antitubercular Activity . . 134
In Vitro Evaluation of Antimicrobial screening . . . . 135
Section - III : Synthesis and biological screening of 4-[4-(Methylsulfonyl)phenyl]-6-aryl
pyrimidin-2-amines
Introduction and Spectral studies... . . . . 136
Experimental . . . . . . 140
Graphical data of In Vitro Evaluation of Antimicrobial screening . . 142
Reference . . . . . . 143
PART - VI : STUDIES ON INDAZOLES
Introduction . . . . . . 146
Section - I : Synthesis and biological screening of Ethyl-4-[4-methylsulfonyl)phenyl]-2
-oxo-6-arylcyclohex-3-ene-1-
carboxylates
Introduction and Spectral studies... . . . . 155
Experimental . . . . . . 159
Graphical data of In Vitro Evaluation of Antimicrobial screening . . 161
Section - II : Synthesis and biological screening of 6-[4-(Methylsulfonyl)pheny]-4-aryl
-2,3a,4-5-tetrahydro-3H-indazol-3-ones
Introduction and Spectral studies... . . . . 162
Experimental . . . . . . 166
Graphical data of In Vitro Evaluation of Antimicrobial screening . . 168
Reference . . . . . . 169
PART - VII : STUDIES ON ISOXAZOLES DERIVATIVES
Introduction . . . . . . 175
Section - I : Synthesis and biological screening of 3-[4- (Methyl sulfonyl)phenyl]-5-aryl
i soxazoles
Introduction and Spectral studies... . . . . 180
Experimental . . . . . . 184
Graphical data of In Vitro Evaluation of Antimicrobial screening . . 186
Reference . . . . . . 187
PART - VIII : STUDIES ON THIAZOLIDINONES DERIVATIVES
Introduction . . . . . . 191
Section - I : Synthesis and biological screening of 3-Amino-5-arylidine-2-methyl
-2-[4-(methylsulfonyl)phenyl]-1,3-thiazolidin-4-ones
Introduction and Spectral studies. . . . . 198
Experimental . . . . . . 202
Graphical data of In Vitro Evaluation of Antimicrobial screening . . 205
Reference . . . . . . 206
LIST OF NEW COMPOUNDS . . . . . . 211
SYNOPSIS
1
The work is incorporated in the thesis with the title “STUDIES ON CHEMICAL
ENTITIES OF THERAPEUTIC INTEREST” has been described as under.
STUDIES ON CHALCONE DERIVATIVES
The chemistry of chalcones containing an active keto-ethylenic linkage has
assumed importance because of their versatility in the synthesis of many heterocyclic
compounds. Furthermore, they are also associated with wide spectrum of pharma-
cological activities and industrial applications. The chalcones are reported to pos-
sess antibacterial, antiviral, agrochemical and diuretic activities. They have been found
to be applicable for photosensitive materials, polymerization catalysts fluorescents
brightening agents, pigments etc. With a view to supplement these valid observa-
tions, it was contemplated to synthesize some novel chalcone derivatives using 1-(4-
methanesulfonyl-phenyl)-ethanone with better biological activities which have been
described as under.
PART - I : STUDIES ON PYRAZOLINES
Pyrazoline derivatives are endowed with different therapeutic activities such
as antibacterial, analgesic, anthelmintic, antiinflammatory, antitubercular etc. These
valid observations led us to synthesize some novel pyrazoline derivatives bearing
methylsulfonyl moiety, which have been described as under.
SECTION-I : Synthesis and biological evaluation of 1-[4-(Methyl
sulfonyl)phenyl]-3-aryl-2-propene-1-ones
Type (I) R = Aryl
O
S
O
CH3
O
R
2
The chalcone derivatives of Type (I) have been synthesized by the
reaction of 1-[4-(methylsulfonyl)phenyl]-ethanone with different aryl aldehyde in
presence of 40% NaOH.
SECTION -II : Synthesis and biological evaluation of 1-Acetyl-3-[4-
(methylsulfonyl)phenyl]-5-aryl-4,5-dihydro-1H-pyrazoles
The pyrazoline derivatives of Type(II) have been synthesized by the
condensation of the chalcones of Type(I) with hydrazine hydrate in glacial acetic
acid.
SECTION - III: Synthesis and biological evaluation of 3-[4-(Methyl
sulfonyl)phenyl]-5-aryl-4,5-dihydro-1H-pyrazoles
The synthesis of pyrazoline derivatives of Type(III) have been undertaken by
the cyclocondensation of the chalcones of Type(I) with hydrazine hydrate.
Type (II) R = Aryl
SCH3
O
O NN
R
CH3
O
Type (III) R = Aryl
SCH3
O
O NNH
R
3
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. In order to developing therapeutically importnat
compounds, it was considered of interest to synthesize some new canopyridine de-
rivatives shown as under.
SECTION-I : Synthesis and biological evaluation of 2-Methoxy-6-[4-
(methylsulfonyl)phenyl]-4-arylnicotinonitriles
Cyanopyridine derivatives of Type(IV) have been prepared by the
reaction of chalcones of Type(I) with malononitrile and sodium methoxide.
PART - III : STUDIES ON CYANOPYRIDONES
Cyanopyridone derivatives are endowed with different therapeutic activities
such as antibacterial, analgesic, anthelmintic, antiinflammatory, antitubercular etc.
These valid observations led us to synthesize some new cyanopyridone derivatives
bearing m ethylsulfonyl moiety, which have been described as under.
SECTION - I: Synthesis and biological evaluation of 6-[4-(Methyl
sulfonyl)phenyl]-2-oxo-4-aryl-1,2dihydropyridine-3-
carbonitriles
Type (IV) R = Aryl
SCH3
O
O N
O CH3
R
N
4
Cyanopyridone derivatives of Type(V) have been prepared by the
reaction of chalcones of Type (I) with ethyl cyano acetate in presence of basic
catalyst like pyridine.
PART - IV : STUDIES ON CYANOPYRANS
Cyanopyran derivatives exhibit various interesting biological properties such
as antimicrobial, antifungal, antiviral, antifilarial and antisecretory. In view of these
facts, it was contemplated to synthesized some new pyrans, which have been
described as under.
SECTION-I : Synthesis and biological evaluation of 2-Amino-6-[4-
(methylsulfonyl)phenyl]-4-aryl-4H-pyran-3-carbonitriles
Cyanopyran derivatives of Type (VI) have been prepared by the reaction of
chalcones of Type (I) with malononitrile in pyridine.
Type (V) R = Aryl
Type (VI) R = Aryl
SCH3
O
O NH
O
R
N
SCH3
O
O O
NH2
R
N
5
PART - V : STUDIES ON PYRIMIDINES
Pyrimidine nucleus possess remarkable pharmaceutical importance and
biological activities, some of their derivatives occur as natural product, like nucleic
acids and vitamin B. Pyrimidine derivatives used for the treatment of AIDS and as
antitumor agents, These valid observations led us to synthesize some novel
pyrimidine in search of agents having more medicinally activities which have been
described as under.
SECTION - I: Synthesis and biological evaluation of 4-[4-(Methyl
sulfonyl)phenyl]-6-arylpyrimidin-2(1H)-ones
Pyrimidinone derivatives of Type (VII) have been prepared by the
condensation of chalcones of Type (I) with urea in presence of acidic catalyst like
HCl.
SECTION-II : Synthesis and biological evaluation of 4-[4-(Methyl
sulfonyl)phenyl]-6-arylpyrimidin-2(1H)-thiones
Type (VII) R = Aryl
SCH3
O
O
NH
N
O
R
SCH3
O
O
NH
N
S
R
Type (VIII) R = Aryl
6
Pyrimidine thione derivatives of Type (VIII) have been prepared by the
condensation of chalcones of Type(I) with thiourea in presence of acidic catalyst
like HCl.
SECTION-III : Synthesis and biological evaluation of 4-[4-(Methyl
sulfonyl)phenyl]-6-arylpyrimidin-2-amines
Aminopyrimidine derivatives of Type (IX) have been synthesized by the
condensation of chalcones of Type (I) with guanidine hydrochloride.
PART - VI : STUDIES ON INDAZOLES
Biological importance of indazole derivatives is well known. They have been
reported to be active as cardiovasscular, sedative, antifungal and antibecterial. In
order to develop medicinally importnat compounds, it was considered of interest to
synthesized some new indazoles which have been described as under.
SECTION - I : Synthesis and biological evaluation of ethyl-4-[4-(methyl
su l fony l )pheny l ] -2 -oxo -6 -ary l cyc lohex -3 -ene -1 -
carboxylates
SCH3
O
O
N
N
NH2
R
SCH3
O
O
O
O
O
CH3
R
Type (IX) R = Aryl
Type (X) R = Aryl
7
Cyclohexenones of Type (X) have been prepared by the cyclocondensation
of chalcones of Type (I) with ethylacetoacetate in the presence of basic catalyst
K2 CO3
SECTION-II : Synthesis and biological evaluation of 6-[4-(Methylsulfo
nyl)pheny]-4-aryl-2,3a,4-5-tetrahydro-3H-indazol-3-ones
Indazole derivatives of Type(XI) have been prepared by the reaction of
cyclohexenones of Type(X) with hydrazine hydrate.
PART - VII : STUDIES ON ISOXAZOLES
Isoxazole derivatives represent one of the modest classes of compound
possessing wide range of therapeutic activities, such as antidepressants, skeleton
muscle relaxant, antidiabetic, anti-inflammatory, analgesic etc. With a view to
mapping better medicinal value and to evaluate its pharmacological profile, we have
synthesized some new isoxazole derivatives, which have been described as under.
SECTION - I : Synthesis and biological evaluation of 3-[4-Methyl
s u l f o n y l ) p h e n y l ] - 5 - a r y l i s o x a z o l e s
SCH3
O
ON
NH
O
R
NO
S
O
O
CH3
R
Type (XII) R = Aryl
Type (XI) R = Aryl
8
Isoxazole derivatives of Type(XII) have been prepared by the reaction of
chalcones of Type(I) with hydroxylamine hydrochloride in presence of sodium
acetate in acetic acid.
PART - VIII : STUDIES ON THIAZOLIDINONES
Compounds bearing thiazolidinone nucleus show wide range of biological
activity such as antimicrobial, CNS depressant, antiinflammatory, antitubercular,
sedative, anticonvulsant, analgesic and antihypertensive. With a view to suppliment
these valid observations, the synthesis of some new thiazolidinones have been
undertaken which have been descried as under.
SECTION - I : Synthes i s and b io log ica l eva luat ion of 3 -Amino-5-
arylidine-2-methyl-2-[4-(methylsulfonyl)phenyl]-1,3-
thiazolidin-4-ones
The thiazolidinone derivatives of Type (XIII) have been undertaken by the
condensation of 3-amino-2-methyl-2-[4-(methylsulfonyl)phenyl]-1,3-thiazolidin-4-
one with different aldehydes in glacial acetic acid.
The constitution of the synthesised compounds have been characterised
using elemental analysis, infrared and 1H nuclear magnetic resonance spectroscopy
and further supported by mass spectrometry. Purity of all the compounds have been
checked by thin layer chromatography.
SCH3
O
O N
S
NH2
CH3
O
R
Type (XIII) R = Aryl
9
In vitro studies on multiple biological activities.
(I) Selected 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 µg/ml using Rifampin as standard drug,
which have been tested by Tuberculosis Antimicrobial Acquisition
Co-ordinating Facility (TAACF), Alabama, U.S.A.
(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 40µg/ml. The
biological activity of the synthesized compounds have been compared with
standard drugs.
INTRODUCTION
STUDIES ON
CHEMICAL ENTITES OF
THERAPEUTIC INTEREST
Studies on chemical entities...
Introduction...
10
Research programs for the discovery of new drugs and for improving the
evolution criteria are under way in many laboratories. In addition knowledge of
specific constituents of the mycobacterium cell and their biochemical roles has
advanced considerably in the recent years and may permit a more rational approach
to the design of new drug action on specific targets. Also, recent improvements in
the knowledge of the mechanism of action of available drugs and the biochemical
mechanism of resistance to them may be used as a basis for design new and better
weapons to fight the mycobacterial diseases.
The cur ren t env i ronment fo r d i scovery and deve lopment o f new
pharmaceuticals agents could hardly be ware challenging. Public policies and
attitudes are requiring reduction in health care expenditures and increase efficiencies,
resulting in major health care reform in the United States. At the sometime, major
diseases remain untreated and paradoxically, scientific progress continues with ever
increasing acceleration.
The last few decades have witnessed massive advances in biochemistry,
physiology, pharmacology and genetics. This has to a better understanding of working
the body at the molecular level. This in turn has resulted a much better understanding
of the structure and function of important drug targets e.g. enzymes and receptors
and that how drugs can be designed for these targets.
Advances in genetics engineering have been used to produce human proteins
and enzymes in fast growing microbial cells, allowing these molecules to be obtained
in far greater yields than if they were extracted from human tissue. This makes it
easier to study these micro molecules and to design drugs that will interact with
them. Mapping of human DNA through human genome project has immense
implications for medicinal chemistry.
INTRODUCTION
Studies on chemical entities...
Introduction...
11
Advances in chemistry have made possible the synthesis of complexes
molecules. Enantiometry is an important process in medicinal chemistry since life is
inherently chiral and the drug targets within the body are chiral. As such, they can
distinguish between the enantiomers of a chiral drug, so the use of recemic drug is
inherently wasteful, since only one enantiomer is ideally designed to interact with
its target. Moreover, the existences of the “wrong” enantiomer could create problems
if it interacted with a different receptor, resulting inside effects.
The focus of drug design has switched from structure oriented to target
oriented research, e.g. development of the antiulcer agent cimetidine . Histamine
was the lead compound for the project and various strategies were used to find an
analog that would prevent it fitting its receptor. Once an antagonist was developed,
a theory was proposed on how it might interact with the histamine receptor at a
molecular level. Further analogs were then synthesized to test theory and the theory
was continusally modified as required.
In the nineteenth century, chemistry developed as a science, both in terms of
experimental procedures and scientific theory. Scientist isolated and purified single
compounds from natural extracts. Method of organic synthesis were developed that
helped chemists altering structures in a predictable way.
The chemists started separating out the various components of ancient
positions to discover whether a single compound was responsible for the medicinal
effect known as the active principle.
Drugs are chemicals of low molecular weight (~100-500) which interact with
macromolecular targets to produce a biological response. The biological response
may be therapeutically useful in the case of medicines or harmful in the case of
poisons. Most drugs used in medicine are potential poisons if taken in higher doses
than recommended.
Studies on chemical entities...
Introduction...
12
Drugs are classified by their chemical structures. Drugs classified in this way
share a common structural feature and often share similar pharmacological activity.
For example, all penicillin’s contain a β-lactum ring and kill bacteria by the same
mechanism, as a result, this classification can sometimes be useful in medicinal
chemistry. However, it is not foolproof. Sulfonamides have a similar structure and
are mostly antibacterial. However some sulfonamides are useful in the treatment of
diabetes. Similarly all steroids have a tetracyclic structure, but the pharmacological
effect of different steroids can be quite different e.g. testosterone is a sex hormone.
Spironolactone is a diuretic .
Finally classifying drugs according to their molecular target is the most useful
classification as far as medicinal chemist is concerned, since it allows a rational
comparison of the structure involved.
Any drug must ideally have a broad spectrum of activity, with a rapid
bactericidal action. Some bacteria produce enzymes that can inactivate or modify
antibiotics action. Some bacteria produce enzymes that can inactivate or modify
antibiotics and insusceptibility of a drug to such degradation or modification could
result in its playing an important part in therapy. Likewise, some bacteria possess
an outer membrane that acts as a permeability barrier to the entry of some, but not
all, antibiotics. Drugs that can readily penetrate this barrier might again be expected
to be of possible clinical importance.
The modern concept of drug discovery supported in 1933 by Gerhand Dumagk
penicillins sulfonamides steroids
N
SCH3
CH3
O
NHH H
COOH
R
O
S
NH2
NHR
OOR''
R'
CH3
H
H
H
CH3R
H
Studies on chemical entities...
Introduction...
13
with his finding of prontosil red a compound responsible for the antibacterial activity.
In 1939 Florey and Chain investigate penicillin-G which was discovered ten years
earlier by Alexander Fleming.
The word drug is described from the french word drogue which mean a dry
herb. According to WHO a drug may be define as “Any substance or product which
is used or intended to be used for modifying on exploring physiological system or
pathological status for the benefit of the recipient.” There are two main division of
medicinal chemistry. The first chemotherapy, concern with the treatment of
infections, parasite or malignant disease by chemical agents, usually substance that
shows selective toxicity towards the pathogen.
During the period of 1940 to 1960 a large number of important drugs have
been introduced and this period is regarded as “Golden Period” of new drug
discovery. These are some of the specific examples representing new therapeutics.
NAME OF DRUGS YEAR USES
Sulfa drugs 1933 First
antibacterial drug
Penicillin 1940 Antibiotics
Chloroquine 1945 Antimalarial
Methyldopa 1950 Antidiabetic
Chlorthiazide 1957 Diuretic
Adrenergic betablockers 1958 Coronary
Vasodilatory
Semi synthetic penicillins 1960 Antibacterial
Trimethoprim 1965 Antimicrobial
Disodium chromoglycoate 1967 Antiallergic
The other division relates to diseases of bodily disfunctioning of enzymes,
the transmission of impulses on the action of hormones on receptors. Heterocyclic
Studies on chemical entities...
Introduction...
14
compounds are used for all these purpose, because they have a specific chemical
reactions. The introduction of heterocyclic groups in to drugs may effect their
physical properties, for examples the disscociation constants of sulpha drugs or
modify their patterns of absorption, metabolisam or toxicity.
During the period of 1930-1950 there was an urgent need for new drugs for
treat diseases which had a high mortality rate, there was only limited appreciation
of the hazard. Such drugs might present and toxicological studies before cinical
trials were fairly radimenting proving the proverb “Necessity is the mother
invention”, during the dacade of 30 and 40s.
Taking in view of the applicability of heterocyclic compounds, we have
undertaken the preparation of heterocycles bearing pyrazole nucleus. The placement
of a wide variety of substituents of these nuclei have been designed in order to
evaluate the synthesised products for their pharmacological profile against several
strains of bacteria and fungi.
AIM AND OBJECTIVES
In the pharmaceutical field, these have always been and will continue to be a
need for new and novel chemical inhibitors of biological function. Our efforts are
focused on the introduction of chemical diversity in the molecular from work in
order to synthesizing pharmacologically interesting compound of widely different
composition.
During the course of our research work, looking to the application of het-
erocyclic compounds, several entities have been designed, generated and character-
ized using spectral studies. The details are as under.
1. To synthesize therapeutically active compounds like pyrazolines,
cyanopyridines, cyanopyridones, cyanopyrans, pyrimidines, indazoles,
isoxazoles and thiazolidinones bearing methylsulfonyl moiety.
Studies on chemical entities...
Introduction...
15
2. To generate several intermediates, like chalcones, cyclohexenone bearing
methanesulfonyl acetophenone moiety.
3. To characterize these products for structure elucidation using several spec-
troscopic techniques like IR, PMR and Mass spectral studies.
4. To assess the reaction and purity of the compounds were done by TLC.
5. To evaluate these products for better drug potential against different strains
of bacteria and fungi.
6. All the compounds have been sent to TAACF, southern Research institute,
and USA; for antitubercular testing.
Taking in to consideration the applicability of heterocyclic compounds, the
placement of variety of substituted in these nuclei has been designed in order to
evaluate the synthesized products for their better pharmaceutical profile.
Studies on chemical entities...
Pyrazolines...
16
INTRODUCTION
The term “chalcone” was first coined by Kotanecki, who did pioneering
work in the synthesis of natural coloring compounds. They are characterized by
their possession of a C6(A)-CO-CH=CH-C6(B), structure in which two aromatic
ring A and B, are linked by an aliphatic three carbon chain.
Chalcones are phenyl styryl ketones containing reactive keto-ethylinic group
(-CO-CH=CH-). They are also known as benzalacetophenones or benzylidene
acetophenones the alternatively names given to chalcone are β-phenyl acrylophenone,
α -oxo-α,β -diphenyl- β-propylene and α -phenyl- β-benzoyl ethylenes.
SYNTHETIC ASPECT
A variety of a methods are available for the synthesis of chalcones. The most
convenient method is the one that involves the Clasien-Schmidt condensation of
equimolar quantities of a aryl methyl ketones with aryl aldehyde in the presence of
alcoholic alkali.1-3
Various condensing agent used are alkali of different strength.4,5
Hydrogen chloride6,7
, Phosphorous oxychloride8, Piperidine
9, Anhydrous aluminium
chloride10
, Boron trifluoride11
, Borax12
, Aminoacids13
, Perchloric acid14
etc.
MECHANISM
The following two mechanisms have been suggested for the synthesis of
chalcones.
O
A B
(I)
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Pyrazolines...
17
REACTIVITY OF CHALCONES
The chalcones have been found to be useful for the synthesis of many
heterocyclic compounds.
1. Chalcone contain a Keto-Ethylenic group and therefore reactive towards a
number of reagents yielding various heterocyclic compounds exhibiting
s ignificant biological activities viz. pyrazolines15
, cyanopyridines16
,
cyanopyrans17
, cyanopyridones18
, pyrimidines19-21
, isoxazoles22
,
indazoles23
etc.
2. Chalcones are intermediate compounds for the synthesis of some naturally
occuring heterocyclic compounds like flavones, flavanones, flavanoids,
dihydro flavanols, benzal coumarinones, anthocyanins etc.
3. The structure of some naturally occurring pigments like chrysin, galangin,
kaempferol and quercetrol were established by their synthesis from suitably
substituted chalcones.24
4. They have been useful in providing structure of some natural products like
cyanomulcurin25
, eviodictoyl26
, hemlocktanin27
, narighenin28
,
plioretin29
etc.
5. Chalcones are also useful for the detection of Fe(II)30
and Ca(II)31
ions in
presence of Ba and Sr as it reacts with number of metal ions. Trihydroxy
chalcones were used as an analytical reagents for amperometric estimation
PhC
O
CH 2
H
+ OH-
PhC
O
CH 2-+
PhC
O
H PhC
O
Ph
O-
PhC
O
PhPh
C
O
Ph
O H -H 2 O
H+
-OH -
OH-
Studies on chemical entities...
Pyrazolines...
18
of copper32
and for spectrophotomatric study of the germanium.33
6. The chalcones are natural biocides34,35
and are well-known key intermidiate
in the synthesis of heterocyclic compounds possessing biodynamic
behaviour.36-38
7. Chalcone and their derivatives are also found to be applicable as light
stabilizing agent39
, sweetening agent40
, oganic brightening agent, photo
sensitive material, polymerisation catalyst, scintillators as well as fluorescent
whitening agent.
THERAPEUTIC IMPORTANCE
Chalcones derivatives have been found to possess wide range of therapeutic
activities as shown below.
1. Antitumor41,42
2. Antispasmodic43
3. Antiulcer44,45
4. Anthelmintics46,47
5. Bactericidal48,49
6. Cardiovascular50
7. Fungicidal51-53
8. Germicidal54
9. Herbicidal55
10. Insecticidal56-58
11. Antiallergic59
12. Anticancer60,61
13. Antiinflammatory62,63
14. Antimalarial64,65
15. Antitubercular66,67
16. Antiviral68
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Pyrazolines...
19
Chalcones are potential biocides, because some naturally occurring
antibiotics69
and aminochalcones70,71
probably owe their biological activity in the
presence of the α ,β-unsaturated carbonyl group. Nelson G. L. et al.72
synthesized
the analogs of prostaglandin (II).
The compound 4-[1-oxo-3-(3,4,5- t r imethoxyphenyl)-2-propenyl]-1-
piperazine acetic acid ethyl ester (III) has been marketed under the name of
‘Cinepazet’ used as vasodilator. The other 5-methoxy-2-methyl-1-(1-oxo-7-phenyl)-
1H-indole-3-acetic acid (IV) has been marketed under the name of ‘Cinmetacin’
and useful as antiinflammatory drug.
O
R1O
R
O
N
N COOCH2CH3
H3CO
H3CO
H3CO
N
O
CH3
COOH
H3CO
(II)
(III)
(IV)
Studies on chemical entities...
Pyrazolines...
20
Some dihydrochalcones are well known for their sweetening property73,74
and appear
to be non-nutritive sweeteners. A dihydrochalcone ‘Uvaretin’ from Uvaria
acuminata has shown antitumor activity75
in lymphocytic leukemia test. V. K.
Ahluwalia et al.76
have noted that 5-cinnamoylchalcones (V) have shown good as
antibacterial activity.
Chalcones have served as starting material for several synthetic manipulations
and a versatile synthon in organic synthesis.
Moreover, Khatib S. et a1.77
synthesized some novel chalcones as potent
tyrosinase inhibitors(VI). Ko H. H. et al.78
have prepared chalcones and found active
against potent inhibition of platelet aggregation. Ziegler H. L. et al.79
reported some
novel chalcones as antiparasitic.
Go M. L. et al.80
have described the synthesis and biological activities of
chalcones as antiplasmodial. Xue C. X. et al.81
synthesized and reported chalcones
as antimalarial agents. Fu Y. et al.82
have synthesized Licochalcone-A
Furthermore, Alcaraz M. J. et al.83
have described the role of nuclear
factor-kappaB and heme oxygenase-1 in the mechanism of act ion of an
anti-inflammatory chalcone derivative in RAW 264.7 cells. Nerya O. et al.84
have
prepared chalcones as potent tyrosinase inhibitors.
OO
R
R1
R
R1
OH
OH
OH
(V)
O
OH
OH
OH
OH
(VI)
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21
STUDIES ON CHALCONE DERIVATIVES
PART - I : STUDIES ON PYRAZOLINES
PART - II : STUDIES ON CYANOPYRIDINES
PART - III : STUDIES ON CYANOPYRIDONES
PART - IV : STUDIES ON CYANOPYRANS
PART - V : STUDIES ON PYRIMIDINES
PART - VI : STUDIES ON INDAZOLES
PART - VII : STUDIES ON ISOXAZOLES
PART - VIII : STUDIES ON THIAZOLIDINONES
Sabzevari O. et al.85
have constructed some new chalcone derivatives as
molecular cytotoxic mechanisms for anticancer activity (VII).
Recently, Ban H. S. et al.86
synthesized some novel chalcones as inhibition of
lipopolysaccharide-induced expression of inducible nitric oxide synthase and tumor
necrosis factor-alpha by 2'-hydroxychalcone derivatives in RAW 264.7 cells. Hollosy
F. et al.87
have prepared some new chalcones as plant-derived protein tyrosine kinase
inhibitors as anticancer agents.
Chalcone have been proved to be an important intermediate for the synthesis
of many heterocyclic compounds in organic chemistry. These facts pormpted us to
sythesize some novel chalcone derivat ives bearing 1-[4-(methylsulfonyl)
phenyl]ethanone, in order to achiving better therapeutic agents, we have undaertaken
the synthesis of chalcones and its derivatiaves, which have been described in fol-
lowing part.
O
OOMe
OH
OMe (VII)
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Pyrazolines...
22
INTRODUCTION
Amongst nitrogen containing five membered heterocycles, pyrazolines have
proved to be the most useful framework for biological activities, Pyrazolines have
attracted attention of medicinal chemists for both with regard to heterocyclic
chemistry and the pharmacological activities associated with them. In 1967 Jacobe,
reviewed the chemistry of pyrazolines, which have been studied extensively for their
biodyndmic behaviour88
and industrial applications.89
SYNTHETIC ASPECT :
Different methods for the preparation of 2-pyrazoline derivatives documented
in literature are as follows.
1. Dipolar cycloaddition of nitrilimines of dimethyl fumarate, fumaronitrile
and the N-aryl maleimides yields the corresponding pyrazolines90
.
2. Epoxidation of chalcones i.e. epoxy ketones which reacted with hydrazine
and phenyl hydrazine to give pyrazolines91
. Furthermore, B. Gyassi et al.92
investigated the one pot synthesis of some pyrazolines in dry media under
microwave irradiation. S. Paul et al.93
and Dandia Anshu et al.94
have
also described the microwave assisted synthesis of 2-pyrazolines.
3. 2-Pyrazolines can be constructed by the cyclocondensation of chalcones with
hydrazine hydrate95
.
4. 2-Pyrazolines can also be prepared by the condensation of chalcone dibromide
with hydrazine96
.
NH
N
(I)
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Pyrazolines...
23
5. 2-Pyrazolines synthesised by the cycloaddition of diazomethane with
substituted chalcones.97
MACHANISIM
The following mechanism seems to be operable for the condensation of
chalcones with hydrazine hydrate.98
Nucleophilic attack by hydrazine at the β-carbon of the α,β -unsaturated
carbonyl system forms species, in which the -ve charge is mainly accomodated by
the electronegative oxygen attom.
Proton transfer from the nitrogen to -ve oxygen produces an intermediate
enol which simultaneously ketonises to ketoamine. 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 carbonyl
amine. The later with a hydroxy group and amino group on the same carbon lose
water molecule to yield the pyrazolines.
R R1
O
N
NH
R
R1
NH 2NH 2.H2O
R1 R
O
NH2 NH R2CH
-R1
C+ R
O-NH
+
R2 NH2
(i) Proton transfer(ii) Ketonization R1 R
ONR2 NH2
intermolecularneucleophilic attack
R1 R
OHN
R2
NH
R1 R
N
R2
N
-H2O
Studies on chemical entities...
Pyrazolines...
24
THERAPEUTIC IMPORTANCE
From the literature survey, it was revealed that 2-pyrazolines are better
therapeutic agents some of them are as shown bellow.
1. Antiallergic99
2. Anticonvulsant100,101
3. Antidiabatic102
4. Antiimplantation103
5. Antiinflammatory104
6. Antitumor105
7. Antineoplastic106
8. Antimicrobial107
9. Analgesic108,109
10. Bactericidal110,111
11. Cardiovascular112
12. Diuretic113
13. Fungicidal114
14. Herbicidal115
15. Hypoglycemic116
16. Insecticidal117
17. Tranquilizer118
Moreover F. Manna and co-worker119
have described 1-acetyl-5-(2'-
bromophenyl)-4,5-dihydro-3-(2'-hydroxyphenyl)-1H-pyrazoline and its derivatives
which acts as potent antiinflammatory, analgesic and antipyratic agents.Udupi R.
H. and Bhatt A. R.120
have reported the synthesis and biological activity of Mannich
bases of certain 1,2-pyrazolines. Nugent Richard121
investigated pyrazolines bis
phosphonate ester as novel antiinflammatory and antiarthritic agent. Fuche Rainer
et al.122
have prepared some new 1H-pyrazoline derivatives and reported them as
Studies on chemical entities...
Pyrazolines...
25
pes t ic ides . Fur thermore , Tsubai e t a l .123
have syn thes ized some new
(phenylcarbamoyl) pyrazolines as an insecticides and at 40% concentration shows
100% mortality of spodopetra litura larve after seven drops.
Shulabh Sharma et al.124
have synthesized pyrazolines and tested their
antiinflammatory activity (II).Ashok Kumar et al.125
have synthesized pyrazolines
as anticonvulsant agents (III). Maurer Fritz et al.126
have synthesized pyrazoles and
screened for their pesticidal activity.
E. Palska et al.127
have prepared 3,5-diphenyl-2-pyrazolines (IV) and cited
their antidepressant activity. B. Shivrama et al.128,129
have synthesized pyrazolines as
antibacterial agents. Hiremath S. P. et al.130
have reported pyrazolines as analgesics,
antiinflammatory and antimicrobial agents. Malhotra V. et al.131
have synthesized
new pyrazolines as a cardiovascular agents (V).
NN
NH
N
N
R
NH S
COCH3
NH
NH
NN
O
O
S
OCH3
COCH3
R1
NNH R2
OMe
OMe N
N
NHR2 S
Ph
R1
(II) (III)
(IV) (V)
Studies on chemical entities...
Pyrazolines...
26
Moreover, T. M. Stivensen et al.132
have also investigated N-substituted pyrazoline
type insecticides. Tanka Katsohori133
have patented pyrazoline derivatives as
herbicides and Johannes et al.134
as insecticides. Moritaz Z. and Hadol135
investigated
a semi emperial molecular orbital study on the reaction of aminopyrazolinyl azodye
with singlet molecular oxygen. Shivnanda M. K. and co-workers136
have
prepared substituted pyrazolines and reported their antibacterial activity.
Almstead J. et al.137
have prepared pyrazolines as vascularization agents. Guniz
Kuchkguzel et al.138
have synthesized pyrazolines as a antimicrobial and
anticonvalsant agents. Gulhan T. Z. and co-workers139
have prepared pyrazolines
as a hypotensive agent.
S. S. Sonarc et al.140
have synthesized-3-(2-acetoxy-4-methoxyphenyl)-5-
(substituted phenyl)-pyrazolines and tested their antimicrobial activity. H. H.
Parekh141
et al. have also synthesized some new pyrazolines as an antimicrobial agent.
G. N. Mishirika et al.142 have also prepared 2-pyrazolines of salicyclic acid possessing
antimicrobial properties. Tunfawy, Atif and co-workers143
have patented 3-methyl-
4'-(substituted phenylazo)-pyrazol-5-ones as antibacterial agents.
Thus, significant biological properties associated with pyrazoline derivatives
have aroused considerable interes to design the compounds with better drug
potentials and to study their pharmacological profile, which have been described as
under.
SECTION-I : SYNTHESIS AND BIOLOGICAL SCREENING OF (2E)1-
[ 4 - ( M E T H Y L S U L F O N Y L ) P H E N Y L ] - 3 - A RY L - 2 -
PROPENE- 1-ONES
SECTION-II : SYNTHESIS AND BIOLOGICAL SCREENING O F 1 -
A C E T Y L - 3 - [ 4 - ( M E T H Y L S U L F O N Y L ) P H E N Y L ] - 5 -
ARYL-4,5-DIHYDRO-1H-PYRAZOLES
SECTION-III : SYNTHESIS AND BIOLOGICAL SCREENING OF 3-[4-
( M E T H Y L S U L F O N Y L ) P H E N Y L ] - 5 - A RY L - 4 , 5 -
DIHYDRO-1H-PYRAZOLES
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Pyrazolines...
27
SECTION - I
SYNTHESIS AND BIOLOGICAL SCREENING OF ( 2 E ) - 1 - [ 4 -
(METHYLS U L F O N Y L ) P H E N Y L ] - 3 - A RYL-2-PROPENE-1-ONES
Chalcone derivatives occupy a unique place in the field of medicinal
chemistry due to wide range of biological activities exhibited by them, prompted
by these facts, the preparation of chalcones of type (I) have been carried out by
condensation of 1-[4-(methylsulfonyl)phenyl]ethanone with various aldehydes in
presence of catalytic amount of alkali.
The structure elucidation of synthesized compounds has been done on the
basis of elemental analyses, Infrared and 1H nuclear magnetic resonance spectroscopy
and further supported by Mass spectrometry.
All the compounds have been evaluated for their in vitro biological assay
like antibacterial activity towards gram positive and gram negative bacterial strains
and antifungal activity towards Aspergillus niger at a concentration of 40µg/ml.
The biological activities of synthesized compounds were compared with standard
drugs.
Moreover, some selected compounds have been evaluated for their in vitro
biological assay towards a strain of Mycobacterium tuberculosis H37Rv at a
concentration of 6.25 µg/ml using Rifampin as a standard drug which have been
tested at Tuberculosis Antimicrobial Acquisition Co-ordinating Facility (TAACF),
Alabama, U. S. A.
S
O
O
CH3
O
CH3
in 40% alkali
R-CHO
R
O
S
O
O
CH3
Type(I)R=Aryl
Studies on chemical entities...
Pyrazolines...
28
S
CH3
AlCl3
(CH3CO)2O
S
CH3
O
CH3
Alcoholic KOH R
O
H
H2O2 in glacial aceticacid
S
CH3
O
R
SCH3
O
O
O
R
REACTION SCHEME
Type-(I) R = Aryl
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Pyrazolines...
29
ANTIMICROBIAL ACTIVITY
Method : Cup-Plate146
Gram positive bacteria : Bacillus cocus
Bacillus subtillis
Gram negative bacteria : Proteus Vulgaris
Escherichia Coli
Fungi : Aspergillus niger
Concentration : 40µg/ml
Solvent : Dimethyl formamide
Standard drugs : Amoxicillin, Ampicillin, Benzyl penicillin,
Norfloxacin, Greseofulvin
The antimicrobial activity was compared with standard drug viz Amoxicillin,
Ampicillin, Benzyl penicillin, Norfloxacin, Greseofulvin 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 : BACTEC 460 Radiometric system.
Bacteria : Mycobacterium Tuberculosis H37Rv
Concentration : 6.25 µg/ml
Standard drug : Rifampin.
MICROBIOLOGICAL EVALUATION
Studies on chemical entities...
Pyrazolines...
30
Instrument : SHIMADZU FTIR 8400 Spectrophotometer; Frequency range: 4000-400
cm-1 (KBr disc.)
0.0
20.0
40.0
60.0
80.0
100.0
%T
500.0750.01000.01250.01500.01750.02000.03250.01/cm
495.7
532.3 596.0
736.8 775.3
815.8 987.51012.6
1031.8
1089.71182.3
1209.3
1224.7
1276.8
1301.9
1330.8
1382.9
1407.9
1490.9
1564.2
1602.71654.8
2916.23028.03087.8
3292.3
3388.7
Type Vibration Frequency in cm-1 Ref. Mode Observed Reported
Alkane C-H str. (asym.) 2916 2975-2950 144-CH3 C-H str. (sym.) 2870 2880-2860 ,,
C-H def. (asym.) 1460 1470-1435 ,,C-H def. (sym.) 1382 1390-1370 ,,
Aromatic C-H str. 3087 3090-3030 145C=C str. 1490 1540-1480 ,,
1089 1125-1090 ,,Halide C-Cl str. 775 800-600 144Sulfonyl SO2 str. 1182 1185-1165 ,,Vinyl CH=CH str. 3028 3050-3000 ,,Chalcone C=C str. 1564 1580-1550 ,,
C=O str. 1654 1672-1652 ,,
IR SPECTRAL STUDIES OF (2E)-1-[4-(METHYLS U L F O N Y L )
PHENYL]-3-(p-CHLOROPHENYL)-2 -PROPENE-1-ONE
SCH3
O
O
O
Cl
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31
Internal Standard : TMS; Solvent : CDCl3 : Instrument : BRUKER
Spectrometer (300 MHz)
1 2.5 3 H singlet -SO2CH3 -
2 7.28-7.31 2 H doublet Ar-H b,b Jba=8.1
3 7.35-7.40 2 H doublet Ar-H c,c Jcd=8.7
4 7.47-7.52 1 H doublet CHe -
5 7.55-7.58 2 H doublet Ar-H a,a Jab=8.4
7 7.71-7.76 1 H doublet CHf -
8 7.91-7.94 2 H doublet Ar-H d,d Jdc=8.1
Signal No.
Signal Position (δppm)
Relative No. of protons
Multiplicity Inference J Value In Hz
NMR SPECTRAL STUDIES OF (2E)-1-[4-(METHYLS U L F O N Y L )
PHENYL]-3-(p-CHLOROPHENYL)-2 -PROPENE-1-ONE
SCH3
O
O O
Cl
a b
a' b'
c
d
c'
d'
e f
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Pyrazolines...
32
TA
BL
E-1
:M
ASS
SP
EC
TR
AL
ST
UD
IES
OF
(2E
)1-[
4-(M
ET
HY
LS
UL
FO
NY
L)P
HE
NY
L]-
3-(P
-CH
LO
RO
PH
EN
YL
)-2
-
PR
OP
EN
E-1
-ON
E
m/z
=32
0
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33
EXPERIMENTAL
SYNTHESIS AND BIOLOGICAL SCREENING OF (2E)-1-[4-(METHYL
SULFONYL)PHENYL]-3-ARY L-2-PROPENE-1-ONES
(A) Synthesis of 1-[4-(methylsulfonyl)phenyl]ethanone
To the solution of 1-[4-(methylthio)phenyl]ethanone in glacial acetic acid
(10 ml), H2O2 (6 ml, 30%) was added and stirred for 5 hr. The stirred content was
kept at room temperature for 24 hr till a crystalline solid was seperated. The
seperated solid was filtered and recrystallized from ethanol Yield 80%, m.p118oC,
Anal. Calcd. for C9H10O3S : Require: C, 54.53, H, 5.08; Found: C, 54.51, H, 5.06
%.
(B) Synthesis of 1-[4-(Methylsu l fony l )pheny l ] -3 -(p-chlorophenyl)- 2 -
propene-1-one
Dissolve 1-[4-(methylsulfonyl)phenyl]ethanone (1.98gm, 0.01mol) in (25 ml)
methanol, to this add p-chlorobenzaldehyde (1.40gm, 0.01mol) in (25 ml) methanol
and stirred at room temperature for 24 hr. in presence of catalytic amount of 40%
KOH. The resulting solution was poured on to crushed ice, thus the solid seprated
was filterated and crystallized from ethanol, Yield 58%, m. p. 120oC, Anal. Calcd.
for C16H13ClO3S Require: C, 59.91, H, 4.08 ; Found: C, 59.89, H, 4.05 %.
Similarly, other compound were prepared. The physical data are recorded in
Table No. 1
(C) Biological screening of 1-[4-(Methylsu l fony l )pheny l ] -3 -aryl- 2 -
propene-1-ones
(a) Antibacterial activity146
The purified products were screened for their antibacterial activity using
cup-plate agar diffusion method. The nutrient agar broth prepared by the usual
method was inoculated aseptically with 0.5 ml of 24 hrs. old subcultures of Bacillus
Studies on chemical entities...
Pyrazolines...
34
Subtilis, Bacillus Coccous, Escherichia coli, Proteus Vulgaris in separate conical
flasks at 40-50oC and mixed well by gentle shaking. About 25 ml content of the
flask was poured and evenly spreaded in a petridish (13 cm diameter) and allowed
to set for 2 hrs. The cups (10 mm diameter) were formed by the help of borer in
agar medium and filled with 0.04ml (40mg) solution of sample in DMF. The plates
were incubated at 37oC for 24 hrs. and the control was also maintained with 0.04ml
of DMF in a similar manner and the zone of inhibition of the bacterial growth were
measured in millimeter and recorded in Graphical Chart No. 1
(b) Antifungal activity146
Aspergilus niger was employed for testing antifungal activity using cup-plate
agar diffusion method. The culture was maintained on sabourauds agar slants
sterilized sabourauds agar medium was inoculated with 72 hrs. old 0.5ml suspension
of fungal spores in a separate flask. About 25ml of the inoculated medium was
evenly spreaded in a petridish (13cm diameter) and allowed to set for 2 hrs. The
cups (10mm diameter) were punched. The plates were incubated at 30oC for 48
hrs. After the completion of incubation period, the zone of inhibition of growth in
the form of diameter in mm was measure. Along the test solution in each petridish
one cup was filled up with solvent, which acts as control. The zone of inhibition of
test solution are recorded in Graphical Chart No. 1
(C)Antitubercular activity
The antitubercular evaluation of the compounds was carried out at
Tuberculosis Antimicrobial Acquisition and Co-ordination Facility (TAACF), USA.
Primary screening of the compounds for the antitubercular activity have been
conducted at 6.25 mg/ml towards Mycobacterium tuberculosis H37Rv in BACTEC
12B using the BACTEC 460 radiometric system. The compounds demonstrating
Studies on chemical entities...
Pyrazolines...
35
atleast>90% inhibition in the primary screening has been tested at lower
concentration towards Mycobacterium tuberculosis H37Rv to determine the actual
minimum inhibitory concentration (MIC) in the BACTEC-460.
The antitubercular data have been compared with standard drug Rifampin at
6.25 mg/ml concentration and it showed 98% inhibition. The primary screening
method is described as under.
Antitubercular activity was determined using the BACTEC 460 system as
modi f i ed be low. S tock so lu t ions as t e s t compounds were p repared in
dimethylsulfoxidie (DMSO) at 1 mg/ml and sterilized by passage through 0.22 mm
PFTE filters (Millex-FG, Millipore, Bedford MA). Fifty microliters was added to
4ml radiometric 7H12 broth (BACTEC 12B; Becton Dickinson Diagnostic
Instrument System, Sparks, MD ) to achieve a final concentration of 6.25 mg/ml.
Controls received 50 ml DMSO. Rifampin(Sigma Chemical Co., St. Louis, MO)
was included as a positive drug control. Rifampin was solublized and diluted in
DMSO and added to BACTEC-12 broth to achieve a range of concentration for
determination of minimum inhibitory (MIC, lowest concentration inhibiting 99% of
the inoculum).
M. Tuberculosis H37Rv (ATCC 27294; American type culture collection,
Rockville, MD) was culture at 37oC on a rotary shaker in middlebrook 7H9 broth
(Difco Laboratories, Detroiet, MI) supplemented with 0.2 v/v glycerol and 0.05%
v/v Tween 80 until the culture turbidity achieved an optical density of 0.45-0.55 at
550nm. Bacteria were then pelleted by centrifugation, washed twice and resuspended
in one fifth the original volume in dulbecco’s phosephate buffered saline (PBS, Irvine
Scientific Santa, Nalgene, Rochester, NY) and aliquots were frozen at 80oC. Cultures
were showed and an appropriate dilution performed such that a BACTEC-12B vial
inoculated with a 0.1 ml would reach a growth index (GI) of 999 in 5 days.
Studies on chemical entities...
Pyrazolines...
36
One tenth of diluted inoculum was used to inoculate 4 ml fresh BACTEC
12B broth containing the compounds. An additional control vial was included which
received a further 1;100 diluted inoculam (as well as 50 ml DMSO) use an calculating
the MIC of Rifampin, respectively by establishing procedures.
Cultures were incubated in 37oC and the GI determined daily until control
cultures achieved a GI og 999. Assays were usually completed in 5-8 days. Percent
inhibition was defined as-1-(GI of test sample/GI of control)x100. Minimum
inhibitory concentration of compound effecting a reduction in daily chang in GI,
which was less than that, observed with a 1:100 diluted control culture one day the
letter reached a GI of at least 30.
The percentage of inhibition data of compounds are recorded in Table No. 2
Studies on chemical entities...
Pyrazolines...
37
Sr.
R M
olec
ular
M
olec
ular
M
.P.
Yie
ld
%
of N
itro
gen
Rf
Sol
vent
No
For
mul
a
Wei
ght
oC
%
Cal
cd.
Fou
nd
V
alue
Sys
tem
1
2
3 4
5
6
7
8 9
10
1aC
6H5-
C16
H14
O3S
286
9660
--
0.51
S 1
1b4-
Cl-
C6H
4-C
16H
13C
lO3S
320
120
58-
-0.
48S 2
1c2-
Cl-
C6H
4-C
16H
13C
lO3S
320
135
65-
-0.
50S 1
1d3-
Cl-
C6H
4-C
16H
13C
lO3S
320
105
62-
-0.
44S 1
1e4-
OC
H3-
C6H
4-C
17H
16O
4S31
615
456
--
0.52
S 2
1f3,
4-(O
CH 3
) 2-C
6H3-
C18
H18
O5S
346
118
58-
-0.
56S 2
1g4-
F-C
6H4-
C16
H13
FO3S
304
180
55-
-0.
49S 2
1h3-
Br-
C6H
4-C
16H
13Br
O3S
365
140
65-
-0.
59S 2
1i3-
C6H
5-O
-C6H
4-C
22H
18O
4S37
894
62-
-0.
47S 1
1j4-
N(C
H3)
2-C
6H4-
C18
H19
NO
3S32
914
260
4.25
4.24
0.46
S 1
1k2-
OH
-C6H
4-C
16H
14O
4S30
213
257
--
0.54
S 2
1l2-
C4H
3O-
C14
H12
O4S
276
184
56-
-0.
43S 2
S 1 H
exan
e:Et
hyl
acet
ate(
5:5)
,
S 2 H
exan
e:Et
hyl
acet
ate(
6:4)
TA
BL
E :
1P
HY
SIC
AL
CO
NST
AN
TS
OF
1-[4
-(M
ET
HY
LS
UL
FO
NY
L)P
HE
NY
L]-
3-A
RY
L-2
-PR
OP
EN
E-1
-ON
ES
Studies on chemical entities...
Pyrazolines...
38
1a 182264 PD-61 C6H5 - Alamar H37R v >6.25 00
1b 182265 PD-62 4-Cl-C6H4 - Alamar H37R v >6.25 00
1c 182266 PD-63 2-Cl-C6H4 - Alamar H37R v >6.25 00
1d 182267 PD-64 3-Cl-C6H4 - Alamar H37R v >6.25 00
1e 182268 PD-65 4-OCH3-C6H4 - Alamar H37R v >6.25 55
1f 182269 PD-66 3,4-(OCH3)2-C6H3 - Alamar H37R v >6.25 18
1g 182270 PD-67 4-F-C6H4 - Alamar H37R v >6.25 42
1h 182271 PD-68 4-Br-C6H4 - Alamar H37R v >6.25 00
1i 182272 PD-69 3-C6H5 O-C6H4 - Alamar H37R v >6.25 11
1j 182273 PD-70 4-N(CH3 )2-C6H4 - Alamar H37R v >6.25 00
1k 182274 PD-71 2-OH-C6H4 - Alamar H37R v >6.25 00
1l 182275 PD-72 2-C4H3O - Alamar H37R v >6.25 10
SrNo.
Sample ID
Corp ID
R Assay MtbStrain
%Inhibi.
MIC µg/ml
TABLE NO-1TAACF, Southern Research Insitute
Primary Assay Summary Report
NAID/Southern Research Insitute/GWL Hansen’s Disease Centre/Colorado State
University proprietary Information
R
O
S
O
O
CH3
ANTITUBERCULAR ACTIVITY OF (2E)- 1-[4-(METHYL S U L F O N Y L )
PHENYL]-3-ARY L-2-PROPENE-1-ONES
Studies on chemical entities...
Pyrazolines...
39
GR
AP
HIC
AL
CH
AR
T N
O.
1 :
(2E
)1-[
4-(M
ET
HY
LS
UL
FO
NY
L)P
HE
NY
L]-
3-A
RY
L-2
-PR
OP
EN
E-1
-ON
ES
Studies on chemical entities...
Pyrazolines...
40
SECTION - II
SYNTHESIS AND BIOLOGICAL SCREENING OF 1 - A C E T Y L - 3 - [ 4 -
(METHYLSULFONYL)PHENYL]-5-ARYL-4,5-DIHYDRO-1H-PYRAZOLES
The broad spectrums of pharmacological properties have been demonstrated
by the pyrazoline nucleus. Inspired by these facts, new pyrazoline derivatives of
Type (II) have been investigated. The 1-[4-(methylsul fonyl )phenyl] -3-ary l -2-
propene-1-ones of type-(I) on treatment with hydrazine hydrate in acetic acid
yielded 1- ace ty l -3- [4-(methylsulfonyl)phenyl]-5-aryl-4,5-dihydro-1H-pyrazoles
derivatives of type (II).
The structure elucidation of synthesized compounds has been done on the
basis of elemental analyses, infrared and 1H nuclear magnetic resonance spectroscopy
and further supported by Mass spectrometry.
All the compounds have been evaluated for their in vitro biological assay
like antibacterial activity towards gram positive and gram negative bacterial strains
and antifungal activity towards Aspergillus niger at a concentration of 40µg/ml.
The biological activities of synthesized compounds were compared with standard
drugs.
Moreover, some selected compounds have been evaluated for their in vitro
biological assay towards a strain of Mycobacterium tuberculosis H37Rv at a
concentration of 6.25 µg/ml using Rifampin as a standard drug which have been
tested at Tuberculosis Antimicrobial Acquisition Co-ordinating Facility (TAACF),
Alabama, U. S. A.
Type(I)Type(II)
NH2-NH2 H2O. S
O
O
CH3
NN R
CO-CH3
in glacial CH3COOH
R
O
S
O
O
CH3
R=Aryl
Studies on chemical entities...
Pyrazolines...
41
Type Vibration Frequency in cm-1 Ref. Mode Observed Reported
Alkane C-H str. (asym.) 2920 2975-2950 144-CH3 C-H str. (sym.) 2850 2880-2860 ,,
C-H def. (asym.) 1490 1470-1435 ,,C-H def. (sym.) 1357 1390-1370 ,,
Aromatic C-H str. 3047 3090-3030 145C=C str. 1544 1540-1480 ,,
1093 1125-1090 ,,1010 1070-1000 ,,
Halide C-Cl str. 819 800-600 144Sulfonyl SO2 str. 1188 1185-1165 ,,Pyrazoline C=O str. 1658 1612-1593 145
C=N str. 1593 1612-1593 ,,N-H str. 3427 3400-3200
0.0
20.0
40.0
60.0
80.0
100.0
%T
500.0750.01000.01250.01500.01750.02000.03250.01/cm
424.3 484.1
542.0
580.5 624.9
673.1
713.6
783.0
819.7
844.8 871.8
960.51010.6
1093.6
1147.6
1188.11245.9
1299.9
1326.91357.8
1400.21415.7
1490.9
1544.9
1593.1
1658.7
2850.6
2920.0
3047.33303.8
3427.3
IR SPECTRAL STUDIES OF 1-ACETYL-3-[4- (METHYLSULFONYL)
PHENYL]-5-(p-CHLOROPHENYL)-4,5-DIHYDRO-1H-PYRAZOLE
SCH3
O
O NN O
CH3
Cl
Instrument : SHIMADZU FTIR 8400 Spectrophotometer; Frequency range: 4000-400
cm-1 (KBr disc.)
Studies on chemical entities...
Pyrazolines...
42
Internal Standard : TMS; Solvent : CDCl3 : Instrument : BRUKER
Spectrometer (300 MHz)
1 2.3 3 H singlet Ar-COCH3 -
2 2.4 3 H singlet Ar-SO2 CH3 -
3 3.03-3.11 1 H d,d Ar-Hf -
4 3.65-3.75 1 H d,d Ar-Hg -
5 5.49-5.55 1 H d,d Ar-He -
6 7.13-7.24 2 H doublet Ar-H b,b' Jba=8.1
7 7.24-7.26 2 H doublet Ar-H c,c' Jcd=8.6
8 7.27-7.28 2 H doublet Ar-H a,a' Jab=8.7
9 7.61-7.63 2 H doublet Ar-H d,d' Jdc=8.1
Signal No.
Signal Position (δppm)
Relative No. of protons
Multiplicity Inference J Value In Hz
NMR SPECTRAL STUDIES OF 1 -ACETYL-3- [4 -(METHYLSULFONYL)
PHENYL]-5-(p-CHLOROPHENYL)-4,5-DIHYDRO-1H-PYRAZOLE
SCH3
O
O NN O
CH3
Cl
HfHg
a b
a' b'
c
d
c'd'
e
Studies on chemical entities...
Pyrazolines...
43
TAB
LE
-2 :
MA
SS
SP
EC
TR
AL
ST
UD
IES
OF
1
-AC
ET
YL
-3-[
4-(
ME
TH
YL
SU
LF
ON
YL
)PH
EN
YL
]-5
-(M
-
BR
OM
OP
HE
NY
L)-
4,5-
DIH
YD
RO
-1H
-PY
RA
ZO
LE
m/z
= 4
21
Studies on chemical entities...
Pyrazolines...
44
EXPERIMENTAL
SYNTHESIS AND BIOLOGICAL SCREENING OF 1 - A C E T Y L - 3 - [ 4 -
(METHYLSULFONYL)PHENYL]-5-ARYL-4,5-DIHYDRO-1H-PYRAZOLES
(A) Synthesis of 1-[4-(Methylsu l fony l )pheny l ] -3 -aryl-2 -propene-1-
ones
See Part-I, Section-I (B).
(B) Synthesis of 1-Acetyl-3-[4-(methylsulfonyl)phenyl]-5-(p-chlorophenyl)-
4,5-dihydro-1H-pyrazole
A mixture of 1- [4-(Methyls u l f o n y l ) p h e n y l ] - 3 - (p-chlorophenyl)- 2 -
propene-1-on e (3.20 gm, 0.01 mol) in glacial acetic acid (25 ml) and hydrazine
hydrate (0.5gm, 0.01 mol) was refluxed for 8 hrs. The product was isolated and
crys ta l l ized f rom e thanol . Yie ld 56%, m.p . 125o C, Anal . Ca lcd . for
C18H17ClN2O3S; Requires: C, 57.35; H, 4.55; N, 7.43 %; Found: C, 57.32; H,
4.53; N, 7.45 %.
Similarly, other 1-acetyl-3-[4-(methylsulfonyl)phenyl]-5-aryl-4,5-dihydro-
1H-pyrazoles were prepared. The physical data are recorded in Table No.2
(C) Biological screening of 1-Acetyl-3-[4-(methylsulfonyl)phenyl]-5-aryl-
4,5-dihydro-1H-pyrazoles.
Antimicrobial testing were carried out as described in Part-I Section-I(C).
The zones of inhibition of test solutions are recorded in Graphical Chart No.2
Studies on chemical entities...
Pyrazolines...
45
3aC
6H5-
C18
H18
N2O
3S34
211
865
8.18
8.19
0.40
S 2
3b4-
Cl-
C 6H
4-C
18H
17C
lN2O
3S37
612
556
7.43
7.45
0.55
S 2
3c2-
Cl-
C 6H
4-C
18H
17C
lN2O
3S37
618
556
7.43
7.44
0.40
S 1
3d3-
Cl-
C 6H
4-C
18H
17C
lN2O
3S37
616
552
7.43
7.42
0.52
S 2
3e4-
OC
H3-
C6H
4-C
19H
20N
2O4S
372
134
597.
527.
510.
56S 2
3f3,
4-(O
CH 3
) 2-C
6H3-
C20
H22
N2O
5S40
211
848
6.96
6.97
0.42
S 1
3g4-
F-C
6H4-
C18
H17
FN2O
3S36
012
661
7.77
7.76
0.41
S 1
3h3-
Br-
C 6H
4-C
18H
17B
rN2O
3S42
114
068
6.65
6.68
0.49
S 2
3i3-
C6H
5-O
-C6H
4-C
24H
22N
2O4S
434
126
496.
456.
420.
46S 1
3j4-
N(C
H3)
2-C
6H4-
C20
H23
N3O
3S38
514
666
10.9
010
.91
0.58
S 1
3k2-
OH
-C6H
4-C
18H
18N
2O4S
358
165
577.
827.
810.
51S 2
3l2-
C4H
3O-
C16
H16
N2O
4S33
213
655
8.43
8.44
0.45
S 1
TA
BL
E :
3P
HY
SIC
AL
CO
NST
AN
TS
OF
1-
AC
ET
YL
-3-[
4-(M
ET
HY
LSU
LF
ON
YL
)PH
EN
YL
]-5-
AR
YL
-4,5
-DIH
YD
RO
-
1H-P
YR
AZ
OL
ES
S 1 H
exan
e:Et
hyl
acet
ate(
5:5)
,
S 2 H
exan
e:Et
hyl
acet
ate(
6:4)
Sr.
R M
olec
ular
M
olec
ular
M
.P.
Yie
ld
%
of N
itro
gen
Rf
Sol
vent
No
For
mul
a
Wei
ght
oC
%
Cal
cd.
Fou
nd
V
alue
Sys
tem
1
2
3 4
5
6
7
8 9
10
Studies on chemical entities...
Pyrazolines...
46
2a 182204 PD-1 C6H5 - Alamar H37R v >6.25 00
2b 182205 PD-2 4-Cl-C6H4 - Alamar H37R v >6.25 00
2c 182206 PD-3 2-Cl-C6H4 - Alamar H37R v >6.25 00
2d 182207 PD-4 3-Cl-C6H4 - Alamar H37R v >6.25 00
2e 182208 PD-5 4-OCH3-C6H4 - Alamar H37R v >6.25 55
2f 182209 PD-6 3,4-(OCH3)2-C6H3 - Alamar H37R v >6.25 18
2g 182210 PD-7 4-F-C6H4 - Alamar H37R v >6.25 42
2h 182211 PD-8 4-Br-C6H4 - Alamar H37R v >6.25 00
2i 182212 PD-9 3-C6H5 O-C6H4 - Alamar H37R v >6.25 11
2j 182213 PD-10 4-N(CH3 )2-C6H4 - Alamar H37R v >6.25 00
2k 182214 PD-11 2-OH-C6H4 - Alamar H37R v >6.25 00
2l 182215 PD-12 2-C4H3O - Alamar H37R v >6.25 10
SrNo.
Sample ID
Corp ID
R Assay MtbStrain
%Inhibi.
MIC µg/ml
TABLE NO-2TAACF, Southern Research Insitute
Primary Assay Summary Report
NAID/Southern Research Insitute/GWL Hansen’s Disease Centre/Colorado State
University proprietary Information
S
O
O
CH3
NN R
CO-CH3
ANTITUBERCULAR ACTIVITY OF 1 - A C E T Y L - 3 - [ 4 - (METHYL
SULFONYL)PHENYL]-5-ARYL-4,5-DIHYDRO-1H-PYRAZOLES
Studies on chemical entities...
Pyrazolines...
47
GR
AP
HIC
AL
CH
AR
T N
O.
2 :
1-A
CE
TY
L-3
-[4-
(ME
TH
YL
SUL
FO
NY
L)P
HE
NY
L]-
5-A
RY
L-4
,5-D
IHY
DR
O-1
H-
PY
RA
ZO
LE
S
Studies on chemical entities...
Pyrazolines...
48
SECTION - III
SYNTHESIS AND BIOLOGICAL SCREENING OF 3 - [ 4 -
( M E T H Y L S U L F O N Y L ) P H E N Y L ] - 5 - A R Y L - 4 , 5 - D I H Y D R O - 1 H -
PYRAZOLES
Therapeutic important of pyrazolines aroused considerable intrest to
synthes ize pyrazol ines of type ( I I I ) by the cyclocondensa t ion of 1 - [ 4 -
(Methylsul fonyl)phenyl] -3-aryl -2-propene-1-ones of type-(I) with hydrazine
hydrate in order to study their biodynamic behaviour.
The structure elucidation of synthesized compounds has been done on the
basis of elemental analyses, infrared and 1H nuclear magnetic resonance spectroscopy
and further supported by Mass spectrometry.
All the compounds have been evaluated for their in vitro biological assay
like antibacterial activity towards gram positive and gram negative bacterial strains
and antifungal activity towards Aspergillus niger at a concentration of 40µg/ml.
The biological activities of synthesized compounds were compared with standard
drugs.
NH2 -NH2 H2Oin ethanol
S
O
O
CH3
NNH
RR
O
S
O
O
CH3
Type(I) Type(III)R=Aryl
Studies on chemical entities...
Pyrazolines...
49
30.0
40.0
50.0
60.0
70.0
80.0
90.0
100.0%T
500.0750.01000.01250.01500.01750.02000.03250.01/cm
536.2
584.4
617.2
709.8
788.8
812.0
935.4
975.91004.8
1028.0
1066.61095.5
1172.6
1245.9
1296.1
1350.1
1398.3
1436.9
1510.2
1583.4
1606.6
2839.02879.52958.63074.3
3340.5
IR SPECTRAL STUDIES OF 3-[4-(METHYLSULFONYL)PHENYL]-5-
(p-METHOXYPHENYL)- 4 , 5 - D I H Y D R O - 1 H - P Y R A Z O L E
Type Vibration Frequency in cm-1 Ref. Mode Observed Reported
Alkane C-H str. (asym.) 2945 2975-2950 144-CH3 C-H str. (sym.) 2879 2880-2860 ,,
C-H def. (asym.) 1436 1470-1435 ,,C-H def. (sym.) 1398 1390-1370 ,,
Aromatic C-H str. 3058 3090-3030 145C=C str. 1510 1540-1480 ,,
1095 1125-1090 ,,1066 1070-1000 ,,
Ether C-O-C str. 1245 1260-1200 144Sulfonyl SO2 str. 1172 1185-1165 ,,Pyrazoline N-H str. 3340 3400-3200 145
C=N str. 1606 1612-1593 ,,
SCH3
O
O NNH
O
CH3
Instrument : SHIMADZU FTIR 8400 Spectrophotometer; Frequency range: 4000-400
cm-1 (KBr disc.)
Studies on chemical entities...
Pyrazolines...
50
Internal Standard : TMS; Solvent : CDCl3 : Instrument : BRUKER
Spectrometer (300 MHz)
1 2.5 3 H singlet Ar-SO2 CH3 -
2 3.9 3 H singlet Ar-OCH3 -
3 2.95-3.04 1 H d,d Ar-Hc -
4 3.36-3.45 1 H d,d Ar-Hg -
5 4.84-4.90 1 H d,d Ar-He -
6 6.85-6.89 2 H doublet Ar-H b,b' Jba=8.1
7 7.22-7.25 2 H doublet Ar-H c,c' Jcd=8.6
8 7.26-7.30 2 H doublet Ar-H a,a' Jab=8.7
9 7.56-7.60 2 H doublet Ar-H d,d' Jdc=8.1
Signal No.
Signal Position (δppm)
Relative No. of protons
Multiplicity Inference J Value In Hz
NMR SPECTRAL STUDIES OF 3-[4-(METHYLSULFONYL)PHENYL]-5-
(p-METHOXYPHENYL)- 4 , 5 - D I H Y D R O - 1 H - P Y R A Z O L E
SCH3
O
O NNH
O
CH3
HfHg
a b
a' b'
c
d
c '
d'
e
Studies on chemical entities...
Pyrazolines...
51
TAB
LE
-3 :
MA
SS S
PE
CT
RA
L S
TU
DIE
S O
F 3
-[4-
(ME
TH
YL
SU
LF
ON
YL
)PH
EN
YL
]-5-
(M-P
HE
NO
XY
PH
EN
YL
)-4
,5-
DIH
YD
RO
-1H
-PY
RA
ZO
LE
m/z
=39
2
Studies on chemical entities...
Pyrazolines...
52
EXPERIMENTAL
SYNTHESIS AND BIOLOGICAL SCREENING OF 3 - [ 4 -
( M E T H Y LS U L F O N Y L ) P H E N Y L ] - 5 - A R Y L - 4 , 5 - D I H Y D R O - 1 H -
PYRAZOLES
(A) Synthesis of 1-[4-(Methylsu l fony l )pheny l ] -3 -aryl-2 -propene-
1-ones
See Part-I, Section-I (B).
(B) Synthesis of 3-[4-(Methylsul fonyl)phenyl] -5-(p-methoxyphenyl)-4,5-
dihydro-1H-pyrazole
A mixture of 1-[4-(Methyls u l f o n y l ) p h e n y l ] - 3 -(p-methoxyphenyl) - 2 -
propene-1-one (3.16 gm, 0.01 mol) in methanol (25 ml) and hydrazine hydrate
(0.5gm, 0.01 mol) was refluxed for 8 hrs. The product was isolated and crystallized
from ethanol. Yield 63%, m.p. 168oC, Anal. Calcd. for C17H18N2O3S; Requires:
C, 61.80; H, 5.49; N, 8.48 %; Found: C, 61.78; H, 5.48; N, 8.46 %.
Similarly, other 3-[4-(methylsulfonyl)phenyl]-5-aryl-4 ,5-dihydro-1H-
pyrazoles were prepared. The physical data are recorded in Table No.3
(C) Biological screening of 3-[4-(Methylsulfonyl)phenyl] -5-aryl-4 ,5-
dihydro-1H-pyrazoles .
Antimicrobial testing were carried out as described in Part-I Section-I(C).
The zones of inhibition of test solutions are recorded in Graphical Chart No.3
Studies on chemical entities...
Pyrazolines...
53
2aC
6H5-
C16
H16
N2O
2S30
012
260
9.33
9.34
0.44
S 2
2b4-
Cl-
C6H
4-C
16H
15C
lN2O
2S33
416
478
8.37
8.36
0.61
S 2
2c2-
Cl-
C6H
4-C
16H
15C
lN2O
2S33
414
562
8.37
8.35
0.56
S 1
2d3-
Cl-
C6H
4-C
16H
15C
lN2O
2S33
413
258
8.37
8.38
0.52
S 2
2e4-
OC
H3-
C6H
4-C
17H
18N
2O3S
330
168
638.
488.
460.
55S 2
2f3,
4-(O
CH 3
) 2-C
6H3-
C18
H20
N2O
4S36
011
852
7.77
7.76
0.64
S 1
2g4-
F-C
6H4-
C16
H15
FN2O
2S31
819
266
8.80
8.81
0.41
S 1
2h3-
Br-
C6H
4-C
16H
15Br
N2O
2S37
914
045
7.39
7.40
0.59
S 2
2i3-
C6H
5-O
-C6H
4-C
22H
20N
2O3S
392
165
627.
147.
120.
44S 1
2j4-
N(C
H3)
2-C
6H4-
C18
H21
N3O
2S34
312
672
12.2
312
.24
0.51
S 2
2k2-
OH
-C6H
4-C
16H
16N
2O3S
316
160
578.
858.
870.
61S 2
2l2-
C4H
3O-
C14
H14
N2O
3S29
014
562
9.65
9.67
0.42
S 1
TA
BL
E :
2P
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CO
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OF
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S 1 H
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Studies on chemical entities...
Pyrazolines...
54
GR
AP
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3 :
3-[4
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Studies on chemical entities...
Pyrazolines...
55
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llluslea & Febiger , (Philadelphia), USA , 180; Biol. Abstr., 1977, 64 , 25183
Studies on chemical entities...
Cyanopyridines...
65
INTRODUCTION
Pyridine is the parent of the series of compounds that is important in
pharmaceutical, agriculture and industrial chemistry. Among a wide range of pyridines
3-cyanopyridines acquired a special attention due to their wide range of therapeutic
activities. Most derivatives are prepared by manipulation of pyridine and its simple
homologues in a manner similar to chemistry of the benzenoid chemistry. However
the simple pyridine compounds are prepared by the cyclization of aliphatic raw
materials.
The pyridine nucleous is found in a large number of commonly used drugs
which have diverse pharmacological activities. Interest in the synthesis of
multicyclic pyridine containing compounds have increased in recent years because
of their biological and pharmacological activities. In our continuation work in the
chemistry of pyridine nucleous, we have undrtaken the synthesis of methylsulfonyl
derivatives such as 2-methoxy-6-[4-(methylsulfonyl)phenyl]-4-phenylnicotinonitrile
via chlacones.
SYNTHETIC ASPECT :
Preparation of 3-cyanopyridines have been cited in literature1-6
with different
methods.
1. Samour and co-worker7 have prepared substi tuted cyanopyridines by
th e condensation of chalcones with malononitrile in presence of ammonium
acetate.
N
COOCH3
H3CO
CNR
Studies on chemical entities...
Cyanopyridines...
66
H2C
CN
CNNaOCH3
HC
CN
CN_
R O
R1
HC
CN
CN_
R O
R1
CN
N
H+
R O
R1
CN
N
R
R1
CN
OCH3ONN
R1
R OCH3
CN
OH
H
N
R1
R OCH3
CN
N
R1
R OCH3
CN-2H
NaOCH3
+
-OH-
H+
H+
NaOCH3
-
-R
R1
CN
OCH3OHN
NaOCH3
MECHANISM :
The reaction proceeds through conjugate addition of active methylene
compounds to the α,β -unsaturated system as shown below.
R1R
O
CH2(CN)2CH3CONH4
N
NH2
R
N
R1
Studies on chemical entities...
Cyanopyridines...
67
THERAPEUTIC IMPORTANCE
The extensive use of cyanopyridine derivatives have been established in medicine
due to its antihypertensive, anticholestemic, antidiabetic, antifungal and antibacterial
properties.Few of them reported as shown below.
1. Antifungal8
2. Antiepileptic9
3. Antibacterial10
4. Anticonvulsant11
5. Antitubercular12
6. Analgesic13
7. Insecticidal14
8. Antisoriasis15
9. Antihypertensive16
The synthesis of cyanopyridines are of current interest owing to their
enormous occurence in biologically active derivaties. Hence, considerable attention
has been focused on the study of efficient and pharamaceutical important
cyanopyridines bearing benzimidazole nucleus.
El-Nabawia et al.17
have prepared 2-amino-3-cyano pyridine derivatives (I)
and studied their antimicrobial activity. S. Guru et al.18
have synthesized various
cyanopyridyl derivatives (II) and documented their multiple biological activities.
O
N
NH2
R
N
NN CH3
CCH3
O
RC
NH2
N
(I) (II)
Studies on chemical entities...
Cyanopyridines...
68
The insecticidal activity of cyanopyridines have been screened by Y. Sasaki19
et al. Umed Ten et al.20
have prepared cyanopyridines as agrochemical fungicides.
The oxide activator bleaching activity of cyanopyridine has been proved by
Rees M.21
, Oshida M.22
prepared cyanopyridine derivatives which inhibit cerebral
edema and delayed neuron death. hence, they are useful as cerebral edema inhibitors
or cerebrovascular disorder remedies.
S. S. Verma et al.23
and M. D. Ankhiwala24
have synthesized 2-amino-3-cyano-
2,6-disubstituted pyrimidines and studied their biological activities. Several workers
have prepared cyanopyridine derivatives and reported their cholinesterase
inhibi tors ,25
ant ihis taminic and ant ia l lergic ,26
adernerg ic ,27
herbicidal ,28
antiinflammatory29
and insecticidal30
activities. Some new 3-cyanopyridine derivatives
synthesized by Hammama A. and coworkers31
showed anticancer and anti HIV-I
activity. Abdallah N. et al.32
have synthesized and reported analgesic and
antiinflammatory activity.
Moreover Miertus et al.33
synthesized 2-formyl pyridine thiosemicarbazone
as a carcinostatic agent. Adriano Afonso et al.34
have found cyanopyridines are
Fernesyl protein t ranferase inhibi tors . Hussain et a l .35
have synthes ized
cyanopyridines as antimicrobial agent. Wu Wenxue et al.36
have synthesized
cyanopyridines as histamine H3 antagonists. Saudi Manal N. S. et al.37
have found
that cyanopyridines have fascialicidal property. Harada Hironori et al.38
have prepared
cyanopyridines and screened for their large conductance calcium activated
potassium channel opener activity.
Dipeptidyl peptidase (DPP-IV) inhibition has the potential to become a
valuable therapy for diabetes. Edwin B. Villhauer and co-worker39
have reported
the first use of solid-phase synthesis in the discovery of a new DPP-IV inhibitor
class and a solution-phase synthesis that is practical up to the multikilogram scale.
One compound, NVP-DPP728 (III), is profiled as a potent, selective and shortacting
Studies on chemical entities...
Cyanopyridines...
69
DPP-IV inhibitor that has excellent oral bioavailability and potent antihyperglycemic
activity.
Marco J. L. et al.40
have synthesized of acetylcholinesterase inhibitors.
Moustafa M. A. et al.41
have prepared antibacterial agents. Rosentreter Ulrich et
al.42
have synthesized a new cyanopyridine as receptor agonists in the treatment of
cancer disease , inflammation, neurodegenerative disease(IV). Gary T. Wang and
co-worker43
have synthesized of o-trifluoromethylbiphenyl substituted 2-amino-
nicotinonitriles as inhibitors of farnesyltransferase(V).
Thus, diverse biological activities have been encountered in compounds
containing cyanopyridine ring system. Therefore it was considered wothwhile to
synthesise cyanopyridine derivatives which have been described as under.
SECTION-I : SYNTHESIS AND BIOLOGICAL SCREENING OF 2 -
METHOXY-6-[4-(METHYLSULFONYL)PHENYL]-4-
A R YLNICOTINONITRILES
N NHNH
O
N
CN
NC
(III)
N
CN
CNR2CH2S
NH2
O(CH2)n OR1
NO
N
N
NC
NR1
R2
F3C
CN
CH3
(IV) (V)
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70
SECTION - I
SYNTHESIS AND BIOLOGICAL SCREENING OF 2-METHOXY-6-[4-
(METHYLSULFONYL)PHENYL]-4-ARYLNICOTINONITRILES
Cyanopyridines play a vital role owing to their range of biological and
physiological activites. In the light of these biological activities and variety of
industrial applications, some new 2-methoxy-6-[4-(methylsulfonyl)phenyl]-4-
a ry ln i co t inon i t r i l e s derivatives of type (IV) have been prepared, by the
cyclocondensation of 1-[4-(methylsulfonyl)phenyl]-3-aryl-2-propene-1-ones of
type (I) with malononitrile in presence of sodium methoxide.
The structure elucidation of synthesized compounds has been done on the
basis of elemental analyses, infrared and 1H nuclear magnetic resonance spectroscopy
and further supported by Mass spectrometry.
All the compounds have been evaluated for their in vitro biological assay
like antibacterial activity towards gram positive and gram negative bacterial strains
and antifungal activity towards Aspergillus niger at a concentration of 40µg/ml.
The biological activities of synthesized compounds were compared with standard
drugs.
Type(I)Type(IV)R=Aryl
CH2(CN)2
NaOCH3 in methanol N
R
O
S
O
O
CH3
CH3
N
R
O
S
O
O
CH3
Studies on chemical entities...
Cyanopyridines...
71
30.0
40.0
50.0
60.0
70.0
80.0
90.0
100.0%T
500.0750.01000.01250.01500.01750.02000.03250.01/cm
482.2
534.2
779.2
819.7
900.7
1010.6
1091.6
1184.2
1209.3
1263.31307.6
1357.8
1380.9
1409.9
1448.41494.7
1546.8
1577.7
1606.6
2221.8
2852.5
2923.9
3222.8
3327.0
Type Vibration Frequency in cm-1 Ref. Mode Observed Reported
Alkane C-H str. (asym.) 2923 2975-2950 44-CH3 C-H str. (sym.) 2852 2880-2860 ,,
C-H def. (asym.) 1448 1470-1435 ,,C-H def. (sym.) 1380 1390-1370 ,,
Aromatic C-H str. 3028 3090-3030 45C=C str. 1494 1540-1480 ,,
1091 1125-1090 ,,1010 1070-1000 ,,
Halide C-Cl str. 819 800-600 44Sulfonyl SO2 str. 1184 1185-1165 ,,Ether C-O-C str. 1209 1260-1200 ,,Pyridine C=C str. 1606 1650-1520 45
C=N str. 1577 1580-1550 ,,Nitrile C=N str. 2221 2240-2120 ,,
IR SPECTRAL STUDIES OF 2-METHOXY-6-[4-(METHYLSULFONYL)
PHENYL]-4-(p-CHLOROPHENYL)NICOTINONITRILE
SCH3
O
O N
O CH3
N
Cl
Instrument : SHIMADZU FTIR 8400 Spectrophotometer; Frequency range: 4000-400
cm-1 (KBr disc.)
Studies on chemical entities...
Cyanopyridines...
72
Internal Standard : TMS; Solvent : CDCl3 : Instrument : BRUKER
Spectrometer (300 MHz)
1 2.4 3 H singlet Ar-SO2 CH3 -
2 3.9 3 H singlet Ar-OCH3 -
3 7.25-7.31 2 H doublet Ar-H b,b Jba=7.8
4 7.40-7.46 2 H doublet Ar-H c,c Jcd=8.4
5 7.43 1 H singlet Ar-He -
6 7.57-7.60 2 H doublet Ar-H a,a Jab=8.1
7 7.97-7.99 2 H doublet Ar-H d,d Jdc=8.1
Signal No.
Signal Position (δppm)
Relative No. of protons
Multiplicity Inference J Value In Hz
NMR SPECTRAL STUDIES OF 2-METHOXY-6-[4-(METHYLSULFONYL)
PHENYL]-4-(p-CHLOROPHENYL)NICOTINONITRILE
SCH3
O
O N
O CH3
N
Cl
a b
a'
c
d
c'
d'
He
b'
Studies on chemical entities...
Cyanopyridines...
73
TAB
LE
-4 :
MA
SS S
PE
CT
RA
L S
TU
DIE
S O
F 2-
ME
TH
OX
Y-6
-[4-
(ME
TH
YL
SU
LF
ON
YL
)PH
EN
YL
]-4-
AR
YL
NIC
OT
INO
NIT
RIL
E
m/z
= 3
64
Studies on chemical entities...
Cyanopyridines...
74
EXPERIMENTAL
SYNTHESIS AND BIOLOGICAL SCREENING OF 2-METHOXY- 6 - [ 4 -
(METHYLSULFONYL)PHENYL]-4-ARYLNICOTINONITRILES
(A) Synthesis of 1-[4-(Methyl su l fony l )pheny l ] -3 -aryl-2 -propene -
1 -ones
See Part-I, Section-I (B).
(B) Synthesis of 2-Methoxy-6-[4-(methylsulfonyl)phenyl]-4-(p-chloro-
phenyl)nicotinonitrile
To a solution of 1-[4-(methylsu l fony l )pheny l ] -3 -(p-chlorophenyl)- 2 -
p r o p e n e - 1 - o n e (3.20 gm, 0.01 mol), malononitrile (0.60gm, 0.01 mol) in
methanol (10ml) and sodium methoxide, which prepared from sodium (46mg) and
absolute methanol (20ml) was added. The content was heated under reflux with
stirring for 12 hr. The reaction mixture was diluted with water and extracted with
chloroform. The excess solvent was distilled off and residue was crystallized from
ethanol. Yield 48%, m.p. 165oC, Anal. Calcd. for C20H15ClN2O3 S; Requires:
C,60.22; H, 3.79; N, 7.02; Found: C, 60.20 ; H, 3.78; N, 7.01 %.
S i m i l a r l y , o t h e r 2 - m e t h o x y - 6 - [ 4 - ( m e t h y l s u l f o n y l ) p h e n y l ] - 4 -
arylnicotinonitriles were prepared. The physical data are recorded in Table No.4
(C) Biological screening of 2-Methoxy-6-[4-(methylsul fonyl )phenyl] -4-
arylnicot inonitr i les
Antimicrobial testing were carried out as described in Part-I Section-1 (C).
The zones of inhabition of test solution are recorded in Graphical Chart No 4.
Studies on chemical entities...
Cyanopyridines...
75
4aC
6H5-
C20
H16
N2O
3S36
412
554
7.69
7.68
0.51
S 1
4b4-
Cl-
C6H
4-C
20H
15C
lN2O
3S39
816
548
7.02
7.01
0.56
S 2
4c2-
Cl-
C6H
4-C
20H
15C
lN2O
3S39
813
253
7.02
7.03
0.41
S 2
4d3-
Cl-
C6H
4-C
20H
15C
lN2O
3S39
814
258
7.02
7.04
0.45
S 1
4e4-
OC
H3-
C6H
4-C
21H
18N
2O4S
394
115
627.
107.
120.
42S 1
4f3,
4-(O
CH 3
) 2-C
6H3-
C22
H20
N2O
5S42
411
858
6.60
6.62
0.56
S 2
4g4-
F-C
6H4-
C20
H15
FN2O
3S38
216
362
7.33
7.34
0.52
S 2
4h3-
Br-
C6H
4-C
20H
15Br
N2O
3S44
314
068
6.32
6.35
0.51
S 2
4i3-
C6H
5-O
-C6H
4-C
26H
20N
2O4S
456
192
596.
146.
150.
42S 1
4j4-
N(C
H3)
2-C
6H4-
C22
H21
N3O
3S40
717
845
10.3
110
.32
0.59
S 2
4k2-
OH
-C6H
4-C
20H
16N
2O4S
380
170
567.
367.
350.
51S 2
4l2-
C4H
3O-
C18
H14
N2O
4S35
414
565
7.90
7.92
0.49
S 1
TA
BL
E :
4P
HY
SIC
AL
CO
NST
AN
TS
OF
2-
ME
TH
OX
Y-6
-[4-
(ME
TH
YL
SU
LF
ON
YL
)PH
EN
YL
]-4-
AR
YL
NIC
OT
INO
NIT
RIL
ES
S 1 H
exan
e:Et
hyl
acet
ate(
5:5)
,
S 2 H
exan
e:Et
hyl
acet
ate(
6:4)
Sr.
R M
olec
ular
M
olec
ular
M
.P.
Yie
ld
%
of N
itro
gen
Rf
Sol
vent
No
For
mul
a
Wei
ght
oC
%
Cal
cd.
Fou
nd
V
alue
Sys
tem
1
2
3 4
5
6
7
8 9
10
Studies on chemical entities...
Cyanopyridines...
76
GR
AP
HIC
AL
CH
AR
T N
O.
4 :
2-M
ET
HO
XY
-6-[
4-(M
ET
HY
LS
UL
FO
NY
L)P
HE
NY
L]-
4-A
RY
LN
ICO
TIN
ON
ITR
ILE
S
Studies on chemical entities...
Cyanopyridines...
77
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Studies on chemical entities...
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80
INTRODUCTION
Pyridone, which belongs to an important group of heterocyclic compounds
have been extensively explored for their applications in the field of medicine.
Pyridones, with a carbonyl group at position 2 (I) have been subject of extensive
study in recent past. Numerous reports have appeared in the literature, which
highlight their chemistry and use.
Pyridones are derivatives of pyrimidines with carbonyl group at 2-position (I).
Some 2-pyridones are physiologically as well as pharmacologically important which
are as under, eg. amrinone (II), ciclopirox (III) and methylprylon (IV).
SYNTHETIC ASPECT :
1. G. Simchen and G. Entemman1 have synthesised 2-pyridone in which the ring
nitrogen comes from a nitrile group in acyclic precursor.
2. K. Folkers and S. A. Harris2 have synthesised 3-cyano-2-pyridone by
the condensation of cyano acetamide with 1,3-diketone or 3-ketoester.
3. M. A. Sluyter and co-workers3 have prepared fused 2-pyridones.
NH
O
N
NH
NH2
O
N
CH3
OH
ONH
O
O
CH3
CH3
CH3
(I)
(II) (III) (IV)
Studies on chemical entities...
Pyridones...
81
THERAPEUTIC IMPORTANCE
Pyridone derivatives have been found to possess variety of therapeutic activities
as shown below.
1. Anticancer4
2. Herbicidal5
3. Pesticidal6 ,7
4. Antimicrobial8
5. Angitensin II antagonist9-11
6. Antiviral12
7. AntiHIV13
Collins et al.14
have prepared heteroaryl pyridones as GABA α,β ligands (V).
Pednekar15
synthesized fused 2-pyridone derivatives (VI), (VII) and (VIII) as useful
heterocyclic moieties as they possess broad spectrum of biological activities such
as antiviral, CNS depressant, bactericidal and ulcer inhibitor.
Moreover, several co-workers have prepared 2-pyridones as S3 site of
thrombin inhibitor16
, herbicidal 17
, SH2 domain inhibitor
18, antimicrobial
19, GABA-A
receptor 20
and antiinflammatory21
.
O
CH3
O
H5C2OH2C
+N
NH2
O NH
CH3
N
CH2OC2H5
O
NH
Z
Y
X
O
NH
O
NC
CH3
N
N
R
N
N
O
NC
CH3
O
CH3
NH
O
NC
O
Ph
Ph
CH3
(VI)(V) (VII) (VIII)
Studies on chemical entities...
Pyridones...
82
Morishita Koji et al. 22
have synthesized m-(2-oxo-l,2-dihydropyridyl) urea
derivatives (IX) possessing cholesterol acyltransterase (ACAT) inhibitory activity
and are useful for the treatment of hyperlipidemia and arteriosclerosis.
Moreover, several co-workers have prereported 2-pyridones as S3 site of
thrombin inhibitors23
, herbicidal24
, SH2 domain inhibitor25
and GABA-A receptor26
.
Peter et al.27
have prepared pyridinyl methyl substituted pyridines and pyridones as
angiotensin II antagonists. H. Posnes28
reported 2-pyridones as physiologically active
compounds. Devdas Balekudru et al.29
prepared substituted pyridinones (X) as
modulators of P38 NAP kinase.
Furthermore, Stenzel Wolfgang et al.30
reported some pyridone derivatives
(XI) as cardiotonic, hypnotics, antiasthematics and antithrombotic. Fischer Reiner
et al.31
prepared (thiazolyl) dihydro-1H-pyridinones (XII) as pesticides and herbicides.
N
NH NH
O
Pr
OCH3
Bu
PrO
N
O
Br
O
Et
(IX)
(X)
Studies on chemical entities...
Pyridones...
83
Peter and co-workers32
have prepared pyridinylmethyl substituted pyridines
and pyridones as angitensin II antagonist. Mukhtar Hussain Khan and co-workers33,34
have prepared 2-pyridone derivatives (XIII) and (XIV) which possess insecticidal
and pesticidal activity.
These observations prompted us to combine this nucleous into well known
pharmaceutical properties of cyanopyridone nucleous so as to enhance the over all
activities of resulting moiety, which have described as under.
SECTION-I : SYNTHESIS AND BIOLOGICAL SCREENING OF 6-[4-
(METHYLSULFONYL)PHENYL]-2 -OXO-4-ARYL-
1,2-DIHYDROPYRIDINE-3-CARBONITRILES
O
OH
N
N
NH
R1
O
NCR2
W
S
N
A B
Q1
Q2
O
X
OG
Y
NH
N
S CN
O
S
R
R
NH
NH
N
R
O
CN
OR
(XI)(XII)
(XIII) (XIV)
Studies on chemical entities...
Pyridones...
84
SECTION - I
SYNTHESIS AND BIOLOGICAL SCREENING OF 6 - [ 4 -
(METHYLSULFONYL)PHENYL]-2-OXO-4-ARYL-1,2DIHYDROPYRIDINE-
3-CARBONITRILES
In view of powerful biological activities shown by cyanopyridones, like
antimicrobial and antitubercular, it was worthwhile to synthesized some cyano
pyridone derivatives possessing better biological activity. Synthesis of some new 6-
[4-(methylsulfonyl)phenyl]-2-oxo-4-aryl-1,2dihydropyridine-3-carbonitriles of
type(V) car r ied out by cyclocondensat ion of chalcones of type(I ) wi th
ethylcyanoacetate in presence of ammonium acetate as under.
The structure elucidation of synthesized compounds has been done on the
basis of elemental analyses, infrared and 1H nuclear magnetic resonance spectroscopy
and further supported by Mass spectrometry.
All the compounds have been evaluated for their in vitro biological assay
like antibacterial activity towards gram positive and gram negative bacterial strains
and antifungal activity towards Aspergillus niger at a concentration of 40µg/ml.
The biological activities of synthesized compounds were compared with standard
drugs.
Moreover, some selected compounds have been evaluated for their in vitro
biological assay towards a strain of Mycobacterium tuberculosis H37Rv at a
concentration of 6.25 µg/ml using Rifampin as a standard drug which have been
tested at Tuberculosis Antimicrobial Acquisition Co-ordinating Facility (TAACF),
Alabama, U. S. A.
Type(I) R=Aryl Type(V)
CN-CH2-COOC2H5
CH3COONH4NH
R
O
S
O
O
CH3
N
R
O
S
O
O
CH3
Studies on chemical entities...
Pyridones...
85
20.0
30.0
40.0
50.0
60.0
70.0
80.0
90.0
100.0%T
500.0750.01000.01250.01500.01750.02000.03250.01/cm
495.7
561.2 715.5
813.9
894.9
977.8
1010.6
1031.8
1091.6
1186.11224.7
1336.6
1363.6
1402.21436.9
1490.9
1529.4
1589.2
1635.5
1652.9
1739.7
1921.0
2218.02856.4
2918.1
3249.8
3406.1
Type Vibration Frequency in cm-1 Ref. Mode Observed Reported
Alkane C-H str. (asym.) 2918 2975-2950 35-CH3 C-H str. (sym.) 2856 2880-2860 ,,
C-H def. (asym.) 1439 1470-1435 ,,C-H def. (sym.) 1363 1390-1370 ,,
Aromatic C-H str. 3043 3090-3030 36C=C str. 1490 1540-1480 ,,
1091 1125-1090 ,,1031 1070-1000 ,,
Halide C-Cl str. 813 800-600 35Sulfonyl SO2 str. 1186 1185-1165 ,,Amide C=O str. 1739 1740-1690 ,,Amine N-H str. 3249 3180-3140 ,,Nitrtile C=N str. 2218 2240-2120 ,,
IR SPECTRAL STUDIES OF 6-[4-(METHYLSULFONYL)PHENYL]-2-
O X O - 4 - ( p - C H L O R O P H E N Y L ) - 1 , 2 - D I H Y D R O P Y R I D I N E - 3 -
CARBONITRILE
SCH3
O
O NH
O
Cl
N
Instrument : SHIMADZU FTIR 8400 Spectrophotometer; Frequency range: 4000-400
cm-1 (KBr disc.)
Studies on chemical entities...
Pyridones...
86
Internal Standard : TMS; Solvent : CDCl3 : Instrument : BRUKER
Spectrometer (300 MHz)
1 2.4 3 H singlet Ar-SO2CH3 -
2 6.6 1 H singlet Ar-He -
3 6.69 1 H singlet Ar-NH -
4 7.32-7.39 2 H doublet Ar-H b,b Jbc=8.1
5 7.41-7.44 2 H doublet Ar-H c,c Jcd=8.4
6 7.54-7.57 2 H doublet Ar-H a,a Jab=8.4
7 7.66-7.69 2 H doublet Ar-H d,d Jdc=8.7
Signal No.
Signal Position (δppm)
Relative No. of protons
Multiplicity Inference J Value In Hz
NMR SPECTRAL STUDIES OF 6-[4-(METHYLSULFONYL)PHENYL]-2-
O X O - 4 - ( p - C H L O R O P H E N Y L ) - 1 , 2 - D I H Y D R O P Y R I D I N E - 3 -
CARBONITRILE
S
CH3
OO
NH
O
N Cl
a
b
a'
b'
cd
c'd'
ef
Studies on chemical entities...
Pyridones...
87
TAB
LE
-5 :
MA
SS S
PE
CT
RA
L S
TU
DIE
S O
F 6
-[4-
(ME
TH
YL
SUL
FO
NY
L)P
HE
NY
L]-
2-O
XO
-4-(
P-C
HL
OR
OP
HE
NY
L)-
1,2-
DIH
YD
RO
PY
RID
INE
-3-C
AR
BO
NIT
RIL
E
m/z
= 3
84
Studies on chemical entities...
Pyridones...
88
EXPERIMENTAL
SYNTHESIS AND BIOLOGICAL SCREENING OF 6 - [ 4 -
(METHYLSULFONYL)PHENYL]-2-OXO-4-ARYL-1,2DIHYDROPYRIDINE-
3-CARBONITRILES
(A) Synthesis of 1-[4-(Methylsu l fony l )pheny l ] -3 -aryl-2 -propene-
1-ones
See Part-I, Section-I (B).
(B) Synthesis of 6-[4-(Methylsulfonyl)phenyl]-2-oxo-4-(p-chlorophenyl)-
1,2dihydropyridine-3-carbonitrile
To a solution of 1-[4-(methylsu l fony l )pheny l ] -3 -(p-chlorophenyl)- 2 -
propene-1-one (3.20 gm, 0.01 mol), ethylcyanoacetate (1.13 gm, 0.01 mol) and
ammonium acetate (5.92gm, 0.08mol) in dioxan(25ml) was refluxed for 8 hr. The
resulting mixture was poured on to crushed ice. The product was isolated and
crys ta l l ized f rom e thanol . Yie ld 52%, m.p . 185o C, Anal . Ca lcd . for
C19H13ClN2O3S; Requires: C, 69.30; H, 3.40; N, 7.28; Found: C, 69.28; H, 3.49
N, 7.25 %.
S i m i l a r l y , o t h e r 6 - [ 4 - ( m e t h y l s u l f o n y l ) p h e n y l ] - 2 - o x o - 4 - a r y l -
1,2dihydropyridine-3-carbonitriles were prepared. The physical data are recorded
in Table No.5
(C) Biological screening of 6-[4-(Methylsulfonyl)phenyl]-2-oxo-4-aryl-
1,2dihydropyridine-3-carbonitriles
Antimicrobial testing were carried out as described in Part-I Section-I(C).
The zones of inhibition of test solution are recorded in Graphical Chart No 5.
Studies on chemical entities...
Pyridones...
89
5aC
6H5-
C19
H14
N2O
3S35
013
465
7.99
7.98
0.45
S 2
5b4-
Cl-
C6H
4-C
19H
13C
lN2O
3S38
418
552
7.28
7.25
0.55
S 1
5c2-
Cl-
C6H
4-C
19H
13C
lN2O
3S38
413
242
7.28
7.25
0.48
S 1
5d3-
Cl-
C6H
4-C
19H
13C
lN2O
3S38
415
453
7.28
7.24
0.45
S 2
5e4-
OC
H3-
C6H
4-C
20H
16N
2O4S
380
136
597.
367.
350.
42S 1
5f3,
4-(O
CH 3
) 2-C
6H3-
C21
H18
N2O
5S41
011
850
6.83
6.84
0.56
S 2
5g4-
F-C
6H4-
C19
H13
FN2O
3S36
816
064
7.60
7.61
0.59
S 2
5h3-
Br-
C6H
4-C
19H
13Br
N2O
3S42
914
068
6.53
6.54
0.59
S 1
5i3-
C6H
5-O
-C6H
4-C
25H
18N
2O4S
442
194
726.
336.
340.
57S 2
5j4-
N(C
H3)
2-C
6H4-
C21
H19
N3O
3S39
317
861
10.6
810
.67
0.44
S 1
5k2-
OH
-C6H
4-C
19H
14N
2O4S
366
162
557.
657.
660.
45S 1
5l2-
C4H
3O-
C17
H12
N2O
4S34
013
868
8.23
8.24
0.51
S 2
TA
BL
E :
5P
HY
SIC
AL
CO
NST
AN
TS
OF
6-
[4-(
ME
TH
YL
SUL
FO
NY
L)P
HE
NY
L]-
2-O
XO
-4-A
RYL
-1,2
-DIH
YD
RO
PY
RID
INE
-3-C
AR
BO
NIT
RIL
ES
S 1
Hex
ane:
Ethy
l ac
etat
e(5:
5),
S2
Hex
ane:
Ethy
l ac
etat
e(6:
4)
Sr.
R M
olec
ular
M
olec
ular
M
.P.
Yie
ld
%
of N
itro
gen
Rf
Sol
vent
No
For
mul
a
Wei
ght
oC
%
Cal
cd.
Fou
nd
V
alue
Sys
tem
1
2
3 4
5
6
7
8 9
10
Studies on chemical entities...
Pyridones...
90
5a 182252 PD-49 C6H5 - Alamar H37R v >6.25 00
5b 182253 PD-50 4-Cl-C6H4 - Alamar H37R v >6.25 00
5c 182254 PD-51 2-Cl-C6H4 - Alamar H37R v >6.25 00
5d 182255 PD-52 3-Cl-C6H4 - Alamar H37R v >6.25 00
5e 182256 PD-53 4-OCH3-C6H4 - Alamar H37R v >6.25 55
5f 182257 PD-54 3,4-(OCH3)2-C6H3 - Alamar H37R v >6.25 18
5g 182258 PD-55 4-F-C6H4 - Alamar H37R v >6.25 42
5h 182259 PD-56 4-Br-C6H4 - Alamar H37R v >6.25 00
5i 182260 PD-57 3-C6H5 O-C6H4 - Alamar H37R v >6.25 11
5j 182261 PD-58 4-N(CH3 )2-C6H4 - Alamar H37R v >6.25 00
5k 182262 PD-59 2-OH-C6H4 - Alamar H37R v >6.25 00
5l 182263 PD-60 2-C4H3O - Alamar H37R v >6.25 10
SrNo.
Sample ID
Corp ID
R Assay MtbStrain
%Inhibi.
MIC µg/ml
TABLE NO-5TAACF, Southern Research Insitute
Primary Assay Summary Report
NAID/Southern Research Insitute/GWL Hansen’s Disease Centre/Colorado State
University proprietary Information
NH
R
O
S
O
O
CH3
N
ANTITUBERCULAR ACTIVITY OF 6-[4-(METHYLSULFONYL)PHENYL]-
2-OXO-4-ARYL-1,2DIHYDROPYRIDINE-3-CARBONITRILES
Studies on chemical entities...
Pyridones...
91
GR
AP
HIC
AL
CH
AR
T N
O.
5 :
6-[4
-(M
ET
HY
L S
UL
FO
NY
L)P
HE
NY
L]-
2-O
XO
-4-A
RY
L-1
,2D
IHY
DR
OP
YR
IDIN
E-3
-
CA
RB
ON
ITR
ILE
S
Studies on chemical entities...
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92
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PCT. Int. Appl. WO 96 30, 342 (Cl. C07D 213/89); Chem. Abstr., 126 , 7993e (1997).
13. F. Al-Omar, A. Abdul Zahar, A. El-Khair, A. Adel;
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16. J. E. Reiner, Lim-Wilby, R. S. Marge, T. K Brunck and Ha-Vong;
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Jpn. KokaiTokkyo Koho JP II 140 , 054 (Cl. C07D 213/64); Chem. Abstr., 131 , 44738a
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(1999).
18. R. Betageri, L. Beaulieu, B. Pierrel ;
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22 M. K Morishita, A. Nagisa and J. Masashi;
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23 Reiner John E., Lim Wilby, Margeu Rita S., Bruncj Terence K. and Ha-Vong Theresa;
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24. Yamagudi Mikio, Ito Voshiniro, Shibaytama Atsushi, Yomaji, Mitsuhiro and Hanai Rgo;
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25. Betageri Rajashekhar, Beaulieu Llinas Brunet, Pierrel;
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26. Harison Timothy, Moyes Christopher, Richard Laewis, Richard Thomas;
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27. Peter Fey, Dressel Juergem, Kanko Rudolf, Huebsch Walter and Kraemer Thomas;
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Der. Offen. DE 10 , 100,175 (Cl. C07D417/04), 11 Jul 2002.
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Studies on chemical entities...
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95
INTRODUCTION
The 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 in 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 α,β or 1,2-pyran or
isolated as in α,δ or 1,4-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 literature1-10
.
1. Reaction between (A) and CH2(CN)2 led to corresponding 2-amino-3-
cyano-4H-pyrans (B)11
.
(A) (II) (B)
O4H-pyran
O2H-pyran
N
O
R1
O O
RCH2(CN)2
N
O
O
O
R
NH2
R1
N
(I)
Studies on chemical entities...
Cyanopyrans...
96
MECHANISM :
The reaction of malononitrile with α,β -unsaturated system leads to the
formation of cyano 4H-pyran via Michael addition as shown in figure.
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. CNS active agent12
2. Cytotoxic 13
3. Inhibitors of cell proliferation14
4. Gastric acid secretion inhibitor15
5. Antimicrobial16
6. Hypolipidemic17
7. Antipyretic18
8. Antiinvasive19
9. Anti HIV20,21
10. Antifungal22-24
11. Antiallergic25
R
R1
OCH2(CN) 2
N
N
R1 R1
O
R R1
N
N OH
O
NH
R
N
R1
O
NH2
R
N
R1
Studies on chemical entities...
Cyanopyrans...
97
12. Analgesic26
13. Antagonist27,28
14. Antitumor29
El-Subbagh and co-workers30
have synthesized cyanopyran derivatives and
showed their antiviral activity. Corbou Romuld et al.31
have reported cyanopyran
derivatives (III) which have significant pharmacological activity.
Some of the pyran derivatives(IV) have been patented for their use as
antihypertensive32
, antiestogens33
, antagonist34,35
, antitumor36
and antiviral37
activities.
Synthesis and biological activity of pyran ring system have been reported by O’Brien
et al.38
Sharanin Y. U. A. et al.39
have suggested new 2-amino-3-cyano-4H-pyran
derivatives (V).
O
N
NH
NH2
OCH3
O
CH3
N
O NH2
NN
N
(III)
(IV)
Studies on chemical entities...
Cyanopyrans...
98
Zwaagstra Mariel40
have newly synthesized pyran derivatives show
antiashamatic activity. Boyer Frederick et al.41
have prepared some new 2-amino-3-
cyano-4H-pyran and reported for anti HIV agent and antiviral activity.
Synthesis and anticancer activity of pyran (VI) containing flourine have been
reported by Mohamed S. Abd et al.42
4H-pyran of type (VII) were prepared to
enhance the anticancer and anti HIV activity.
Moreover, Fathy F. Abdel-Latif et al.43
have reported the synthesis of 2-amino-
3-cyanopyran derivatives and studied their biological activity. Piao Minz, Zhu et.
al.44
have prepared biologically active 2-amino pyran derivatives.
Recently, Hanafusa T, et al45
have reported some new cyanopyran as functional
promoter upstream p53 regulatory sequence of IGFBP3 that is silenced by tumor
specific methylation. Williamson H. S. et al46
have described pyran as a truncated
O
O
O
CH3 NH2
N
R
N
N S
O
CH3
HOOC
F
Cl
NH2
N
X
ONH2
N
(V)
(VI) (VII)
Studies on chemical entities...
Cyanopyrans...
99
protein from enteropathogenic Escherichia coli acts as an antagonist. Yeo H. and Li
Y. et al.47
have described the synthesis and antiviral activity of helioxanthin analogues.
David-Cordonnier M. H. et al.48
have synthesized as antitumor agents.
Morever, Asche C. et al.49
have reported some novel cyanopyran as antitumour
activity and structure-activity relationships of 5H-benzo[b]carbazoles. Moon C.H.
et al.50
have found some novel benzopyran analog, attenuates hypoxia-induced cell
death via mitochondrial KATP channel and protein kinase C-epsilon in heart-derived
H9c2 cells. Howe A.Y. et al.51 have described some novel nonnucleoside inhibitor
of hepatitis C virus RNA-dependent RNA polymerase. Kim KY et al.52
Anti-apoptotic
action of (2S,3S,4R)-N”-cyano-N-(6-amino-3,4-dihydro-3-hydroxy-2-methyl-2-
dimethoxymethyl-2H-benzopyran-4-yl)-N’-benzylguanidine.
Thus, diverse biological activities have been encountered in compounds
containing cynopyran ring system. Therefore it was considered wothwhile to
synthesized cyanopyran derivatives containing methylsulfonyl derivatives which have
been descried as under.
SECTION-I :SYNTHESIS AND BIOLOGICAL SCREENING OF 2-AMINO-
6 - [ 4 -(METHYLSULFONYL)PHENYL]-4-ARYL-4H-PYRAN-3-
CARBONITRILES
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100
SECTION - I
SYNTHESIS AND BIOLOGICAL SCREENING OF 2 - A M I N O - 6 - [ 4 -
(METHYLSULFONYL)PHENYL]-4-ARYL-4H-PYRAN-3-CARBONITRILES
Cyanopyran derivatives have been found to be associated with various
pharmacological activities. These findings encouraged us to synthesized, some new
2-amino-6-[4-(methylsulfonyl)phenyl]-4-aryl-4H-pyran-3-carbonitrile derivatives of
type (VI) by the cyclocondensation of 1-[4-(methylsulfonyl)phenyl]-3-aryl-2-
propene-1-ones of type-(I) with malononitrile in pyridine.
The structure elucidation of synthesized compounds has been done on the
basis of elemental analyses, infrared and 1H nuclear magnetic resonance spectroscopy
and further supported by Mass spectrometry.
All the compounds have been evaluated for their in vitro biological assay
like antibacterial activity towards gram positive and gram negative bacterial strains
and antifungal activity towards Aspergillus niger at a concentration of 40µg/ml.
The biological activities of synthesized compounds were compared with standard
drugs.
Moreover, some selected compounds have been evaluated for their in vitro
biological assay towards a strain of Mycobacterium tuberculosis H37Rv at a
concentration of 6.25 µg/ml using Rifampin as a standard drug which have been
tested at Tuberculosis Antimicrobial Acquisition Co-ordinating Facility (TAACF),
Alabama, U. S. A.
R=ArylType(I) Type(VI)
CH2(CN)2
in pyridine O
R
NH2
S
O
O
CH3
N
R
O
S
O
O
CH3
Studies on chemical entities...
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101
20.0
30.0
40.0
50.0
60.0
70.0
80.0
90.0
100.0%T
500.0750.01000.01250.01500.01750.02000.03250.01/cm
530.4 561.2
777.3
821.6
966.3
1028.0
1095.5
1180.4
1247.9
1305.71346.2
1407.91436.9
1461.91494.7
1514.01566.1
1583.41606.6
2046.3
2150.5
2185.22204.5
2372.3
2837.12922.0
3004.9
3352.1
Type Vibration Frequency in cm-1 Ref.
Mode Observed Reported
Alkane C-H str. (asym.) 2922 2975-2950 53
-CH3 C-H str. (sym.) 2837 2880-2860 ,,
C-H def. (asym.) 1461 1470-1435 ,,
C-H def. (sym.) 1346 1390-1370 ,,
Aromatic C-H str. 3004 3090-3030 54
C=C str. 1514 1540-1480 ,,
1095 1125-1090 ,,
1028 1070-1000 ,,
Halide C-Cl str. 821 800-600 53
Sulfonyl SO2 str. 1180 1185-1165 ,,
Pyran C=C str. 1566 1650-1520 54
Nitrile C=N str. 2204 2240-2120 53
Amine N-H str. 3352 3380-3350 ,,
IR SPECTRAL STUDIES OF 2 - A M I N O - 6 - [ 4 -(METHYLSULFONYL)
PHENYL]-4-(p-CHLOROPHENYL)-4H-PYRAN-3-CARBONITRILE
SCH3
O
O O
NH2
Cl
N
Instrument : SHIMADZU FTIR 8400 Spectrophotometer; Frequency range: 4000-400
cm-1 (KBr disc.)
Studies on chemical entities...
Cyanopyrans...
102
Internal Standard : TMS; Solvent : CDCl3 : Instrument : BRUKER
Spectrometer (300 MHz)
Signal No.
Signal Position (δppm)
Relative No. of protons
Multiplicity Inference
1 2.5 3 H singlet Ar-SO2 CH3 -
2 5.39 1 H singlet Ar-He -
3 7.33-7.36 2 H doublet Ar-Hb,b’ Jba=8.4
4 7.46-7.49 2 H doublet Ar-H c,c’ Jcd=8.1
5 7.49 2 H singlet Ar-NH2 -
6 7.55-7.56 2 H doublet Ar-H a,a’ Jab=8.7
7 7.56-7.62 2 H doublet Ar-H d,d’ Jdc=8.3
NMR SPECTRAL STUDIES OF 2 - A M I N O - 6 - [ 4 -(METHYLSULFONYL)
PHENYL]-4-(p-CHLOROPHENYL)-4H-PYRAN-3-CARBONITRILE
SCH3
O
O O
NH2
Cl
N
a b
a' b'
c
d
c'
d'
e f
J Value In Hz
Studies on chemical entities...
Cyanopyrans...
103
TAB
LE
-6 :
MA
SS S
PE
CT
RA
L S
TU
DIE
S O
F 2
-AM
INO
-6-[
4-(
ME
TH
YL
SUL
FO
NY
L)P
HE
NY
L]-
4-(P
-ME
TH
OX
Y
PH
EN
YL
)-4H
-PY
RA
N-3
-CA
RB
ON
ITR
ILE
m/z
= 3
82
Studies on chemical entities...
Cyanopyrans...
104
EXPERIMENTAL
(A) Synthesis of 1-[4-(Methylsu l fony l )pheny l ] -3 -aryl-2 -propene-
1-ones
See Part-I, Section-I (B).
B) Synthesis of 2-Amino-6-[4-(methylsulfonyl)phenyl]-4-(p-chlorophenyl)-
4H-pyran-3-carbonitrile
To a solution of 1-[4-(Methylsu l fony l )pheny l ] -3 -(p-chlorophenyl)- 2 -
propene-1-one. (3.20 gm, 0.01 mol) and malononitrile (0.66gm, 0.01 mol) dissolved
in pyridine (20 ml). The content was heated under reflux for 10 hr. on oilbath. The
reaction mixture was cooled and poured on to crushed ice. The residue was
neutralized with 20% HCl, where upon a solid separated out, which was filtered
and crys ta l l ized f rom ethanol . Yie ld 58%, m.p .143o C Anal . Ca lcd . for
C19H15ClN2O3S; Requires: C,58.99; H, 3.91; N, 7.24 %; Found: C, 58.98; H,
3.89; N, 7.23 %.
Similarly, other 2-amino-6-[4-(methylsulfonyl)phenyl]-4-aryl-4H-pyran-3-
carbonitriles were prepared. The physical data are recorded in Table No.6
(C) Biological screening of 2-Amino-6-[4-(methylsulfonyl)phenyl]-4-aryl-
4H-pyran-3-carbonitriles
Antimicrobial testing were carried out as described in Part-I, Section-I(C).
The zones of inhibition or test solution are recorded in Graphical Chart No.6
Studies on chemical entities...
Cyanopyrans...
105
6aC
6H5-
C19
H16
N2O
3S35
216
568
7.95
7.92
0.56
S 2
6b4-
Cl-
C6H
4-C
19H
15C
lN2O
3S38
614
358
7.24
7.23
0.44
S 1
6c2-
Cl-
C6H
4-C
19H
15C
lN2O
3S38
616
862
7.24
7.25
0.50
S 1
6d3-
Cl-
C6H
4-C
19H
15C
lN2O
3S38
615
546
7.24
7.22
0.55
S 2
6e4-
OC
H3-
C6H
4-C
20H
18N
2O4S
382
170
567.
337.
340.
53S 1
6f3,
4-(O
CH 3
) 2-C
6H3-
C21
H20
N2O
5S41
211
854
6.79
6.80
0.46
S 2
6g4-
F-C
6H4-
C19
H15
FN2O
3S37
016
064
7.56
7.57
0.49
S 2
6h3-
Br-
C6H
4-C
19H
15Br
N2O
3S43
114
069
6.50
6.52
0.49
S 1
6i3-
C6H
5-O
-C6H
4-C
25H
20N
2O4S
444
194
516.
306.
320.
55S 2
6j4-
N(C
H3)
2-C
6H4-
C21
H21
N3O
3S39
517
860
10.3
610
.37
0.46
S 1
6k2-
OH
-C6H
4-C
19H
16N
2O4S
368
142
577.
607.
620.
54S 1
6l2-
C4H
3O-
C17
H14
N2O
4S34
213
965
8.18
8.19
0.55
S 2
TA
BL
E :
6P
HY
SIC
AL
CO
NST
AN
TS
OF
2-
AM
INO
-6-[
4-(M
ET
HY
LSU
LF
ON
YL
)PH
EN
YL
]-4-
AR
YL
-4H
-PY
RA
N-3
-
CA
RB
ON
ITR
ILE
S
S 1
Hex
ane:
Ethy
l ac
etat
e(5:
5),
S2
Hex
ane:
Ethy
l ac
etat
e(6:
4)
Sr.
R M
olec
ular
M
olec
ular
M
.P.
Yie
ld
%
of N
itro
gen
Rf
Sol
vent
No
For
mul
a
Wei
ght
oC
%
Cal
cd.
Fou
nd
V
alue
Sys
tem
1
2
3 4
5
6
7
8 9
10
Studies on chemical entities...
Cyanopyrans...
106
6a 182240 PD-37 C6H5 - Alamar H37R v >6.25 00
6b 182241 PD-38 4-Cl-C6H4 - Alamar H37R v >6.25 00
6c 182242 PD-39 2-Cl-C6H4 - Alamar H37R v >6.25 00
6d 182243 PD-40 3-Cl-C6H4 - Alamar H37R v >6.25 00
6e 182244 PD-41 4-OCH3-C6H4 - Alamar H37R v >6.25 55
6f 182245 PD-42 3,4-(OCH3)2-C6H3 - Alamar H37R v >6.25 18
6g 182246 PD-43 4-F-C6H4 - Alamar H37R v >6.25 42
6h 182247 PD-44 4-Br-C6H4 - Alamar H37R v >6.25 00
6i 182248 PD-45 3-C6H5 O-C6H4 - Alamar H37R v >6.25 11
6j 182249 PD-46 4-N(CH3 )2-C6H4 - Alamar H37R v >6.25 00
6k 182250 PD-47 2-OH-C6H4 - Alamar H37R v >6.25 00
6l 182251 PD-48 2-C4H3O - Alamar H37R v >6.25 10
SrNo.
Sample ID
Corp ID
R Assay MtbStrain
%Inhibi.
MIC µg/ml
TABLE NO-6TAACF, Southern Research Insitute
Primary Assay Summary Report
NAID/Southern Research Insitute/GWL Hansen’s Disease Centre/Colorado State
University proprietary Information
O
R
NH2
S
O
O
CH3
N
ANTITUBERCULAR ACTIVITY OF 2-AMINO-6-[4-(METHYLSULFONYL)
PHENYL]-4-ARYL-4H-PYRAN-3-CARBONITRILES
Studies on chemical entities...
Cyanopyrans...
107
GR
AP
HIC
AL
CH
AR
T N
O.
6 :
2-A
MI
NO
-6-[
4-(
ME
TH
YL
SU
LF
ON
YL
)PH
EN
YL
]-4
-AR
YL
-4H
-PY
RA
N-3
-
CA
RB
ON
ITR
ILE
S
Studies on chemical entities...
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108
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112
INTRODUCTION
Pyrimidine is the most important member of all the diazines as this ring system
occurs widely in living organisms. Pyrimidine and its derivatives have gained
prominence bacause of their potential pharmaceutical values. Many pyrimidine
derivatives play vital role in many physiological action. They are among those
molecules that make life possible as being some of the building blocks of DNA and
RNA.
Pyrimidine is considered to be a resonance hybrid of the charged and
uncharged cannonical structures, its resonance energy has been found to be less
than benzene or pyridine. The naturally occuring pyrimidine derivatives was first
isolated by Gabrial and Colman in 1870, and its structure was confirmed in 1953 as
5-β-D-gluco-pyranoside of divicine.
SYNTHETIC ASPECT
A very important general method for preparing pyrimidines is the condensation
between a three carbon compounds of the type YCH2Z, where Y and Z = COR,
CO2R, CN, and compounds having the amidine structure R(C=NH)NH2, where R
= R (an amidine), OH (urea), SH or SR (thiourea or its s-derivative), NH2
(guanidine); the condensation is carried out in the presence of sodium hydroxide or
sodium ethoxide. This general reaction may be illustrate by the condensation of
acetamidine with ethylacetoacetate to form 4-hydroxy-2,6-dimethylpyrimidine.
NN
NH2 NH
NH2
+ CH2
CCH3O
O
H5C2O NaOC2H5
N
NH
NH2 CH3
O
N
N
OH
NH2 CH3
(I)
Studies on chemical entities...
Pyrimidines...
113
Pyrimidines can also be prepared by cycloaddition reaction of 1,3,5-
triazines,which act as electron deficient dienes.
There are many other methods of pyrimidine ring synthesis which are of more
limited scope. The reaction of 1,3-dicarbonyl compound or an equivalent reagent
with formamide provides a route of several pyrimidine which are unsubstituted at
the 2-position.
Some other examples of pyrimidine synthesis are as under.
REACTION MECHANISM
The reaction mechanism for the formation of pyrimidine derivatives described
as under.
N
N
N CH3 C N(C2H5)2 N
N
CH3
(H5C2)2N
(PhCO)2CH2 +
CHO
NH4OAc
Me2SO, 80C
N
N
Ph
Ph Ph
N
N
Ph
Ph Ph
CH3 C N3KOMe
140C
N
N
CH3
NH
CH3
N
NCH3 CH3
NH2
PhNMeCH=CH-CHOHCONH 2
200'CHCONHCH=CH-CHO
HCONH 2
N
N
Studies on chemical entities...
Pyrimidines...
114
THERAPEUTIC IMPORTANCE
It is revealed from the literature survey that pyrimidine derivatives have been
found possessing biological activities reported as under.
1. Fungicidal1
2. Insecticidal2
3. Anticonvulsant3
4. Antitubercular4
5. Tranquilizing5
6. Antidiabetic6
7. Antihypertensive7
8. Analgesic8
9. Antibacterial9
10. Diuretic10
S. S. Sangapure and S. M. Mulagi11
have tested the antimicrobial activity of
benzofuro[3,2-d]pyrimidine derivatives (II). El Sayed12
and A. M. Badaway have
synthesized alkylated substituted mercapto pyrimidine derivatives (III) and studied
RC
CHCH
R1
O
+NH2NH2
R2
Alkali RC
R1
O NH
R2
NH2
R CR1
OH
NH
R2
NH
R CR1
N
R2
N
R CR1
N
R2
N
OH-
-H+_
-H
R2 = SH, NH 2
Studies on chemical entities...
Pyrimidines...
115
ON
NH
NH2
S
N
N
CH3
Cl
H3CS
NH
NH
O
R
O
N
NH
NH2
O
NNH
O
CH3
O
O
N3
OH
N
N
ClNH2
H5C2 NH2
N
N
O
O
O
NH2NH2
CH3
CH3
CH3
their anticancer and antineoplastic activity. H. Y. Moustafa13
have reported some
pyrimidine derivatives and studied their biological activities.
The pyrimidines uracil (IVa), thyamine (IVb) and cytosine (V) occur very
widely in nature since they are components of nucleic acids, in the form of N-
substituted sugar derivatives. Several analogues have been used as compounds that
interfere with the synthesis and functioning of nucleic acids: examples are fluorouracil
(IVc) and the anti-AIDS drug Zidovudine (AZT) (VI). Some diaminopyrimidines ,
including pyrimethamine (VII) and trimethoprim (VIII) are antimalarial agents;
trimethoprim is also an effective antibacterial agent when used in combination with
a sulphonamide. Minoxidil (IX) is a vasodilator which has been used in the treatment
of hypertension. Vitamine B1(X) is also a pyrimidine.
(II) (III)
(IV) (V) (VI)
(VII) (VIII)
Studies on chemical entities...
Pyrimidines...
116
NH
N N
NH2
R3
R1
R2
CH3 N N
R4
R3
R2
R1
SH
R5
N
N
N+
O
NH2
NH2
N
N+
CH3
NH2
N+
S
CH3
HOH2CH2C
H
Patil L. R. et al.14
have synthesized some new pyrimidines bearing paracetamol
and imidazolyl moieties. B. J. Ghiya et al.15
synthesized some mercapto pyrimidine
derivatives (XI) and screened for their anticancer, antitubercular and anti HIV
activities.Kaplina N. V. and co-workers16
shows herpes inhibiting activity of some
mercapto pyrimidine derivatives.
Moreover, Chaudhari Bipinchandra et al.17
prepared N6-(2-aminopyrimidin-
4-yl)-quinoline-4,6-diamine (XII) as N-type calcium channel antagonists for the
treatment of pain. Devi E. Sree and co-workers18
have prepared pyrimidine
derivatives and tested for antimicrobial activity. Kovalenko A. L.19
synthesized and
reported antifungal activity of pyrimidine derivatives. Shiv P. Singh and co-workers20
synthesized 4-(4-pyrazolyl)-2-aminopyrimidines(H) and tested them for their
antimicrobial activity.
Some pyrazolo thienopyrimidine derivatives exhibit antiulcer activity21
.
Skolova A. S. and co-workers22
have synthesized 5-amino-6-mercapto pyrimidine
possessing antitumor and cytostatic activity. Hozein Zeinab et al.23
and Khalafallah
(IX) (X)
(XI) (XII)
Studies on chemical entities...
Pyrimidines...
117
Ali Kamel24
have prepared mercapto derivatives and screened for their antibacterial
and antifungal activity.
H. S. Joshi et al.25 have sythesized some new pyrimidines as antitubercular
and atimicrobial activity(XIII).
Marie Gompel and co-worker26
have showed that meridianins inhibit various
protein kinases such as cyclin-dependent kinases, glycogen synthase kinase-3, cyclic
nucleotide-dependent kinases and casein kinase (XIV). Alistair H et al27
have
synthesized a novel series of aminopyrimidine IKK2 inhibitors which show excellent
in vitro inhibition of this enzyme and good selectivity over the IKK1 isoform. The
relative potency and selectivity of these compounds has been rationalized using
QSAR and structure-based modelling (XV).
Aleem Gangjee et al.28
have designed and synthesized some novel analogues
of N -{4-[2-(2-Amino-4-ethylpyrrolo[2,3-d ]pyrimidin-5-yl)ethyl]benzoyl}-L-
glutamic acid as potential inhibitors of thymidylate synthase (TS), dihydrofolate
NH
N
N
NH2
R
R
R
R
Meridianin A OH H H HMeridianin B OH H Br HMeridianin C H Br H HMeridianin D H H Br HMeridianin E OH H H BrMeridianin F H Br Br HMeridianin G H H H H
N
N NH
S
N
NH
O O
R
(XIV)
NH
N
Br
R SH
(XIII)
(XV)
Studies on chemical entities...
Pyrimidines...
118
reductase (DHFR) and as antitumor agents (XVI). Antonello Mai et al.29
have
descr ibed 2 -a lky lamino-6- [1 - (2 ,6 -d i f luorophenyl )a lky l ] -3 ,4 -d ihydro-5-
alkylpyrimidin-4(3H)-ones (F2-NH-DABOs) 4, 5 belonging to the dihydro-alkoxy-
benzyl-oxopyrimidine (DABO) family and bearing different alkyl and arylamino side
chains at the C2-position of the pyrimidine ring were active against wild type (wt)
human immunodeficiency virus (HIV-1) and some relevant HIV-1 mutants(XVII).
Viney Lather and co-worker30
have been proposed to predict the anti-HIV
activity of dihydro (alkylthio) (naphthylmethyl) oxopyrimidines. These models are
capable of providing lead structures for development of potent but safe anti-HIV
agents(XVIII).
Gompel M et al.31
have prepared new family of protein kinase inhibitors
isolated from the ascidian aplidium meridianum. Mai A et al.32
have synthesized 5-
alkyl-2-alkylamino-6-(2,6-difluorophenylalkyl)-3,4-dihydropyrimidin-4(3H)-ones, a
new series of potent, broad-spectrum non-nucleoside reverse transcriptase inhibitors
N
N
NH
NH2
R
NH
O COOH
COOH
CH3
(XVI)
N
NH
O
R
NH
X F F
R1
R = R1 =H, Me ; X = alkyl,aryl, arylalkyl
(XVII)
N
NH
X-S
O
R
R1
(XVIII)
Studies on chemical entities...
Pyrimidines...
119
belonging to the DABO family. Yamamoto I. et al.33
have reported some
oxopyrimidines searching for the novel antagonist or agonist of barbiturates to the
sleep mechanism based on the uridine receptor. Huang YL et al.34
have synthesized
non-classical antifolates, 5-(N-phenylpyrrolidin-3-yl)-2,4,6-triaminopyrimidines
and 2,4-diamino-6(5H)-oxopyrimidines as antitumor activity.
Shimizu T., Kimura T. et al.35
have described N3-substituted uridine and
related pyrimidine nucleosides as antinociceptive effects in mice. Sanmartin C et
al.36
have prepared new symmetrical derivatives as cytotoxic agents and apoptosis
inducers. Agarwal A. et al.37
have synthesized 2,4,6-trisubstituted pyrimidine
derivatives as pregnancy interceptive agents.
Whittingham J. L. et al.38
have described pyrimidine ring as a platform for
antimalarial drug for the selectivity of a class of nucleoside inhibitors. Han G. Z. et
al.39
documented the pyr imidine der ivat ives as ant icancer ac t ions of 2-
methoxyestradiol and microtubule-disrupting agents in human breast cancer. Tack
D. K. et al.40
reported anthracycline vs nonanthracycline therapy for breast cancer.
Cano-Soldado P. et al.41
have described pyrimidine nucleous as interaction of
nucleoside inhibitors of HIV-1 reverse transcriptase with the concentrative nucleoside
transporter-1 (SLC28A1). Gompel M. et al.42
have isolated a new family of protein
kinase inhibitors from the ascidian aplidium meridianum. Junmei Wang et al.43 have
prepared and described for HIV-1 Reverse Transcriptase(XIX)
NHNH F
F
F
O
Cl
(XIX)
Studies on chemical entities...
Pyrimidines...
120
Looking to the diversified activities exhibited and in continuation of our work
on the synthesis of biologically active heterocycles, the synthesis and biological
screening of pyrimidine derivatives have been described as under.
SECTION-I : SYNTHESIS AND BIOLOGICAL SCREENING OF 4 -
[ 4 - ( M E T H Y L S U L F O N Y L ) P H E N Y L ] - 6 -
A RYLPYRIMIDIN-2(1H)-ONES
SECTION-II : SYNTHESIS AND BIOLOGICAL SCREENING OF 4-[4-
(METHYLSULFONYL)PHENYL]-6-ARYLPYRIMIDIN-
2(1H)-THIONES
SECTION-III : SYNTHESIS AND BIOLOGICAL SCREENING OF 4-[4-
(METHYLSULFONYL)PHENYL]-6-ARYLPYRIMIDIN-
2-AMINES
Studies on chemical entities...
Pyrimidines...
121
SECTION - I
SYNTHESIS AND BIOLOGICAL SCREENING OF 4 - [ 4 -
(METHYLSULFONYL)PHENYL]-6-ARYLPYRIMIDIN-2(1H)-ONES
In the past years considerable evidence has been accumulated to demonstrate
the efficiency of pyrimidinones. 4-[4-(methylsulfonyl)phenyl]-6-arylpyrimidin-
2(1H)-one of type (VII) have been prepared by the condensation of 1-[4-
(methylsu l fony l )pheny l ] -3 -a ry l -2 -p ropene -1 -ones of type-(I) with urea in
presence of catalytic amount of conc. HCl as shown under.
The structure elucidation of synthesized compounds has been done on the
basis of elemental analyses, infrared and 1H nuclear magnetic resonance spectroscopy
and further supported by Mass spectrometry.
All the compounds have been evaluated for their in vitro biological assay
like antibacterial activity towards gram positive and gram negative bacterial strains
and antifungal activity towards Aspergillus niger at a concentration of 40µg/ml.
The biological activities of synthesized compounds were compared with standard
drugs.
Moreover, some selected compounds have been evaluated for their in vitro
biological assay towards a strain of Mycobacterium tuberculosis H37Rv at a
concentration of 6.25 µg/ml using Rifampin as a standard drug which have been
tested at Tuberculosis Antimicrobial Acquisition Co-ordinating Facility (TAACF),
Alabama, U. S. A.
C
O
NH2 NH2 NHN
R
O
S
O
O
CH3R
O
S
O
O
CH3
R=Aryl Type(VII)Type(I)
Studies on chemical entities...
Pyrimidines...
122
0.0
20.0
40.0
60.0
80.0
100.0
%T
500.0750.01000.01250.01500.01750.02000.03250.01/cm
474.5 518.8
596.0
657.7
698.2
773.4 810.0
918.1 947.0
995.21029.9
1074.31157.2
1182.3
1247.9
1340.4
1394.4
1431.1
1460.0
1492.8
1514.0
1620.1
2380.0
2675.12738.7
2856.42920.0
3030.03242.1
3404.1
Type Vibration Frequency in cm-1 Ref. Mode Observed Reported
Alkane C-H str. (asym.) 2920 2975-2950 44
-CH3 C-H str. (sym.) 2856 2880-2860 ,,
C-H def. (asym.) 1460 1470-1435 ,,
C-H def. (sym.) 1394 1390-1370 ,,
Aromatic C-H str. 3030 3090-3030 45
C=C str. 1514 1540-1480 ,,
1089 1125-1090 ,,
1029 1070-1000 ,,
Halide C-Cl str. 773 800-600 44
Sulfonyl SO2 str. 1182 1185-1165 ,,
Vinyl CH=CH str. 3025 3050-3000 45
oxopyri. C=O str. 1654 1672-1652 ,,
IR SPECTRAL STUDIES OF 4-[4-(METHYLSULFONYL)PHENYL]-
6- ( p-CHLOROPHENYL)PYRIMIDIN-2(1H)-ONE
SCH3
O
O
NH
N
O
Cl
Instrument : SHIMADZU FTIR 8400 Spectrophotometer; Frequency range: 4000-400
cm-1 (KBr disc.)
Studies on chemical entities...
Pyrimidines...
123
Internal Standard : TMS; Solvent : CDCl3 : Instrument : BRUKER
Spectrometer (300 MHz)
1 2.5 3 H singlet Ar-SO2 CH3 -
2 7.35 1 H singlet Ar-Hf -
3 7.46-7.51 2 H doublet Ar-H b,b’ Jba=8.1
4 7.66-7.77 2 H doublet Ar-H c,c’ Jcd=7.8
5 7.62 1 H singlet Ar-He -
6 7.88-7.91 2 H doublet Ar-H a,a’ Jab=8.4
7 7.94-7.97 2 H doublet Ar-H d,d’ Jdc=7.8
Signal No.
Signal Position (δppm)
Relative No. of protons
Multiplicity Inference J Value In Hz
NMR SPECTRAL STUDIES OF 4-[4-(METHYLSULFONYL)PHENYL]-6-
(p-CHLOROPHENYL)PYRIMIDIN-2(1H)-ONE
SCH3
O
O
NH
N
O
Cl
ba
a' b'
c
d
c'
d'
e
f
Studies on chemical entities...
Pyrimidines...
124
TAB
LE
-7 :
MA
SS S
PE
CT
RA
L S
TU
DIE
S O
F 4
-[4-
(ME
TH
YL
SU
LF
ON
YL
)PH
EN
YL
]-6-
(P-C
HL
OR
OP
HE
NY
L)
PY
RIM
IDIN
-2(1
H)-
ON
E
m/z
= 3
60
Studies on chemical entities...
Pyrimidines...
125
EXPERIMENTAL
SYNTHESIS AND BIOLOGICAL SCREENING OF
(A) Synthesis of 1-[4-(Methylsulfonyl)phenyl]-3-aryl-2-propene-1-ones
See Part-I, Section-I (B).
(B) Synthesis of 4-[4-(Methylsul fonyl )phenyl ] -6-(p-chlorophenyl)
pyrimidin-2(1H)-one
To a solution of 1-[4-(methylsu l fony l )pheny l ] -3 -(p-chlorophenyl)- 2 -
propene-1-one. (3.20 gm, 0.01 mol) and urea (0.60gm, 0.01 mol) in dioxane(15
ml) was refluxed in presence of alcoholic KOH for 10 hr. The excess solvent was
distilled off and the residue was neutralized with dilute HCl, the separated solid
was filtered out and crystallized from ethanol. Yield 48 %, m.p. 165oC Anal. Calcd.
for C17H13ClN2O3S Requires: C, 56.99; H, 3.63; N, 7.76 % Found: C, 56.96; H,
3.62, N, 7.74 %.
Similarly, other 4-[4-(methylsulfonyl)phenyl]-6-arylpyr imidin-2(1H)-
ones were prepared.The physical data are recorded in Table No. 7.
(C) Biological screening of 4-[4-(Methylsulfonyl)phenyl]-6-aryl
pyrimidin-2(1H)-ones
Antimicrobial testing were carried out as described in Part-I, Section-I(C).
The zones of inhibition of test solution are reported in Graphical Chart No. 7.
Studies on chemical entities...
Pyrimidines...
126
7aC
6H5-
C17
H14
N2O
3S32
613
561
8.58
8.53
0.56
S 2
7b4-
Cl-
C6H
4-C
17H
13C
lN2O
3S36
016
548
7.76
7.74
0.49
S 1
7c2-
Cl-
C6H
4-C
17H
13C
lN2O
3S36
016
952
7.76
7.74
0.54
S1
7d3-
Cl-
C6H
4-C
17H
13C
lN2O
3S36
015
558
7.76
7.75
0.43
S 2
7e4-
OC
H3-
C6H
4-C
18H
16N
2O4S
356
170
567.
867.
870.
53S 2
7f3,
4-(O
CH 3
) 2-C
6H3-
C19
H18
N2O
5S38
611
851
7.25
7.26
0.56
S 1
7g4-
F-C
6H4-
C17
H13
FN2O
3S34
416
062
8.13
8.14
0.48
S 2
7h3-
Br-
C6H
4-C
17H
13Br
N2O
3S40
514
048
6.91
6.90
0.54
S 1
7i3-
C6H
5-O
-C6H
4-C
23H
18N
2O4S
418
194
626.
696.
700.
46S 1
7j4-
N(C
H3)
2-C
6H4-
C19
H19
N3O
3S36
917
851
11.3
711
..34
0.48
S 2
7k2-
OH
-C6H
4-C
17H
14N
2O4S
342
126
578.
188.
190.
54S 2
7l2-
C4H
3O-
C15
H12
N2O
4S31
620
562
8.86
8.87
0.58
S 1
S 1 H
exan
e:Et
hyl
acet
ate(
5:5)
,
S 2 H
exan
e:Et
hyl
acet
ate(
6:4)
TA
BL
E :
7P
HY
SIC
AL
CO
NST
AN
TS
OF
4-[
4-(M
ET
HY
LS
UL
FO
NY
L)P
HE
NY
L]-
6-A
RY
LP
YR
IMID
IN-2
(1H
)-O
NE
S
Sr.
R M
olec
ular
M
olec
ular
M
.P.
Yie
ld
%
of N
itro
gen
Rf
Sol
vent
No
For
mul
a
Wei
ght
oC
%
Cal
cd.
Fou
nd
V
alue
Sys
tem
1
2
3 4
5
6
7
8 9
10
Studies on chemical entities...
Pyrimidines...
127
7a 182216 PD-13 C6H5 - Alamar H37R v >6.25 00
7b 182217 PD-14 4-Cl-C6H4 - Alamar H37R v >6.25 00
7c 182218 PD-15 2-Cl-C6H4 - Alamar H37R v >6.25 00
7d 182219 PD-16 3-Cl-C6H4 - Alamar H37R v >6.25 00
7e 182220 PD-17 4-OCH3-C6H4 - Alamar H37R v >6.25 55
7f 182221 PD-18 3,4-(OCH3)2-C6H3 - Alamar H37R v >6.25 18
7g 182222 PD-19 4-F-C6H4 - Alamar H37R v >6.25 42
7h 182223 PD-20 4-Br-C6H4 - Alamar H37R v >6.25 00
7i 182224 PD-21 3-C6H5 O-C6H4 - Alamar H37R v >6.25 11
7j 182225 PD-22 4-N(CH3 )2-C6H4 - Alamar H37R v >6.25 00
7k 182226 PD-23 2-OH-C6H4 - Alamar H37R v >6.25 00
7l 182227 PD-24 2-C4H3O - Alamar H37R v >6.25 10
SrNo.
Sample ID
Corp ID
R Assay MtbStrain
%Inhibi.
MIC µg/ml
TABLE NO-7TAACF, Southern Research Insitute
Primary Assay Summary Report
NAID/Southern Research Insitute/GWL Hansen’s Disease Centre/Colorado State
University proprietary Information
NHN
R
O
S
O
O
CH3
ANTITUBERCULAR ACTIVITY OF 4-[4-(METHYLSULFONYL)PHENYL]
- 6 - A RYLPYRIMIDIN-2(1H)-ONES
Studies on chemical entities...
Pyrimidines...
128
GR
AP
HIC
AL
CH
AR
T N
O.
7 :
4-[4
-(M
ET
HY
LS
UL
FO
NY
L)P
HE
NY
L]-
6-A
RY
LP
YR
IMID
IN-2
(1H
)-O
NE
S
Studies on chemical entities...
Pyrimidines...
129
SECTION - II
SYNTHESIS AND BIOLOGICAL SCREENING OF 4 - [ 4 -
(METHYLSULFONYL)PHENYL]-6-ARYLPYRIMIDIN-2(1H)-THIONES
Thiopyrimidines represent one of the most active classes of compounds
possessing a wide spectrum of biological activities, such as significant in vitro activity
against unrelated DNA and RNA viruses including Polio Viruses, diuretic,
antitubercular spermidical etc. These valid observation led us to synthesize 4-[4-
(m ethylsulfonyl)phenyl]-6-arylpyrimidin-2(1H)-thiones of type (VIII) by
cyclocondensation of 1-[4-(methylsulfonyl)phenyl]-3-aryl-2-propene-1-ones of
type-(I) and thiourea in presence of HCl as catalyst.
The structure elucidation of synthesized compounds has been done on the
basis of elemental analyses, infrared and 1 H nuclear magnetic resonance
spectroscopy and further supported by Mass spectrometry.
All the compounds have been evaluated for their in vitro biological assay
like antibacterial activity towards gram positive and gram negative bacterial strains
and antifungal activity towards Aspergillus niger at a concentration of 40µg/ml.
The biological activities of synthesized compounds were compared with standard
drugs.
Moreover, some selected compounds have been evaluated for their in vitro
biological assay towards a strain of Mycobacterium tuberculosis H37Rv at a
concentration of 6.25 µg/ml using Rifampin as a standard drug which have been
tested at Tuberculosis Antimicrobial Acquisition Co-ordinating Facility (TAACF),
Alabama, U. S. A.
NHN
R
S
S
O
O
CH3C
S
NH2 NH2R
O
S
O
O
CH3
Type(VIII)Type(I) R=Aryl
Studies on chemical entities...
Pyrimidines...
130
30.0
40.0
50.0
60.0
70.0
80.0
90.0
100.0%T
500.0750.01000.01250.01500.01750.02000.03250.01/cm
474.5 493.7
532.3
596.0 669.3
734.8 773.4
812.0
983.6
1014.51031.8
1087.81182.3
1207.4
1224.7
1276.81301.9
1332.7
1382.91406.0
1490.9
1546.8
1564.2
1604.7
1658.7
2339.52362.6
2854.5
2918.1
3342.4
Type Vibration Frequency in cm-1 Ref.
Mode Observed Reported
Alkane C-H str. (asym.) 2918 2975-2950 44
-CH3 C-H str. (sym.) 2854 2880-2860 ,,
C-H def. (asym.) 1490 1470-1435 ,,
C-H def. (sym.) 1382 1390-1370 ,,
Aromatic C-H str. 3045 3090-3030 45
C=C str. 1546 1540-1480 ,,
1087 1125-1090 ,,
1031 1070-1000 ,,
Sulfonyl SO2 str. 1182 1185-1165 44
Amine N-H str. 3342 3300-3150 45
C=C str. 1658 ,,
IR SPECTRAL STUDIES OF 4 - [4 - (METHYLSULFONYL)PHENYL]-6-
AR YLPYRIMIDIN-2(1H)-THIONE
SCH3
O
O
NH
N
S
Instrument : SHIMADZU FTIR 8400 Spectrophotometer; Frequency range: 4000-400
cm-1 (KBr disc.)
Studies on chemical entities...
Pyrimidines...
131
Internal Standard : TMS; Solvent : CDCl3 : Instrument : BRUKER
Spectrometer (300 MHz)
1 2.5 3 H singlet Ar-SO2 CH3 -
2 7.26 1 H singlet Ar-NH -
3 7.26-7.32 2 H doublet Ar-Hb,b’ Jba=8.4
4 7.52-7.61 5 H multiplet Ar-H(c-g) -
5 7.94-7.96 2 H doublet Ar-Ha,a’ Jab=8.4
6 7.73 1 H singlet Ar-He -
Signal No.
Signal Position (δppm)
Relative No. of protons
Multiplicity Inference J Value In Hz
NMR SPECTRAL STUDIES OF 4 - [4 - (METHYLSULFONYL)PHENYL]-6-
AR YLPYRIMIDIN-2(1H)-THIONE
SCH3
O
O
NH
N
S
a b
a' b'
c
d
g
f
e
h
i
Studies on chemical entities...
Pyrimidines...
132
TAB
LE
-8 :
MA
SS S
PE
CT
RA
L S
TU
DIE
S O
F 4-
[4-(
ME
TH
YL
SU
LF
ON
YL
)PH
EN
YL
]-6-
AR
YL
PY
RIM
IDIN
-2(1
H)-
TH
ION
E
m/z
= 3
42
Studies on chemical entities...
Pyrimidines...
133
EXPERIMENTAL
SYNTHESIS AND BIOLOGICAL SCREENING OF 4 - [ 4 -
(METHYLSULFONYL)PHENYL]-6-ARYLPYRIMIDIN-2(1H)-THIONES
(A) Synthesis of 1-[4-(Methylsu l fony l )pheny l ] -3 -aryl-2-propene-ones
See Part-I, Section-I (B).
(B) Synthesis of 4-[4-(Methylsulfonyl)phenyl]-6-(phenyl)pyrimidin-2(1H)-
thione
A mixture of 1-[4-(methylsulfonyl)phenyl]-3-phenyl-2-propene-one (2.86
gm, 0.01 mole) and thiourea (0.78gm, 0.01 mol)in dioxane(15 ml) was refluxed on
a oil-bath in presence of alcoholic KOH for 10 hr. The solvent was distilled off and
the residue was neutralized with dilute HCl, the separated solid was filtered out and
crystallized from ethanol. Yield 62 %, m.p. 182oC Anal. Calcd. for C17H14N2O2S2
Requires: C, 59.63; H, 4.12; N, 8.18 % Found: C, 59.61; H, 4.10, N, 8.19 %.
Similarly, other 4-[4-(m ethylsulfonyl)phenyl]-6-arylpyrimidin-2(1H)-
thiones were prepared. The physical data are recorded in Table No. 8.
(C) Biological screening of 4-[4-(Methylsulfonyl)phenyl]-6-arylpyrimidin-
2(1H)-thiones
Antimicrobial testing were carried out as described in Part-I, Section-I(C).
The zones of inhibition of test solution are reported in Graphical Chart No. 8.
Studies on chemical entities...
Pyrimidines...
134
8aC
6H5-
C17
H14
N2O
2S2
342
182
628.
188.
190.
62S 2
8b4-
Cl-
C6H
4-C
17H
13C
lN2O
2S2
376
165
517.
437.
440.
42S 1
8c2-
Cl-
C6H
4-C
17H
13C
lN2O
2S2
376
162
587.
437.
420.
54S 1
8d3-
Cl-
C6H
4-C
17H
13C
lN2O
2S2
376
155
547.
437.
450.
48S 1
8e4-
OC
H3-
C6H
4-C
18H
16N
2O3S
237
217
046
7.52
7.51
0.56
S 2
8f3,
4-(O
CH 3
) 2-C
6H3-
C19
H18
N2O
4S2
402
118
516.
966.
.97
0.54
S 1
8g4-
F-C
6H4-
C17
H13
FN2O
2S2
360
160
597.
777.
780.
48S 2
8h3-
Br-
C6H
4-C
17H
13Br
N2O
2S2
421
140
676.
656.
640.
51S 1
8i3-
C6H
5-O
-C6H
4-C
23H
18N
2O3S
243
416
558
6.45
5.44
0.47
S 1
8j4-
N(C
H3)
2-C
6H4-
C19
H19
N3O
2S2
385
172
6610
.90
10.9
10.
49S 2
8k2-
OH
-C6H
4-C
17H
14N
2O3S
235
813
654
7.82
7.81
0.54
S 1
8l2-
C4H
3O-
C15
H12
N2O
3S2
332
160
588.
437.
440.
61S 2
TA
BL
E :
8P
HY
SIC
AL
CO
NST
AN
TS
OF
4
-[4
-(M
ET
HY
LS
UL
FO
NY
L)P
HE
NY
L]-
6-A
RY
LP
YR
IMID
IN-2
(1H
)-
TH
ION
ES
S1
Hex
ane:
Ethy
l ac
etat
e(5:
5),
S 2
Hex
ane:
Ethy
l ac
etat
e(6:
4)
Sr.
R M
olec
ular
M
olec
ular
M
.P.
Yie
ld
%
of N
itro
gen
Rf
Sol
vent
No
For
mul
a
Wei
ght
oC
%
Cal
cd.
Fou
nd
V
alue
Sys
tem
1
2
3 4
5
6
7
8 9
10
Studies on chemical entities...
Pyrimidines...
135
8a 182228 PD-25 C6H5 - Alamar H37R v >6.25 00
8b 182229 PD-26 4-Cl-C6H4 - Alamar H37R v >6.25 00
8c 182230 PD-27 2-Cl-C6H4 - Alamar H37R v >6.25 00
8d 182231 PD-28 3-Cl-C6H4 - Alamar H37R v >6.25 00
8e 182232 PD-29 4-OCH3-C6H4 - Alamar H37R v >6.25 55
8f 182233 PD-30 3,4-(OCH3)2-C6H3 - Alamar H37R v >6.25 18
8g 182234 PD-31 4-F-C6H4 - Alamar H37R v >6.25 42
8h 182235 PD-32 4-Br-C6H4 - Alamar H37R v >6.25 00
8i 182236 PD-33 3-C6H5 O-C6H4 - Alamar H37R v >6.25 11
8j 182237 PD-34 4-N(CH3 )2-C6H4 - Alamar H37R v >6.25 00
8k 182238 PD-35 2-OH-C6H4 - Alamar H37R v >6.25 00
8l 182239 PD-36 2-C4H3O - Alamar H37R v >6.25 10
SrNo.
Sample ID
Corp ID
R Assay MtbStrain
%Inhibi.
MIC µg/ml
TABLE NO-8TAACF, Southern Research Insitute
Primary Assay Summary Report
NAID/Southern Research Insitute/GWL Hansen’s Disease Centre/Colorado State
University proprietary Information
NHN
R
S
S
O
O
CH3
ANTITUBERCULAR ACTIVITY OF 4-[4-(METHYLSULFONYL)PHENYL]-
6-ARYLPYRIMIDIN-2(1H)-THIONES
Studies on chemical entities...
Pyrimidines...
136
GR
AP
HIC
AL
CH
AR
T N
O.
8 :
4-[4
-(M
ET
HY
LS
UL
FO
NY
L)P
HE
NY
L]-
6-A
RY
LP
YR
IMID
IN-2
(1H
)-T
HIO
NE
S
Studies on chemical entities...
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137
SECTION - III
SYNTHESIS AND BIOLOGICAL SCREENING OF 4 - [ 4 -
(METHYLSULFONYL)PHENYL]-6-ARYLPYRIMIDIN-2-AMINES
Compounds containing pyrimidine ring are widely distributed in nature. Many
amino pyrimidine derivatives are reported to possess different biological activities.
In view of these findings, it was considered worthwhile to synthesize some new 4-
[4 - (methylsulfonyl)phenyl]-6-arylpyrimidin-2-amines of type-(IX) to study their
biological activities. Amino pyrimidine derivatives of type-(IX) have been prepared
by the reaction of the chalcones of type- (I) with guanidine hydrochloride in presence
of potassium tertiary-butoxide in tertiary-butanol shown as under.
The structure elucidation of synthesized compounds has been done on the
basis of elemental analysis, infrared and 1H nuclear magnetic resonance spectroscopy
and further supported by Mass spectrometry.
All the compounds have been evaluated for their in vitro biological assay
like antibacterial activity towards gram positive and gram negative bacterial strains
and antifungal activity towards Aspergillus niger at a concentration of 40µg/ml.
The biological activities of synthesized compounds were compared with standard
drugs.
C
S
NH2 NH2 .HClNN
R
NH2
S
O
O
CH3
R
O
S
O
O
CH3
Type(I) Type(IX)R=Aryl
Studies on chemical entities...
Pyrimidines...
138
50.0
60.0
70.0
80.0
90.0
100.0
%T
500.0750.01000.01250.01500.01750.02000.03250.01/cm
451.3
491.8
804.3
964.3
1010.6
1089.7
1218.9
1319.2
1355.9
1436.9
1490.9
1527.5
1571.9
1645.2
2339.52360.7
2852.52920.0
3211.3
3336.6
Type Vibration Frequency in cm-1 Ref. Mode Observed Reported
Alkane C-H str. (asym.) 2920 2975-2950 44-CH3 C-H str. (sym.) 2852 2880-2860 ,,
C-H def. (asym.) 1436 1470-1435 ,,C-H def. (sym.) 1355 1390-1370 ,,
Aromatic C-H str. 3085 3090-3030 45C=C str. 1645 1620-1430 ,,
1089 1125-1090 ,,1010 1070-1000 ,,
Halide C-Cl str. 804 800-600 44Sulfonyl SO2 str. 1175 1185-1165 ,,Pyrimidine C=N str. 1571 1580-1520 45Primary Amine N-H str. 3336 3554-3350 ,,
IR SPECTRAL STUDIES OF 4 - [4 - ( METHYLSULFONYL)PHENYL]-6-
(p-CHLOROPHENYL)PYRIMIDIN-2-AMINE
SCH3
O
O
N
N
NH2
Cl
Instrument : SHIMADZU FTIR 8400 Spectrophotometer; Frequency range: 4000-400
cm-1 (KBr disc.)
Studies on chemical entities...
Pyrimidines...
139
Internal Standard : TMS; Solvent : CDCl3 : Instrument : BRUKER
Spectrometer (300 MHz)
1 2.4 3 H singlet Ar-SO2 CH3 -
2 5.25 2 H singlet Ar-NH2 -
3 7.30-7.34 2 H doublet Ar-Hb,b’ Jba=8.7
4 7.37 1 H singlet Ar-He -
5 7.42-7.46 2 H doublet Ar-Hc,c’ Jcd=9.6
6 7.96-7.97 2 H doublet Ar-Ha,a’ Jab=8.4
7 7.97-8.01 2 H doublet Ar-Hd,d’ Jdc=8.5
Signal No.
Signal Position (δppm)
Relative No. of protons
Multiplicity Inference J Value In Hz
NMR SPECTRAL STUDIES OF 4 - [4 - (METHYLSULFONYL)PHENYL]-6-(p-
CHLOROPHENYL)PYRIMIDIN-2-AMINE
SCH3
O
O
N
N
NH2
Cl
a b
a' b'
c
d
c'
d'
e
f
Studies on chemical entities...
Pyrimidines...
140
TAB
LE
-9 :
MA
SS S
PE
CT
RA
L S
TU
DIE
S O
F 4
-[4
-(M
ET
HY
LSU
LF
ON
YL
)PH
EN
YL
]-6-
(M-P
HE
NO
XY
PH
EN
YL
)
PY
RIM
IDIN
-2-A
MIN
E
m/z
= 4
17
Studies on chemical entities...
Pyrimidines...
141
EXPERIMENTAL
SYNTHESIS AND BIOLOGICAL SCREENING OF 4 - [ 4 -
(METHYLSULFONYL)PHENYL]-6-ARYLPYRIMIDIN-2-AMINES
(A) Synthesis of 1-[4-(Methylsu l fony l )pheny l ] -3 -aryl-2-propene-ones
See Part-I, Section-I (B).
(B) Synthesis of 4-[4-(Methylsulfonyl)phenyl]-6-(p-chlorophenyl)pyrimidin-
2-amine
A mixture of 1-[4-(methylsulfonyl)phenyl]-3-(p-chlorophenyl) -2-propene-
1-one. (3.20 gm, 0.01 mol) and guanidine hydrochloride (1.10gm, 0.01 mol) in
dioxane (20 ml) was refluxed on oil-bath in presence of alcoholic KOH for 8 hr. The
excess solvent was distilled off and the residue was neutralized with 20 % HCl, the
separated solid was filtered out and crystallized from ethanol. Yield 51 %, m.p.
166oC Anal. Calcd. for C17H14ClN3O2S Requires: C, 56.74; H, 3.92; N, 11.68 %
Found: C, 56.72; H, 3.91, N, 11.67 %.
Similarly, other 4-[4-(methylsulfonyl)phenyl]-6-arylpyrimidin-2-amines were
prepared. The physical data are recorded in Table No. 9.
(C) Biological screening of 4-[4-(Methylsulfonyl)phenyl]-6-arylpyrimidin-
2-amines
Antimicrobial testing were carried out as described in Part-I, Section-I(C).
The zones of inhibition of test solution are reported in Graphical Chart No. 9.
Studies on chemical entities...
Pyrimidines...
142
9aC
6H5-
C17
H15
N3O
2S32
512
455
12.9
112
.92
0.46
S 1
9b4-
Cl-
C6H
4-C
17H
14C
lN3O
2S35
916
651
11.6
811
.67
0.44
S 1
9c2-
Cl-
C6H
4-C
17H
14C
lN3O
2S35
916
248
11.6
811
.66
0.56
S 2
9d3-
Cl-
C6H
4-C
17H
14C
lN3O
2S35
913
463
11.6
811
.69
0.44
S 1
9e4-
OC
H3-
C6H
4-C
18H
17N
3O3S
355
186
5811
.82
11.8
10.
54S 2
9f3,
4-(O
CH 3
) 2-C
6H3-
C19
H19
N3O
4S38
514
971
10.9
010
.92
0.56
S 2
9g4-
F-C
6H4-
C17
H14
FN3O
2S34
313
759
12.2
412
.26
0.48
S 2
9h3-
Br-
C6H
4-C
17H
14Br
N3O
2S40
414
065
10.3
910
.38
0.58
S 1
9i3-
C6H
5-O
-C6H
4-C
23H
19N
3O3S
417
182
6410
.07
10.0
80.
47S 1
9j4-
N(C
H3)
2-C
6H4-
C19
H20
N4O
2S36
816
453
15.2
115
.22
0.45
S 2
9k2-
OH
-C6H
4-C
17H
15N
3O3S
341
194
5912
.31
12.3
20.
51S 2
9l2-
C4H
3O-
C15
H13
N3O
3S31
516
156
13.3
312
.34
0.62
S 1
TA
BL
E :
9P
HY
SIC
AL
CO
NST
AN
TS
OF
4-[
4-(
ME
TH
YL
SUL
FO
NY
L)P
HE
NY
L]-
6-A
RY
LP
YR
IMID
IN-2
-AM
INE
S
S 1 H
exan
e:Et
hyl
acet
ate(
5:5)
,
S 2 H
exan
e:Et
hyl
acet
ate(
6:4)
Sr.
R M
olec
ular
M
olec
ular
M
.P.
Yie
ld
%
of N
itro
gen
Rf
Sol
vent
No
For
mul
a
Wei
ght
oC
%
Cal
cd.
Fou
nd
V
alue
Sys
tem
1
2
3 4
5
6
7
8 9
10
Studies on chemical entities...
Pyrimidines...
143
GR
AP
HIC
AL
CH
AR
T N
O.
9 :
4-[
4-(
ME
TH
YL
SU
LF
ON
YL
)PH
EN
YL
]-6-
AR
YL
PY
RIM
IDIN
-2-A
MIN
ES
Studies on chemical entities...
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144
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Studies on chemical entities...
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147
INTRODUCTION
Cyclohexenone is the parent of a series of compounds that is important in
agricultural and medicinal chemistry. Cyclohexenones are derivatives of cyclohexane
with carbonyl group at 1-position and double bond at 2-position (I). Cyclohexenones
can be conveniently synthesized by the treatment of α,β - unsaturated carbonyl
compounds with ethylacetoacetate in basic media.
In recent years cyclohexenone derivatives have gained lots of interest because
of its prominent pharmaceutical properties.
SYNTHETIC ASPECT
Different methods for the synthesis of cyclohexenone derivatives have been
described in literature.1-7
1. N. Nanjundaswami et al.8 have prepared 6,7-dimethoxy-1-aryl-4-oxo-2-
naphthoate derivatives (II) by the reaction of dimethoxyphenyl aryl ketone
with diethyl succinate in presence of t-potassium butoxide.
O
OCH3
O
CH3 O
R
OCH3
O
CH3
O
R
O
O CH3
t-Buok
CH2 COOEt
CH2 COOEt
(I)
(II)
Studies on chemical entities...
Indazoles...
148
MECHANISM
The addition reaction between ethylacetoacetate and α,β -unsaturated ketone
give cyclohexenone via Michael addition. This reaction has been carried out in basic
media by using sodium ethoxide or anhydrous K2CO3 in acetone. During the reaction
nucleophillic addition of carbanion take place to the C=C of the acceptor. The α,β -
unsaturated compound is known as acceptor and ethylacetoacetate is known as donor.
THERAPEUTIC EVALUATION
Cyclohexenone and its derivatives are widely used in pharmaceutical industry.
Considerable interest has been shown in the chemistry of cyclohexenones due to
their wide spectrum of therapeutic activities which can be listed as under.
1. Antibacterial9
2. Antithrombitics10
3. Antagonist11
4. Antibiotic12,13
5. Cardiovascular14
R
O
R1 R CH
CH C
O
R1+
-
CH3
O
COOC2H5
CH3 C
O
CH COOC2H5-
+ H+OH-
[A]
[A] + H+
R CH
O
R1+
+CH3CH
O
H5C2OOC
-CH3
O
H5C2OOC
R R1
O
O
H5C2OOC
R R1
[B]
-H2O
Studies on chemical entities...
Indazoles...
149
6. Herbicidal15
7. Analgesic16
8. Antiinflammatory17
9. Anticonvulsant18
Hermann S. e t a l .19
have repor ted cyc lohexenones as he rb ic ides .
Anticonvulsant activity of some cyclohexenone derivatives (III) have been reported
by Natalie D. et al.20
Bastiaan and co-workers21
have synthesized novel cyclohexenone
derivatives (IV) which are useful in the treatment of parkinson’s disease.
Cyclohexenones (V) as anticancer and antiinflammatory agents have been
investigated.22
Cyclohexenone derivatives which possess plant growth regulatory activity
have been repor ted .23,24
Nagao et al.25
have repor ted cyc lohexenones as
antiarrhythmic.Collins and co-workers26
have documented estrogenic activity of
cyclohexenones. Tvanov et al.27
have reported antimicrobial activity of some
cyclohexenone derivatives. V. K. Ahluwalia and co-workers28
have assessed
cyclohexenone derivatives for anti HIV-I, gastric secretion inhibitors and pesticidal
activity. Cyclohexenone derivatives have been reported to be active as allergy
inhibitors, platelet aggregation inhibitors and fibrinogen antagonist.29
Antimicrobial activity of cyclohexenone derivatives has been studied by
O
NR
R
CH3
O
CH3CH3
CH3
O
N
O
CH3 NH
O
O
CH3
N
O
R
(III) (IV) (V)
Studies on chemical entities...
Indazoles...
150
Salama and Atshikh30
. Takehiro and co-workers31
have reported cyclohexenones
possessing neutropeptide β-receptor antagonist activity. Kimura and co-workers32
have prepared cyclohexenones as inhibitory activity of penienone and remarkable
inhibitory activity against the growth of lettuce seedlings. Broughton H. et al.33
have demonstrated cyclohexenones as GABA α,β−5 receptor ligands for enhancing
cognition properties.
Rheinheimer J . et al .34
have synthesized 5-(dioxabicyclohept-6-yl)
cyclohexenone oxime ethers as herbicides and plant growth regulators. Harimaya
and co-workers35
have synthesized new cyclohexenone derivatives possessing
progesteron receptor binding inhibitory activity. The herbicidal activity of
cyclohexenone derivatives (VI) has been investigated.36
Zhang C. et al.37
have prepared tricyclic heterocycles, containing furan and
cyclohexenone nucleus for treating hyper-proliferative disorders.
With a view to getting better therapeutic agent, it was contemplated to
synthesized cyclohexenones bearing furan nucleus to enhance the overall activity of
resulting compounds, which have been described as under.
CH2
CH3
CH3
OH
O
Cl
Cl
O
CH3CH3
(VI)
Studies on chemical entities...
Indazoles...
151
INTRODUCTION
Heterocyclic compounds bearing 1,2-diazole ring system i.e. pyrazole ring
system, attached to benzene ring system are known as benzopyrazole or indazole
(I). Indazole was first described by Buchner in 1869.
Although the chemistry of indazoles has been extensively studied, they have
not been found in natural products and are at the present time of little commercial
use.Indazole can be considered as either azaindazoles or azaisoindazoles.The
compounds of medicinal interest in this group so far have been non-steridol
antiinflammatory agents or analgesic.
SYNTHETIC ASPECT
Several methods have been reported in the literature38,39,40,41,42,43
for the
preparation of indazoles.
1. Cyclocondensation of activated acetylenes with hydrazine afforded indazole
derivatives.44
2. B. V. Badami et al.45 have synthesized indazoles from chalcone derivatives
via cyclohexenone derivatives as follow.
N
NH
Cl
N+
O-
O
R
NH2NH2.H2O
N
NH
R
N+
O-
O
(I)
Studies on chemical entities...
Indazoles...
152
3. A facile synthesis of substituted indazoles from 2-acyl mesylates and
hydrazines has been described by Caron S. et al.46
THERAPEUTIC EVALUATION
It is revealed from the literature survey that indazole derivatives are better
therapeutic agents and they have been found possessing various biological activities
reported as under.
1. Antiallergic47
2. Antiviral48
3. Antipsychotics49
4. Herbicidal50
5. Fungicidal51
6. Antibacterial52
7. Cardiovascular53
8. Antidepressant54
9. Antineoplastic55
10. Antitumor56,57
Balakrishna and co-workers58
have synthesized indazole derivatives and
evaluated them as antiinflammatory and analgesic activity. Malmstroem J.et al.59
have prepared indazoles (II) as inhibitors of Jun N-terminal kinases (JNK).
Aminoindazoles (III) are useful in the treatment of central and peripheral nervous
R R1
O
NH
N
O
R
R1
K2CO3
Ethylacetoacetate
in dry acetone
NH2NH2.H2OOR
R1
COOEt
Studies on chemical entities...
Indazoles...
153
system diseases have been synthesized.60
Butera J. A. et al.61 have prepared some indazole derivatives which showed
antihypertensive, muscle relaxant and potassium activator activity. Several workers
have patented indazole derivatives useful as hypolipidemic agent62
, 5-HT3
antagonist63
, enzyme inhibitor64
etc. Some indazole derivatives investigated as a
novel antiasthametic agents.65
Ooe T. et al.66
synthesized indazoles which have been
found to possess varied biological activities such as hematinics, immunostimulants
and antitumor agents. The remarkable cytotoxic activity of indazoles have been
reported.67
Some indazoles (IV) have been synthesized by Duzinska-Usarewicz et al.68
and found to possess antiinflammatory activity. Effland R. et al.69
synthesized 3-
(pyridyl amino)-indazoles (V) and reported as antidepressant and anxiolytics.
Newshaw R. and co-workers70
have prepared 4-amino ethoxy indazoles and
reported them as dopamine D2 agonists. Kania R. et al.71
have synthesized indazole
N
NH
RR1
NNH
NH
N
(V)(IV)
NH
N
NH
Cl
Ph
N
NH
NH
O
ClCOOH
(II) (III)
Studies on chemical entities...
Indazoles...
154
derivatives as protein kinase inhibitors. Indazole derivatives are reported as inhibitors
of cell proliferation.72
The remarkable antipsychotic activity73
of indazoles (VI) have
been reported.
Lavielle G. et al.74
prepared [(pyrolidinyl) methyl]-indazoles and suggested
them for the treatment of migrains. Marfat Anthony75
has patented indazole
derivatives as phosphodiesterase and tumor necrosis factor production inhibitors.
Indazole derivatives have been evaluated as α,β -adrenoreceptor agonists.76
Antiviral
activity77
of indazoles have been reported. Badran M. et al.78
synthesized some novel
indazole derivatives by fusing with triazines and triazoles for exploring their
antiinflammatory activity.
Moreover, Hwang I. T. et al.79
have synthesized some new 2-phenyl-4,5,6,7-
tetrahydro-2H-indazole derivatives as paddy field herbicides. Tanitame A. et al.80
have reported the designed, synthesized and studied structure-activity relationship
of novel indazole analogues as DNA gyrase inhibitors with Gram-positive
antibacterial activity(VII). Nasr M. N. et al.81
have prepared some novel 3,3a,4,5,6,7-
hexahydroindazole and arylthiazolylpyrazoline derivatives as anti-inflammatory
agents. Pinna G. A. et al.82
have described the synthesis of Chromophore-modified
bis-benzo[g]indole carboxamides.
Recently, Abouzid K. A. et al.83
have Synthesized and demonstrate anti-
inflammatory activity of novel indazolones. Wang Q. et al.84,85
have described the
syn thes i s and he rb ic ida l ac t iv i ty o f 2 -cyano-3-subs t i tu ted-
N
NH
O
O
R1
Z
R
Z = (un)-substituted piperazine
pyridino etc(VI)
Studies on chemical entities...
Indazoles...
155
pyridinemethylaminoacrylates. Kakimoto T. et al.86
have prepared some novel
3,3a,5,9b-tetrahydro-2H-furo[3,2-c][2] benzopyran derivatives of chiral glycol
benzyl ether herbicides. Ikeguchi M. et al.87
have documented the synthesis and
herbicidal activity of new oxazinone herbicides with a long-lasting herbicidal activity
against Echinochloa oryzicola.
Among variety of pharmacological properties have been encountered with
indazole systems, keeping the above in mind some novel indazole derivatives have
been synthesized which have been described as under.
SECTION-I : SYNTHESIS AND BIOLOGICAL SCREENING O F
ETHYL-4-[ 4 - ( M E T H Y L S U L F O N Y L ) P H E N Y L ] - 2 -
O X O - 6 - A R Y L C Y C L O H E X - 3 - E N E - 1 -
CARBOXYLATES
SECTION - II : SYNTHESIS AND BIOLOGICAL SCREENING OF 6-[4-
(METHYLSULFONYL)PHENY]-4-ARY L - 2 ,3a , 4 - 5 -
TETRAHYDRO-3H-INDAZOL-3-ONES
NH
N NH
EtOOC
O Cl
Cl
(VII)
Studies on chemical entities...
Indazoles...
156
SECTION - I
SYNTHESIS AND BIOLOGICAL SCREENING OF ETHYL-4-[4-
(METHYLS U L F O N Y L ) P H E N Y L ] - 2 - O X O - 6 - A RY L C Y C L O H E X - 3 -
E N E - 1 -CARBOXYLATES
Cyclohexenones are endowed with variety of pharmacodynamic activities such
as anticonvulsant,antidiabatic etc. Looking to the interesting properties of
cyclohexenones aroused considerable interest to synthesis of e thyl-4-[4-
(methyls u l f o n y l ) p h e n y l ] - 2 - o x o - 6 - a r y l c y c l o h e x - 3 - e n e - 1 -carboxylates of the
type (X) by the cyclocondensation of 1-[4-(methylsu l fonyl )phenyl ] -3-ary l -2-
propene-1-ones with ethylacetoacetate in the presence of anhydrous K2CO3 in
order to study their biodynamic behavior.
The structure elucidation of synthesized compounds has been done on the
basis of elemental analyses, infrared and 1H nuclear magnetic resonance spectroscopy
and further supported by Mass spectrometry.
All the compounds have been evaluated for their in vitro biological assay
like antibacterial activity towards gram positive and gram negative bacterial strains
and antifungal activity towards Aspergillus niger at a concentration of 40µg/ml.
The biological activities of synthesized compounds were compared with standard
drugs.
R
O
S
O
O
CH3
R
O
S
O
O
CH3
O
OC2H5
K2CO3
CH3COCH2COOC2H5
Type(I)Type(I)Type(X)R=Aryl
Studies on chemical entities...
Indazoles...
157
0.0
20.0
40.0
60.0
80.0
100.0
%T
500.0750.01000.01250.01500.01750.02000.03250.01/cm
466.7
513.0
538.1 594.0
621.0
702.0 759.9
781.1
813.9
856.3 918.1
956.6
997.1
1031.8
1051.11076.2
1095.5
1159.1
1244.0
1278.71299.9
1315.41353.9
1373.21388.7
1431.1
1494.7
1564.2
1598.9
1741.6
2852.5
2920.0
2976.0
3408.0
Type Vibration Frequency in cm-1 Ref. Mode Observed Reported
Alkane C-H str. (asym.) 2920 2975-2950 88-CH3 C-H str. (sym.) 2852 2880-2860 ,,
C-H def. (asym.) 1494 1470-1435 ,,C-H def. (sym.) 1388 1390-1370 ,,
Aromatic C-H str. 3080 3090-3030 89C=C str. 1564 1540-1480 ,,
1095 1125-1090 ,,1031 1070-1000 ,,
Ether C-O-C str. 1244 1080-1250 88Sulfonyl SO2 str. 1159 1185-1165 ,,Ester C=O-O str. 1741 1735-1717 ,,Hexenone C=O str. 1675 1685-1665 89(cyclo)
IR SPECTRAL STUDIES OF ETHYL-4-[4-(METHYLS U L F O N Y L )
P H E N Y L ] - 2 - O X O - 6 - A RY L C Y C L O H E X - 3 - E N E - 1 -CARBOXYLATE
SCH3
O
O
O
O
OC2H5
Instrument : SHIMADZU FTIR 8400 Spectrophotometer; Frequency range: 4000-400
cm-1 (KBr disc.)
Studies on chemical entities...
Indazoles...
158
Internal Standard : TMS; Solvent : CDCl3 : Instrument : BRUKER
Spectrometer (300 MHz)
1 1.04-1.25 3 H triplet Ar-CH2CH3 -
2 1.26-1.30 3 H singlet Ar-SO2 CH3 -
3 2.4 1 H singlet Ar-Hk -
4 2.30 2 H quartet Ar-CH2CH3 -
5 3.99-4.03 1 H doublet Ar-Hh -
6 3.74-3.96 1 H doublet Ar-Hj -
7 2.72-2.76 1 H doublet Ar-Hi -
8 2.77-3.07 1 H doublet Ar-Hl -
9 7.21-7.23 2 H doublet Ar-Hb,b’ Jba=8.6
10 7.29-7.31 5 H multiplet Ar-H(c-g) -
11 7.39-7.41 2 H doublet Ar-Ha,a’ Jab=8.4
Signal No.
Signal Position (δppm)
Relative No. of protons
Multiplicity Inference J Value In Hz
NMR SPECTRAL STUDIES OF ETHYL-4-[4-(METHYLS U L F O N Y L )
PHENYL]-2-OXO-6-ARYLCYCLOHEX-3-ENE-1-CARBOXYLATE
SCH3
O
O
O
O
O
CH3
HiHj
a b
a' b'
c
d e
f
g
Hh
Hl
Hk
Studies on chemical entities...
Indazoles...
159
TAB
LE
-10
:MA
SS S
PE
CT
RA
L S
TU
DIE
S O
F E
TH
YL
-4-[
4-(M
ET
HY
LS
UL
FO
NY
L)P
HE
NY
L]-
2-O
XO
-6-(
P-
FL
UO
RO
PH
EN
YL
)CY
CL
OH
EX
-3-E
NE
-1-C
AR
BO
XY
LA
TE
m/z
= 4
16
Studies on chemical entities...
Indazoles...
160
EXPERIMENTAL
SYNTHESIS AND BIOLOGICAL SCREENING OF ETHYL-4-[4-
(METHYLS U L F O N Y L ) P H E N Y L ] - 2 - O X O - 6 - A RY L C Y C L O H E X - 3 -
E N E - 1 -CARBOXYLATES
(A) Synthesis of 1-[4-(Methylsu l fony l )pheny l ] -3 -aryl-2 -propene-1-ones
See Part-I, Section-I (B).
(B) Preparation of ethyl-4-[4-(methyls u l f o n y l ) p h e n y l ] - 2 - o x o - 6 -phenyl-
c y c l o h e x - 3 - e n e - 1 -carboxylate
To a solution of 1-[4-(methylsul fonyl)phenyl] -3-(phenyl) -2-propene-1-
one (2.86 gm, 0.01 mol) in dry acetone, anhydrous K2CO3 (5.42gm, 0.04 mol) and
ethyl acetoacetate(2.60 gm, 0.02 mol) was added and the reaction mixture was stirred
at room temperature for overnight and was filtered. The solvent from the filtrate on
distill off gave a solid, which was crystallized from methanol to gave desired product
. Yield 45%, m.p. 164oC, Anal.Calcd. for C22H22O5S; Requires: C, 66.31; H, 5.56;
Found : C, 66.30; H, 5.54; %.
Similar ly, other e thy l -4 - [4- (methy ls u l f o n y l ) p h e n y l ] - 2 - o x o - 6 -
a ry lcyc lohex-3-ene-1 - carboxylates were prepared. The physical data are recorded
in Table No.10
(C) Biological screening of ethyl-4-[4-(methyls u l f o n y l ) p h e n y l ] - 2 - o x o - 6 -
a r y l c y c l o h e x - 3 - e n e - 1 -carboxylates
Antimicrobial testing were carried out as described in Part-I, Section (C).
The zones of inhibition of test solutions are recorded in Graphical Chart No.10
Studies on chemical entities...
Indazoles...
161
10a
C6H
5-C
22H
22O
5S39
816
445
--
0.61
S 1
10b
4-C
l-C 6
H4-
C22
H21
ClO
5S43
217
951
--
0.42
S 2
10c
2-C
l-C 6
H4-
C22
H21
ClO
5S43
216
258
--
0.56
S 1
10d
3-C
l-C 6
H4-
C22
H21
ClO
5S43
213
464
--
0.45
S 2
10e
4-O
CH
3-C
6H4-
C23
H24
O6S
428
167
46-
-0.
53S 1
10f
3,4-
(OC
H 3) 2
-C6H
3-C
24H
26O
7S45
811
454
--
0.56
S 1
10g
4-F-
C6H
4-C
22H
21FO
5S41
616
961
--
0.43
S 2
10h
3-B
r-C 6
H4-
C22
H21
BrO
5S47
714
068
--
0.58
S 1
10i
3-C
6H5-
O-C
6H4-
C28
H26
O6S
490
198
45-
-0.
49S 2
10j
4-N
(CH
3)2-
C6H
4-C
24H
27N
O5S
441
184
513.
173.
180.
42S 2
10k
2-O
H-C
6H4-
C22
H22
O6S
414
157
53-
-0.
51S 1
10l
2-C
4H3O
-C
20H
20O
6S38
816
464
--
0.56
S 2
TA
BL
E :
10
PH
YSI
CA
L C
ON
STA
NT
S O
F
ET
HY
L-4
-[4-
(ME
TH
YL
SU
LF
ON
YL
)PH
EN
YL
]-2
-OX
O-6
-AR
YL
CY
CL
O
HE
X-3
-EN
E-1
-CA
RB
OX
YL
AT
ES
S 1 H
exan
e:Et
hyl
acet
ate(
5:5)
,
S 2 H
exan
e:Et
hyl
acet
ate(
6:4)
Sr.
R M
olec
ular
M
olec
ular
M
.P.
Yie
ld
%
of N
itro
gen
Rf
Sol
vent
No
For
mul
a
Wei
ght
oC
%
Cal
cd.
Fou
nd
V
alue
Sys
tem
1
2
3 4
5
6
7
8 9
10
Studies on chemical entities...
Indazoles...
162
GR
AP
HIC
AL
CH
AR
T N
O.
10 :
ET
HY
L-4
-[4-
(ME
TH
YL
SU
LF
ON
YL
)PH
EN
YL
]-2
-OX
O-6
-AR
YL
CY
CL
OH
EX
-3-
EN
E-1
-CA
RB
OX
YL
AT
ES
Studies on chemical entities...
Indazoles...
163
SECTION - II
SYNTHESIS AND BIOLOGICAL SCREENING OF 6 - [ 4 -
(METHYLSULFONYL)PHENYL]-4-ARYL-2,3a ,4,5-TETRAHYDRO-3H-
INDAZOL-3-ONES
The synthesis of indazole has attracted the attention of chemists because of
their potential pharmcodynamic properties. Looking to the interesting properties
of indazoles , i t appeared of in te res t to synthes ize a ser ies of 6 - [ 4 -
(methylsulfonyl)pheny]-4-aryl-2,3a,4-5-tetrahydro-3H-indazol-3-ones of type (XI)
for obtaining biologically potent agents, which were prepared by reacting ethyl-4-
[4-(methyls u l f o n y l ) p h e n y l ] - 2 - o x o - 6 - a r y l c y c l o h e x - 3 - e n e - 1 -carboxylates of
the type (X) with hydrazine hydrate in presence of glacial acetic acid.
The structure elucidation of synthesized compounds has been done on the
basis of elemental analyses, infrared and 1H nuclear magnetic resonance spectroscopy
and further supported by Mass spectrometry.
All the compounds have been evaluated for their in vitro biological assay
like antibacterial activity towards gram positive and gram negative bacterial strains
and antifungal activity towards Aspergillus niger at a concentration of 40µg/ml.
The biological activities of synthesized compounds were compared with standard
drugs.
NH2NH2.H2O
R
N
S
O
O
CH3
NH
O
IN CH3COOH
R
O
S
O
O
CH3
O
CH3 R=ArylType(X) Type(XI)
Studies on chemical entities...
Indazoles...
164
0.0
20.0
40.0
60.0
80.0
100.0
%T
500.0750.01000.01250.01500.01750.02000.03250.01/cm
501.5
542.0 567.0
596.0 651.9
692.4
723.3 759.9
835.1 869.8
916.1 962.4
1028.01118.6
1176.51282.6
1328.9
1371.3
1465.81573.81672.2
1874.7
1944.1
2802.4
2898.8
2981.7
3105.23176.5
3328.9
Type Vibration Frequency in cm-1 Ref. Mode Observed Reported
Alkane C-H str. (asym.) 2981 2975-2950 88-CH3 C-H str. (sym.) 2898 2880-2860 ,,
C-H def. (asym.) 1465 1470-1435 ,,C-H def. (sym.) 1371 1390-1370 ,,
Aromatic C-H str. 3028 3090-3030 89C=C str. 1465 1540-1480 ,,
1118 1125-1090 ,,1028 1070-1000 ,,
Ether C-O-C str. 1282 1150-1350 88Sulfonyl SO2 str. 1176 1185-1165 ,,Amide NH-C=O-str 1672 1680-1636 ,,Indazole C=N str. 1573 1660-1480 89Amine N-H str. 3228 3300-3140 ,,
IR SPECTRAL STUDIES OF 6-[4-(METHYLSULFONYL)PHENYL]-4-
ARYL-2,3a,4,5-TETRAHYDRO-3H-INDAZOL-3-ONE
SCH3
O
ON
NH
O
Instrument : SHIMADZU FTIR 8400 Spectrophotometer; Frequency range: 4000-400
cm-1 (KBr disc.)
Studies on chemical entities...
Indazoles...
165
Internal Standard : TMS; Solvent : CDCl3 : Instrument : BRUKER
Spectrometer (300 MHz)
1 1.26 1 H singlet Ar-Hl -
2 2.5 3 H singlet Ar-SO2 CH3 -
3 3.14-3.20 1 H d,d Ar-Hj -
4 3.26-3.30 1 H d,d Ar-Hi -
5 4.31-4.36 1 H d,d Ar-Hh -
6 6.64 2 H singlet Ar-NH -
7 7.27-7.34 5 H multiplet Ar-H(c-g) -
8 7.36 1 H singlet Ar-Hk -
9 7.34-7.43 2 H doublet Ar-Hb,b’ Jba=8.5
10 7.46-7.60 2 H doublet Ar-Ha,a’ Jab=8.7
Signal No.
Signal Position (δppm)
Relative No. of protons
Multiplicity Inference J Value In Hz
NMR SPECTRAL STUDIES OF 6-[4-(METHYLSULFONYL)PHENYL]-4-
ARYL-2,3a,4,5-TETRAHYDRO-3H-INDAZOL-3-ONE
SCH3
O
ON
NH
O
Hi Hja b
a' b'
c
d e
f
g
HhHl
Hk
Studies on chemical entities...
Indazoles...
166
TAB
LE
-11
:M
ASS
SP
EC
TR
AL
ST
UD
IES
OF
6-[
4-(M
ET
HY
LSU
LF
ON
YL
)PH
EN
YL
]-4-
(P-M
ET
HO
XY
PH
EN
YL
)-2,
3a,4
-
5-T
ET
RA
HY
DR
O-3
H-I
ND
AZ
OL
-3-O
NE
m/z
= 3
96
Studies on chemical entities...
Indazoles...
167
EXEPERIMENTAL
SYNTHESIS AND BIOLOGICAL SCREENING OF 6 - [ 4 -
(METHYLSULFONYL)PHENYL]-4-ARYL-2,3a ,4,5-TETRAHYDRO-3H-
INDAZOL-3-ONES
(A) Synthesis of 1-[4-(Methyl su l fony l )phenyl ] -3 -ary l -2 -propene-1-
ones
See Part-I, Section-I (B),
(B) Preparation of Ethyl-4-[4-(methyls u l f o n y l ) p h e n y l ] - 2 - o x o - 6 - a r y l
c y c l o h e x - 3 - e n e - 1 -carboxylates
See Part-VI, Section-I(B).
(C) Preparation of 6-[4-(Methylsulfonyl)phenyl]-4-phenyl-2,3a,4,5-tetra
hydro-3H-indazol-3-one
To a solution of ethyl-4-[4-(methyls u l f o n y l ) p h e n y l ] - 2 - o x o - 6 -phenyl
c y c l o h e x - 3 - e n e - 1 -carboxylate (3.98gm, 0.01 mol) in ethanol (20 ml), hydrazine
hydrate (0.5gm 0.01 mol) and acetic acid (2 ml) was added. The content was refluxed
at 80oC for 4 hr on water bath. The residue obtained after cooling was filtered and
isolated. The product was crystallized from methanol. Yield 55 %, m. p. 134oC.
Anal. Calcd. for C20H18N2O3S Requires C, 65.95; H, 4.95; N, 7.64% Found C,
65.93; H, 4.92; N, 7.62%.
Similarly other, 6-[4-(methylsulfonyl)pheny]-4-aryl-2,3a,4-5-tetrahydro-3H-
indazol-3-ones were prepared. The physical data are recorded in Table No. 11.
(C) Biological screening of 6-[4-(Methylsulfonyl)phenyl]-4-aryl-2,3a,4,5-
tetrahydro-3H-indazol-3-ones
Antimicrobial testing were carried out as described in Part-I, Section (C).
The zones of inhibition of test solutions are recorded in Graphical Chart No.11
Studies on chemical entities...
Indazoles...
168
11a
C6H
5-C
20H
18N
2O3S
366
134
557.
647.
620.
49S 2
11b
4-C
l-C
6H4-
C20
H17
ClN
2O3S
400
167
596.
996.
970.
53S 1
11c
2-C
l-C
6H4-
C20
H17
ClN
2O3S
400
128
486.
996.
960.
58S 2
11d
3-C
l-C
6H4-
C20
H17
ClN
2O3S
400
164
566.
996.
970.
46S 1
11e
4-O
CH
3-C
6H4-
C21
H20
N2O
4S39
619
244
7.07
7.02
0.51
S 2
11f
3,4-
(OC
H 3) 2
-C6H
3-C
22H
22N
2O5S
426
115
496.
576.
570.
57S 2
11g
4-F-
C6H
4-C
20H
17FN
2O3S
384
148
517.
297.
260.
48S 1
11h
3-B
r-C
6H4-
C20
H17
BrN
2O3S
445
142
686.
296.
280.
53S 1
11i
3-C
6H5-
O-C
6H4-
C26
H22
N2O
4S45
818
151
6.11
6.70
0.48
S 2
11j
4-N
(CH
3)2-
C6H
4-C
22H
23N
3O3S
409
175
5610
.26
10.2
40.
44S 1
11k
2-O
H-C
6H4-
C20
H18
N2O
4S38
216
248
7.33
7.32
0.54
S 1
11l
2-C
4H3O
-C
18H
16N
2O4S
356
187
547.
867.
850.
52S 2
TA
BL
E :
11
PH
YSI
CA
L C
ON
STA
NT
S O
F
6-[4
-(M
ET
HY
LSU
LF
ON
YL
)PH
EN
YL
]-4-
AR
YL
-2,3
a,4
,5-T
ET
RA
HY
DR
O-3
H-
IN
DA
ZO
L-3
-ON
ES
S 1 H
exan
e:Et
hyl
acet
ate(
5:5)
,
S 2 H
exan
e:Et
hyl
acet
ate(
6:4)
Sr.
R M
olec
ular
M
olec
ular
M
.P.
Yie
ld
%
of N
itro
gen
Rf
Sol
vent
No
For
mul
a
Wei
ght
oC
%
Cal
cd.
Fou
nd
V
alue
Sys
tem
1
2
3 4
5
6
7
8 9
10
Studies on chemical entities...
Indazoles...
169
GR
AP
HIC
AL
CH
AR
T N
O.
11 :
6-[
4-(M
ET
HY
LSU
LF
ON
YL
)PH
EN
YL
]-4-
AR
YL
-2,3
a,4
,5-T
ET
RA
HY
DR
O-3
H-I
ND
AZ
OL
-
3-O
NE
S
Studies on chemical entities...
Indazoles...
170
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Studies on chemical entities...
Isoxazoles...
176
INTRODUCTION
Isoxazole is a five membered heterocyclic compound having two hetero atom:
oxygen at position 1 and nitrogen at position 2. Claisen first reported an isoxazole
(I) for a product from the reaction of 1,3 diketone with hydroxylamine.1 It was
shown to possess typical properties of an aromatic system but under certain reaction
conditions. Particularly in reducing or basic media, it becomes very highly labile.
The next important contribution to the chemistry of isoxazoles was made by
Quelico2 in 1945, when he begain to study the formation of isoxazoles from nitrile
N-oxide and unsaturated compounds.
SYNTHETIC ASPECT
Isoxazoles can be prepared by various method, which are described as under.
1. Tayade V. B. et al.3 synthesized some new 3,5-diarylisoxazoles from the
reaction of 2-aryl acetophenones with hydroxyl amine hydrochloride in
presence of alkali.
2. Dawood Kamal et al.4 prepared isoxazole derivatives from enamino
nitriles.
3. Crawley L. S. and Fan shawe W. J.5 prepared isoxazole from α,β -unsaturated
carbonyl compounds, hydroxyl amine hydrochloride and KOH in methanol.
(I)O
N
R R1
O
+ NH2OH.HClKOH
ON
R
R1
Studies on chemical entities...
Isoxazoles...
177
4. J. F. Hansen and S. A. Strong6 synthesized isoxazole from α,β -unsaturated
ketones and N-bromo succinimide.
REACTION MECHANISM
THERAPEUTIC IMPORTANCE
Isoxazole derivatives exhibit various biological activities such as,
1. Anthelmintics7
2. Adenosine antagonist8
3. Fungicidal9-11
4. Herbicidal12,13
5. Hypoglycemic14
6. Muscle relaxant15,16
7. Nematocidal17
8. Insecticidal18
9. Antibacterial19-21
10. Anticonvulsant22,23
11. Anticholestermic24
12. Antiinflammatory25-28
R O
R1
OH-NH2.HCl
R O
R1
OH
NH2
-H+
R O
R1
O
NH2
_
:
H+
:R
O
R1
O
NH2+
_
ROH
R1
O
NH
H2O_
H +
R
R1
O
NH
R
R1
O
NR
R1
O
N
2H
_
+_ H_ +
OH
proton transfer
Studies on chemical entities...
Isoxazoles...
178
13. Antimicrobial29
14. Antiviral30
Aicher Thomas D. et al.31
reported isoxazoles (II) as hypoglycemic agents.
H. H. Parekh et al.32
have synthesis 3-(p-methoxyphenyl)-5-(2 '-chloro-7 '-
methylquinolin-3'-yl)-isoxazole (III) and studied thier biologcal activity.
Talley John and co-workers33
and Mishra et al.34
have synthesized isoxazoles
and reported their analgesic and antiinflammatory activities. Masatosh et al.35
have
documented synthesized isoxazole derivatives as analgesic agent. Some other drugs
viz. sulfisoxazoles (IV) is a well known antibiotic and activicin (V)36
is an antitumor
agent having isoxazole moiety.
Moreover, S. Rung and D. Dus37
have synthesized some new isoxazoles as
remedy for leukemia. M. Scobie and co-workers38
have prepared isoxazole
derivatives and studied their antitumor activity. G. Daidone et al.39
synthesized novel
3-(isoxazol-3-yl)-quinazolin-4-(3H)-one derivative and tested for their analgesic
and antiinflammatory activities as well as for their acute toxicity and ulcerogenic
N
O
CH2O
Cl
Cl
Cl N
O
N
R
ClCH3
SO
NH
ON
R1
CH3
O
NH2
ON
Cl
NH2
H
HOOC
(II) (III)
(IV) (V)
Studies on chemical entities...
Isoxazoles...
179
effect.
Some i soxazo les a re found to possess he rb ic ida l40-42
p o t e n t i a l
antiinflammatory43,44, antimicrobial agents
45,46, estrogen receptor modulators47
and inhibitor of p38 MAP kinase activities.48
Masui et al.49
have prepared isoxazoles having pesticidal activity. Some
excellent herbicidal results obtained by Reddy et al.50
C. B. Xue et al.51
have reported
on oral antiplatelet effect in dogs.
H. S. Joshi et al.52
have synthesized isoxazole derivatives (VI) and reported
their antitubercular and antimicrobial activity.
Salter M. W. et al .53
have prepared some novel isoxazole as cellular
neuroplasticity mechanisms mediating pain persistence. Matringe M. et al.54
have
reported some new p-hydroxyphenylpyruvate dioxygenase inhibitor-resistant plants.
Mehlisch D. R. et al.55
have synthesized isoxazole derivative as analgesic efficacy
of intramuscular parecoxib sodium in postoperative dental pain. Ray W. A. et al.56
have reported isoxazole derivative as cardiovascular toxicity of valdecoxib.
Welsing P. M. et al.57
have documented the isoxazole as tumor necrosis factor-
blocking agents and leflunomide for treating rheumatoid arthritis in the Netherlands.
Bingham S. J. et al.58
have synthesized as antiuclear. Barbachyn M. R. et al.59
have
described the phenylisoxazolines as novel and viable antibacterial agents active
against Gram-positive pathogens.
ON
Br
R
(VI)
Studies on chemical entities...
Isoxazoles...
180
With an intension of preparing the compounds possessing better therapeutic
activity, we have under taken the preparation of isoxazoles bearing methylsulfonyl
derivatives which have been described as follows.
SECTION-I : SYNTHESIS AND BIOLOGICAL SCREENING O F 3 - [ 4 -
METHYLS U L F O N Y L ) P H E N Y L ] - 5 -ARY LI S O X A Z O L E S
Studies on chemical entities...
Isoxazoles...
181
SECTION - I
SYNTHESIS AND BIOLOGICAL SCREENING OF 3 - [ 4 - M E T H Y L
S U L F O N Y L ) P H E N Y L ] - 5 - A RY L I S O X A Z O L E S
Isoxazoles have been reported to have various pharmacological activities
like antibacterial, antifungal, insecticidal etc. In order to achieving better drug
potency , we have prepared i soxazole der iva t ives of type (XII ) by the
cyclocondensation of 1-[4-(methylsulfonyl)phenyl]-3-aryl-2-propene-1-ones of
type(I) with hydroxylamine hydrochloride in presence of sodium acetate in glacial
aletic acid.
The structure elucidation of synthesized compounds has been done on the
basis of elemental analyses, infrared and 1 H nuclear magnetic resonance
spectroscopy and further supported by Mass spectrometry.
All the compounds have been evaluated for their in vitro biological assay
like antibacterial activity towards gram positive and gram negative bacterial strains
and antifungal activity towards Aspergillus niger at a concentration of 40µg/ml.
The biological activities of synthesized compounds were compared with standard
drugs.
NH2OH.HCl
gl. CH3COOH
S
O
O
CH3
NO R
R
O
S
O
O
CH3
Type(XII)Type(I) R=Aryl
Studies on chemical entities...
Isoxazoles...
182
60.0
70.0
80.0
90.0
100.0
%T
500.0750.01000.01250.01500.01750.02000.03250.01/cm
528.5 565.1
592.1 717.5
779.2 819.7
835.1
891.1
925.8
966.3
1014.51037.6
1058.81097.4
1159.1
1245.91344.3
1411.81512.1
1600.8
1641.3
2362.6
2854.5
2918.13076.23211.3
Type Vibration Frequency in cm-1 Ref. Mode Observed Reported
Alkane C-H str. (asym.) 2918 2975-2950 60-CH3 C-H str. (sym.) 2854 2880-2860 ,,
C-H def. (asym.) 1411 1470-1435 ,,C-H def. (sym.) 1344 1390-1370 ,,
Aromatic C-H str. 3076 3090-3030 61C=C str. 1512 1540-1480 ,,
1097 1125-1090 ,,1037 1070-1000 ,,
Halide C-Cl str. 779 800-600 60Sulfonyl SO2 str. 1159 1185-1165 ,,Isoxazole C=C str. 1641 1680-1550 61
C=N str. 1600 1690-1460 ,,N-O str. 835 850-810 ,,
IR SPECTRAL STUDIES OF 3-[4-METHYLS U L F O N Y L ) P H E N Y L ] -
5 - ( p-CHLOROPHENYL)I S O X A Z O L E
NO
S
O
O
CH3
Cl
Instrument : SHIMADZU FTIR 8400 Spectrophotometer; Frequency range: 4000-400
cm-1 (KBr disc.)
Studies on chemical entities...
Isoxazoles...
183
Internal Standard : TMS; Solvent : CDCl3 : Instrument : BRUKER
Spectrometer (300 MHz)
1 2.47 3 H singlet Ar-SO2 CH3 -
2 6.67-6.93 2 H doublet Ar-Hb,b’ Jba=8.7
3 7.05-7.07 2 H doublet Ar-Hc,c’ Jcd=7.8
4 7.25 1 H singlet Ar-He -
5 7.45-7.46 2 H doublet Ar-Ha,a’ Jab=8.4
6 7.57-7.58 2 H doublet Ar-Hd,d’ Jdc=8.4
Signal No.
Signal Position (δppm)
Relative No. of protons
Multiplicity Inference J Value In Hz
NMR SPECTRAL STUDIES OF 3-[4-METHYLS U L F O N Y L ) P H E N Y L ] - 5 -
(p-CHLOROPHENYL)I S O X A Z O L E
NO
S
O
O
CH3
Cl
a b
a' b'
c
d
c'
d'e
Studies on chemical entities...
Isoxazoles...
184
TAB
LE
-12
:MA
SS S
PE
CT
RA
L S
TU
DIE
S O
F 3
-[4-
ME
TH
YL
SU
LF
ON
YL
)PH
EN
YL
]-5
-(P
-FL
UO
RO
PH
EN
YL
)
ISO
XA
ZO
LE
m/z
= 3
17
Studies on chemical entities...
Isoxazoles...
185
EXPERIMENTAL
SYNTHESIS AND BIOLOGICAL SCREENING OF 3 - [ 4 -
METHYLS U L F O N Y L ) P H E N Y L ] - 5 - A RY L I S O X A Z O L E S
(A) Synthesis of 1-[4-(Methylsu l fony l )pheny l ] -3 -aryl-2 -propene-1-ones
See Part-I, Section-I (B).
(B) Synthesis of 3-[4-Methyl s u l f o n y l ) p h e n y l ] - 5 - (p-chlorophenyl)-
i soxazo le
To a solution of 1-[4-(methyls u l f o n y l ) p h e n y l ] - 3 -(p-chlorophenyl)- 2 -
propene- 1-one (3.20 gm, 0.01 mol) in ethanol (25 ml), anhydrous sodium acetate
(0.739gm, 0.01 mol) and hydroxylamine hydrochloride(0.59 gm, 0.01 mol) in acetic
acid were added. The reaction mixture was refluxed on oil bath for 7-8 hr. The
product was isolated and crystallized from ethanol. Yield 56 %, m.p. 154oC Anal.
Calcd. For C16H12ClNO3S Requires ; C, 57.57; H, 3.62; N, 4.20; Found C, 57.56,
H, 3.61; N, 4.21%.
Similarly, other 3 - [ 4 -methyls u l f o n y l ) p h e n y l ] - 5 - a r y l i s o x a z o l e s were
prepared. The physical data are recorded in Table No.12.
(C) Biological screening of 3-[4-Methyls u l f o n y l ) p h e n y l ] - 5 - a r y l
i s o x a z o l e s
Antimicrobial testing were carried out as described in Part-I Section-1 (C).
The zones of inhibition of test solution are reported in Graphical Chart No 12.
Studies on chemical entities...
Isoxazoles...
186
12a
C6H
5-C
16H
13N
O3S
299
162
424.
684.
670.
58S 2
12b
4-C
l-C
6H4-
C16
H12
ClN
O3S
333
154
564.
204.
210.
44S 2
12c
2-C
l-C
6H4-
C16
H12
ClN
O3S
333
148
644.
204.
230.
50S 1
12d
3-C
l-C
6H4-
C16
H12
ClN
O3S
333
193
574.
204.
220.
41S 1
12e
4-O
CH
3-C
6H4-
C17
H15
NO
4S32
917
461
4.25
4..2
60.
52S 2
12f
3,4-
(OC
H 3) 2
-C6H
3-C
18H
17N
O5S
359
163
683.
903.
910.
56S 1
12g
4-F-
C6H
4-C
16H
12FN
O3S
317
160
544.
414.
420.
43S 2
12h
3-B
r-C
6H4-
C16
H12
BrN
O3S
378
170
483.
703.
720.
57S 1
12i
3-C
6H5-
O-C
6H4-
C22
H17
NO
4S39
114
658
3.58
3.59
0.41
S 1
12j
4-N
(CH
3)2-
C6H
4-C
18H
18N
2O3S
342
162
668.
188.
190.
46S 2
12k
2-O
H-C
6H4-
C16
H13
NO
4S31
517
045
4.44
4.45
0.53
S 1
12l
2-C
4H3O
-C
14H
11N
O4S
289
161
564.
844.
850.
51S 1
TA
BL
E :
12
PH
YSI
CA
L C
ON
STA
NT
S O
F
3-[4
-ME
TH
YL
SU
LF
ON
YL
)PH
EN
YL
]-5
-AR
YL
ISO
XA
ZO
LE
S
S 1 H
exan
e:Et
hyl
acet
ate(
5:5)
,
S 2 H
exan
e:Et
hyl
acet
ate(
6:4)
Sr.
R M
olec
ular
M
olec
ular
M
.P.
Yie
ld
%
of N
itro
gen
Rf
Sol
vent
No
For
mul
a
Wei
ght
oC
%
Cal
cd.
Fou
nd
V
alue
Sys
tem
1
2
3 4
5
6
7
8 9
10
Studies on chemical entities...
Isoxazoles...
187
GR
AP
HIC
AL
CH
AR
T N
O.
12 :
3-[4
-ME
TH
YL
SU
LF
ON
YL
)PH
EN
YL
]-5
-AR
YL
ISO
XA
ZO
LE
S
Studies on chemical entities...
Isoxazoles...
188
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Studies on chemical entities...
Thiazolidinones...
192
INTRODUCTION
Thiazolidinone, 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), and 5
(III), have been subjects of extensive study in the recent past. Numerous reports
have appeared in the literature which highlight their chemistry and use.
4-Thiazolidinones are derivatives of thiazolidine with carbonyl group at 4
position (II) substituent in the 2,3 and 5 position may be varied, but the greatest
difference 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 products of
hydrolysis of 2-phenyl-3-phenylamino-4-thiazolidinones.1
The chemistry of 4-thiazolidinones was reviewed in depth by F. Brown2 in
1961 and G. Newkome and A. Nayak3 in 1979.
SYNTHETIC ASPECT
4-Thiazolidinones are synthesized either by cyclisation of acyclic compounds
or by interconversion among appropriately substituted thiazolidinone derivatives.
α -Mercapto alkanoics acids have been extensively used for the synthesis of
4-thiazolidinones.
S
NH
O12
345
S
NH
O
12
345
S
NH
O 12
345
(I) (III)(II)
Studies on chemical entities...
Thiazolidinones...
193
R = Alky or aryl
R1 = Aryl or heterocyclic
R2 = H or alkyl
R3 = H or alkyl
R2, R3 = Arylidene
The substi tuted and unsubsti tuted α -mercapto alkanoic acids react
conveniently with Schiff’s bases of aromatic heterocyclic aldehyde and aliphatic or
aromatic amines in different solvent to give a variety of 2-substituted-4-
thiazolidinones4-6
(IV).
MECHANISM
The reaction proceeds by the attack of the mercapto acetic acid upon the
C=N group, with the HS-CH2-COOH adding to the carbon atom followed by the
capture of a proton by nitrogen and subsequent cyclisation.
In there reaction, the uncyclised intermediate is formed in several cases. The
uncyclised product has been isolated.7 Phosphorous pentoxide in dioxan was used
R
N
R1
H
+ COOH
R2
SH
R3
S
R2
NH
R
R1
R2COOH
NH
S
R1
O
R3
R2
R
N
R1
H
+OH
O
SH
N
S
OH
O
R1
R
N
SO
R
R1-H2O
(IV)
Studies on chemical entities...
Thiazolidinones...
194
for subsequent cyclisation of certain uncyclised products.8 In may instance 4-
thiazolidinones can conveniently be prepared by refluxing the mixture of
thioglycolic acid and Schiff’s bases in benzene9 or dry ether
10 or ethanol.
11
The nucleophilic attack of mercapto acetic acid anion on carbon of
azomethine, which has got possitive character while nitrogen has negative character
is evidenced, simultaneously removal of water as it forms in reaction, helps in
condensation and determination of the reaction time.
THERAPEUTIC IMPORTANCE
The thiazolidinones, substituted at 2 and 3 position showed a wide variety of
biologically activity. The frequent occurrence of the group HN-CO-NH or its
tautomer in compounds possess in vitro tuberculostatic activity12
.
The biological activity of following types have been reported.
1. Antiviral13
2. Anthelmintics14,15
3. Cardiovascular16
4. Herbicidal17
5. Hypnotic18-20
6. Insecticidal21
7. Mosquito repellent22
8. Local anaesthetic23
9. Analgesic24
10. Antibacterial25,26
11. Antidiabetic27
12. Antifungal28-30
13. Anti HIV and anticancer31
14. Antimicrobial32,33
Studies on chemical entities...
Thiazolidinones...
195
15. Antiulcer34,35
16. Antitumor36
17. Antitubercular37,38
Moreover Albuquerque and co-workers39
have prepared 4-thiazolidinones
which show antidiabetic and antiinflammatory activity. Tagami et al.40
have
synthesized thiazolidinone derivatives as allergy inhibitor. Mohammad et al.41
have
prepared substituted thiazolidinones and reported their antibacterial, antifungal,
antithyroid and amoebicidal properties (V).
R. S. Lodhi and co-worker42
have been synthesized and studied antimicrobial,
antiinflammatory and analgesic property of 4-thiazolidinone and arylidene
derivatives (VI). Goel Bhawna et al.43 have documented thiazolidinone derivatives
and compared their antiinflammation potency, ulcerogenic liability, cardiovascular
and CNS effect. Pawar and co-workers44
reported synthesis and in vitro antibacterial
activity of some 4-thiazolidinone derivatives. In other study, some thiazolidinone
derivatives have been found to be promising antibacterial agent.45,46
N
S
S
R1
R2
O R5R4
R3
N
N
O
NH N S
O Z
R1
R1 = (un) Substituted aryl
Z = H2Z = CH2R2R1 , R2 = Substituted aryl
R1 = OH
R2, R4, R5 = H
R3 = Me(V)
(VI)
Studies on chemical entities...
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196
H. S. Joshi et al.47
have synthesized microwave assisted 4-thiazolidinones
and reported their biological activity.
Tamura et al.48
have reported antimicrobial activity of 4-thiazolidinone
derivatives. B. Lohary et al.49
have documented and reported hypolipidemic activity
of 4-thiazolidinone derivatives. Bhawana et al.50
have assessed some new 4-
thiazolidinones as antiinflammatory agents. Antifungal and antibacterial activity51
of thiazolidinones has been reported. Many workers have reported 4-thiazolidinone
as antibacterial,52
anticancer,53 antiinflammatory and analgesic agent.
54
Mayer et al.55
have prepared thiazolidinones and studied their herbicidal
activity. Archana and Srivastava56
have synthesized 4-thiazolidinones (VII) as potent
anticonvulsant agent. S. K. Srivastava et al.57
have formulated some new 4-
thiazolidinones (VIII) as antibacterial, antifungal, analgesic and diuretic agents.
Dayam R. et al.58
have reported some new thiazolidinone derivative as novel
class of HIV- integrase inhibitors. Sonawane N. D. et al.59
have synthesized some
new thiazolidinone derivatives as in vivo pharmacology and antidiarrheal efficacy
of CFTR inhibitor in rodents. Shih M. H. et al.60
have described the synthesis and
evaluation of antioxidant activity of sydnonyl substituted thiazolidinone and
thiazoline derivatives (IX).
Moreover, Salinas D. B. et al.61
documented the thiazolidinone derivatives
as CFTR inhibitor. Wang X. F. et al.62
have synthesized some novel thiazolidinone
N
N
NNH
O
N
S
O
H
Ar
H
Ar
N
N
NH
O
CH3
N N
S
NS
Ar
O
(VII) (VIII)
Studies on chemical entities...
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197
derivatives and described as new cystic fibrosis transmembrane conductance
regulator inhibitor on Cl- conductance in human sweat ducts. Ur F. et al.63
have
constructed some new 6-methylimidazo[2,1-b]thiazole-5-carbohydrazide derivatives
and studied their antimicrobial activities.
Furthermore, Reigada D.et al.64
have reported some novel thiazolidinone
derivatives as release of ATP from retinal pigment epithelial cells involves both
CFTR and vesicular transport. Rao A. et al .65
have described some novel
thiazolidinone derivatives as 2-(2,6-dihalophenyl)-3-(pyrimidin-2-yl)-1,3-thiazolidin-
4-ones as non-nucleoside HIV-1 reverse transcriptase inhibitors. Muanprasat C. et
al.66 have prepared some new thiazolidinone derivatives as CFTR inhibitors.
Recently, Maclean D. et al.67
have reported thiazolidinone library as agonists
of the stimulating hormone receptor (X). Thiagarajah J. R. et al.68,69
have synthesized
a small molecule as CFTR inhibitor. Taddei A. et al.70
have been constructed some
new thiazolidinone as CFTR inhibition.
N
S
NH
OR3
O
R1
R2
(IX)
S
N
O
BnO
NH
O NHO
NH2
Cl
(X)
Studies on chemical entities...
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198
In view of the therapeutic activities of 4-thiazolidinones and methylsulfonyl
derivatives, it was contemplated to synthesis some new 4-thiazolidinones in search
of agents possessing higher biological activity with least side effect, which have
been described as under.
SECTION-I : SYNTHESIS AND BIOLOGICAL SCREENING OF 3- AMINO-
5 - A R YLIDINE-2-METHYL-2- [4 -METHYLSULFONYL)
PHENYL]-1,3-THIAZOLIDIN-4-ONES
Studies on chemical entities...
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199
SECTION - I
SYNTHESIS AND BIOLOGICAL SCREENING OF 3 - A M I N O - 5 -
A RY LI D I N E - 2 - M E T H Y L - 2 - [ 4 - ( M E T H Y L S U L F O N Y L ) P H E N Y L ] - 1 , 3 -
THIAZOLIDIN-4-ONES
4-Thiazolidinone and its derivatives represent one of the most active classes
of compounds possessing wide spectrm of pharmacological activity. Looking to
their versatile properties, it was planned to genarate a series of 3- am i n o - 5 -
arylidine-2-methyl-2-[4-(methylsulfonyl)phenyl]-1,3-thiazolidin-4-ones of type
(XIII) by heterocyclisation of 3-amino-2-methyl-2-[4-(methylsulfonyl)phenyl]-1,3-
thiazolidin-5-one with arylaldehyde acid.
The structure elucidation of synthesized compounds has been done on the
basis of elemental analyses, infrared and 1 H nuclear magnetic resonance
spectroscopy and further supported by Mass spectrometry.
All the compounds have been evaluated for their in vitro biological assay
like antibacterial activity towards gram positive and gram negative bacterial strains
and antifungal activity towards Aspergillus niger at a concentration of 40µg/ml.
The biological activities of synthesized compounds were compared with standard
drugs.
S
O
O
CH3
S
N
CH3
O
NH2
R-CHO
CH3COONa ingla.CH3COOH
S
O
O
CH3
S
N
CH3
O
CHR
NH2
Type(XIII)R=Aryl
Studies on chemical entities...
Thiazolidinones...
200
0.0
20.0
40.0
60.0
80.0
100.0
%T
500.0750.01000.01250.01500.01750.02000.03250.01/cm
453.2 470.6
516.9
590.2
621.0
717.5
761.8
815.8
958.6
1010.6
1028.0
1070.4
1099.3
1172.6
1253.6
1288.4
1307.6
1357.81398.3
1431.1
1494.7
1512.1
1556.4
1591.21668.3
2312.52769.6
2839.0
2918.12989.5
3325.0
Type Vibration Frequency in cm-1 Ref.
Mode Observed Reported
Alkane C-H str. (asym.) 2918 2975-2950 71
-CH3 C-H str. (sym.) 2839 2880-2860 ,,
C-H def. (asym.) 1431 1470-1435 ,,
C-H def. (sym.) 1398 1390-1370 ,,
Aromatic C-H str. 3035 3090-3030 72
C=C str. 1512 1540-1480 ,,
1070 1125-1090 ,,
1028 1070-1000 ,,
Sulfonyl SO2 str. 1172 1185-1165 ,,
Amide NH-C=O str. 1668 1680-1636 71
Amine NH- str. 3325 3380-3350 ,,
IR SPECTRAL STUDIES OF 3 - AM I N O - 5 -ARYLIDINE-2-METHYL-2-
[4-(METHYLSULFONYL)PHENYL]-1,3-THIAZOLIDIN-4-ONE
SCH3
O
O N
S
NH2
CH3
O
Instrument : SHIMADZU FTIR 8400 Spectrophotometer; Frequency range: 4000-400
cm-1 (KBr disc.)
Studies on chemical entities...
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201
Internal Standard : TMS; Solvent : CDCl3 : Instrument : BRUKER
Spectrometer (300 MHz)
1 2.33 3 H singlet Ar-CH3 -
2 2.40 3 H singlet Ar-SO2 CH3 -
3 3.69-3.71 2 H doublet Ar-NH2 -
4 7.26-7.29 5 H multiplet Ar-H(c,g) -
5 7.65-7.68 2 H doublet Ar-Hb,b’ J=9.
6 7.74-7.77 2 H doublet Ar-Ha,a’ J=9
7 9.02 1 H singlet Hh -
Signal No.
Signal Position (δppm)
Relative No. of protons
Multiplicity Inference J Value In Hz
NMR SPECTRAL STUDIES OF 3 - A M I N O - 5 -ARYLIDINE-2-METHYL-2-
[4-(METHYLSULFONYL)PHENYL]-1,3-THIAZOLIDIN-4-ONE
a b
a' b'
SCH3
O
O N
S
NH2
CH3
O
cd
e
fg
h
Studies on chemical entities...
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202
TAB
LE
-13
:MA
SS S
PE
CT
RA
L S
TU
DIE
S O
F 3
-AM
INO
-5-(
P-C
HL
OR
OB
EN
ZY
LID
EN
E)-
2-M
ET
HY
L-2
-[4-
(ME
TH
YL
SU
LF
ON
YL
)PH
EN
YL
]-1,
3-T
HIA
ZO
LID
IN-4
-ON
E
m/z
= 4
08
Studies on chemical entities...
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203
EXPERIMENTAL
SYNTHESIS AND BIOLOGICAL SCREENING OF 3 - A M I N O - 5 -
A RY LI D I N E - 2 - M E T H Y L - 2 - [ 4 - ( M E T H Y L S U L F O N Y L ) P H E N Y L ] - 1 , 3 -
THIAZOLIDIN-4-ONES
(A) Synthesis of 3-Amino-2-[4-(methylsulfonyl)phenyl]-1,3-thiazolidin-5-one
To a solution of 1-[4-(methylsulfonyl)phenyl]ethanone hydrazone (2.12 gm,
0.01 mol) and mercaptoacetic acid (0.92 gm, 0.01 mol) in dry toluene(20ml) was
refluxed on heating mentle using dean stark water separator for 10 hr. The reaction
mixture was cooled and excess toluene was distilled in vacuo. An oily liquid was
obtained, which was poured into hexene and kept overnight. The solid separated
was filtered and recrystlized from ethanol.Yield 48%; M.P. 168oC; Anal. Calcd. for
C11H14N2O3S2 Requires: C,46.13; H,4.93; N, 9.78 %; Found: C, 46.11; H, 4.92;
N, 9.76 %.
(B) Synthesis of 3- Amino- 4- benzylidine-2-methyl-2-[4-(methylsulfonyl)
phenyl]-1,3-thiazolidin-5-ones
To a solution of 3-amino-2-[4-(methylsulfonyl)phenyl]-1,3-thiazolidin-5-one
(2.54 gm, 0.01 mol) and benzaldehyde(1.06 gm, 0.01 mol) and anhydrous sodium
acetate(0.79 gm, 0.01 mol) in glacial acetic acid (20 ml) was refluxed on heating
mentle at 120oC for 12 hr. The reaction mixture was cooled and tritruted with 10%
sodiumsulphate solution. The product was crystallized from ethanol. Yield 48%;
M.P. 168oC; Anal. Calcd. for C18H18N2O3S2 Requires: C,57.73; H, 4.84; N, 7.48%;
Found: C, 57.71; H, 4.82; N, 7.49%.
Similarly other 3 - am i n o - 5 - ary lidine-2-methyl-2-[4-(methylsulfonyl)
phenyl]-1,3-thiazolidin-5-ones have been prepared the physical constants are
recorded in Table No. 13.
Studies on chemical entities...
Thiazolidinones...
204
(C) Biological screening of 3- Amino- 4- benzylidine-2-methyl-2-[4-
(methylsulfonyl)phenyl]-1,3-thiazolidin-5-ones
Antimicrobial testing were carried out as described in Part-I Section-1 (C).
The zones of inhibition of test solution are reported in Graphical Chart No 13.
Studies on chemical entities...
Thiazolidinones...
205
13a
C6H
5-C
18H
18N
2O3S
237
416
848
7.48
7.49
0.51
S 2
13b
4-C
l-C
6H4-
C18
H17
ClN
2O3S
240
812
852
6.85
6.84
0.46
S 1
13c
2-C
l-C
6H4-
C18
H17
ClN
2O3S
240
815
244
6.85
6.86
0.58
S 2
13d
3-C
l-C
6H4-
C18
H17
ClN
2O3S
240
818
561
6.85
6.82
0.46
S 2
13e
4-O
CH
3-C
6H4-
C19
H20
N2O
4S2
404
138
466.
936.
920.
54S 1
13f
3,4-
(OC
H 3) 2
-C6H
3-C
20H
22N
2O5S
243
415
867
6.45
6.44
0.56
S 2
13g
4-F-
C6H
4-C
18H
17FN
2O3S
239
219
163
7.14
7.15
0.44
S 2
13h
3-B
r-C
6H4-
C18
H17
BrN
2O3S
245
314
668
6.18
6.19
0.59
S 1
13i
3-C
6H5-
O-C
6H4-
C24
H22
N2O
4S2
462
183
596.
006.
020.
47S 2
13j
4-N
(CH
3)2-
C6H
4-C
20H
23N
3O3S
241
716
459
10.0
610
.07
0.56
S 1
13k
2-O
H-C
6H4-
C18
H18
N2O
4S2
390
172
437.
107.
110.
41S 2
13l
2-C
4H3O
-C
16H
16N
2O4S
236
414
656
7.69
7.70
0.53
S 2
TA
BL
E :
13
PH
YSI
CA
L C
ON
STA
NT
S O
F 3
-AM
INO
-5A
RY
LID
INE
-2-M
ET
HY
L-2
-[4-
(ME
TH
YL
SU
LF
ON
YL
)
PH
EN
YL
]-1,
3-T
HIA
ZO
LID
IN-4
-ON
ES
S 1 H
exan
e:Et
hyl
acet
ate(
5:5)
,
S 2 H
exan
e:Et
hyl
acet
ate(
6:4)
Sr.
R M
olec
ular
M
olec
ular
M
.P.
Yie
ld
%
of N
itro
gen
Rf
Sol
vent
No
For
mul
a
Wei
ght
oC
%
Cal
cd.
Fou
nd
V
alue
Sys
tem
1
2
3 4
5
6
7
8 9
10
Studies on chemical entities...
Thiazolidinones...
206
GR
AP
HIC
AL
CH
AR
T N
O.
13 :
3-A
MIN
O-5
-AR
YL
IDIN
E-2
-ME
TH
YL
-2-[
4-(M
ET
HY
LS
UL
FO
NY
L)P
HE
NY
L]-
1,3-
TH
IAZ
OL
IDIN
-4-O
NE
S
Studies on chemical entities...
Thiazolidinones...
207
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