CHAPTER I

INTRODUCTION AND

LITERATURE REVIEW OF

QUINAZOLINONE,

TRIAZOLE,

QUINOXALINE &

IMIDAZOLONE

SECTION I

INTRODUCTION AND

LITERATURE REVIEW OF

QUINAZOLINONE

1.1.1 Introduction and literature review

Quinazoline or 1,3-diazonaphthalene represented by structure I has also been

given names like phenmiazine, benzo-1, 3-diazine or 5,6-benzopyrimidine. Peter

Gries was the first in 1869 to report a compound containing the quinazolin nucleus,

denoted his compound by the term bycyano midobenzyl, now known as 2-cyano-4-

quinazolin, this original nomenclature used until 1885.

I

Quinazoline is a compound made up of two fused six member simple aromatic

rings-benzene & pyrimidine ring. It is a yellow colored compound, found usually in

crystalline form. Medicinally it is used as antimalarial agent. It was first prepared by

Gabriel in 1903 and first isolated from the Chinese plant aseru. The development of

research on biological activity of quinazoline compounds started when the compound

2-methyl-1,3-aryl-4-quinazoline derivative was synthesized. This compound has

soporific & sedative action. In last 10 to 15 years of research for medicinal has been

characterized by significant advances. In 1968 only two derivatives were used,

soporific & anticonvulsant- methaqualone and diuretic quinathazone. By 1980, about

50 kinds of derivatives of this class includes medicinal with different biological

actions like ‘soporific, sedative, tranquilizing, analgesic, anticonvulsant, antitussive,

myorelexant, antirheumatic, hypotensive, antiallergic, bronchodilating, antidiabetic,

cholagogue, diuretic, cystatic, antimalarial, spermicidal etc. The search for substances

of cardiovascular agents begun in quinazoline derivatives after pharmacological

screening of hypotensive activity of quinazoline that have a glycine amide or β-

alanine amide residue in 3rd position.

Quinazolinones will be classified into the following five categories. 2-

Substituted-4(3H)-quinazolinones, 3-substituted-4(3H)-quinazolinones, 4-substituted-

quinazolines, 2,3-disubstituted-4(3H)-quinazolinones, 2,4-disubstituted-4(3H)-

quinazolinones. Quinazoline is a compound made up of two fused six-membered

aromatic rings, that is a benzene ring and a pyrimidine ring. The benzene ring

modifies the chemistry of pyrimidine ring in a number of ways and thus it shows a

profound effect on the properties of the pyrimidine structure. It causes the

2

delocalization of π electrons of the 3, 4-double bond making its reactivity like that of

an isolated double bond. As a consequence quinazoline is very reactive toward

nucleophiles. The name quinazoline (chinazolin) is today universally used to denote

the 1,3-benzodiazine ring system I. Widdige first proposed it in 1887 on observing

that compound was isomeric with the known cinnoline II and quinaxaline III

derivatives.

II III

In 1889 numbering II was first adopted by Paal and Buch, as suggested by

Knorr and designated individual atoms of a ring with numbers. Compounds

containing the quinazoline nucleus fall into three distinct classes i.e. quinazoline,

hydrogenated quinazoline and hydroxy quinazoline or quinazolinone, on the basis of

their physical and chemical properties and their means and ease of preparation.The

second distinct class of compounds containing the quinazoline nucleus is the

hydrogenated quinazoline. Most important compound is 3,4-dihydroquinazoline IV.

This partially hydrogenated quinazoline are unique in heterocyclic chemistry in their

unexpected stability and ease of preparation.

IV

Theoretical treatment by Brown has led electron density diagram for

quinazoline V these values were obtained by molecular orbital calculations using

uniform parameters. They are self-consistent and give dipole moment in agreement

with experiment [1].

V

3

The first quinazolinone based drug, which was used as sedative hypnotic was

methaqualone VIII. This compound is prepared by the fusion of N-acetyl anthranilic

acid VI with o-toludine VII and POCl3 or PCl5 are used as catalyst to facilitate the

reaction more smoothly [2].

VI VII VIII

Acylation of amide with 2-azidobenzoyl chloride IX forms imide X, which

upon treatment with triphenylphosphine in the course of consecutive staudinger

reaction/intramolecular aza-wittig reaction quantitatively give 2,3-

disubstitutedquinazolin-4(3H)ones XI [3-5].

IX X XI

Anthranilic acid XII on reaction with acid chloride also forms benzoxazinone

XIII which on reaction with primary amine yield 2-3-disubstituted-quinazolin-

4(3H)ones XIV [6,7].

XII XIII XIV

Acetanthranil (3,1,4- benzoxazinone) XVI can be easily prepared by heating

anthranilic acid or a substituted anthranilic acid XV with an acid anhydride.

Zentmayer and Wagner developed a convenient and fairly general procedure for

preparation of acylanthranils or 3,1,4- benzoxazinone [8]. 2-Amidobenzoic acid on

refluxing with acetic anhydride yield benzoxazinone, which reacts exothermally with

ammonia and most amine in aqueous media to give high yield of quinazolin-

4

4(3H)ones XVII [9-11]. Reactions of substituted aromatic amine with acetanthranil

have been extensively studied by Erred et al [12-14].

XV XVI XVII

The synthetic methodology commence with the synthesis of anthranilamide

XIX by the oxidation of 2-amino benzonitrile, followed by its amidation using acid

chloride and triethylamine to give the uncyclized amide intermediate XX, which on

oxidative ring closure under basic conditions, using potassium hydroxide yield 2-

substituted-quinazolin-4(3H)ones XVIII [15-17].

XVIII XIX XX

Docking of ligands and quantitative structure activity relationship analysis of

2,8-disubstituted-quinazolin-4(3H)ones were performed by Costantino et al as

poly(ADP-ribose)polymerase (PARP) inhibitors [18]. Kulcsar et al [19] and Griffin et

al [20] have synthesized 4-quinazolinones and studied their action to inhibitors of the

DNA repair enzyme poly (ADP-ribose) polymerase (PARP). Inhibitors of DNA

gyrase activity have been investigated by Sui et al [21]. The 3D-QSAR analysis of 2-

methyl-6-substituted-quinazolin-4(3H)ones XXI derivatives with dithiocarbamate

side chains on thymidylate synthase were studied by Liu et al [22].

XXI

Patel and his research team have synthesized quinazolin-4(3H)ones of 2-[(2,6-

dichlorophenyl)amino]phenyl acetic acid XXII with aryl [23], aryl acetamides [24],

4-thiazolidinones [25,26], 2-azetidonones [27], aryl sulfonamides [28] and thiazoles

[29-31] as possible antimicrobial agents.

5

XXII

Hennequin et al and Marsham et al have introduced quinazoline antifolates

thymidylate synthase inhibitors [32,33].

Monoamine oxidase inhibitory activities of substituted quinazolinones were

reported by several researchers [34,35]. Novel ATP-competitive kinesin spindle

protein inhibitory activities of 7-chloro-2,3-disubstituted quinazolin-4(3H)ones XXIII

were introduced by Parrish et al [36].

XXIII

2-(3-Aminopiperidin-1-yl)-3-(2-cyanobenzyl)-quinazolin-4(3H)ones XXIV

were synthesized by Feng et al and studied their inhibitory activity against dipeptidyl

peptidase [37].

XXIV

6

Na et al have synthesized novel quinazolinone derivatives XXV as 5-HT7

receptor ligands [38].

XXV

Quantitative structure activity relation study on a series of 2,3,7-substituted

quinazolinone derivatives XXVI is performed for their AT1 selective angiotensin II

receptor antagonist by Pandya and Chaturvedi [39]. A number of researchers have

studied angiotensin II receptor antagonist activities of quinazolinone derivatives [40-

45].

XXVI

Quinazolin-4(3H)ones incorporated with substituted biphenyls XXVII-

XXVIII were designated by Ismail et al as angiotensin II AT1 receptor antagonists

[46].

XXVII XXVIII

Structure-activity relationships of 2-(1-substitutedaminoethyl)-3-(4-

substitutedphenyl)-quinazolin-4(3H)ones XXIX as CXCR3 receptor antagonists were

assessed by Storelli et al [47].

7

Culshaw et al have studied biological profile of 7-isopropyl-2-substituted-6-

substitutedphenyl-quinazolin-4(3H)ones XXX as novel TRPV1 antagonists that are

effective in models of chronic pain [48].

XXIX XXX

Somers et al synthesized 2-alkylamino-6-halogenoquinazolin-4(3H)ones

XXXI for insulin secretion and smooth muscle contractile activity [49].Gngr et al

have synthesized 3-arylquinazolinone derivatives as selective estrogen receptor beta

modulators [50].

XXXI

Brunton have synthesized 2,3-disubstituted-quinazolin-4(3H)ones XXXII as

potent inhibitors of the hedgehog signaling pathway [51].

XXXII

Raffa et al have investigated antiproliferative activity of 3-(indazol-3-yl)-

quinazolin-4(3H)ones XXXIII derivatives [52].

XXXIII

8

Elvam have synthesized 2-phenyl-3-substitutedaryl-quinazolin-4(3H)-ones

XXXIV-XXXV and studied their antiviral and cytotoxic activities [53].

XXXIV XXXV

Pandey and his co-worker synthesized 6-(N-ethylphthalimido)-3-[2-(5-

arylkyl-1,3,4-thiadiazolyl-2-phenyl-4-oxo-3(H)-quinazolines XXXVI as potential

antiviral and antihypertensive agent [54].

XXXVI

Potential antiviral agents 1-(2'-aryl-4'-oxo-(3H)-quinazolyl)-3-aryl-5-phenyl-

formazans XXXVII have been synthesized by Pandey and Negi, which were active

against Vaccinia virus [55].

XXXVII

Antihistaminic activity of 2-mercapto-3-(substitutedmethylamino)quinazolin-

4(3H)ones were reported by Alagarsamy et al [56]. Shukla and co-workers have

studied anthelmintic activity of quinazolinones XXXVIII [57].

XXXVIII

9

Ramarao and co-workers have synthesized antihistaminic agents i.e. 3-[(N,N-

dialkylamino)alkyl]-6-halo-2-phenyl-3,4-dihydro-quinazolin-4(3H)-ones XXXIX

[58].

XXXIX

Cytotoxicity and inhibitory effects on tubulin polymerization of a new 3-

heterocyclo substituted 2-styrylquinazolinones XL have been synthesized by Raffa et

al [59].

XL

Liu et al have synthesized 2-substitutedstyryl-3-substitutedethyl-quinazolin-

4(3H)ones XLI and studied their cytotoxicity activity [60]. Primary cytotoxicity

evaluation of 3-[[(3-phenyl-4(3H)-quinazolinone-2-yl)mercaptoacetyl]hydrazono]-

1H-2-indolinones XLII have been given by Gursoy and Karali [61].

XLI XLII

Forsch and co-workers have studied inhibitors of the growth of CCRF-CEM

human leukemic lymphoblasts of N-[5-[N-(2-substituted-5-chloro-3,4-dihydro-4-

oxoquinazolin-6-yl)methylamino]-2-thenoyl]-L-glutamic acids XLIII [62].

XLIII

10

Murugan have synthesized 2-alkyl-3-aryl-4(3H)quinazolinones XLIV as

possible antitumor agents [63].

XLIV

Quinazolin-4(3H)one based water soluble analogues XLV- XLVI of CB30865

were synthesized by Bavetsias et al as antitumor agents [64]. Xia et al have

synthesized 2-substitutedphenyl/naphthyl-quinazolin-4(3H)ones as antitumor agents

[65].

XLV

XLVI

2-Methyl-quinazolin-4(3H)one with dithiocarbamate side chains XLVII were

synthesized by Cao et al and studied in vitro antitumor activity [66].

XLVII

Girija et al have synthesized novel 2,3-disubstituted quinazolin-4(3H)ones

XLVIII and screened for in vitro cytostatic activity against adult T. lymphocyte

leukemia (MT-4) cells [67].

11

XLVIII

Murugan et al synthesized 4-chloro-1-[4-(6,8-disubstituted-2-chloromethyl

quinazolin-4-one-3-yl)-phenyl]-butane-1,3-dione XLIX and 2-(N-

morpholinomethyl)-3-(acetophenon-4-yl)-4(3H)-quinazolinone L for their anticancer

activity [68].

XLIX L

Substituted-3-{[(1E)-(substituted-2-furyl)methylene]amino}quinazolin-4(3H)-

ones LI were synthesized by Raghavendra et al and tested their antitubercular and

anticancer activities [69].

LI

Ramasharma and co-workers synthesized quinazolinoyl thiadiazoles LII

which were exhibited significant protection against carrageenan induced rat paw

edema [70].

LII

12

Acute toxicity, analgesic, anti-inflammatory and ulcerogenic activity of ethyl

1-methyl-5-(substituted-3,4-dihydro-4-oxoquinazolin-3-yl)-1H-pyrazole-4-acetates

LIII have been given by Maggio et al [71].

LIII

Antimicrobial, anti-inflammatory, ulcerogenic and COX-1 and COX-2

catalyzed prostaglandin biosynthesis assay of substituted-2-phenyl-3-

substitutedbenzothiazolyl-quinazolin-4(3H)ones LIV were investigated by Laddha

and co-workers [72].

LIV

Kumar et al have synthesized some novel 2,3,6-trisubstituted quinazolinones

LV as potent anti-inflammatory, analgesic and COX-II inhibitors [73].

LV

Daidone et al have studied analgesic, anti-inflammatory and ulcerogenic

activity of 3-(isoxazol-3-yl)-quinazolin-4(3H)ones LVI derivatives [74].

LVI

13

Alagarsamy et al have studied analgesic, anti-inflammatory and antibacterial

activities of 2-3-disubstituted-quinazolin-4-(3H)ones LVII derivatives [75-78].

Analgesic, anti-inflammatory and ulcerogenic activity of 3-cyclohexyl/4-

methylphenyl-2-substitutedhydrazino-quinazolin-4(3H)ones LVII-LIX were also

studied by Alagarsamy et al [79-81].

LVII LVIII LIX

Analgesic and anti-inflammatory activity of 2-substitutedamino-3-(benzyl)-

quinazolin-4(3H)ones LX, 2-substitutedamino-3-(4-methoxyphenyl)-quinazolin-

4(3H)ones LXI and 2-benzylamino-3-substitutedamino-quinazolin-4(3H)ones LXII

have been investigated by Alagarsamy and co-workers [82-84].

LX LXI LXII

CNS depressant and anticonvulsant activities of some novel 3-[5-substituted

1,3,4-thiadiazole-2-yl]-2-styrylquinazoline-4(3H)-ones LXIII have been reported by

Jatav et al [85].

LXIII

CNS depressant activity of some novel bioactive 1-(4-substituted-

phenyl)-3-(4-oxo-2-phenyl/ethyl-4H-quinazolin-3-yl)-urea LXIV have been

studied by Sushil et al [86].

14

N

N NH NH

OO

R

X

LXIV

Anticonvulsant activity of thiadiazolyl and thiazolidinonyl quinazolin-4(3H)-

ones LXVhave been reported by Archana and co-workers [87].

LXV

Substituted quinazolinonyl-2-oxo/thiobarbituric acids LXVI were synthesized

by Archana and co-workers as potent anticonvulsant agents [88].

LXVI

Laddha and Bhatnagar have synthesized 6,8-disubstituted-2-phenyl-3-

(benzothiazol-2-yl)-quinazolin-4(3H)ones LXVII as anticonvulsants [89].

LXVII

Antibacterial, antifungal and anti-HIV activities of 2-methyl-3-(substituted

methylamino)-quinazolin-4(3H)ones LXVIII were assessed by Alagarsamy et al

[90].

15

LXVIII

Antiviral and antifungal bioactivities of 2-aryl- or 2-methyl-3-(substituted-

benzalamino)-quinazolin-4(3H)one derivatives were reported by Gao et al [91].

Pandey and co-workers have synthesized 2-aryl-3-[5-aralkyl-1,3,4-thiadiazolyl-{2-

(3,4-diphenyl-1-oxo-isoquinolinyl)}]-4-oxo-3H-quinazolines LXIX and studied their

antiviral and antifungal activities [92].

LXIX

Trivedi and his co-workers have synthesized series of 2-(substitutedphenyl)-3-

[(2-phenyl-4-oxo-3-quinazolinyl)-thiocarbonyl]-4-oxo-thiazolidine LXX and studied

their antibacterial and antitubercular activities [93]. Kumar et al have reported

antitubercular activities of quinazolin-4(3H)one derivatives [94].

LXX

Antibacterial, antifungal and antimalarial activities of 3-[4-(4-substituted

phenyl-5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3-yl-methoxy)-phenyl]-2-phenyl-

quinazolin-4(3H)ones LXXI have been reported by Havaldar and Patil [95].

16

LXXI

Radadia and his co-workers have synthesized 2-{1-[(4-chlorophenyl)-2-

methyl propyl]}3-N-(aryl)-quinazolin-4(3H)one LXXII for their antimicrobial

activity [96]. Habib and Khali have also reported antimicrobial activities of

quinazolin-4(3H)one derivatives [97]. Antibacterial, antifungal and antiacetyl

cholinesterase activities were assessed by Gupta and Misra [98].

LXXII

Antibacterial and antifungal activities of 3-phenyl-6-methyl-4(3H)-

quinazolinon-2-yl-mercaptoacetic acid arylidenehydrazides LXXIII have been done

by Gursoy et al [99].

LXXIII

Pattan et al synthesized series of N'-3-[4-(4-chlorophenylthiazolo-2-yl)-2-

aminomethyl]-quinazolin-4(3H)ones LXXIV showed promising antifungal and

antibacterial activity [100].

LXXIV

17

Padamkant and Saksena synthesized new 2-phenyl-3-p-(2-methyl-3-aryl-4-

oxo-thiazolin-2-yl)phenylquinazolin-4-ones LXXV and 2-phenyl-3-P-(1-aryl-3-

phthalimindo-4-methylazetidine-2-one-4-yl)phenylquinazolin-4-ones LXXVI and

screened for their antibacterial and antifungal activities [101].

LXXV LXXVI

El-Sharief et al synthesized triazinoquinazolinones, triazepinoquinazolinones

and triazocinoquinazolinones LXXVII as possible antibacterial and antifungal agent

[102].

LXXVII

El-Sayed and Wasfy have studied antibacterial and antifungal activities of 1-

(3-substituted-4-oxo-3,4-dihydroquinazolin-2-yl)heptadecane-1-sodiumsulfonates

LXXVIII [103].

LXXVIII

Antibacterial and antifungal activities of substituted-2-methyl/phenyl-3-{[(3-

methyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl)carbonyl]methyl/phenyl}quinazolin-

4(3H) ones LXXIX were reported by Desai and Desai [104].

18

LXXIX

Patel and co-workers have synthesized 6-bromo-2-methyl/phenyl-3-{[phenyl

(phenyldiazenyl)methylene]amino}quinazoline-4(3H)ones LXXX as antimicrobial

agents [105].

LXXX

2-Methyl-3-(1,3,4-thiadiazolyl)-quinazolin-4(3H)ones LXXXI were

synthesized by Jatav et al as antibacterial and antifungal agents [106].

LXXXI

Several investigators [107-130] have reported the various syntheses of

quinazolinone derivatives involving microwave techniques, one pot reactions and

solid phase reactions.

Raghavendra and co-workers have observed antibacterial and antifungal

activities of substituted piperazinyl-quinazolin-3(4H)ones LXXXII [131]. Novel

quinazolone derivatives LXXXIII of nalidixic acid have been synthesized by Grover

and Kini as potential antibacterial and antifungal agents [132].

LXXXII LXXXIII

19

Antibacterial and antifungal activities of 3-[(2-hydroxy-quinolin-3-

ylmethylene)-amino]-2-phenyl-quinazolin-4(3H)ones LXXXIV was reported by

Siddappa et al [133].

LXXXIV

Alafeefy have introduced 1-[6-iodo-4-oxo-2-phenylquinazolin-3(4H)-yl]-3-

substituted thioureas LXXXV and 6-iodo-2-phenyl-3-[4-substituted-2-thioxothiazol-

3(2H)-yl]-quinazolin-4(3H)ones LXXXVI as antimicrobial agents [134].

LXXXV LXXXVI

Antibatcerial and antifungal activity of 3-[5-(4-substituted)phenyl-1,3,4-

oxadiazol-2yl]-2-styrylquinazoline-4(3H)ones LXXXVII have been reported by

Gupta et al [135].

LXXXVII

Structure activity relationships of novel 2,3-disubstitiuted quinazolin-

4(3H)ones LXXXVIII and LXXXIX of fungal efflux pump inhibitors with respect to

potentiation of the activity of fluconazole against strains of C. albicans and C.

20

glabrata over-expressing ABC-type efflux pumps were explored by Watkins et al

[136].

LXXXVIII LXXXIX

2-Substitutedmethylthio-3-(4-substitutedsulphonamido)phenyl-quinazolin-

4(3H) ones XC were synthesized by EL-Gaby as antibacterial agents [137].

XC

Nanda and co-workers have reported preliminary QSAR studies of 3-

(arylideneamino)-2-phenylquinazoline-4(3H)ones XCI as antibacterial agents [138].

Sayyed and his co-workers have also reported antibacterial activities of 6-iodo/bromo-

3-(arylideneamino)-2-methylquinazolin-4(3H)ones XCII [139].

XCI XCII

21

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SECTION II

INTRODUCTION AND

LITERATURE REVIEW OF

TRIAZOLE

1.2.1 Introduction and literature review

The success of imidazole as an important moiety of number of medicinal

agents led to introduction of the triazoles. The triazoles are said to be the isosters of

imidazoles in which the carbon atom of imidazole is isosterically replaced by

nitrogen. Triazole is one of a class of organic heterocyclic compounds containing a

five-membered ring structure composed of three nitrogen atoms and two carbon

atoms at nonadjacent positions. The simplest member of the triazole family is triazole

I itself, white to pale yellow crystalline solids with a weak characteristic odour;

soluble in water and alcohol, melts at 120°C, boils at 260°C. Triazole and its

derivatives are used for biological activities such as antiviral, antibacterial, antifungal

and antituberculous. Mostly 1,2,4-triazole I and 1,2,3-triazole II are very important in

pharmaceutical industry. Heterocycles bearing symmetrical triazole ring I is reported

to show a broad spectrum of biological activities.

I II

1,2,3-Triazoles find numerous applications in industry, namely as dyestuffs,

fluorescent whiteners, photostabilizers of polymers, optical brightening agents,

corrosion inhibitors and as photographic photoreceptors Also, due to their extensive

biological activities, they find successful application in medicine and as

agrochemicals. Beyond this, these compounds are intensively studied by many

research groups due to their theoretical interest and synthetic usefulness.

The derivatization of triazole ring is based on the phenomenon of bioisosterism in

which replacement of oxygen of oxadiazole nucleus with nitrogen atom yields triazole

analogue. Out of the two triazoles 1,2,4- triazole have wide variety of activity [1]. The

first synthesised clinical useful 1,2,4-triazole which is known as ‘amitrole’ III. Some

novel 1,2,4-triazole IV act as internal standard inhibitors for nitric oxide synthase in

rat plasma and urine.

III IV

30

Substituted 1,2,3-triazoles can be produced using theazide lkyne Huisgen

cycloaddition in which an azide and an alkyne undergo a 1,3-dipolar cycloaddition

reaction. It is a surprisingly stable structure compared to other organic compounds

with three adjacent nitrogen atoms. However, flash vacuum pyrolysis at 500 °C leads

to loss of molecular nitrogen (N2) to produce aziridine. Certain triazoles are relatively

easy to cleave due to so-called ring-chain tautomerism. One manifestation is found in

the Dimroth rearrangement. 1,2,3-Triazole finds use in research as a building block

for more complex chemical compounds, such as pharmaceutical drugs like

tazobactam.

Fungicidal and bactericidal [2] potential of (1H-1,2,4-triazol-1-yl methyl)phenols,

anilines, N-alkyl anilines and N,N-dialkyl anilines have been evaluated by El-Zemity

and co-worker.

El-Sayed has synthesized new 1,2,4-triazoles and studied their surface activity

and evaluated as antibacterial agent [3].

Desai et al [4] have synthesized 1,2,4-triazole derivatives; 1,2,4-triazole bearing

benzothiophene nucleus prepared by Thaker and co-worker [5] and studied their

antimicrobial acivities.

Collin et al have prepared 1,2,4-triazolo mercapto and aminonitriles as potent

antifungal agents [6].

Osyanin and co-worker synthesized 4-(1H-1,2,4-triazol-1-yl-methyl)phenol and

inferred as genotoxicity activity [7].

Havaldar et al [8] have synthesized 1,2,4-triazoles V; quinoline based triazoles

VI synthesized by Keshk et al [9] and evaluated their antibacterial and antifungal

activity.

N

N

ON

N NH

SO

R1

R2

NN

N N

SH

R

V VI

Zhou and co-workers [10] 1,2,4-triazoles; 3,5-diaryl-1,2,4-triazole prepared by

Serdar et al [11] and investigated their antimicrobial activity.

31

Abdullah et al have synthesized novel 1,2,4-triazoles, thiazoles and bisthiazoles

bearing a sulfonamide moiety VII have synthesized and studied their antimicrobial

activity [12].

VII

Ezabadi and co-worker have synthesized sulphonamide-1,2,4-triazoles as

antifungal and antibacterial agents [13] and studied their lipophilicity and

conformational properties. Tetrahydronapthyl azole oxime ethers as conformationally

rigid analogues of oxiconazole VIII and IX as antibacterials [14] have been

synthesized by Bhandari and co-worker.

VIII IX

Moise and co-worker [15] have synthesized 1,2,4-triazole derivatives X

containing phenylalanine; quinoline derivative carrying 1,2,4-triazole XI synthesized

by Eswaran and co-worker [16] and investigated their antimicrobial activity.

X XI

Barbuceanu et al have synthesized [1,3]thiazolo[3,2-b][1,2,4]triazoles

incorporating diphenyl sulfonyl moiety showing good antimicrobial activity [17].

A series of new coumarin based 1,2,4-triazol derivatives has been synthesized

and evaluated for antimicrobial activities by Shi Y and Zhau C [18].

32

Sarva et al have synthesized 1,2,4-triazole derivatives XII as 5-HT1A serotonin

receptor ligands [19].

XII

A.M. Vijesh and coworker [20] synthesized some new pyrazole derivatives

containing 1,2,4-triazoles and benzoxazoles as potent antimicrobial and analgesic.

Saha and co-worker have synthesized novel series of potent inhibitors of Ras

farnesyl transferase possessing a 1,2,4-triazole pharmacophore XIII. These inhibitors

were discovered from a parallel synthesis effort and were subsequently optimized as

an in vitro IC50 value of less than 1 Nm XIV [21].

XIII XIV

Kim et al have synthesized 2-pyridinyl-[1,2,4]triazoles as inhibitors of

transforming growth factor a1 type 1 receptor [22]. High-throughput screening using

CHO cells expressing the cloned human V1A receptor and further pharmacological

evaluation led to the identification of XV which was an antagonist for the human V1A

receptor with the 4,5-diphenyl-1,2,4-triazole structure by Kakefuda and co-worker

[23].

N

N N

CH3

OCH3

XV

33

Structure activity relationships of uniconazole XVI, XVII and XVIII a potent

inhibitor of ABA 8′-hydroxylase, with a focus on hydrophilic functional groups and

conformation [24] was given by Todoroki and co-worker.

XVI XVII XVIII

Hua and co-worker have synthesized 1,2,4-triazole derivative XIX and studied

the distinctive molecular inhibition mechanisms for selective inhibitors of human

11α-hydroxysteroid dehydrogenase type 1 [25].

XIX

Sato and co-worker have synthesized 3-phenyl-5-pyridyl-1,2,4-triazole

derivatives and studied their pharmacological and pharmacodynamic activities as

xanthine oxidoreductase inhibitors [26]. The best compound XX had the most potent

serum UA-lowering activity and moderate PK pharmacokinetic profile without

CYP3A4 inhibition.

XX

Idrees et al have synthesized 2-(naphthalen-2-yl-oxy)propionic acid

derivatives XXI and XXII as desmethyl fibrate analogous and evaluated

hypolipidemic activity [27].

XXI XXII

34

Kamble et al have synthesized 1,2,4-triazoles incorporating 1,2,4-triazine ring

XXIII and evaluated antihaemostatic activity [28].

XXIII

Lee and co-workers synthesized 3-substituted -4-(4-hexyloxyphenyl) -4H-

1,2,4 -triazoles XXIV and evaluated anticonvulsant activity [29].

XXIV

Salgyn-Goksen and co-worker [30] have synthesized 1,2,4-triazole containing

5-methyl-2-benzoxazolinones XXV; 6-disubstituted-1,2,4-triazolo [3,4-b]-1,3,4-

thiadiazoles XXVI prepared by Mathew and co-worker and evaluated analgesic, anti-

inflammatory and antimicrobial activities.

N

O

N

N NH

S

R1

H3C

O

XXV XXVI

Abdel-Megeed et al [31] have carried out molecular modelling studies on

acetylated 1,2,4-triazole-3-acetates XXVII; newer analogues of 4-hydroxyphenyl

acetic acid with 1,2,4-triazole XXVIII have been prepared by Mohammad and co-

worker [32] with potential anti-inflammatory activity.

XXVII XXVIII

35

Aytac and co-worker have synthesized 3,6-disubstituted-4H-1,2,4-

triazolo[3,4-b]-1,3,4-thiadiazines XXIX and XXX as potent analgesic and anti-

inflammatory agents [33].

XXIX XXX

Klimesova and co-worker [34] have synthesized 1,2,4-triazole-3-

benzylsulfanyl derivatives XXXI, XXXII and XXXIII; 4-methyl -1-substituted -1H-

1,2,4- triazole-5(4H)-thione have been synthesized by Wujec et al [35] and evaluated

antimycobacterial activity.

XXXI XXXII XXXIII

Shiradkar et al [36] have synthesized thiazolyl triazole derivatives under

microwave; 3-alkylsulfanyl-1,2,4-triazole derivatives XXXIV were synthesized by

Kalpancikli et al [37] and evaluated as potential antitubercular agents.

SCH2 N

N N

S CH CH2 C

O

S

NH2

R

XXXIV

Joshi et al have synthesized new 4-pyrrol-1-yl benzoic acid hydrazide based

triazoleXXXVand evaluated as potential antibacterial and antitubercular agents [38].

XXXV

36

Ouyang and co-worker have synthesized 1,2,4-triazoles XXXVI as a novel

class of potent tubulin polymerization inhibitors [39] and studied their structure-

activity relationships.

XXXVI

Zhang et al have synthesized triazole derivatives XXXVII and XXXVIII

and inferred that compounds posses’ highly potent triazole-based tubulin

polymerization inhibitors [40].

XXXVII XXXVIII

Almajan and co-worker have synthesized 1,2,4-triazole-thiols XXXIX and

XL as carbonic anhydrase inhibitors [41].

XXXIX XL

Formagio and co-worker [42] have synthesized 3-(5-substituted-1,2,4-triazol-

3-yl) α-carboline derivatives XLI; new sulfonyl 1,2,4-triazole derivative XLII

prepared by Padmavati et al [43] and inferred as antimicrobial and antitumor

activities.

XLI XLII

37

Hassan has synthesized new fused heterocyclic derivatives of 1,2,4-triazole

XLIII, XLIV, XLV and XLVI and evaluated their cytotoxic activity [44].

XLIII XLIV XLV XLVI

Mavrova and co-worker have synthesized 4,5-substituted-1,2,4-triazole-3-

thiones derivatives XLVII and XLVIII and evaluated for their cytotoxicity [45]. High

cytotoxicity was ascertained in vitro against thymocytes and lymphocytes and a

general stimulating effect on B-cells response.

S

N

N

NHR1

RS

H3C

S

N

N

NHR1

RS

H2N

XLVII XLVIII

Arora et al have studied 1,2,4-triazole derivative XLIX as a novel microtubule

polymerization inhibitor with potent antiproliferative and antitumor activity [46].

XLIX

Bhat and co-worker synthesized 1,2,4-triazoles carrying 2,4-dichloro -5-

fluorophenyl moiety L and evaluated antitumor activity [47].

L

38

Al-Soudi et al have synthesized 1,2,4-triazollyl coumarin LI and LII as anti-

HIV agents [48] and inferred that majority of compounds have higher selectivity

index than thiazobenzimidazole (TBZ).

LI LII

Barreiro et al have synthesized sulfonyl triazole LIII and LIV derivatives and

studied docking false-positive to active anti-HIV agent [49].

LIII LIV

S-Triazolo[1,5-c]pyrimidines are important as potential therapeutic agents

[50,51]; 3-amino-1,2,4-triazole (ATZ), 3-mercapto-1,2,4-triazole (MTZ) and 3-nitro-

1,2,4-triazole (NTZ) derivatives showed antithyroid activity [52]. In recent work [53]

thienopyrimido-1,2,4-triazoles LV have been synthesized as pharmacologically

interesting compounds. Some acyclic 1,2,4-triazole C-nucleosides [54] lacked

antiviral properties against herpes simplex virus 1 and 2 (HSV-1 and -2) along with

other viruses.

LV

Triazole derivatives are also considered as an angiotensin II receptor

antagonists [55-59], LVI and LVII are used to increase the blood pressure.

Furthermore, various 1,2,4-triazole derivatives have been reported as fungicidal [60],

insecticidal [61], antimicrobial [62,63], and antiastmatic [64] agents, anticonvulsants

[65], antidepressants [66] and plant growth regulators [67]. Moreover vorozole

LVIII, letrozole LIX, and anastrozole LX, appeared to be very effective aromatase

inhibitors, which in turn prevented breast cancer [68-74]. 1,2,4-triazole also interact

39

strongly with haeme iron and aromatic substituents on the triazoles are very effective

for interacting with the active site of aromatase [71]. Same biological activities of the

triazole family are also reported in literature [72-74].

LVI LVII

N

N

N

ClCl

LVIII Vorozole LIX Letrozole

LX Anastrozole

Ribose N-glycoside LXI [75-79] is a broad spectrum antiviral agent

containing the 3-aminocarbonyltriazole and active against both RNA and DNA

viruses and is used in an aerosol for lower respiratory tract viral disease as well as in

the treatment of influenza, Lassa fever and Hantaan virus [80, 81]. Amidine and

guanidine derivatives LXII (R = H·HCl, Me, CN) exhibiting a broad spectrum

antiviral activity [82] have been prepared.

LXI LXII

40

1.2.2 References

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SECTION III

INTRODUCTION AND

LITERATURE REVIEW OF

QUINOXALINE

1.3.1 Introduction and literature review

Quinoxalines are well known and important nitrogen containing heterocyclic

compounds containing a ring complex made up of a benzene ring and a pyrazine ring.

Diversely substituted quinoxalines and their derivatives embedded with variety of

functional groups are important biological agents and a significant amount of research

activity has been directed towards this class. Various methods have been worked out

for their synthesis. Numerous quinoxaline derivatives have been found to possess

considerable biological activities, which stimulated the research activity in this field.

They have several prominent pharmacological effects, such as antimicrobial,

antimycobacterial, antifungal, antiviral, antiprotozoal, antimalarial, antiinflammatory,

anticonvulsant, antidepressant and anticancer activities. They also possess some

potent receptor selective biological activity like AMPA receptor antagonist activity.

Quinoxaline 1,4-di-N-oxides seem to be the most frequently studied quinoxaline type

compounds

Quinoxaline is commonly called 1,4-diazonaphthalene or benzopyrazine I.

The approved number of the ring atoms is shown below.

I

Important synthesis of quinoxalines IV is that involving the condensation of

an o-phenylenediamine II with 1,2-dicarbonyl III compound. The reaction was

discovered independently by Korner and Hinsberg in 1884.

II III IV

Reaction of aryliminonitriles VI with o-phenylendiamine V arises

aminoquinoxaline VII derivative [1].

46

V VI VII

The direct condensation of various benzene-1,2-diamines XIII and 1,2-

dicarbonyl IX compounds has been successfully achieved mostly in excellent yields

(95-100%) using (NH4Cl-CH3OH) as a mild, efficient, cost-effective, readily

available, acid-free, metal-free and eco-friendly catalyst system at room temperature

[2].

NH2

NH2

+

O

O

NH4Cl

methanolN

N

VIII IX X

Lead oxide is used as an efficient oxidizing agent in the oxidation and

condensation reaction of hydroxy ketone XI with diamine XII leading to form

quinoxaline derivatives XIII. The method is simple, cost effective and gives good

yields in shorter reaction times [3].

XI XII XIII

When the N,S-acetal XIV was exposed to Vilsmeier reaction conditions, the

product (60%) isolated was characterized as 3-chloro-7-methoxy 2-(methylthio)

quinoxaline. Subsequently, it was found that the reaction proceeded smoothly in the

absence of DMF and under optimized conditions, the quinoxaline XV was obtained in

improved yield (70%) when N,S-acetal XIV was reacted with POCl3 in acetonitrile at

80°C [4].

XIV XV

47

Lumma et al have synthesized piperazinylquinoxalines XVI and studied their

serotoninmimetic activity. In general, introduction of a 6-substituent into the

piperazinylquinoxaline enhanced serotonin reuptake blocking activity and diminished

serotoninmimetic activity. Unsubstituted and 3-hydroxypiperazinylquinoxalines had

primarily serotoninmimetic activity [5].

XVI

Love et al have synthesized 1,2,4-triazolo[4,3-a]quinoxaline-l,4-diones XVII and

studied their antiallergic activity [6].

XVII

4-Amino[1,2,4]triazolo[4,3-a]quinoxalines XVIII were synthesized by Sarges et

al as antidepressant agents [7].

XVIII

Two series of 3,6,7-trisubstituted-2-(1H-imidazol-2-ylsulfanyl)-quinoxalines XIX

and 2-(quinoxalin-2-yl)-isothioureas XX were prepared by Bahekar et al as

antidiabetic agents [8].

XIX XX

48

Some 1,4-bisamides of 1,2,3,4-tetrahydroquinoxalines XXI and XXII were

prepared by Schuyler et al as antineoplastic agents [9].

XXI XXII

Yoo et al have synthesized and reported cytotoxicity of 2-methyl -4,9- dihydro -

1- substituted-1H-imidazo[4,5-g]quinoxaline-4,9-diones XXIII [10].

XXIII

Several investigators displaying a broad spectrum of biological activities of

quinoxaline and its derivatives viz. antibacterial [11-18], antifungal [19-24], antiviral

[25,26], antineoplastic activity [27], cytotoxicity [28], antitumor [29], antidepressant

[30], hypoglycemic activity [31], anti-inflammatory [32], antiglaucoma [33],

antiparasite [34] and anticancer [35-37].

Yan et al have synthesized quinoxaline derivatives XXIV and studied their

cytotoxic activities [38].

XXIV

Antihypertensive activity of l-N -butyl-3-(3-methylquinoxalin-2-yl)guanidine

XXV have been assessed by Chapleo et al [39].

49

XXV

Antihypertensive activity of tetrahydropyrrolo[1,2-a]quinoxalines XXVI have

been carried out by Gharbia et al [40].

N

N

O

H

XXVI

Pinguet et al have synthesized new imidazo[1,2-a]quinoxalines XXVII and

studied their in vitro activity against human melanoma [41].

XXVII

Antiprotozoal activity of some new substituted quinoxalines XXVIII has been

reported by Hui et al [42].

XXVIII

Romeiro et al have synthesized novel quinoxaline-N-acylhydrazones XXIX and

evaluate their trypanocidal activity and docking studies [43].

XXIX

Guillon et al have synthesized 4-substituted pyrrolo[1,2-a]quinoxalines XXX as

antileishmanial agents [44].

50

XXX

Fabio et al have synthesized amidines and sulfonamides of 5-and 6-amino-2,3-bis

(4-alkyl-1-piperazinyl)quinoxalines XXXI and studied their antiamebic activity [45].

XXXI

Budakoti et al have synthesized new 2-(5-substituted-3-phenyl -2-pyrazolinyl)-

1,3-thiazolino[5,4-b]quinoxalines XXXII and studied their antiamoebic activity [46].

XXXII

Chen et al have synthesized 2,3-substituted quinoxalin-6-amine XXXIII analogs

and observed their antiproliferative activity [47].

XXXIII

Ryu et al have synthesized 6-phenylamino-quinoxaline-5,8-diones XXXIV as

antiproliferative activity [48].

XXXIV

51

Antiamoebic activity of 1-(thiazolo [4,5-b]quinoxaline -2-yl)-3-phenyl -2-

pyrazolines XXXV have been done by Abid et al [49].

XXXV

Antiamoebic activity of 3-(3-bromo phenyl)-5-phenyl-1-(thiazolo [4,5-b]

quinoxaline-2-yl)-2-pyrazolines XXXVI have been reported by Budakoti et al [50].

XXXVI

Substituted 5,8-dimethoxyquinoxalines XXXVII have been synthesized by Fisher

et al as possible antimalarial agents [51].

XXXVII

Antimalarial activity of N,N-dialkylaminomethyl 2-quinoxalinyl ketoximes

XXXVIII have been introduced by Moreno et al [52].

XXXVIII

Antimalarial activity of (dialkylaminomethyl)-6-chloro-2-quinoxaline methanols

XXXIX have been reported by Moreno and Schultz [53].

52

XXXIX

Elslager et al have synthesized 2-{[(dialkyl-amino)alkyl]amino}-3- (2-

pyridyl)quinoxalines XL and reported their antimalarial activity [54].

XL

Lipunova et al have synthesized 1-(6-fluoroquinoxalin-7-yl)amino-6,8-difluoro -

7-(pyrrolidin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylicacid XLI as

antituberculous [55].

XLI

Shinde and Pal have synthesized quinoxalines XLII as antitubercular agents.

[56].

XLII

Wagle and coworkers have synthesized some new 4-styryltetrazolo[1,5-a]

quinoxalines XLIII as anticonvulsants agents [57].

53

XLIII

Anticonvulsant activity of 3-(2-aminophenyl)quinoxalin-2(1H)-one XLIV have

been done by Olayiwola and coworkers [58].

N

HN O

H2N

XLIV

Pyrrolo[1,2-a]quinoxalines XLV were prepared by Bares et al as antimalarial

agents [59].

XLV

Fonseca et al have synthesized methyl 2’,3’-substituted-13,14- pyrazinyl-

deisopropyldehydroabietates XLVI and studied their antiviral activity [60].

XLVI

Antiviral activity of quinoxalines XLVII observed by Campiani et al [61].

54

XLVII

Antiviral activity and cytotoxicity of imidazo[4,5-b]quinoxaline ribonucleosidesa

XLVIII have been reported by Zhu et al [62].

XLVIII

Antitubercular activity of quinoxalines XLIX has been reported by Li et al [63].

XLIX

Antitubercular activity of quinoxalines L has been investigated by Silva et al

[64].

L

Ali and coworkers have synthesized 5-(2,6,7-substitutedquinoxalin -3-

yloxy)pentane-1,2-diols LI and studied their anti-HIV activity [65].

55

LI

Anti-HIV activity of quinoxaline analogues LII observed by Eizzo et al [66].

LII

Anti-HIV activity of 3-[3-quinoxaline(1H)-one]propionic acid LIII introduced by

Rodrigo et al [67].

LIII

Shibinskaya et al have synthesized 6-(2-aminoethyl)-6H-indolo[2,3-b]

quinoxalines LIV and done their cytotoxicity and antiviral activities [68].

LIV

Deady et al observed antitumor activity of N-[2-(dimethylamino)ethyl]

carboxamides LV of quinoxalines [69].

LV

56

Antioxidant, anti-inflammatory and anti-hyperglycaemic activities of heterocyclic

homoprostanoid derivatives LVI introduced by Reddy et al [70].

LVI

In vitro anti-inflammatory activity of piperazinyl quinoxalines LVII have been

carried out by Smits et al [71].

LVII

Nasr and Said have synthesized quinoxalines LVIII as anti-inflammatory agents

[72].

LVIII

Anti-HIV activity of N4-(hetero)arylsulfonylquinoxalinones LIX introduced by

Xu et al [73].

LIX

Anticancer activity of quinoxalines LX and LXI have been evaluated by Kotb

et al [74].

57

LX LXI

Antitumor activity of methyl 4-{4-[(7-chloro-2-quinoxalinyl)oxy] phenyl}

butyrate LXII have been carried out by Hazeldine et al [75].

LXII

Anticancer activity of 7-dialkylaminomethyl benzo[g] quinoxaline-5,10-diones

LXIII have been done by Lee et al [76].

LXIII

Anticancer, anti-tuberculosis and antifungal activities of 2,3-bifunctionalized

quinoxalines LXIV have been reported by Waring et al [77].

LXIV

Antitumor activity of 2-{4-[(2-quinoxalinyl)oxy]phenoxy}propionic acids LXV

reported by Corbett et al [78].

58

LXV

Corona et al have synthesized quinoxaline derivatives LXVI and studied their

antitumor activity. [79].

LXVI

Diana et al have synthesized isoindolo[2,1-a]quinoxalines LXVII and studied

their antitumor activity [80].

LXVII

Antitumor activities of N’-pyrrolo[1,2-a]quinoxalin-4-yl-hydrazides LXVIII

have been assessed by Grande et al [81].

LXVIII

Mashevskaya et al have synthesized quinoxalines LXIX and studied their

analgesic and antibacterial activity [82].

59

LXIX

Antimicrobial activity of 6-benzoyl-3-substituted styryl-2(1H)quinoxalines LXXI

have been reported by Ali et al [83].

N

HN

Ph

O

O

CH

CH

LXX

Antimicrobial activity of 2-(1-piperidinomethyl-5-substituted oxindol-3-

ylidene hydrazino)-3-methylquinoxalines LXXI have been assessed by El-Gendy et al

[84].

LXXI

Anticancer activity of new 1-[(5or6-substituted-2-alkoxyquinoxalin-3-yl)

aminocarbonyl]-4-(hetero)arylpiperazines LXXII have been reported by Lee et al

[85].

LXXII

60

Mashevskaya et al have synthesized 3-aroyl(heteroyl)methylene-1,2,3,4-

tetrahydro-2-quinoxalones LXXIII as antimicrobial agents [86].

LXXIII

Seitz and coworkers have synthesized quinoxalines LXXIV and reported their

antimycobacterial activity [87].

LXXIV

Fused 1,2,4-triazolo[4,3-a]quinoxalines LXXV and oxopyrimido[2’,1’:5,1]-

1,2,4-triazolo[4,3-a]quinoxalines LXXVI have been synthesized by Nasr as

antibacterial agents [88].

LXXV LXXVI

Antibacterial and analgesic activity of 3-acyl-1,2,4,5–tetrahydro-[1,2-a]

quinoxaline-1,2,4-triones LXXVII have been carried out by Mashevskaya et al [89].

LXXVII

61

Antimicrobial activity of 2,9,10-trisubstituted-6-oxo-7,12-dihydro-chromeno

[3,4-] quinoxalines LXXVIII have been assessed by Kotharkar et al [90].

LXXVIII

Antibacterial activity of triazolo[4,3-a]quinoxalines LXXIX have been carried

out by Corona et al[91].

LXXIX

Reffat et al have synthesized 2-[4-(5-aryl-1,3,4-oxadiazol-2-yl)anilino]-3-methyl

quinoxalines LXXX and investigated their antimicrobial activity [92].

LXXX

Antimicrobial activity of 5-methyl-1-phenyl-3-phenylcarbamoyl-4-(quinoxalin -

2-yl)-1H-pyrazole LXXXI have been carried out by Farag [93].

LXXXI

Antibacterial evaluation of new steroidal-5-en-7-thiazoloquinoxalines LXXXII

has been reported by Khan and coworkers [94].

62

LXXXII

In vitro antibacterial activity of new steroidal thiazoloquinoxalines LXXXIII has

been reported by Khan et al [95].

LXXXIII

Antimicrobial activity of 3-(2-cyclopentylidenehydrazinyl)quinoxalin-2(1H)-

one LXXXIV and 3-[2-(2-substituted cyclohexylidene) hydrazinyl]quinoxalin-2(1H)-

ones LXXXV introduced by Ajani and coworkers [96].

LXXXIV LXXXV

In vitro antitubercular and antimicrobial activities of 1-substituted quinoxaline -

2,3(1H,4H)-diones LXXXVI and LXXXVII have been carried out by Ramalingam et

al [97].

N

HN O

O

R

LXXXVI LXXXVII

63

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SECTION IV

INTRODUCTION AND

LITERATURE REVIEW OF

IMIDAZOLONE

1.4.1 Introduction and literature review

Imidazole was first synthesized by Heinrich Debus in 1858, but various

imidazole derivatives had been discovered as early as the 1840s. Named first as

gluoxaline because it was first synthesized with glyoxal and formaldehyde in

ammonia. Imidazolones are also known as oximidazoline. Imidazolones five

membered cyclic compounds are of many types especially as 2-imidazolone I, 4-

imidazolone II and 5-imidazolone III.

I II III

Imidazole (1,3-diaza-2,4-cyclopentadiene) is a planar five-member ring system

with 3C and 2N atom in 1 and 3 positions. The simplest member of the imidazole

family is imidazole itself, a compound with molecular formula C3H4N2. The systemic

name for the compound is 1, 3 diazole, one of the annular N bear a H atom and can be

regarded as a pyrole type N. It is soluble in water and other polar solvents. It exists in

two equivalent tautomeric forms because the hydrogen atom can be located on either

of the two nitrogen atoms. Imidazole is a highly polar compound, as evidenced by a

calculated dipole of 3.61D, and is entirely soluble in water. The compound is

classified as aromatic due to the presence of a sextet of π-electrons, consisting of a

pair of electrons from the protonated nitrogen atom and one from each of the

remaining four atoms of the ring. Imidazole is amphoteric, i.e. it can function as both

an acid and as a base. As an acid, the pKa of imidazole is 14.5, making it less acidic

than carboxylic acids, phenols, and imides, but slightly more acidic than alcohols.

Imidazole is incorporated into many important biological molecules. The most

pervasive is the amino acid “histidine”, which has an imidazole side chain. Histidine

is present in many proteins and enzymes and plays a vital part in the structure and

binding functions of haemoglobin. Histidine can be decarboxylated to histamine,

which is also a common biological compound. One of the applications of imidazole is

in the purification of tagged proteins in immobilised metal affinity chromatography

(IMAC).

Imidazole has become an important part of many pharmaceuticals. Synthetic

imidazoles are present in many fungicides and antifungal, antiprotozoal, and

70

antihypertensive medications. Imidazole is part of the theophylline molecule, found in

tea leaves and coffee beans, which stimulates the central nervous system. Apart of its

use for pharmaceutical purpose it also have varying applications in industries, the

imidazole has been used extensively as a corrosion inhibitor on certain transition

metals, such as copper. Preventing copper corrosion is important, especially in

aqueous systems, where the conductivity of the copper decreases due to corrosion.

Many compounds of industrial and technological importance contain imidazole

derivatives. The thermostable polybenzimidazole (PBI) contains imidazole fused to a

benzene ring and linked to benzene, and acts as a fire retardant. Imidazole can also be

found in various compounds which are used for photography and electronics.

Reaction of hippuric acid and cyclohexane using acetic anhydride gave 2-phenyl-

4-cyclohexylidene-1,3-oxozolo-5-one; which on condensation with amine gave

imidazolones IV.

IV

Wadia and Patel have synthesized 3-(4-aminophenyl)-5-benzylidene -2-

substitutedphenyl -3, 5-dihydroimidazol-4-ones V as acid dyes [1].

V

Fujimoto et al have prepared 2-(1-{3-[(6-chloronaphthalene-2-yl)sulfonyl] -2-

hydroxypropanoyl}piperidin-4-yl)-5-methyl-1,2–dihydro-3H-imidazo[1,5-c]imidazol

-3-one VI as antithrombotic agent [2].

71

VI

Cytotoxi¢ity of l-arylsulfonylimidazolidinones VII and 3-arylsulfonyl

imidazolidinones VIII have been reported by Jung et al. As a result, a series of 4-

phenyl-1(N)-arylsulfonylimidazolidinones have been found to be the potential

anticancer agent [3].

.

VII

VIII

Jung et al have synthesized 4-phenyl-1-arylsulfonylimidazolidinones IX as

antitumor agents. Among them compound (C6H4(4-NH2) exhibits much more potent

cytotoxicities than doxorubicin and highly effective antitumor activities against

murine [4].

IX

72

Anticancer activity of imidazolinone X has been reported by El-Gendy et al

[5].

X

In vitro antitumor activity of new 1,4-diarylimidazole-2-ones XI and their 2-

thione analogues have been conceded by Congiu et al. Compounds bearing a 3,4,5-

trimethoxyphenyl ring linked to either N-1 or C-4 position of the imidazole core

demonstrated an interesting profile of cytotoxicity with preferential activity against

leukemic cell lines. Compound XII exhibited a potent antitumor activity against

MOLT-4 (GI50 = 20 nM) and SR (GI50 = 32 nM) cell lines [6].

XI

XII

2,3-Dihydro-N,3-bis(3,4,5-trimethoxyphenyl)-4-(substituted-4-methoxy phenyl) -

2- oxo-1H-imidazole-1-carboxamides XIII were synthesized by Xue et al and studied

their antitumor activities [7].

XIII

73

In vitro anticancer activity of 5-arylidene-2-methylthio-1H-imidazol-4(5H)-ones

XIV have been reported by Subtelna et al [8].

XIV

Kamal and co-workers have synthesized chalcone linked imidazolones XV as

anti-cancer activity [9].

XV

Anthelmintic activity of (5E)-5-[4-(dimethylamino) benzylidene]-3-(5-

substituted-1,3,4-oxadiazol-2-yl)-2-phenyl-3,5-dihydro-4H-imidazol-4-ones XVI

have been evaluated by Patel et al [10].

XVI

Witvrouw et al have synthesized imidazolones XVII as anti-HIV agents [11].

XVII

Kazmierski et al have synthesized and studies anti-HIV-1 activities of 2-

imidazolidinones XVIII [12].

74

XVIII

Flosi et al have synthesized imidazolidine-2,4-diones XIX and reported their anti-

HIV activity [13].

XIX

Anti-HIV-1 activity of N1-arylsulfonyl-1,3-dihydro-2H-benzimidazol-2-ones XX

have been reported by Barreca et al [14].

XX

Khodarahmia and co-workers have reported cytotoxicity of 4-sulfonamide

substitutedbenzamidobenzimidazolones XXI and an acyl benzimidazolone [15].

XXI

Antibacterial activity of 4,5-bis (3,5-dichlorophenyl)-2-trifluoro methyl -1H-

imidazoleanalogues XXII have been studied by Antolini et al.[16].

75

XXII

2-Alkylthio-3-phenylamino-5-arylmethylene-4H-imidazol-4-ones XXIII were

prepared by Ding and co-workers and studied their fungicidal activities. [17].

XXIII

Sun and Ding synthesized bis-(2-alkylthio-furfurylidene-4H-imidazol-4-one)

derivatives XXIV and screened for their fungicidal activities [18].

XXIV

Fungicidal activities of 2-benzothiazolylthio-substituted 4H-imidazol-4-ones

XXV have been investigated by Hu and co-workers [19].

XXV

Sun et al have syntesized imidazo[2,1-b]-1,3,4-thiadiazol-5(6H)-ones XXVI and

studied their fungicidal activity [20].

XXVI

Fungicidal and herbicidal activities of 2-alkythio-5-(2-chlorophenyl

methylidene)-4H-imidazolin-4-ones XXVII were reported by Huang and co-workers

[21].

76

XXVII

Ali and co-workers have prepared 5-(6-methyl-4-oxo-4H-chromen-3-yl-

methylene)-3-{4-[(6-chloro-4-oxo-4H-chromen-3-ylmethylene)amino]phenyl}-2-

phenyl-3,5-dihydro imidazol-4-ones XXVIII as antifungal agents [22].

XXVIII

Antibacterial and antifungal activities of 1-[2-(2-methyl-5-nitroimidazol-1-yl)

ethyl]-2-phenyl-4-arylideneimidazolin-5-ones XXIX have been studied by Benkli et

al [23].

XXIX

Antimicrobial and antitubercular activity of 2-phenyl-1-(3′,5′-dichloro-2′-

benzo(b)thiophenoylamino)-4-arylidine-5-imidazolones XXX have been reported by

Thaker et al [24].

XXX

Saravanan et al have studied antibacterial activity of imidazolone-5-(4H)ones

XXXI [25].

77

XXXI

Antimicrobial activity of 3-imino[(4-benzylidene-2-phenyl-imidazole-5-one-1-(4-

bezoylhydrazono)]-indole-2-ones XXXII have been carried out by Patel et al [26].

XXXII

Suthakaran et al have synthesized 3-(2-(4Z)-4-substituted benzylidene-4,5-

dihydro-5-oxo-2-phenylimidazol-1-yl)ethyl)-6,8-un/dibromosubstituted-2-substituted

quinazoline-(3H)-ones XXXIII and studied their antimicrobial activities [27].

XXXIII

Solankee and coworkers have synthesized 1-(5’-bromofuran -2’-carboxamido) -2-

phenyl-4-(benzylidene/substitutedbenzylidene)-5-imidazolones XXXIV and reported

their antibacterial activity [28].

XXXIV

78

5-Substituted imidazolones XXXV have been prepared by khan et al as

antibacterial and antifungal agents [29].

XXXV

5-Arylidene-3-(6,7-dichloro-1,3-benzothiazol-2-yl)-2-phenyl-3,5-dihydro-4H-

imidazol-4-ones XXXVI were prepared by Baldaniya as antibacterial and antifungal

agents [30].

XXXVI

4-Benzylidene-1-{4-[3-(substitutedphenyl)prop-2-enoyl]phenyl}-2-phenyl-

imidazol-5-ones XXXVII have been prepared by Shah et al as antibacterial and

antifungal agents [31].

XXXVII

Patel and co-workers have synthesized 1-acetyl-5-(substituted phenyl)-{3-[4-(2-

methyl-4-benzylidene-5-oxo-imidazol-1-yl)]phenyl}-4,5-dihydropyrazols XXXVIII

and studied their antibacterial activity [32].

XXXVIII

79

In vitro antibacterial and antifungal activity of 4-(substituted benzylidene)-1-(5-

(4-nitrophenyl)-1,3,4-thiadiazol-2-yl)-2-phenyl-1H-imidazol-5(4H)-ones XXXIX

have been reported by Bharadwaj et al [33].

XXXIX

4-(Substitutedbenzylidene)-1-(5-(4-chlorophenyl)-1,3,4-thiadiazol-2-yl)-2-

phenyl-1(H)imidazol-5(4H)-ones XL were prepared by Bhanat and co-workers as

antimicrobial agent [34].

XL

2”-Methyl-[m-nitro-1’,3’-dioxo-1’,3’-dihydro-(2’H)-isoindole-2’-yl)-

1”,3”,4”-thiadiazol-5”-yl]-4-{benzylidene/substitutedbenzylidene}-4,5-dihydro-2-

phenyl-imidazol-5-ones XLI have been prepared by Sha et al as antibacterial and

antifungal agents [35].

XLI

80

Several investigators has been shown various activities such as antibacterial

[36-38], antimicrobial [39-42], antifungicidal [43-45], anticonvulsant [46-49],

antiviral [50], anti-HIV [51], antitumer [52], inflammatory [53,54], anticancer [55],

antiparkinsonian [56-58], anthelmintics [59], antileshmanial [60], antiprotozoal [61]

and antioxidant [62].

Tomohiko Kawate and coworker have synthesized and studied structure–activity

relationships of phenyl-substituted coumarins with anti-tubercular activity that target

FadD32 [63]. Among them, compounds XLII showed improved activity with IC90 of

2 μM and 0.5 μM, respectively. Further optimization provided compound 3b with

better physiochemical properties with IC90 0.4 μM which had activity in a mouse

model of infection.

XLII

Jyoti Pandey et al synthesized a series of imidazole derivatives and compounds

were screened against M .tuberculosis and compound XLIII showed good

antitubercular activity [64].

XLIII

Preeti Gupta et al describe antimycobacterium tuberculosis activities of ring

substituted-1H-imidazole-4-carboxylic acid derivatives and 3-(2-alkyl-1H-imidazole-

4-yl)-propionic acid derivatives against durg-sensetive and durg-resistent M.

tuberculosis strains. XLIV and XLVcompounds were most potent compound [65].

XLIV XLV

81

Puratchikody A. et al studies on 2-substituted-4,5-diphenyl-1H-imidazoles XLVI

and checked the anti-inflammatory activity based on Carrageenan-inducedpawedema

method. Compound shows maximum activity and indomethacinusedas reference drug

[66].

XLVI

Kavitha C.S. et al has synthesized a series of 2-methylaminobenzimidazole

derivatives XLVII and newly synthesized compounds were screened for analgesic

and anti-inflammatory activities. Compound shows analgesic activity and compared

with standard nimesulide drug [67].

XLVII

Compound XLVIII shows potent anti-inflammatory activity and also compared

with nimesulide [68].

XLVIII

Kalpana bhandari et al have synthesized a series of substituted aryloxy alkyl and

aryloxy aryl alkylimidazole XLIX and evaluated in vitro as antileishmanial against

Leshmania donovani. Among all compounds exhibited 94–100% inhibition [69].

XLIX

Farzin Hadizadeh et al have synthesized moclobemide analogues by replacing

moclobemide phenylring with substituted imidazole and studied for the antidepressant

82

activity using forced swimming test. Analogues LX was found to be more potent

than moclobemide [70].

LX

Tsung-Chih Chen et al have designed novel anthra[1,2-d]imidazole-6,11-

dione homologues LI and studied their cytostatic and cytotoxic [71].

LI

Cenzo congiu et al have synthesized a series of 1,4-diarylimidazole-2(3H)-one

LII derivatives and their 2-thione analogues and evaluated antitumor activity.

Compound show potent antitumor activity [72].

LII

Yusuf Ozkay et al have synthesized many novel imidazole-(Benz) azole and

imidazole epiperazinederivatives LIII in order to investigate the anticancer activity.

[73].

LIII

83

Erik Serrao et al have discovered a novel 5-carbonyl-1H-imidazole-4-

carboxamide LIV class of inhibitors of the HIV-1 integrase–LEDGF/p75 interaction

[74].

LIV

Michele Tonelli et al synthesized seventy six 2-phenylbenzimidazole derivatives

and evaluated for cytotoxicity and anti viral activity against a panel of RNA and DNA

viruses. Compound ([5,6- dichloro-2-(4-nitrophenyl) benzimidazole]) LVexhibited a

high activity resulting more potent than reference drugs smycophenolic acid and 6-

azauridine [75].

LV

Deepika Sharma et al have synthesized imidazole derivatives and the antiviral

screening of (substituted phenyl)-[2-(substituted phenyl)-imidazol-1-yl]-methanones

against viral strains indicated that compound LVI selected as the most potent antiviral

agents. Ribavirin was used as standard drug [76].

LVI

84

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89

1.5 Present work

In the heterocyclic systems, compounds containing hetero atoms such as

nitrogen and/or sulfur e.g., imidazolone, benzothiazole, quinoxaline, oxadiazole,

triazole, quinazolinone etc. have great importance due to their diverse biological

activity. Hence, we have also decided to work which is dealing with the synthesis and

biological studies of such nitrogen, oxygen, fluorine, chlorine and sulfur containing

heterocycles.

As per the literature survey and our previous work on benzothiazole,

oxadiazole, triazole and quinazolinone molecular framework by incorporating

different substituted amines, acetamides, thiazolidinone, 4-oxazolidinones and 2-

azetidinones on C-3 position of quinazolinone and studied their antimicrobial

activities therefore, we expand the work to synthesize several new heterocycles such

as oxazolone from hippuric acid, imidazolone from oxazolone, benzothiazole from

substituted amines, hydrazide of quinoxaline, triazole from oxadiazole, oxadiazole

from hydrazide and substituted various acids, quinazolinone from benzoxazin via

various substituted acid and anthranilic acid. Thus, present work includes synthesis of

seven different series described as follows:

Series-1 includes synthesis of 7-chloro-2-(substituted)-3-(4-(6-

methylbenzo[d]thiazol-2-yl)phenyl)quinazolin-4(3H)-ones 1-12 and their

antibacterial, antifungal and antitubercular activities.

Series-2 includes synthesis of N-(3-(substituted)-5-((1-phenyl-1H-1,2,4-

triazol-3-yloxy)methyl)-4H-1,2,4-triazol-4-yl)-2-(quinoxalin-2-yloxy)acetamides 13-

24 and their antibacterial, antifungal and antitubercular activities.

Series-3 includes synthesis of N-(3-(substituted)-5-((quinoxalin-2-

yloxy)methyl)-4H-1,2,4-triazol-4-yl)-2-(1-phenyl-1H-1,2,4-triazol-3-yloxy)

acetamides 25-36 and their antibacterial, antifungal and antitubercular activities.

90

Series-4 includes synthesis of 2,3,4,5-tetrafluoro-N-(3-(substituted)-5-

((quinoxalin-2-yloxy)methyl)-4H-1,2,4-triazol-4-yl)benzamides 37-48 and their

antibacterial, antifungal and antitubercular activities.

Series-5 includes synthesis of N-(3-(substituted)-5-((quinoxalin-2-

yloxy)methyl)-4H-1,2,4-triazol-4-yl)-2,3,4,5,6-pentafluorobenzamides 49-60 and

their antibacterial, antifungal and antitubercular activities.

Series-6 includes synthesis of N-(3-(substituted)-5-((quinoxalin-2-

yloxy)methyl)-4H-1,2,4-triazol-4-yl)-1H-benzo[d]imidazol-2-amines 61-72 and their

antibacterial, antifungal and antitubercular activities.

91

R=

Series-7 includes synthesis of (Z)-4-(substituted)-1-(4-(6-

methylbenzo[d]thiazol-2-yl)phenyl)-2-phenyl-1H-imidazol-5(4H)-ones 73-87 and

their antibacterial, antifungal, antitubercular, anti-HIV-1 and anticancer activities.

R=

a= 4-F d= 3-Br g= 4-OCH3 j=3-OCH3,4-OH, 5-NO2 m= 4-N(CH3)2

b= 2-Cl e= 2-OH h= 2,5-(CH3)2 k= 2-NO2 n=Thiophene 2-aldehyde

c= 4-Cl f= 4-OH i= 3- OCH3 ,4-OH l= 4-CH3 o= 1-H