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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
1. Kartritzky A. R., Hand Book of Heterocyclic Chemistry, 1st edn.,
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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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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