introduction - shodhgangashodhganga.inflibnet.ac.in/bitstream/10603/38569/6/06_chapter 1.pdf · ii....

INTRODUCTION

Introduction

For centuries humans have observed not only those natural substances could be used for their

nutritional value and for treatment of diseases, but they could also bring about toxic or lethal

effects. Although the majority o f the drugs used from antiquity to the 19'^ century came from

natural sources in the past century a new era was brought about by treatment of diseases with

synthetic drug or by the modification of natural products through various synthetic processes.

The task of the scientific community is to develop potent, selective therapeutic agents is

dependent upon methods for rapidly assembling compounds o f high molecular diversity in

rational and efficient ways. Furthermore the ability of chemists to optimize newly discovered

lead compounds as well as to produce analogues or mimics of biologically active natural

products relies upon the advancement of synthetic technology. Medicinal chemistry is

discipline concerned with the determination of the influence of chemical structure on

biological activity. As such, it is therefore necessary for the medicinal chemist to understand

not only the mechanism by which a drug exerts its effects, but also the physicochemical

properties of the molecule. The term physicochemical properties to the influence of the

organic functional groups present within a molecule on its acid/base properties, water

solubility, partition coefficient, crystal structure, stereochemistry etc. All of these properties

influence the absorption, distribution, metabolism and excretion (ADME) of the molecule. In

order to design better medicinal agents, the medicinal chemist needs to understand the

relative contributions that each functional group makes to tlie overall physical chemical

properties of the molecule. Studies of this type involve modification of the molecule in a

systematic fashion and determination of how these changes effects biological activities. Such

studies are referred to as studies of structure activity relationships i.e. what structural feature

of the molecule contribute to take away from the desired biological activity o f molecule of

the interest. For drug discovery a rational approach is used for identifying a lead compound

which is based on a molecular understanding of the drug and receptor. Once a lead

compound has been obtained it is subjected to structure variation with the aim of optimizing

its biological properties in the desired direction.

LITERATURE REVIEW

PYRAZOLINESI. INTRODUCTION

The azoles are five membered-cyclic systems, which contain in addition to carbon and

nitrogen at least one other heteroatom. Thus oxazole contain an oxygen atom; thiazole a

sulphur atom; and pyrazole a nitrogen atom. This group comprises all those compounds, the

molecules of which contain a ring composed of tliree carbon and two nitrogen atoms

airanged as follows-

Pyrazolines____________________________________________________ Literature Review

The parent substance of these compounds, pyi'azole, is a pyrole in which a methine group has

been replaced by nitrogen.

Mething

The nomenclature of the pyrazole group is based on that suggested by knorr for pyrrole

derivatives. Similai' as dihydro-pyrrole is known as pyrroline and tetrahydro-pyrrole as

pyn’olidine, so the dihydropyrazoles are termed pyrazolines and the completely reduced

tetrahydro derivatives, pyrazolidines.

//4 3(5 3'N

H H H

A

The position of a substituent group in the pyrazole nucleus is indicated by the numbers 1 to 5.

Numbering commences with the nitrogen atom of the imino- group and proceeds in an anti

clockwise direction to the second nitrogen atom.

Our laiowledge of the pyiazole series is largely due to the work of knorr^, who described the

first representatives of this group in 1883. The pyrazole ring system I, consist of a doubly

unsaturated five membered ring containing two adjacent nitrogen atoms. Knorr^ first

synthesized a compound containing this system in 1883 by the reaction o f ethyl acetoacetate

with phenyl hydrazine, which yields l-phenyl-3-methyl-5-pyra2olone, II. His interest in

Pyrazolines Literature Review

quinine led to tests of the antifebrile action of this and related compounds, which resulted in

the discovery of antipyrine III, an important febrifuge.

,C H ,

NH

III

CHa

NH

Knon- introduced the name pyrazole for these compounds to denote that the nucleous was

derived from pyrole by replacement of a carbon by nitrogen; he synthesized many members

of the class and systematically investigated their properties'*. Special attention was given to 1-

phenylpyrazoles because phenyl hydrazine was most readily available hydrazine and these

continue to be most carefully investigated derivatives. Since many drugs and dyes contain the

pyrazole nucleus, the class has been widely studied and the field continues to be active today

even though antipyrine and related medicinal ai'e no longer common use.

II. General methods for preparation of pyrazole derivatives

Most pyrazole syntheses involve the use of hydrazine or its derivatives (knorr) or aliphatic

diazo-compounds (Buchner).

1. Hydrazine are condensed with fi-dicarbonyl compounds (e.g. fl-diketones and fi-keto

aldehyde).H3C o

CH3

H

CH,

N + 2HP

2 . Hydrazine are condensed with er fi-unsaturated aldehydes, ketones.

NHp

HPyrazoline


3. Acetylene reacts with diazomethane

HC= ^ CH + H2C=N— N- o

H4. From imines

Base produced reaction of benzenes with any imines afforded aryl pyrazole"''

NH-

NaOH/DMF

5. 1, 3 dicarbonyl compounds and hydrazine

CH3

^ + H N-----H3C----o

o

6 . From alkenes

Pyrazoles can be prepared by aikenes and alkynes

H2C = C H 2

+

HoC--------N = N

7. From alkynes0

oCH CH3

+HqC----N;:EEE=N

CH-,

S. Oi ft Unsaturated ketones


III. Chemical reactions o f pyrazoline’.

Addition at Nitrogen

Protonation direct linking of two hetero atoms has a very marked .base weakening effect, as

in hydi’azine and hydroxyl amine, and this is minored in the 1, 2 azoles.

O "N

NH

Acylation at Nitrogen

The introduction of an acyl or phenyl sulfonyl group on to pyrazole nitrogen is usually

achieved in the presence of a weak base such as pyridine; such processes proceed via

azomethane nitrogen acylation then deprotonation. Since acylation unlike alkylation, is

reversible, the more stable product is obtained.

O 'ACOCI/Pyridine

HNiAc

Alkylation at Nitrogen

The 1, 2 azoles are more difficult to quatemise than their 1, 3 analogues

CH3IN + N----- -CH3

Substitution at Nitrogen & Carbon

Nitration

Pyrazole and isothiazole undergo straight forward nitration at C-4OoN

HNO3/AC2O / = ^

ACOH/37“C

HsSO, / 0°C

'NO,

Acylation

Pyrazole have useful electrophilic substitution involving carbon electrophiks been described.

Only N-substituted pyrazoles react well, perhaps because of inhibition of Na'^salt formation.

Pyrazolines_________________________________ _________________ Literature Review

Stereo chemical consideration in the synthesis o f pyrazoline

Very little mention has been made of the effect of the stereo isomeric forms (syn or anti) of

phenyl hydrazones on pyrazoline formation, although it has been suggested that the

phototropic phenyl hydrazones formed from 1-phenyl-l-penten-3-one and 1-phenyl-1-hexen-

3-one are in the jyn-alkyl forms shown below do not yield the pyrazoline.

Whereas the nonphototropic phenyl hydrazones of these compounds believed to be anti-

alkyl, do yield pyrazolines. However, the phenyl hydrazones to which matei assigned the

5yn-alkyl fonn was reported*** to form a pyrazoline. No attempt has been made to coijelate

ease of pyrazoline formation with cis Jind trans arrangement of the double bond in

'H but the cis and trans forms of ketones like 3-ethyl-3-penten-2-one give

the same pyrazoline^^

A variety of conditions and reagents have served for cyclizing hydrazones, common is to

heat the hydrazone, although this was reported to give a lower yield than refluxing with

acetic acid* . Formic acid gives lower yields than acetic acid*^ and boiling with toluene or

xylene may be ineffective*^, whereas acetic anhydride acetylates the phenyl hydrazone

without forming a pyrazoline. Hydrochloric acid in alcohol gives some pyrazoline formation,

but hydrolysis to the carbonyl compound also occurs*^. Pyrazolines are obtained in many

instances at room temperature in acetic acid, alcohol (usually containing a little acetic acid).


or without solvent. Pyridine doesn’t retard pyrazoline formation. Hydrazine, semicarbazide,

and substituted phenyl hydrazines have been employed frequently to prepare derivatives of

a, P-unsatui'ated carbonyl compounds, but very little attempt has been made to study the case

of rearrangement of the various hydrazones (when they can be obtained) to pyrazolines.

Frequently, no attempt is made to show whether the derivative is cyclic or not. Hydrazine

appeal's to give pyrazoline rather commonly, and semicarbazide often yields a

semicarbazone. Although the semicarbazone may cyclize in boiling acetic acid, this is often

accompanied by hydrolytic removal of the 1-carbamido group. It would be expected that

electron withdrawing groups in the phenyl group of substituted phenylhydrazines would

decrease the ease of pyrazoline formation.

It is not always easy to distinguish phenyl hydrazones from the pyrazolines they yield*^.

Perhaps the best chemical method consists of reduction with sodium amalgam which gives

aniline with phenyl hydrazones and has no action with pyrazolines*'*’ .

Nomenclature and structure

Knorr first described and correctly formed acid pyrazole in 1883. The systematic name is 1, 2

diazole.

140.6)

Pyrole side139.8(138.2)

135.6{137.0)

>

109.6(108.4)

Pyridine side of pyrazole is best 135.0(134,0) by a mesomeric structure (or) by a set of resonance structure

103.6(99.6)

NH

NH NH

RECENT ADVANCEMENT

Chemistry of compounds having pyrazoline moiety have immense biological profile. Living

organism find difficulty in construction of N-N bonds that limit the natural abundance of

compounds having such bonds. Pyrazoline and their derivatives, a class of compounds


containing N-N bond exhibit a wide variety of biological activities. In recent times, syntheses

of novel pyrazoline derivatives and investigation of their chemical and biological behavior

have gained more importance for biological, medical and agricuhure purposes

Category: Antidepressant and anticonvulsant activities.

Ozdemir et.al reported synthesis and studies on antidepressant and anticonvulsant activities

of some 3-(2-furyl) - pyrazoline derivatives^®.

Ar = Aryl substituted, R = Aryl, CSNH2, CSNHC2H5, CSNHCH3. CSNHCfiHs

Only two of the synthesized compounds (6 and 11) have shown significant antidepressant

activity, but the synthesized compounds having a 2-furyl substituent at the fifth position of

the pyrazoline ring (2, 4, 9-12) possess remarkable anticonvulsant activity. Therefore they

seem to be really promising compounds for their anticonvulsant activities.

Category: Antidepressant

Prasad et.al reported synthesis and antidepressant activity of some 1, 3, 5- ti'iphenyl-2-

pyrazolines and 3-(2”-hydroxy naphthalene - l ”-yl-l, 5-diphenyI-2-pyrazolines)^\

The synthesis of different substituted 2-pyrazolines from the corresponding chalcones by

condensation with phenyl hydrazine hydrochloride is reported. The chalcones employed in

this reaction were reported by condensing appropriate acetophenones with benzaldehyde

derivatives in dilute ethanolic potassium hydroxide solution. Majority of the compounds

synthesized possessed significant anti depress ant activity in mice (p<0.05) in the porsolt

behavioral despair test.

Ka-e) 2(a-e)

Category: Antimycobacterial

Shahar Yai- et.al reported synthesis and in-vitro antimycobacterial activity of N' - nicotinoyl-

3-(4 ’ -hydroxy-3,-methyl phenyl)-5- [(sub) phenyI]-2-pyrazolines^^.

In this series compound (a-k) were tested for their antimycobacterial activity in-vitro against

MTB and INHR-MTB by agai' dilution method, using double dilution technique. Among the

11 compounds synthesized, 4 compounds were found to be most active compounds with

minimum inhibitory concentration of less than Ipm and were to be more active than INH

against MTB compounds, Among them compounds with 2-chlorophenyl and 4-flurophenyl

substituents were found to be most active and were > 2-fold more active than INH against

M.tuberculosis with MIC of ~ 0.26 |am. Against INHR-MTB, all the synthesized compound

were more active than INH with MIC of less than 8 pm. Among the compounds 2 -

chlorophenyl and 2, 6- dichlorophenyl substituent were found to be promising and were ~

50-fold more potent than INH.

Pyrazolines _____________________________________________ Literature Review

Category: Anti-inflammatory, analgesic agents.

Amir et.al reported synthesis and pharmacological evaluation of pyrazoline derivatives as

new anti-inflammatory and analgesic agents^^.

A series of 3-(4-biphenyl)-5-substituted phenyI-2-pyrazolines 2 (a-h) and l-benzoyl-5-

substituted phenyl-2-pyrazolines 3 (a-h) were synthesized by condensation of chalcones with

hydrazine hydrate in solvent system ethanol and DMF. The newly synthesized compounds

were screened for their anti-inflammatory and analgesic agents, and were compared with

standai'd drug. Among the compounds studied, compound 3-(4-biphenyl)-5-(4’-methyl

phenyl )-2-pyrazoline showed more potent anti-inflanraiatory activity than the standard drug

flurbiprofen.



Plaska ei.al reported synthesis and antidepressant activities of some 3, 5-diphenyl-2-

pyrazolines^.

The antidepressant activities of these compounds were evaluated by the ‘ ‘porsolt behavioral

despair test” on Swiss Webster mice. 3-{4-methoxypheny])-5-(3,4-dimethoxyphenyl)-2-

pyrazoline,3-(4-meyhoxyphenyl)-5-(dimethoxyphenyl)-2-Pyrazoline,3-(4-methoxyphenyl)-5-

(2-chloro-3,4-dimethoxyphenyl)-2-pyrazolinereduced 41.94-48.62% immobility times at 100

rag/ kg dose level. In addition it was found that 4-methoxy and 4-chloro substituents on the

phenyl ring at position 3 of the pyrazoline ring increased the antidepressant activity, the

replacement of these groups by bromo and methyl substituents decreased activity in mice.

R, =H,Cl,Br,CH3,OCH3 R2 = H,CI

Category: Antimicrobial activity

Ozdemir et.al reported synthesis and antimicrobial activity of 1-(4-aryl-2-thiazolyl)-3- (2-

thienyl)-5-aryl-2-pyrazoline derivatives

In comparison with MIC values with chloramphenicol, all compounds were effective against

S.faecalis. Compounds 6a and 6d especially showed very high activity. Compounds 6i and 6j

showed strong activity. Compounds 6b, 6c, 6e, 6f, 6g, 6h, 6k, 61, 6m, and 6n showed a

similar level of activity with chloramphenicol and 6o showed moderate activity when

compared with reference agent. All compounds were effective against A.hydrophila

10

compounds 6a and 6j showed very high activity. Compounds 6d, 6k, 6k and 6m especially

showed strong activity. On the other hand the compounds exhibited comparable activities

against S. aureus. Compounds 6a showed high activity and compounds 6j showed equal

activity. Compound 6d show moderate activity. The antifungal activity of the compounds

was studied with two pathogenic fungi C.albicans and C.glabrata. Fluconazole has been

used as reference for inhibitory activity against fungi. All compounds showed good

antifungal activity. When compared to fluconazole twelve compounds are more active (MIC

<250[ig / ml) against C.albicans and C.glabrata

Pyrazolines__________ __________________________________________ Literature Review

Ar = pyridyl; R = H, CH3, OCH3, Cl NO,

Category: Antitubercular

Ali et.al reported synthesis, structure activity relationship and antitubercular activity of novel

pyrazoline derivatives^^

A series of 5-(4-(substituted) phenyl)-3-(4-hydroxy-3-methylphenyl)-4,5 dihydro-lH-1-

pyrazoIyl-2-toluidine methanethione and 5-(substituted)phenyl-3-(4-hydroxy-3-(methyl

phenyl)-5-dihydro-l/i/-pyrazolyl-2-pyrazolyl-2-methoxyamlino methanethione were

synthesized by the reaction between hydrazine hydrate and chalcones followed by

condensation with appropriate aryl isothiocyanate which yielded N-substituted pyrazoline

derivatives. Newly synthesized compounds were tested for their in-vzYro antitubercular

activity against mycobacterium tuberculosis H37Ry using BACTEC 460 radiometric system.

Among the synthesized compounds, compounds anilino-3-(4-hydroxy-3-methylphenyl)-5-

(2,6-dichlorophenyl)-4, 5-dihydrO"lHl-pyrazolylmethanethione (6i) was found to be more

active agent against M.tuberculosis H37Rv with minimum inhibitory concentration of

0.0034pM

11


6(a-k)

When R = 2, 6-dichloro phenyl, 6i (most active compound)

Category: Anticancer

Johnson et.al reported design, synthesis and biological testing of pyrazoline derivatives of

Combretastatin-A4^’.

Fourteen N-acetylated and non acetylated 3, 4, 5 - Tri or 2, 5- dimethoxy pyrazoline analogs

of combretastatin~A4 (1) were synthesized. A non acetylated derivative with the same

substituents as CA4 (1) was the most active compound in the series, with IC50 values of 2.1

and 0.5|jM in B16 and L I20 cell lines, respectively. In contrast, a similar- compound with an

acetyl group at N1 of the pyrazoline ring showed poor activity on the cell lines studied.

CH3

Category: Antibacterial, Antifungal

Pramila et.al reported synthesis and biological evaluation of certain 4-substituted aryl

methylene 4 , 3 ,5-Trisubstituted pyrazoline derivatives^*.

4(31-920)

12

All the compounds (4a]-a2o) were screened for their antibacterial and antifungal activity at

50mg/ml and lOOrag/ml concentration against the test organism S.aureus, B.pumilis, E.coli,

P.arugginosa, A.niger. Ampicilin was used as standard drug, antibacterial activity and

griseofulvin was used as standard drug for antifungal screening. It was observed that

compounds 4a6, 4ag, 4aio, 4ai5 and 4a2o (16-19mm, 18-21mm) have comparable activity with

arapicillin against S', aureus (17-21mm), B.pumilis (16-18mm), and E.coli (18-20mm) and

weak activity against P.arugginosa at the concentrations 50[ig/ml and lOO^ig/ml

respectively. Rest of the compounds showed moderate activity with ampicilin against the

organism. Compounds 4as, 4ai3 4aM (14-16 mm and 18-20 mm) have equipotent

antifungal activity with griseofulvin (14-18 mm) against at the same concentration.


Kugiikgiizel et.al reported synthesis, characterization of novel coupling products and 4-

arylhydrazono-2-pyrazoJine-5-ones as antimycobacterial agents **.

PyrazoUnes ________________________________Literature Review

X = Aryl substituted, R, = OH, CHj R2 = OH, OC2H5

The synthesized compounds in the present study were tested for their antimycobacterial

activity against M. tuberculosis H37Rv and M.avium using the BACTEC 460 radiometric

system, Rifampicin was used as the standard in the assays for M tuberculosis H37Rv. The

compounds which exhibited < 90% inhibition in the primary screen (Initial screening

concentrations were 12,5 fjg/jtnl for the remaining compounds) were not evaluated further.

Compounds exhibiting >90% inliibition in the primary screen at 12.5 jig/ml was re-tested at

lower concentrations against M H37Rv.

Category: anticancer, antituhercular, antimicrobial

Nimvat et.al reported synthesis of anticancer, antitubercular and antimicrobial activity of 1-

substituted 3-ai7l-5-(3’-bromophenyl)-pyrazolines^".

13


Anticancer activity

The study was related with in vitro anticancer screen aimed at identifying agents having cell

type specificity using batteries of cell lines derived from human solid tumors. At its primary

anticancer assay, a 3-ceIl panel consisting of NCL-H460 (Lung), MCF-7(Breast)

and SF-268 (CNS) have been used; 48 hr continuous drug exposure protocol was used to

estimate cell viability or growth.

Antitubercular activity

Primai-y screening of the compounds for antitubercular activity has conducted at 6.25|Lig/mI

against M. tuberculosis H37Rv in BACTEC 12B medium using the Alamar radiometric

system. The antimycobacterial activity data were compared with standard drug Rifampicin at

0,25 pg/ml concenti'ations, which showed 98% inhibition, all the compounds being less

active than the standard.

Antimicrobial activity

The antimicrobial activity was assayed by using the cup- plate agar diffusion method by

measuring the zone of inhibition in mm.

All the compounds were screened in-vitro for their antimicrobial activity against bacterial

strains such as E.coli, P.vulgaris, B.mega, S.aureus and fungi A.n/ger at 40 |ig/ml

concentration. Standard drugs like Amoxicillin, Ampicillin, Ciprofloxacin, Ei7 thromycin and

Griseofulvin were used for the comparison purpose.

Category: Anti-hypercholesterolemic

Jeong et.al reported novel 2, 3, 5-Tiaryl pyrazolines as anti-hypercholesterolemic activity by

the treatment of l-(3,5-di-tertbutyl-4-hydroxyphenyl) ethanol with 3,5-di or 2,3,5-

trisubstituted 4-hydroxybenzaIdehydes which gave a , p unsaturated ketones which on further

reaction with hydrazine monohydrate afforded pyrazolines^^

14

Pyrazolines _____ Literature Review

3(a-j)

R, = H. R. = Ra = t-Bu, i-Pr, CH3, F, t-Ph, OCH3, NO2, H

Category: Anti-atherogenic

Jeong et.al reported synthesis and anti- atherogenic activity of some novel 2, 3, 5-Tiaryl

pyrazohnes derivatives'^^.

3(a-j)

R, = H. R. = R3 = t-Bu, i-Pr, CH3, F, t-Ph, OCH3, NO2, H

Category: Antiviral

Ali el.al reported synthesis of 5-(4-hydroxy-3-metliylpheiiyl)-5- (substituted phenyl) 4, 5-

dihydro-1//-1-pyrazol yl-4-pyi-idylmethanone^^

Antiviral activity was tested against Heipes simplex virus-1 (KOS), Herpes simplex virus-2

(G), Vaccinia virus. Vesicular stomatitis virus. Herpes Simplex virus-1 TK-KOS ACV* (in

HeL cell culture); Vesicular stomatitis virus, Coxsackie virusB4, Respiratory syncytial virus

(in HeLa cell culture); Para-influenza-3 viais, Reovirus-1, Sindbis virus, Coxsackie virusB4,

Punta Toro virus (in Vero cell culture). For each compound, the 50% Minimum Cytotoxic

Concentration (MCC) and the Minimum Inhibitory Concentration (MIC) were obtained.

Ribavirin, Brivudin, Acyclovir, Ganciclovir, and (S)-DHPA were used as the standards in the

study. Both antiviral activity and cytotoxicity were determined by means of the MTS

method.

Category: Analgesic

Giirsoy et.al reported synthesis and preliminary evaluation of new 5-pyrazolinone derivatives

as analgesic agents, "*

15

Selected entries from the oxazole series (6) were evaluated for analgesic and anti

inflammatory activity against acetic acid induced writhing (modified Koster’s test) and

foniialdehyde-induced paw oedema, respectively. Antipyrine and aminopyrine were used as

the standards in both tests. The results demonstrate that the presence of an ethyl residue at

position 5- of the oxazole ring enhances analgesic activity significantly. Thus 5-ethyl

substituted derivatives were more active than 5-methyl substituted compounds.

The increase observed in the analgesic activity tliat parallels the elongation of the side chain

may be attributed to the change in the overall lipophilicity of 6, which in turn improves the

pharmacokinetic parameter of the molecule. None of the tested compounds reduced

formaldehyde induced paw oedema.

PyrazoUnes___________________________________________________ Literature Review

Category: Hypotensive

Gulhan et.al reported synthesis of some thiazolyl-pyrazoline derivatives and preliminary

investigation of their hypotensive activity '"'

The tested compounds showed hypotensive activity as magnitude of their effects after acute

i.p. administration of single doses (20 mg/kg) was less pronounced than that of an optimal

dosage of the reference drug clonidine (0.5 mg/kg) in the same experimental conditions.

Category: Anti-viral and anti-fungal

Kidwai a/reported antiviral and anti-fungal activity of 1-(5-methyl-1, 3, 4-thiadiazol-2-yl

thio aceto / teyra-l-yl-aceto)-3-(substituted phenyl) 4-formyl pyrazole synthesized from l -(5-

methyl-1, 3, 4-thiadiazol-2-yl thio methyl/tetrazol-l-yl methyl) hydrazones, DMF and

P0Cl3^'‘

16


Category: Antimicrobial

Bharmal et.al reported synthesis of some pyrazoline derivatives as biologically active

agents',37

Category: Analgesic, antimicrobial antthelmentic

Vagdevi ^/.«/reported analgesic, antimicrobial, anthelmintic activity of novel Naptho [2, 1-

b] furo pyrazolines^^.

^ Ar

Ar = R= Substituted aryl


Shenoy et.al reported synthesis and antimicrobial activities of 1, 3, 5 trisubstituted 2-

pyrazolines39

Ar = Aryl substituted, R = H, 2-Cl, 4-Cl, 4-CHj, 4-OCHa,

4-Br 2.4-Cl. 3.4-OCH3

Category: Antibacterial, analgesic

Waheed reported synthesis of certain substituted 1, 2-pyrazolines from Nalidixic acid as

antibacterial agents'*®

17


l(a-g)

Compd R, R2 R., R4 R5

la H 0CH3 OCH3 OCH., H

lb H H Br H HIc H Br H H H

Id Cl H G1 H H

le H H Cl H H

If Cl H H H H

Ig Cl H H H Cl


Abunada et.al reported synthesis and biological activity of some new pyrazoline and

pyiTolo [3, 4-c] pyrazole-4, 6-dione derivatives: Reaction of nitrilimines with some

dipolarophiles'**

✓ /

Four of the newly synthesized compounds were screened for their antibacterial activity

against the Gram ~ve bacteria Escherchia coll and the Gram +ve bacteria Staphylococcus

aureus, in addition to their antifungal activity against Asperagillu.s flavus and Candida

albicans using the agar diffusion method at a concentration 20 mg/raL.


Mansour et.al reported synthesis and reactions of some new heterocyclic carbohydrazides

and related compounds as potential anticancer agents'^^

Ar = C6H5, 2-GHjO-C6H4

38

Acylation of 3-hydrazino-5, 6-diphenyl-1, 2, 4-triazine and hydrazine hydrate with 4-aryl-l,

3, 7-triphenyl-8-oxa-l, 2, 6-triazaspiro [4.4] nona-2,6~dien-9-ones gave the coiresponding

heterocyclic carbohydrazides 6a, b and 8a, b . Conversion of compounds 8a, b into the

versatile carbohydrazide derivatives 9a-g, 10, 13 and the related oxadiazoles 11, 12a, b was

undertaken, A primary in vitro test of a compound 8a (concentration 10“' M) showed activity

against leukemia cell lines (CCRFCEM, K-256, MOLT-4, PRMI-8226. SR).

Category: anti-inflammatory, antioxidant, antibacterial

Babu et.al reported synthesis and biological evaluation of some novel pyrazolines'*‘\

Pyrazolines_________________ _________ __________________________ Literature Review

4(a-o) 5(a-o)

Ar = aryl substituted Ar = aryl substituted

Among the 7 compounds that were screened for anti-inflammatory activity, compounds 4g

and 5m showed 83.4% and 80.5% inhibition of oedema volume, while the standai’d drug

(ibuprofen) showed inliibition of 91.9%. Compounds 4k and 5h showed moderate activity of

72.8% and 59.6% respectively. All the 30 compounds were tested for antioxidant activity at

1000, 500, 250, 100, 50, 25 and 10 mg/ml concentrations against standard drug ascorbic acid.

Compounds 4g, 4h, 4k, 4m, 5g, 5h, 5k and 5m showed excellent antioxidant activity as

compared with ascorbic acid. Among the 30 compounds that were screened against two

Gram +\e (Staphylococcus aureus and Bacillus subtilis ) and two gram -ve (Escherichia coli

and Pseudomonas aeruginosa) organisms, compounds possessing 7?-chloro, /?-fluoro, 2-

amino-5-bromo, 2-hydroxy-5-nitro and 3, 5-dichloro substitutions on the phenyl ring showed

good activity against Escherichia coli m d Bacillus subtilis. The activity is comparable with

that of the standard drug ciprofloxacin.

Category: Antiviral

Shahar Yar e/.a/ reported synthesis and evaluation of in v//ra antiviral activity of novel

phenoxy acetic acid derivatives'*^'

_ „ — - .■■■ ■ ■■ 'jg . ■, ■" ■ ;■ .. .. ; .

PyrazqUnes Literature Review

3(a-m); R = aiyl substituted

Several substituted phenoxy acetic acid derived pyrazolines were synthesized by the reaction

between 2-{4-[3-(2,4-dihydroxyphenyl)-3-oxo-l-propeny]]-2-methoxyphenoxy} acetic acid and

substituted acid hydrazides and were tested for their in vitro cytotoxicity and antiviral

activity. None of the compounds showed any specific antiviral activity [50%antivirally

effective concentration (EC50) ^ 5 fold lower than minimum cytotoxic concentration]. The

most cytotoxic of the series was 2-{4-[3-(2,4-dihydroxyphenyl)-!-(2- hydroxybenzoyl)-4,5-

dihydro-lH-5-pyrazolyl]-2-methoxyphenoxy}acetic acid (3j), with a minimum catatonic

concentration of 0.16 pg/mL in human embryonic lung (HEL) cells.

Category: Antiamoebic

Abid et.al reported synthesis, characterization and antiamoebic activity of ]-(thiazo]o[4,5-

b]]quinoxaline-2-yl)-3-phenyl-2-pyrazoline derivatives'*®.

X = H . B n C i ;R = H,CH3

Category: Anti-inflammatory

Reddy et.al reported design, synthesis, and biological evaluation of l-(4-sulfamylphenyl)-3-

trifluoromethyl-5-indolylpyrazolines as cyclooxygenase-2 (COX-2) and lipoxygenase (LGX)

inhibitors'*^.

Category: Antiamoebic

Abid et.al reported synthesis, spectral characterization and antiamoebic activity of new 1-N-

substituted thiocarbamoyl-3-phenyl-2-pyrazolines‘'’.

Thirty new pyrazoline derivatives were syntliesized by cyclization of Mannich bases with

thiosemicarbazides being substituted by different cyclic and aromatic amines. The in vitro

antianioebic activity was evaluated against Entamoeba histolytica in comparison with

metronidazole used as reference substance. Out of 30 compounds screened for antianioebic

activity, 10 were found to be better inhibitors of E. histolytica.

Category: Antitubercular, antimicrobial

Chovatia et.al reported synthesis and selective antitubercular and antimicrobial inhibitory

activity of 1-acetyl-3, 5-diphenyl-4, 5-dihydro-(i/-0-pyrazole derivatives"**.

Pyrazolines_____________________________■ Literature Review

These compounds (3a-l, 4a-l) were tested in vitro for their antitubercular and antimicrobial

activities. The in vitro antimycobacteria] activity of the newly synthesized compounds was

investigated against Mycobacterium tuberculosis H37RV (ATCC 27294) in BACTEC 12B

medium using the ALAMAR radiometric system. The antimicrobial in v/rro activity was

tested against Bacillus coccous, Bacillus subtilis, Escherichia coli, Proteus vulgaris and

antifungal activity against Aspergillus niger.

Category: Antibacterial, antifungal

Shekarchi et.al reported synthesis, antibacterial and antifungal activities of 3-aryl-5-(pyridin-

3-yl)-4, 5-dihydropyrazole-l-cai'bothioamide derivatives'*^.

HaR] = R 2 = R 3 = H .C H 3 .O C H 3

21

PyrazoUnes Literature Review


Ashok et.al reported convenient synthesis of some 3, 5-arylated -2-pyrazolines carrying 4-

raethylthiophenol moiety and evaluation of their antimicrobial activity^®.

22

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1. Knorr,Ser, 16, 1883,2597.

2. K non,B er,]l, 1884, 2032.

3. KnoiT, Blank, Ber, 18,1885, 311.

4. H Suzuki, Organic leit, 2, 2000,413.

5. Cabarrocas G, Temihederon: Asymmetry, 11, 2000, 2483.

6. Norman R O C , Coxon J M, Principles o f organic synthesis, 3"' edition, 278.

7. P Veddso, J Chem, 67, 2002, ASAP.

8. Gheorghiu and Matei, Bull Soc chim France, 5 ,1939, 1324.

9. Matei, Ann sci univ fassy, 17,1943, 29.

10. Auwers V and Voss, Ber, 42, 1909,4411.

11. Locquin and Heilmann,’ Compi rend, 186,1928, 705.

12. Auwers V and Muller, Ber, 4 1,1908, 4230.

13. Peterson and Raiford, proc Iowa Acad Sci, 42,1935, 123.

14. Auwers V and Kreuder, 58,1925, 1974.

15. Raiford and Peterson, 7 <9rg 1937, 544.

16. Raiford and Grundy, J Org Chem, 1,1938, 265.

17. Raiford and Manley, J 5, 1940,590.

18. Raiford and Hill, JA/n C/?ew 5oc, 5,1934, 174.

19. T afel,5er,22 ,1889, 1854.

20. Ozdemir Z, Kandilci H B, Giimiisel B, U, Bilgin A A, Eur J Med Chem, 42,

2007,373.

21. Prasad Y R, Rao A L, Prasoona L, Murali K, Kumar P R,Bioorg & Med Chem Lett,

15,2005,5030.

22. Shahai- Yar M, Siddiqui A A, Ali M A, Sriram D, Yogeshwari P, Bioorg & Med

Chem Lett, 16, 2 m 6 ,m i :

23. Amir M.Kumai-H, Khan S A, B/oorg c& Mi’c/C/im Lert, 18,2008, 918.

24. PlaskaE,A ytem irM ,U zbayIT,ErolD ,£M rJM ^rfC^m , 36,2001,539. V

25. Ozdemir A, Turan-Zitouni G, Kaplancikli Z A, Revial G, Giiven K, Eur J Med

Oie/n, 42,2007, 403.

26. AH M A, Shahar Yar M, Siddiqui A A, 7 Met/Ctem, 42, 2006, 268.

Pyrazolines____________________________________________________ Literature Review

_ _ ■ :.. 23 ■ ■'

27. Johnson M, Brent, Younglove, Lee L, LeBlan R, Holt H, Patrice H Jr, Hilary,

Mackay, Brown T, Moobeny S L, Lee M, Bioorg & Med Chem Lett, 17, 2007, 5897.

28. Pi'amila T, Doshi N, Bheemchari, Udupi R H, Oriental J of Chem, 23, 2007, 583.

29. Kiifiikgiizel S G, Rollas S, IL Farmaco, 57, 2002, 583.

30. Nimvat K S, Popat K H, Joshi H S, Indian J Heterocycl Chem, 12, 2003, 225.

31. Jeong S T, Kira K S, Sangkulee, Lee W S, Bioorg & Med Chem Lett, 14, 2004,

2715.

32. Jeong S T, Kim K S, Sangkulee, Lee W S, Bioorg & Med Chem Lett, 14, 2004,

2719.

33. Ali M A, Shahar Yar M, Clercq E D, J Enzyme Inhibition and Medicinal Chemistry,

22, 2007, 702.

34. Giirsoy A, Demirayak S, Qapan G, Erol K, Vural K, Eur J Med Chem, 35, 2000, 359.

35. Gulhan T-Z, Chevalletb P, Kiligc F S, Erol K, Eur J Med Chem, 35, 2000, 635.

36. Kidwai M, Kumar S, Goel Y, Kumar K, Indian J Chem, 36(B), 1997, 175.

37. Bharmal M F, Kaneriya J D, Parekh H H, Indian J Heterocycl Chem, 10, 2000,

189.

38. Vagdevi H, Latha K, Vaidya V, Kumar M V, Pal R, Indian J Pharm Sci, 63,

2001, 286.

39. Shenoy G G, Bhat A R, Bhat V G, Kotian M, Indian J Heterocycl Chem, 10, 2001,

197.

40. Waheed A, Khan S A, Indian J Heterocycl Chem, 11,2001, 59.

41. Abunada M N, Hassaneen M H, Kandile G N, Miqdad A O, Molecules, 13, 2008,

1011.

42. MansourK, Eid M M, Khalil S A, Nasser M, Molecules, 2003,14A.

43. Babu V H, Sridevi C H , Jo.seph A, Srinivasan K K, Indian J Pharm Sci, 69,

2007,470.

44. Shahar Yar M, Bakht M A, Siddiqui A A, Abdullah M M, Clercq E D, I Enzyme

Inhibition and Medicinal Chemistry, 2008, 1 (Article in Pre.sS).

45. AhidM , Azam A, Bioorg & Med Chem Lett, 16, 20Q6,2S12.

P y r a z o l i n e s ____________________________________ Literature Review

24

46. Reddy MV, Billa VK, Pallela VR, Mallireddigari MR, Boominathan R, Gabriel JL,

Reddy EP, 5/oorg C/zem, 16, 2008, 3907.

47. Abid M, Bhat A R, Athar F, Azam A, Eur J Med Chenu 44, 2009, 417.

48. Chovatia P T, Akabari J D, Kachhadia P K, Zalavadia P D, Josh H S, J Seri> Chern

5oc, 71, 2007,713.

49. Shekarchi M, Pirali-Hamedani M, Navidpour L, Abid N, Sliafiee A, J Iran Chem Soc,

5,2008,150.

50. Ashok M, Holla B S, 7 o f Pharmacol and Toxicol, 1, 2006,464.

PyrazoUnes____________________________________________ ______ Literature Review

25

Oxadiazoles Literature Review

OXADIAZOLES

I. INTRODUCTION

Oxadiazole are the compounds having five membered ring with two nitrogen atoms and

one oxygen atom.

NHO

1, 2, 3-oxadiazole furo[ab] diazole diazoxide

r \

< o >1, 2, 5-oxadiazole furo[aa,] diazole furazan azoxazole

1, 2, 4-oxadiazole furo[ab] diazole azoxime

N-----N

O1,3, 4-oxadiazolefuro[bb.] diazolebiazole oxybiazole oxadiazole

Although 1, 3, 4-oxadiazoles have been known for about 80 years^'^, it is only in the last

decade that investigations in this field have been intensified. This is primarily due to the large

number of uses of 1, 3 ,4-oxadiazoles in the most diverse areas, for example in dnig synthesis

scintillating materials, and the dye stuffs industry. Moreover, ring cleavage reactions of the 1,

3, 4-oxadiazole has also excited great interest in vai'ious fields, since they lead to new

aliphatic nitrogen- containing compounds and to other ring system.

II. PREPARATION OF 1 ,3 ,4-OXADIAZOLES

A. Preparation by ring closure of chains with a preformed 1, 3 ,4-oxadiazoIe skeleton

1. Ring Closure by means o f a condensation Reaction

a. Condensation with elimination o f water. Mono- and diacid hydrazides,

N— N

RCONHNHCOR'-H,0

26

acylsemicai'bazides, and the related compounds produce the oxadiazole by ring closure. The

well-known conversion of N,N’-diacid hydrazides to 2,5-diaiyl (alkyI)-l,3,4-oxadiazoles has

been described by Stolle.^

b. Condensation with elimination o f alcohol. 1-Acyihydrazine-2-carboxylic acid esters are

converted on heating to 1,3, 4-oxadiazolin 5-ones with the elimination of alcohol.'*’^

R'/

Oxadiazoles______________ ________________________________ Literature Review

RCONHNR'iCOjC Hs)

c. Condensation with elimination of carboxylic acids and carboxylic anhydrides.

Tetracylated hydrazines, which may be obtained as intermediates by heating diacyldiimides

in an inert solvent or directly from anhydrous hydrazine and an excess of carboxylic acid

ester, produce on heating 2, 5-disubstituted 1, 3, 4-oxadiazoIes^’’ with the elimination of 2

moles of acid anhydride. The reaction of dibenzoyldiimide with triethyl phosphite yields,

depending on the solvent, either 2, 5-diphenyl-1, 3, 4-oxadiazole (in ether) or tribenzoic

hydrazide (in chloroform). Acylated -1, 3, 4-oxadiazoIines are formed by treating the

acylhydrazones of carbonyl compounds such as benzaldehyde, acetone, and cyclohexanone

with acetic anhydride or polyphosphoric acid, with the elimination of a mole of acid. In

contrast to the acylation of benzoylbenzalhydrazone (R=R’= CeHs R”= H) which

occasionally produces 2, 5-diphenyl -1, 3, 4-oxadiazole, the corresponding treatment of

acetone acetylhydrazone (R=R’= R”=CH3) yields no 2, 5-dime£hyl -1, 3 ,4-oxadiazole.

(CHjOopRCONHN=C

R"

2. Oxidative cyclization ofhydrazones and semicarbazones to give 2, 5- disubstituted

1,3,4-Oxadiazoles '

Oxidation of benzal-benzhydrazone (also as the silver salt), usually by free halogen, give 2,

5-diphenyl-1, 3 ,4-oxadiazole.*

_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _


N----- N

halogenCeH,CH=NNHCOCgHg------------ - CgHs

B. Syntheses from acid hydrazides by the introduction of a one-carbon fragment

1. Syntheses from acid hydrazides and ortho esters

The reaction of acid hydrazides with orthoformic esters proceeds via elimination of alcohol

to give 2-substituted 1,3, 4-oxadiazoles. The reaction is mostly carried out with the reactants

at the boiling point of the orthoformic ester or in an inert solvent at a higher temperature,

thus the acid hydrazides can be cyclized only when R is sufficiently electrophilic; an

ai'omatic group, however, is not necessary/^

(CH(0 R ')3 .r 'O H n— NRCONHNH2 --------------- (RC0 NHN=CH0 R‘)

o

2. Syntheses from acid hydrazides and imido esters or imidochlorides

A universal method for the prepai’ation of 2, 5-dialkyl (aryl)-l, 3, 4-oxadiazoles is the

reaction of acid hydrazides with imido esters or their hydrochlorides.

R'C(OR')=NHCI N----- NBCONHNH2 — — ^

O ' '''

3. Syntheses from acid hydrazides with phosgene, thiophosgene, carbon disulfide, or

isocyanide dichlorides

Acid hydrazides with phosgene produce 1 ,3 , 4-oxadia2olin-5-ones. Particular attention has

been devoted recently to heterocyclic substituents and also to certain aromatic derivatives.

For example, 2-(2~nitro-5-furyI) - 1, 3, 4-oxadiazolin-5-one, 2-pyrazinyl-l, 3, 4-oxadiazolin-

5-one, and derivatives of isonicotinic acid hydrazide and of /?-amino salicylic acid hydrazide

have been described.

28


R’/

N----- N

RCONHNHR'COCIj

O ' °

III. REACTIVITY OF THE 1, 3 ,4-OXADIAZOLES

A. Substitution reaction and structure of 1, 3, 4-oxadiazoles

1. Direct ring substitutions

The direct introduction of functional groups into the oxadiazole nucleus is possible in only a

few cases. The protonation of the nuclear niti'ogen in acidic media reduces extrejneJy

strongly the possibility to electrophilic attack. Thus no nitrations or sulfonations of

unsubstituted oxadiazoles are known in the literature. Halogenation also has not so far been

described although in this case the deactivating effect of the oxadiazole nucleus is not so

i m p o r t a n t . T h e introduction of other functional groups into the oxadiazole nucleus by

nucleophilic substitution of substituted 1, 3, 4-oxadiazoles is also difficult. The few known

examples proceed with low yield. Thus 2-phenyl-5-amino-l, 3, 4-oxadiazole is obtained by

ammonolysis of 2-phenyI--5-methanesuIfonyI“l, 3 ,4-oxadiazoIe.

M NH.

HgCOjS CgHs

2. Alkylation and acylation

1, 3, 4-Oxadiazoline-5-thione, 1, 3, 4-oxadiazolin-5-one, 2-amino-1, 3, 4-oxadiazole, and 2-

benzyl-5-aryl-l, 3, 4-oxadiazole may be alkylated and acylated. As a result of the

mesomerism of these compounds the ring nitrogen can also be substituted. Alkylation has

been earned out onm any 1, 3, 4-oxadiazbline-5-thiones. (They also react with other active

halogen compounds such as perchloromethylmeracptan and 2, 4-dinitrochlorobenzene). Thus

2-(2-nitro-5-furyl) 1, 3, 4-oxadiazoline-5-thione is methylated by the action of methyl iodide

in the presence of ethanolic potassium hydroxide. Since the absorption in the IR spectrum at

7.57 and 7.65 ji is greatly reduced and moreover no N-CH3 band appears, the compound 2-

(2-nitro-5-furyl)-5-methyIthio-l, 3, 4-oxadiazole is probably formed.

29


SCH3

B. Reactions proceeding with ring cleavage

In contrast to its high thermal stabihty the 1, 3, 4-oxadiazole ring proves extremely labile to

chemical agents. Ring cleavage reactions of 1, 3 ,4-oxadiazoles can be achieved by the action

of reducing agents and by nucleophilic reagents; in special cases tlie ring opening is possible

either by thermolysis or photolysis. Although in reduction cleavage of the N-N bond takes

place with amide formation, in an attack by a nucleophilic reagent the C-O bond of the 1, 3,

4-oxadiazole is opened. Of the two ring-opening reactions the latter makes up a relatively

greater portion of the more recent work. The ring-opening tendency, assuming equal

solubility in the reaction medium concerned, is controlled in general by the electron density

at the C-2 or C-5 atom, which is largely dependent on the substituents, and by the

nucleophilicity of the reactants. Ethanol, water, aqueous carbonate solution, ethoxide,

ethanolic and aqueous hydroxide, ammonia, amines, hydrazines, hydi'azides hydrogen

sulfide, and mineral acids have all been used as nucleophilic reagents.

1. Ring cleavage of alkyl-, aryl-, and heterocyclic-substituted 1, 3, 4-oxadiazoles

N -NH or OH H orOH

RCONHNHR* NHgNH, + RCOOH + R'COOH

0Ring cleavage of the 2, 5-dialkyl-l, 3, 4-oxadiazoles by either acid or base leading to

cai'boxylic acids and hydrazine or acid hydrazides has been known for some time.

Investigation of the acid hydrolysis of alkyl- and aryl-substituted 1, 3, 4-oxadiazoles and its

dependence on the'substituents has recently been reinvestigated. In general, the aryl-

substituted 1, 3, 4-oxadiazoles are less sensitive to acid than the alkyl-substituted derivatives,

2. Ring Cleavage of 2-Amino-l, 3, 4-oxadiazole

The action of nucleophilic reagents on 2-amino-l, 3, 4-oxadia2oles leads to acyclic

compounds which often cyclize immediately to triazoles. Thus 2-amino-l, 3, 4-oxadiazoles

with caustic alkali yield 1, 2 ,4-triazoJinones.^‘*’*®

30


Fusion alkaliN— N p.fjH ^ RCONHNHC(NHR‘)=NH ---'

^ RC(NHR')=NNHCONH, -------------- ------»-

Cai'efiil hydrolysis of 2-amino-5~phenyl-l, 3 ,4-oxadiazole with dilute Ba(OH)2 or 4% NaOH

yields l-benzoylsemicarbazide which on boiling with NaOH solution, can be cyclized to 3-

phenyl-1, 3, 4-oxadiazolin-5-one. This reaction has been carried out on an extended series of

2-amino-l, 3 ,4-oxadiazole derivatives by heating for a short time with 10% caustic soda,

3. Ring cleavage o f 1, 3, 4-oxadiazolines and 1, 3, 4-oxadiazolidines

Reduced 1, 3, 4-oxadiazoles very easily succumb to ring cleavage. 2, 3, 5-Triphenyl-2, 3-

dihydro-1, 3, 4-oxadiazole is cleaved by boiling in aqueous methanol to give benzoyl-2-

phenylhydrazine and benzaldehyde.**

CH3OH/H2O------ -----------CgHsCONHNHCgHg + CjHsCHO

IV. PHYSICAL PROPERTIES OF -1 ,3 ,4-OXADIAZOLES

In the IR field, the oxadiazole ring has been chai'acterized primarily by the bands at about

970 1020-1030 cm'’ due to the C-0 bond and at 1560-1640 cm'Mue to the C=N

valence vibration. 2, 5-Dialkyl derivatives in this case fall in the longer-w'avelength region

and oxadiazoline thiones in the shorter-wavelength region. The C=0 absorption in -1, 3, 4-

oxadiazolin-5-ones lies at 1740-1785 era’’ even in condensed systems. The presence of C=S

bands at 1300-1325 cm'’ or 1350-1370 cm '\ C-NH bands at 1438-1538 cm'' as well as NH

vibrations at 3165 and 3450 cm,’’ is only compatible with a thione structure.

1, 3, 4-oxadiazole system has an electronic spectrum equivalent to that o f benzene and the

maxima of the oxadiazole derivatives are only slightly shifted hypsochromically compared

with benzene. Thus, for example, diphenyl and 2-phenyl-l, 3, 4-Oxadiazole absorb almost

identically at 248 m/i and /j-terphenyl and 2, 5-diphenyl-1, 3 ,4-oxadiazole absorb at 276 and

280 m)i, respectively. The oxadiazole system is effective in the conjugative transmis.sion of

31

the effects of substituents. 2, 5-Diaryl-], 3, 4-oxadiazoles exhibit strong fluorescence in

solution on stimulation by UV or P-irradiation, particularly 2-biphenylyl-5- phenyl- and 2-

biphenyl-5-(l-naphtyl)- 1, 3, 4-oxadiazole. Few pK values of 1, 3, 4-oxadiazoles have been

measured, partly because of the poor water solubility of aromatic substituted oxadiazoles. A

pKb value of 11.63 (in water) is given for 2-amino-5-methyl-l, 3, 4-oxadiazole and its mono

and dimethylamino derivatives have approximate pKa values between 2.7 and 2.9 of 2-imino-

3-methyl-5-phenyl-l, 3, 4-oxadiazoline and of 2-methylimino- 3-methyl-5-phenyl-l, 3, 4-

oxadiazole are 6.31 and 6.38, respectively.

RECENT ADVANCEMENT

The growing patent literature of recent years demonstrates that the 1, 3, 4 oxadiazoles ai'e

becoming of great practical significance. A group of 1, 3, 4 oxadiazole-5-ones and 1, 3, 4-

oxadiazoline-5- thiones show antitubercular activity. They have been investigated with

regal'd to their mode of action. Oxadiazolin-5-ones and oxadiazoline-5-thiones also possess

variously analgesic, antipyretic, and antiphlogistic properties. The 2-[5’-nitrofuryl-(2’)]-l, 3,

4-oxadiazolin-5-ones have been thoroughly investigated as fungicidal and bactericidal

agents.** The sulfonamide derivatives of 1, 3, 4-oxadiazole are established not only as

bactericides but also as hypoglycemic agents. 1, 3, 4-oxadiazoles are acquiring greater

significance in the stabilizing and preparation of macromolecular materials. Thus poly- 1, 3,

4-oxadiazoles with aliphatic substituents is used as films, although aryl derivatives can be

used neither as fibers nor films.

Category: Anticonvulsant

Zarghi et.al reported synthesis and anticonvulsant activity of new 2-substituted-5-(2-

benzyloxyphenyl)-!, 3, 4-oxadiazoles*®

Pharmacological evaluations of the synthesized compounds are shown below

Oxadiazoles ___________________ ____________________________ Literature Review

32


Compound

4a

4b

4c

6a

6b

6c

Diazepam

R,

H

Cl

H

H

H

H

R2

NH,

NH,

NH,

SH

SCH3

SC2H5

SBZ

ED50 mg/kgPTZ

'85.2(62.1-125.9)“

2.5(1.5-4.1)'’

>100

>100

91.2(55.1-196.4)“

>100

>1001.4(1.1-2.0)'’

MES

63.2(41,9-82.9)"

3.3(2.1-5.1)“

>100

>100

>100

>100

>1001.8(L l-2.6)'’

= 10, 95% confidence limits in parentheses, LD50 of all compounds > 300 mg/kg.

’’ED50 significantly increased in the presence of flumazenil lOmg/kg (F<0.05).

In the series of 2-alkylthio oxadiazoles, only compound 6a had a weak anticonvulsant

activity but the compounds 5, 6b and 6c did not have any significant anticonvulsant activities

in both models.


NavaiTete-Vazquez et.al reported synthesis and antimycobacterial activity of 4-(5--

substituted-1, 3 ,4-oxadiazole-2-yl) pyi'idines^®

A series of 4-(5-substituted-l, 3, 4-oxadiazole-2-yl) pyridines was synthesized and tested

against M. tuberculosis dmg-resistant strains. The present results highlight the importance of

lipophilicity of these compounds to present good antimycobacterial activity.


Aboraia er.a/reported synthesis of novel 5-(2-hydroxyphenyl)-3-substituted-2, 3-dihydro-l,

3, 4 oxadiazole-2’-thione derivatives: promising anticancer agents^^

Synthesized 5-(2-hydroxyphenyl)-3-substituted-2, 3-dihydro^l, 3, 4 oxadiazole-2-thione

derivatives were chosen by NCI as prototypes. They were evaluated in the 3-cell line panel

33

consisting of NCI-H460 (lung), MCF7 (breast), and SF-268 (CNS). Primary anticancer assay

was performed in accordance with the protocol of the drug evaluation branch, National

cancer institute, Bethesda. Some compounds were selected for a full 60-cell panel screen

where they showed non- selective broad spectrum and promising activity against all cancer

cell lines.


Gaonkar el.al reported synthesis and antimicrobial studies of new series of 2-{4-[2-(5~

ethylpyridin-2-yI) ethoxy] phenyl )-5-substituted-l, 3, 4-oxadiazoles^^

V8(a-k)

Al! the synthesized oxadiazole derivatives were evaluated for antimicrobial activity by

diffusion and micro dilution method against the various strains. Streptomycin and

tetracycline were used as standard drugs against bacteria and nystatin was used against fungi,

hi all the determinations tests were performed in triplicate and the results were taken as a

mean of at least three determinations. The significant inhibition shown by the presence of

two chloro groups present on benzene ring attached to C5 of oxadiazole moiety. The

moderate activity was observed due to chloro group, nitro group and methoxy group

respectively at para position of benzene ring. The moderate activity was also observed due to

4-pyridinyl ring attached C5 of oxadiazole. Remaining compounds were not active against

any of the strains tested.


Macaev et.al reported synthesis of novel 5-aryI-2-thio-1, 3, 4-oxadiazoles and the study of

their .structure-antimycobacterial activities^^

Oxadiazoles___________________________________________________ Literature Review

R] = R2 = R3 = R4 = Aryl substituted

34

The synthesized compounds 4a-4i in the present study were tested for the in vitro anti-

mycobacterial activity against mycobacterium tuberculosis H37Rv using the Alaraar Blue

assay method. Rifampicin was used as the control standard in the assays for in vitro

inhibition of M. tuberculosis H37Rv, It was found that substituting a halogen to hydroxyl

group increased bioactivity to 17%. The ether of 4- sulfanylmethylpyridine showed activity

with a PI of 39%.


Karabasanagouda et.al reported a .series of new 2-[(4“a]kylthio/alkylsu]fonyl phenoxy)

methyl]-5-substituted-l, 3, 4-oxadiazoles have been reported to possess moderate to good

antimicrobial and amifungal activities against pathogenic strains^.

Oxadiazoles_____ ______________________________________________ Literature Review

R = CH,,C,H, R ^CH yCjH , R = H, CH3. C.H , CH,COOH

Category; Anticancer

Holla et.al reported synthesis of 2-chloro-l, 4-biS"(5-substituted-l, 3, 4-oxadiazol-2-

ylmethyleneoxy) phenylene derivative '"’

Category: antiproliferative

Liszkiewiez et.al reported synthesis and in vitro antiproliferative activity of 5-(2- araino-3-

pyridyl)-2-thioxo-3H-l, 3 ,4-oxadiazole derivatives on 4 human cancer cell line^^.

35


SCHjCO R

R= -NH 2. -N(CH 3)2, -NHNH

A-N

VN O

v_yCategory: Anti-inflammatory

Saxena et.al synthesized 5-(2-hydroxyphenyl)-3-(aryl amino ethyl) 1, 3, 4-oxadiazole- 2-

(3//)-thiones and screened for their anti-inflammatoiy activity by paw edema method in

rats ’.


Kagthara et.al reported synthesis and antitubercular activity of Aryl sulphonamido-5-[2’-

(benzimidazol-2” -yl)]-13,4-oxadiazolcs and 2-benzoylamino-5-[2’-(benzimidazol-2” -yl)>\Q

phenylj-1, 3 ,4-oxadiazoles against mycobacterium tuberculosis H37Rv .

HN---- SO?—B

R = Substituted aryl

Category: Anticonvulsant

Almasirad et.al reported synthesis and anticonvulsant activity of 2-subsituted- 5-[2- (2-

fl«orophenoxy)phenyl]-l,3.4-oxadiazoles^®

36


Category: Spasmolytic

R= NH., SH. SCH,, OH

Mishra et.al reported the spasmolytic and hypotensive activity of 2'(substituted acetyl)

amino-5-alkyl-l, 3, 4-oxadiazoles‘®.

CjHs


Cai et.al reported the preparation of 3, 5-disubstituted-[ 1, 2, 4-] oxadiazoles and analogs as

activators of caspases and induces of apoptosis'^*.

Category: Antimycobttcterial

Mamolo et.al reported antimycobacterial activity of new 3-substituted 5-(pyridin-4-yl)-3H-

1, 3, 4-oxadiazol-2-one and 2 thione derivatives'^^ With the aim to obtain new

antimycobacterial agents, synthesized a series of 5-(p>'ridin-4'yl)-3i¥-l, 3, 4-Gxadiazol-2-

thione (la-1) and 5-(pyridin-4-yl)-3H-l, 3, 4-oxadiazol-2-one (2a-l) derivatives; The m-vz7rd

antimycobacterial activities of derivatives (1 a-1) and (2a-l) M'ere tested against a strain of M

tuberculosis

37


X = Aryl substituted

Category: Antimycobacterial, antibacterial

Joshi et.al reported synthesis of new 4-pyrrol-1-ylbenzoic acid hydrazide analogs and some

derived oxadiazole, triazole and pyrrole ring systems: A novel class of potential antibacterial

and antitubercular agents^^.

R = CfiHj, 2,6-C1-C(,H3

Category: Insecticidal

Holla et.al reported synthesis and insecticidal activity of some 1,3,4-oxadiazoles derived

from 2-chloropyridine-5-acetic acid "*.

^ . 1 r \R = H, Cl, R CH3, OCH3

Category: Anti-inflammatory, analgesics, ulcerogenic

Bhandari et.al reported synthesis and evaluation of anti-inflammatory, analgesics and

ulcerogenicity studies of novel S-substituted phenacyi-1, 3, 4-oxadiazole-2-thiol and schiff

bases of Diclofenac acid as nonulcerogenic derivatives' '"'.

38

REFERENCES

1. Boyer J H, Heterocyclic compounds, 7,1961, 525.

2. Dupont G and Locquin R, Traite de chimie organique, 21,1953, 997.

3. (a) Stolle R, Ber, 32,1889, 797.

(b) Stolle, JPrakt Chem, 68,1903, 130.

4. Rupe H and Gebnardt H, fie/-, 32,1899, 10.

5. Geistlich E and Sohne A G, Swiss patent, 1959, 338463.

6. Stolle R and Reichert W, J Prakt Chem, 123, 1929, 82.

7. Young J A, Durell W S, Dresdner R D, J Am Chem Soc, 84,1962, 2105.

8. Schwechten H W and Neef R, German patent, 1024,1958, 971.

9. Grekov A P and Salv’eva M S, Zh Olxshch Khim, 30,1960, 1644.

10. Ponomarev A A and Til Z V, Zh Olxshch Khim, 33,1963, 2368.

11. Vincent M, Maillard J, Benard M, Bull Soc Chim,32, 1962, 1580.

12. Werber G and Maggio F , C / j f m , 52,1962, 747.

13. Domow A and Lupfert S, Arch Pharm, 288, 1955, 311.

14. Maggio F, Werber G, Lombardo G, 50,1960,491.

15. Gehlen H, Ann, 563,1949, 185.

16. Huisgen R, Graschey R, Seidel M, Knupfer H, Schmidt R, A;w, 658,1962, 169.

17. Blankenstein G and Mockel K, Z 2,1962, 69.

18. Sherman WR, J 26,1961, 88.

19. Zai'ghi A, Tabatabai S A, Faizi M, Ahadian A, Nayabi P, Zanganesh V, Shafiee A,

Bioorg& Med Chem Lett, l S , m 5 , \ m .

Oxadiazoles _______________ Literature Review

_ _ _ ________ _ _ ■'39' : ' ' ^

20. Navarrete-Va'zquez G, Molina-Salinas G M, Duarte-Fajardo Z V, Vargas- Villarreal J,

Estrada-Soto S, Gonzalez-Salazar F, Hema'ndez-Nu'irez E, Said Ferna'ndez S, Bioorg

& Med Chern, 15, 2007, 5502.

21. Aboraia A S, Abdel-Rahman H M, Mahfouz N M, EL-Gendy M A, Bioorg & Med

Chem, 14, 2006, 1236.

22. Gaonkar S L, Rai K M L, Prabhuswamy B, Eur J Med Chem, 41, 2006, 841.

23. Macaev F, Rusu G, Pogrebnoi S, Gudima A, Stingaci E, Vlad L, Shvets N,

Kandemirli F, Dimoglo A, Reynolds R, Bioorg & Med Chem, 13, 2005, 4842.

24. Karabasanagouda T, Adhikari AV, Shetty N S, Phosphorus, Sulfur, and Silicon, 182,

2007, 2925.

25. Holla B S, Poojary K N, Bhatt K S, Ashok K M, Poojary B, Ind J Chem, 44(B), 2005,

1669.

26. Liszkiewiez H, Kowalska M W, Wietrzyk J, OpoLski A, Ind J Chem, 42(B), 2003,

2846.

27. Saxena S, Verma M, Ind J Pharm Sci, 54,199, 69.

28. Kaghtara P R, Shah N S, Doshi R K, Parekh H H, Ind J Chem, 38(B), 1999, 572.

29. Almasirad A, Tabatabai S A, Faizi M, Kebriaeezadeh A, Mehrabi N, Dalvandi A,

Shafiee A, Bioorg & Med Chem, 14, 2004, 6057.

30. Mishra P, Gopal, Joshi K , P / m / o cfe P/wraflco/, 36,1992, 347.

31. Cai S X, Zhang H Z, Kuemmerle, Zhang H, Kemnitzer W E, U S Pa/, 2003, U S,

40308 200331238,2004.

32. Mamolo G M, Zampieri D, Vio L, Fermeglia M, Ferrone M, Piid S, Scialino G,

Banfi E, 5/oor^ cfe Ctew, 13, 2005,3797.

33. Joshi S D, Vagdevi H M, Vaidya V P, Gadaginamath G S, Eur J Med Chem, 2007, I

(Article in Press).

Oxadiazoles__________________________ Literature Review

40

34. Holla B S, Pi-asarma C S, Poojary B, Rao K S, Sliridhara K, Bhat U G, Ind J Chem,

43(B), 2004, 864.

35. Bhandari S V, Bothara K G, Raut M K, Patial A A, Sarkate A P, Mokale V J, Bioorg &

Med Chem, 2008 (Article in Press).

Oxadiazoles___________________________ _______________ Literature Review

41

Isoxazolines Literature Review

ISOXAZOLINESI. INTRODUCTION

These classes of dihydro derivatives of isoxazole are theoretically possible, depending on the

location (2, 3, 4, or 4-5) of the two hydrogen atoms. These ai’e the 4- isoxazolines (I), the 3-

isoxazolines (II), and the 2- isoxazolines (III).

II. METHODS OF PREPARATION OF ISOXAZOLINES

A. From a, P- unsaturated ketones and hydroxylamine

Synthesis o f isoxazoles from a - acetylene ketones and hydroxylamine^

KRCOCH=CHR'NHjOH

\-R'

OH

I c H 3

° CH3

B. From ethylenic derivatives and nitrile oxides

A general method for the synthesis of isoxazolines has been applied to a wide variety of

ethylenic derivatives. This reaction^ probably involves the resonance structures.R

R— c

M,X .

R----- C®

O

®c

0 c

C. From isoxazoline N-Oxides

2- Isoxazoline N-oxides, similarly to most N-oxides, release their oxygen atom when treated

with phosphorus pentachloride. Thus, triphenyl isoxazoline has been obtained from its N-

oxide^.

PCI.

oC„H,

H C

H

42

3 ,4-diphenyl-5, 5’-dicarbethoxy-2-isoxazoline N-oxide gives the corresponding isoxazoline

on the same treatment'*.

III. THE CHEMICAL BEHAVIOR OF ISOXAZOLINES

Aliphatic isoxazolines are liquids which can be vacuum-distilled unchanged, whereas aryl

isoxazolines are crystalline solids. They are endowed with weakly basic cha'acter, only

slightly stronger than that of the corresponding isoxazoles. The isoxazoline ring is

remarkably stable toward acids and alkali. Reduction of 3, 5-diphenylisoxazoline with

concentrated hydriodic acid has been reported to give 4-phenyl-3-dihydro- carbostyryl and

other products^. Isoxazolines containing unsaturated side chains can be oxidized to

carboxylic acids without rupture or oxidation of the ring®. For example, 3- pheny]-5-vinyI-2-

isoxazole-4-carboxylic acids, isoxazoline-4-carboxylic acids eliminate carbon dioxide when

heated above their melting points to give the corresponding Isoxazolines in good yields’’®.

Thus, 3-phenyl-2-isoxazoline-4, 5-dicarboxylic Acid loses carbon dioxide to give 3-phenyl-

2-isoxa2oline-5-carboxylic acid loses carbon dioxide to give 3-phenyl-2-isoxazoline-5-

caj'boxylic acid and 3, 5-diphenyl-2- isoxazoline-4-carboxylic acid gives 3, 5-diphenyl-2-

isoxazoline.

IV. SUBSTITUTED ISOXAZOLINES

A. Halo derivatives

Only a few isoxazolines containing halogens in the ring or in side chains have been reported.

They have been prepared by addition of nitrile oxides to P-bromostyrene or to allyl halides^’®

3'PhenyJ-5-dich]oromethyHsoxazoIine is formed by treatment of W-dichlorobenzoylacetone

with hydroxylamine^®.

B. Hydroxy derivatives

The labile 5-hydroxyisoxazolines are possible intermediates in the synthesis of isoxazoles

from P-dicarbonyl compounds and hydroxyl amine or nitrile oxides. 3-pbenyl-5-

dichloromethyl-5-hydroxy-2-isoxazoline,^® phenoxy-2-isoxazoline, from w-dichlorobenzo yl

acetone, and 3-phenyl-5-phenoxy-5~hydroxy-2-isoxazoline^\ from phenoxy acetyl acetone

are known.

C. Alcohols, Aldehydes, and Ketones

Isoxazoline alcohols can be prepared by the reaction of nitrile oxides with allyl alcohols.

Thus, allyl alcohol gives 3-phenyl-5-hydroxymethyl'2-isoxazoline-’®. Isoxazoline ketones

Isoxazolines_______ ___________________________________________ Literature Review

43


have been synthesized from unsaturated a-diketones monoximes by treatment with acids^^’

and from a-ethylenic ketones with nitrile oxides^’

D. Stereochemistry of 2-isoxazolines

Isoxazolines, like other cyclic systems, show cis-trans isomerism. Assuming the planarity of

the isoxazoline ring, derivatives of the types I and II should exist in two stereoisomeric forms

a and b, which are optical isomers. Two different forms of I and II has been reported, but it

is to be expected that the compounds such as 3-phenylisoxazolines-5-cai'boxylic acid (I with

R = CfiHs and R’= COOH) could be resolved into two optically active forms. Four

stereoisomer are possible for isoxazolines containing identical substituents in the 4- and 5-

positions. These are the two cis (III) and two trans (IV) forms Ilia and IVa and Illb and IVb

are distereoisomeric, where as Ilia and Illb and IVa and and IVb are enantiomorphic.

H

O 'R'(la)

>R‘

O(Ila)

44

RECENT ADVANCEMENT


Tangallapally et.al reported discovery of novel isoxazolines as anti-tuberculosis agents*^

Isoxazolines_________________________ ________________ _________ Literature Review

Isoxazoline linked nitrofurans were synthesized that had better antituberculosis activity in-

vitro and had improved serum half lives over coixesponding compounds in the previous

nitrofuranyl amide series, demonstrating that the strategy of replacacing the amide bond with

isoxazoline ring was successful. However series still possessed limited in vivo efficacy.

Category: Antimicrobial, Anti-inflammatory

Shivakumar et.al reported synthesis of substituted fluoro-isoxazoles, isoxazolines and

pyridones as antimicrobial and anti-inflammatory agents^*

The six compounds (0.02mm) were screened for in-vitro anti-inflammatory studies by

inliibition of bovine serum albumin denaturation using reverence drugs as Ibuprofen and

Indomethacin. Inhibition of bovine serum albumin denaturation was studies accordind to the

method of Elias and Rao. The percentage inhibition of bovine serum albumin is ranged from

11.96 to 33.6%, reference drugs Indomethacin and Ibuprofen shows inhibition of bovine

serum albumin denaturation 79.71% and 68.47%

The prepared compound which has shown 33.6% inhibition of bovine serum albumin

denaturation was subjected for in-vivo anti-inflammatory activity by carrageenin induced rat

paw edema, initially the compound was taken up for toxicity studies, compounds did not

show any toxicity. The compound showed edema inhibitory activity of 49.8% while the

standard drug Indomethacin showed an inliibition of 85.7%.

All the compounds were screened for antibacterial activity at lOpg and 20|jg concentrations

against the test organisms, E.coli, S.aureus and B.subtilis by paper disc diffusion method.

Chloramphenicol and Ampicillin were used as standard drugs. The mean zone of inhibition

after 24hr was recorded.

45

Category: Antibacterial, herbicidal

Singhal et.al reported synthesis, antibacterial and herbicidal activities of some new 3-[4’-

(4” - nitrophenoxy)-phenyl]'5-substituted phenyl-2-pyrazolines and 2-isoxazolines^’.

All the synthesized compounds were screened for antibacterial activity by cup diffusion

method at a concentration of 25|ag in DMF using giam positive S.albus, S.pyogenes,

S.viridans and gram negative K. pneumoniae, E.coU, P.mirabilis & S.typhosa bacteria. The

zone of inhibition was measured in mm & the activity was compared with gentamycin

(25)11 g/ml) as standard drug.

Category: Antifungal

Basappa et al. reported solution-phase synthesis of novel D2-isoxazoline libraries via

1, 3-dipolar cycloaddition and their antifungal properties^*^

All newly synthsized isoxazoline derivatives were evaluated for antifungal activity. Nystatin,

a known antifungal compound, was used for comparison. The minimum inhibitory

concentration (MIC) nM of synthesized compounds and nystatin against the fungal strains

Aspergillus flavus, Fusariurn monilifonne and Botiydiplodia theobromae are determined.


Shahar Yar et.al reported synthesis and antimycobacteria] activity of 4-[5"(sub.stituted

phenyl)-4, 5-dihydro-3-isoxazolyl]-2-methylphenols^^.

hoxazolines_____________________ _____________________________ Literature Review

CH,

__-O H

R

3(a-m )

The synthesized compounds were tested for their antimycobacterial activity in vitro against

MTB and INHR-MTB by using the agar dilution method and bactec 460 for the

determination of the Minimum Inhibitory Concentration (MIC). Among the thirteen

compounds synthesized, three compounds were found to be most active compounds with

MICs of less than ImM, against MTB. In general compounds with halogen-substituted

phenyl group showed more activity. Among the synthesized compounds, compounds 4-[5-(4-

bromophenyl)- 4, 5-dihydro-3-isoxazolyl]-2-methylphenoI, was found to be the most active

agent against MTB and INHR MTB with MIC of 0.62 mM. Compounds with a 4-chl6ro

phenyl or 2-chlorophenyl substituent were also found to be active against MTB with MIC of

46

0.83, and 0.72 mM, respectively. Among these compounds that with the 4- bromophenyl

substituent was found to be 1.12-fold and 3.0-fold more active than INH against MTB and

INHR-MTB, respectively. However fluorophenyl and nitropheny] substitutions produced

moderate inhibitory activity against MTB and INHR-MTB. On the other hand the analogues

with an electron donating gi’oup (OCH3) 4-methoxyphenyl 3’, 4’- dimethoxy phenyl and 3’,

4’, 5 ’- trimethoxy phenyl exhibited relatively low inhibitory activity against MTB and

INHR-MTB.

Category: Antiviral

Kai et.al reported Anti-influenza virus activities of 2-allcoxyimino- N-(2-isoxazolin-3-

ylmethyl) acetamides^®

hoxazolines ____________________________ Literature Review

A series of 2-alkoxyimino-N-(2-isoxazo]in-3-y}methy]) acetaraides and related compounds

were synthesized and their antiviral activities against human influenza A virus were assessed.

Studies of the stracture-activity relationships revealed the strongest antiviral activity when

position-5 of the isoxazoline ring was substituted with a tert-butyl group. When the

alkoxyimino moiety was substituted with a methyl, ethyl, isopropyl or allyl group, good

antiviral activity was obtained. Among the geometrical isomers at the oxime moiety, the E-

isomers were more active than the Z-isomers. Among the compounds examined, (E)-2-

allyloxyimino-2-cyano-N-(5-tert-butyl-2-isoxazolin-3-ylmethyl) acetamide (Ij) was the most

active inhibitor with an EC50 of 3 mg/ml.


Rakesh et.al reported synthesis, optimization and structure activity relationships of 3, 5-

disubstituted isoxazolines as new anti-tuberculosis agents^\

In this study anti-tuberaalosis structure activity relationship of the isoxazohne ester

compound through systematic modification of the 3, 5-di-substituted isoxazoline was

reported. Two approaches were used: (i) modification of the potentially metabolically labile

ester functionality at the 3 position with acids, amines, amides, reverse amides, alcohols,

hydrazides, and 1,3,4- oxadiazoles; (ii) substitution of the distal benzyl piperazine ring in the

47


5 position of the isoxazoline ring with piperazyl-ureas, piperazylcarbamates, biaryl systems,

piperidines and morpholine. Attempts to replace the ester group at C-3 position of

isoxazoline with a variety of bioisosteric head groups led to significant loss of the

tuberculosis inhibition indicating that an ester is required for anti-tuberculosis activity.

Optimization of the isoxazoline C-5 position produced compounds with improved anti

tuberculosis activity, most notably the piperazyl-urea and piperazyl-carbamate analogs.


Jayashankara et.al reported synthesis and evaluation of antimicrobial activity of a new series

of bis (isoxazoline) derivatives^^.

A series of ether-linked bis (isoxazoline) derivatives 4 were prepared by 1, 3-dipolar

cycloaddition reactions of nitrile oxides with allyl alcohol and allyl ethers.

R, R’ = 4-McC6H4, 3, 4, 5-(MeO)3 CjHa, 4-NO2C6H4, 2.4-ClCaH3

Category: Antibacterial, antifungal

Desai et.al reported a convenient, rapid and eco-friendly synthesis of isoxazoline

heterocyclic moiety containing bridge at 2°-amine as potential pharmacological agent^— s

*23

R = 2-OCH3, 4 -0 CH3, 3,4,5-( OCH3X 4-N(CH3)2, 4-OH


Prsad et.al reported synthesis and antidepressant activity of some new 3-(2” -hydroxy

napthalen- 1 ” -yl)'5-phenyl-2-isox azolines^.

48


Category: Antibacterial

Shah et.al reported synthesis and antibacterial studies of some novel isoxazolines

derivatives^^

A series of 3-[3-(2, 4-dichloro-5-fluorophenyl)-5-(2-furyl)-4, 5-dihydro-IH-pyrazol-1-ylJ-5-

(substituted phenyl/2-thienyl) isoxazolines 4(a-j) were prepai'ed. The compounds were

screened for their in vitro antibacterial activity using gram-positive bacteria and gram-

negative bacteria.

F 4(a-j)

R = Aryl substitutedCategory: Miscellaneous

Soro et.al reported one step synthesis of diazadihydroacenapthyllene derivatives with an

isoxazoline ring, starting from 1 -benzylamino- 1 -methylsulfanyl-2-nitroethenes^^.

SMe

R = H,OMe,Me,F

Category: Miscellaneous

Kumar er.a/reported a novel one pot synthesis of hydroximoyl chlorides and 2- isoxazolines

using N-tert-butyl-N- chlorocyanamide^’.


Marei ef.a/ reported a new conversion of 5-hydroxy-2-isoxazo]ines and their conversion into

isoxazoles^.

49


O—'N

R = 4- Me-CfiH4, 4-MeO- C6H4,4-Br- C6H4,4-Cl-


Kim et.al reported synthesis of 2-cyanomethyl-3-hydroxy-5-iodomethyltetrahydrofuran from

various isoxazolines: Effects of 3-substituents in the diastereoselective lodoetheration

reactions of isoxazolines^^


Xu et.al reported an efficient deselenenyiation reaction to the synthesis of 3, 5-disubstituted

isoxazoline and isoxazole^®.

o'■N

50

REFERENCES

1. Rupe and Schneider, Ber, 2 8 ,1895,957.

2. Quilico, Stagno d’ Alcontres, GrUnanger, Nature, 166,1956, 226.

3. Kohler and Ban'ctt, J Am Chem Soc, 46,1924, 2105.

4. Kohler and Ban-ett, J Am Chem Soc, 48,1926, 1770.

5. Perold and Reiche V, JA;?z C/tem i oc, 79,1957, 465.

6. Quilico, GrUnanger, Mazzini, Gazz. chim ital, 82,1952, 349.

7. Quilico, Stagno d ’ Alcontres, GrUnanger, Gazz chim ital, 80,1950, 479.

8. Monforte and Lo Vecchio, Gazz chim ital, 82,1952, 130.

9. Stagno d’ Alcontres and Griinanger, Gazz chim ital, 80,1950, 831.

10. Panizzi, c/i/m iVfl/, 72,1942, 99.

11. Fusco and Mazzucchi, Gazz chim ital, 71,1941,406.

12. Diels and Sha-koff, Ber, 46,1913,1862.

13. Diels and Roching, 5er, 51,1918, 828.

14. GrUnanger and Grasso, Gazz chim ital, 85,1955, 1271.

15. Tangallapally R P, Sun D, Rakesh, Budha N, Lee R E B, Lenaerts A J M, Meibohm B,

L&eRE, Bioorg &Med ChemLett, 11, 2007, 6638.

16. Shivakumar B, Nai-gund L V G , 7 C/j«n, 8,1998, 27.

17. Singhal M, Verma B L, 7nJ / CAem, 14, 2005, 343.

18. Basappa, Sadashiva M P, Mantelingu K, Swamy S N, Rangappa K S, Bioorg & Med

C W 11,2003,4539.

19. Shahar Yar M, Ali M A, Bakht M A, Murugan V, J Enzyme Inhibition and Medicinal

C/z£f7n«/?3', 23, 2008,432.

Isoxazolines __________________________________________Literature Review

51

20. Kai H, Matsumoto H, Hattori N, Takase A, Fujiwarab T, Sugimotob H, Bioorg & Med

ChemLettM, 2001, 1997.

21. Rakesh, Sun D, Lee R B, Tangallapally R P, Lee R E, European J o f Med Chem, 2008,

1 (Article in Press).

22. Jayashankara B, Rai K M L, Arkivoc, 11, 2008, 75.

23. Desai J T, Desai C K, Desai K R, J Iran Chem Sac, 5, 2008, 67.

24. Prasad V R, Kumar P R, Ramesh B, Int J Chem Sci, 5, 2007, 542.

25. Shah T, Desai V, J Serb Chem Sac, 72, 2007,443.

26. Soro Y, Bamba F, Siaka S, Coustai'd J-M, Terahederon lett, 47,2006, 3315.

27. Kumar V, Kaushik M P, Terahederon lett, 47, 2006, 1457.

28. Marei M A, Ghonaim R A, 7 Islamic Academy Sciences, 5,1992, 81,

29. Kim H C, Seo M J, Kim K J, Lee J-D, No Z, Kim H R, Bull Korean Chem Soc, 25 ,

2004, 133.

30. Xu W M, Wang Y G, Chen Z H, Huang X, Chinese Chemical Letters, 16,2005, 995.

Isoxazolines _____________Literature Review

52

RESEARCH ENVISAGED

Research envisaged

Several human diseases ai-e alarming signal for the discovery of newer drugs having better

potency and lesser toxic side effects. There are many cardiovascular ailments like

hypertension for which diuretics are best suited as a first line therapy. Amongst the various

illness to the human diseases certain viral and tubercular infections ai'e more common and

because of their tendency to develop new strains under any circumstances for developing

resistance with the available drugs. Therefore scientists ax-e trying to combat resistance

developed by these dmg, Therefore, there is a need of deep research on several molecules

and study of their structure activity relationship (SAR). Diuretics are the most efficient to

treat cardiovascular ailments like hypertension and hence, recently in WHO-ISH guidelines

for the management of hypertension have also describe the importance of diuretics as one

of the most valuable class of drugs^. As monotherapy, diuretics are as efficacious as drugs

from each of the other commonly used classes of antihypertensive drugs -a and p blockers,

ACE inhibitors, calcium channel antagonists and centrally acting drugs. Diuretics are

probably more effective in older patients, and therefore they have been used as a first-line

therapy. This is the major outcome studies of the treatment of hypertension in the elderly.

The effects of diuretics on plasma concentrations of electrolytes and urate have been well

characterized. They are clearly dose-dependent and are minimized at the doses now cujTently

recommended in the management of hypertension^. In contrast, diuretics are inexpensive,

effective, generally well tolerated in low doses and have cleai'ly been shown to prevent major

cardiovascular events in a variety of hypertensive patient gi'oups, particularly in elderly, and

as a component of any combination. Several phenoxy acetic acid derivatives as potential

diuretic agents are also reported^’'*’ ^

While great progress has been made in the development of antibiotics for the treatment of

bacterial infections, there are only a limited number of antiviral drugs that can be used

clinically. The strength of anti-viral therapy raises a number of public health concerns

regarding the optimal use of drugs. Specificity against virus replication is the key issue in

antiviral chemotherapy. Because of the close interaction between virus replication and

normal cellular metabolism, it was originally too difficult to interrupt the virus replicative

cycle without adversely affecting the host cell metabolism. It is now clear that several events

in the virus replicative cycle either do not occui- in normal uninfected cells or are controlled

by virus-specified enzymes that differ structurally and functionally from the conesponding

53

Research envisaged

host cell enzymes. The intrinsic property of viruses as obligate intracellular parasites has

been major stumbling block in developing antiviral drugs because chemicals that inhibit vii'al

replication also iiiliibit host cellular functions that leads to drug toxicity. The expanding list

of emerging or re-emerging viral infections that requires treatment has invoked significant

attention; in addition, resistance to antiviral drugs has also become a serious concern *.

Tuberculosis (TB) is a bacteilal disease caused by Mycobacterium tuberculosis, and

occasionally by other species of the Mycobacterium tuberculosis complex that includes

Mycobacterium hovis, Mycobacterium africanurn and Mycobacterium canetti. These

organisms are also known as tubercle bacilli or Acid-Fast bacilli (AFB)^. Among infectious

diseases, tuberculosis (TB) is the number one killer with over two million casualties annually

worldwide. The WHO considers tuberculosis, to be the most dangerous chronic

commiunicable disease in the world^*’. The emergence of AIDS, decline of socioeconomic

standards and a reduced emphasis on tuberculosis control programme contribute to the

disease’s resurgence in industrialized countries*^ Resistance of mycobacterium tuberculosis

strains to anti-mycobacterial agents is an increasing problems worldwide^^’ ’ '*, However,

powerful new anti-TB drugs with new mechanisms of action have not been developed in the

last forty years. From many decade, most of the heterocyclic systems, having pyrazoline,

oxadiazole, and isoxazolines moieties playing vital role in discovering antiviral, anti-

tubercular and diuretic agents. In view of above facts we inspired and envisaged to

synthesize heterocycles like pyrazolines, oxadiazoles and isoxazolines, in relation to

infectious diseases viz: antiviral and anti-tubercular. From extensive research survey, it was

considered worth while to work on the above mentioned heterocycles.

So, it was planned to explore some novel substituted pyrazolines, oxadiazoles and

isoxazolines moieties, with diuretic, antiviral & anti-tubercular activities

Following steps were plaraied-:

(I) Synthesize three different series of biologically active heterocycles viz; pyrazolines,(

oxadiazoles and isoxazohnes.

(II) Ascertain their structure by characterization studies (IR, NMR, and Mass

spectrophotometry.

(III) Explore their diuretic, antiviral and anti-tubercular activities by adopting standard

protocol.

Research envisaged

REFERENCES

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Hypertension. 1999 World Health Organizatio-International Society of Hypertension.

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6. Clercq D E, Amimicroh Agents Chemother, 2 8 ,1985, 84.

7. Clercq D E, Clin Microbiol Rev, 8, 1995, 200.

8. Crumpacker CS,A^^vv S i5 /JA f^ ^ ,2 5 ,1989, 321.

9. Jenkins A, In: Davies P D 0 , Clinical tuberculosis, 2'“' ed, London: Champon and

Hall, 69.

10. Bloom BR, MuiTay C J L, Tuberculosis, 257 ,1992, 1055.

11. Banies P F, Blotch A B, David.son P T, Snider D E Jr, N Eng J Med, 324,1991,1644.

12. SbarbaroJA,C//ei’/, 111, 1997,1149.

13. Fujiwara P I, Cook S V, Rutherford C M, Crawford J T, Glickman S E, Kreiswirth B

N, Sachdev P S, Osahan S S, Ebrahimzadeh A, Frieden T R, Arch Intern Med, 157,

1997,531.

14. Schaberg T, Gloger G, Reicheit B, Mauch H, Lode R, Pneimologie, 5 0 ,1996, 21.

55

SCHEMES

Schemes

Scheme-I

HO .0 -C H O

KOH / CH,OH

CH3H'

C H ,

HO"CH,

(I-VI)

R= H, Cl, OCH3, OH, OH, NO2 (I-VI)

R’= H (MV& VI), OH (V)

Glacial CH3COOH R'CONHNH,

(VII-LXXI)

HjC,

-Q-CH,

R” = CeHs, 0-aQ^U.u p- ClQ,H4,/> BrQH4,/7- N02C6H4,p- CH3C6H4,•d'CH,

•0 -CH 2 CH3 -0 -CH.,

, o-OHC6H4, CftHs-CHs,

56

Schemes

Scheme-II

HQ p

\

-CHO

CHo

KOH / CH3OHCH,

R'CONHNH, POCL

R =H, OCH3, OH, NO2

R’ = C6Hs, ;;-C1-C6H4, ;?-Br-QH4,/>N02-QH4,;?-CHrC6H4,0-0H-C6H4, CsHs- OCH2.

Scheme-Ill

C H ,

HoC

-O H

NaOH + R-CHO ------—

C H ,

OH

CH3COOH

NHjOH.HCI

CH3

\ /

(CXIII-CXXV)

- O H

57

EXPERIMENTAL

Pyrazolines Experimental

Scheme-I

-C H O

CH,

(I-VI)R = H , Cl, OCH}, OH, OH, NO2 (I-Vl)

R’=H(I-IV& VI), OH(V)

Glacial CHXOOH R'CONHNH,

HaC

-0 -CH'

R ’ = Q H 5, o-OC(,H^,p- a C o R i,p - B tQ H 4,p - N O a C g H i .p - C H 3C 6H 4,

•O-CH,

-O-CHa'

-CH3 -0-CH;//

V J V

,0-0HC6H4, C6H5-CH2 , \ _ / V /

58


General procedure for the synthesis of phenoxy acetic acid chakone (I-VI)

2-(4-formy]-2-raeihoxyphenoxy) acetic acid (0.01 mole) and appropriate acetophenone (0.01

mole) in oxygen free methanol were stiired in presence of potassium hydroxide (30%; 5 ml)

till completion of the reaction. The resulting solution was allowed to stand o\'eniight & then

poured into ice-cold water followed by neutralization with HCl. The solid so separated was

filtered, dried and purified from ethanol. The purity of the compounds was veiified with the

help ofTLC.

2-Methoxy-4'l3-oxo-3-phenylprop-l-enyl]phenoxy acetic acid (I)

H O \

C H ,

C H O H3C

HO. '‘CH3

(I)

IR: (KBr) cm'^ 3174 (COOH), 1682 (C=0), 1560 (C=C). ^H-NMR (DMSO-ds) ppm:

10.1 (IH, s, COOH); 7.2-S.3 (8H, m, H 1, 2,3, 6, 1, 8, 9,10); 6,8 (IH, d, H 4, J = 12.9 Hz);

6.6 (IH, d, H 5, J = 12.6 Hz); 4.5 (2H, s, H 11); 3.7 (3H, s, OCH3); mJz: 313(M-"’).

4-[3-(4-Chlorophenyl)-3-oxoprop-l-enyl]-2-methoxyphenoxy acetic acid (II)

HO 0-

‘ _/- C H O H3C

K O H /C H ,O H

CH5

(II)

IR: (KBr) cm'^ 3171 (COOH), 1689 (C=0), 1577 (C=C). ^H-NMR (DMSO-de) ppm:

10.3 (IH, s, COOH);7.8 (2H, s,H 7 ,8); 7.8-S.3 (5H, m, H I, 2 ,3 .6,9); 7.1(lH,:d, H 4,1 =

12.7 Hz); 6.8 (IH, d, H 5, J = 12.7 Hz); 4.5 (2H, s, H 10); 3.6 (3H, s, OCH3); m/z;

347(M^').

59


2~Methoxy-4-[3-(4-methoxyphenyl)-3-oxoprop-J-enyl]phenoxy acetic acid (III)

KOH/CH.OH

CHjCH3 CHa CHa

(III)

IR: (KBr) cm ^ 3188 (COOH), 1686 (C=0), 1540 (C=C). ^H-NMR (DMSO-ds) ppm;

10.5 (IH, s, COOH); 7.2 (2H, s, H 7, 8); 7.8-8.3 ( 2H, m, H 6, 9); 7.1 (IH, d, H 4, J = 12.7

Hz): 7.0 (IH, d, H 5, J = 12.7 Hz); 4.5 (2H, s, H 10); 3.8 (3H, s, OCHaXm/z; 341 (M'‘).

4-[3~(4-Hydroxyphenyl)~3-0xoprop-l-enyl]-2-metkoxyphenoxy acetic acid (IV)

(IV)

I: R (KBr) cm'*: 3092 (COOH), 1682 (C=0), 1539 ( C=C). ^H-NMR (DMSO-ds) ppm:

9.8 (IH, s, COOH); 7.8 (5H, m, H 1, 2, 3, 6, 9); 7.4 (IH, d, H 4, J = 13 Hz); 6.9 (IH, d, H 5,

J = 13 Hz); 6.8 (2H, s, H 7, 8); 4.5 (2H, s, H 10); 3.8 (3H, s, OCH3); )Wz: 329(M"').

4-/5-(2,4-Dikydroxyphenyl)''3-oxoprop-l-enyl]-2-methoxyphenoxy acetic acid fV)

HO

HQ

-CHO

+ / w K 0 H /C H 3 0 H-OH

CH3

c

(V). ; '

IR: (KBr) cm'\' 3033 (COOH), 1682 (C=0), 1572 (C=C). ’H-NMR (DMSO-dg) ppm:

10.1 (IH, s, COOH); 9.2 (2H, s, 2xOH); 6,5-8.3 (6H, itl, H I, 2,3, 6,7, 8); 6.3 (IH, d, H 4, J

= 8.4 Hz); 6.1 (IH, d, H 5, J = 6.9 Hz); 4.5 (2H, s, H 9); 3.6 ( 3H, s, OCH3); ni/z: 342(M'^).

60


2-Methoxy-4'[3-(4-nitrophenyl)-3-oxoprop-l-enyl]phenoxy acetic acid (VI)

-CHO %C

CHa

(VI)

IR: (KBr) cm *: 3152 ( COOH), 1689 (C=0), 1541 (C=C). ^H-NMR (DMSO-d^) ppm;

10.2 (IH, s, COOH); 8.3 (2H, s, H 7, 8); 7.2-8.1 (5H, m, H 1, 2, 3, 6, 9); 7.1 (IH, d, H 4, J

= J3.3 Bz); 7.0 (JH, d, H 5, J = 13,3 Bz); 4.5 (2H, s, H JO); 3.7 (3H, .s, OCH3); jk/z;

358(M'-’),

General procedure for synthesis of pyrazoline derivatives VII- LXXI

An equimolar quantity of respective compound I-V and appropriate ai-yl acid hydrazide was

dissolved in 15 inl of glacial acetic acid. The solution was reftiixed for 12 hour and after

completion of reaction excess of solvent was removed under reduced pressure and the

reaction mixture was poured onto crushed ice (20gm). The product VII- LXXI so obtained

was filtered, washed with water and purified by column chromatography (Peitroleum:

hexaiie, 3:1 )-

2'[4-{l-Benzoyl-3-phonyl-4,5-dihydro-lH-5-pyrazolyl)-2-methoxyphenoxy]aceticacid (VII)

+

IR: (KBr) cm'^: 3174 (COOH), 1682 (C=0), 1560 (C=N), 1361 (C-N). ^H-NMR (DMSO-

ds) ppm; 10.8 (IH, s, COOH); 7.02-8.39 (13H, m, H 3, 4, 5, 6, 7, 8, 9,10, H, 12, 13,14,

15); 6.2 (IH, dd, Hx. J = 5.1, 5.4 Hz); 4.2 (2B, s,H16)j 3.8 (lH, dd, % . J = 12.3, 12.3 Hz);

3.4 (3H, s, OCH3); 3.2 (IH, dd, Ha. J = 5.4, 5.4 Hz); Wz: 429 (M’’); Anal.ealcd.fbr

C25H22N2O5: C, 69.76; H, 5.15; N, 6.5]%. Found: C, 69.72; H, 5.18; N, 6.52%.

61


2-{4-[l-(2-Chlorobenzoyl)~3-phenyl-4,5-dihydro~lH~5-pyrazolyl]~2-mefhoxyphenoxy) acetic acid (VIII)

HO1 “" lD cS h3

IR: (KBr) crn'^ 3178 (COOH), 1732 (C=0), 1560 (C=N), 1343 (C-N), ^H-NMK (DMSO-

ds) ppm: 10.3 (IH, s, COOH); 6.53-8.36 (12H, m, H 5, 6, 7, 8, 9, 10, 11,12, 13, 14, 15,

16); 4.9 CIH, t, H 4); 4.2 (2H, s, H 17); 3.8 (2H, d, H 3, J = 8.1); 3,6 (3H, s, OCHj); ;iVz;

466 (M^’); Anal.Calcd.for C2SH21CIN2O5; C, 64.59; H, 4.55; N, 6.03%. Found: C, 64.62; H,

4.57; N, 6.06%.

2-{4-[I-(4-Chlorobenzoyl)-3-phenyl-4,S~dihydro~lH~S-pyrazofyl]'2-methoxyphemxy}

acetic acid (IX)

f + a-■CH3 i /

IH,

(IX)

IR: (KBr) cm'^ 3082 (COOH), 1749 (C=0), 1558 (C=N), 1352 (C-N). ^H-NMK (DMSO-

(!<;) ppm: 10.5 (IH, s, COOH); 8.3 (2H, s, H 12,13); 7.02 -8.31 (lOH, m, H 3,4, 3, 6, 7, 8,

9, 10,11, 14); 6.3 (IH, dd, Hx, J = 5.4, 5,4 Hz); 4.2 (2H, s, H 15); 3,9 (JH, dd, Hb, J = 12.3,

12.3 Hz); 3.5 (3H, s, OGH3); 3.2 (IH, dd, H a, J = 5.4, 5.4 Hz); m/z: 466 (M-^’ );

Anal.Calcd.for CasHsiClNaOj: C, 64.59; H, 4.55; N, 6.03%. Found: G, 64.62; H, 4.57; N,

6.06%.

62


2-{4-[l'(4~Bromobenzoyl)-3-phenyl‘4,5~dihydro-lHS'pyrazolyl]-2-niethoxyphenoxy}

acetic acid (X)

(X)

I I : (KBr) cm'^: 3165 (COOH), 1697 (C=0), 1564 (C=N), 1349 (C-N). ^H-NMR (DMSO-

d«) ppm: 10.2 (IH, s, COOH); 8.2 (2H, s, H 12,13); 6.72-7.62 (lOH, in, H 3, 4, 5, 6, 7, 8,

9, 10, 11, 14); 6.3 (3H, dd, H,, J = 5.3, 5.1 Hz); 4.5 (2H, s, H 15); 3.8 (IH, dd, Hb. J = 11.7,

11.7 Hz); 3.5 (3H, s, OCH3); 3.2 (IH, dd, Ha. J = 5.4, 5.4 Hz); nVz: 510(M^’); Anal.Calcd.for

C25H2jBrN205: C, 58.94; H, 4.16; N, 5.50%. Found: C, 58.93; H, 4.18; N, 5.52%.

2-{2-Methoxy-4-[l-(4-nitrobenzoyl)-3-phenyl-4,5~dihydro-lE-5-pyrazolyl]phenoxy) acetic

acid (XI)

OjN- CONHNHj

(XI)

IR: (KBr) cm'*: 3199 (COOH), 1685 (C=0), 1560 (C=N), 1362 (C-N). *H-NMR (DMSO-

dfi) ppm: U S (IH, s, COOH); 6.95-8.42 (12H, m, H 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,14);

6.4 (IH, dd, Hx. J = 5.4, 5.4 Hz); 4.7 (2H, s, H 15); 3.8 (IH, dd, Hb, J = 10.2, 10.2 Hz); 3.6

(3H, s, OCH3); 3.2 (IH, dd, Ha. J = 5.4, 5.1 Hz); m/z: 476(M*’); Anal.Calcd.for G25H2)N3Q7;

C, 63,15; H, 4.45; N, 8.84%. Found; C, 63,18;H, 4.48; N, 8.81%.

63

PyrazoUnes Experimental

2-{2-Methoxy-4-[l-(4-methylbenzoyl)-3-phenyl-4,S-dihydro-lH-5-pyrazolyl]phenoxy} acetic acid (XII)

HO

CONHNHj

IR: (KBr) cm"*; 3230 (COOH), 1689 (C=0), 1559 (C=N), 1376 (C-N). *H-NMR (DMSO-

d6)ppm: 10.1 (IH, s, COOH); 7.18-8.32 (lOH, m,H 3,4,5, 6,7, 8,9,10, 11, 14); 6.8 (2H,

s, H 12,13); 6.3 (IH, dd, H,. J = 6.6, 6.6 Hz); 4.2 (2H, s, H 15); 3.8 (IH, dd, Hb. J = 12.3,

12.0 Hz ); 3.6 (3H, s, OCH3); 3.3 (IH, dd, Ha. J = 5.4, 5.1 Hz); 2.3 (3H, s, CH3); m/z;

445(M^‘); Anal.Calcd.for C26H24N2O5: C, 70.26; H, 5.44; N, 6.30%. Found; C, 70.21; H,

5.48; N, 6.32%.

2'(2~Methoxy-4-{l-[2-(2-methylphenoxy)acetyl]-3-phenyl-4,5-dihydro-lH'S-pyrazolyl}

phenoxy) acetic acid (XIII)

. (XIII)

IR: (KBr) cm'^ 3174 (COOH), 1682 (C=0), 1558 (C=N), 1378 (C-N). *H-NMR (DMSO-

d«) ppm; 10.4 (IH, s, COOH); 7.21-8.18 (12H, m, H 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,

16); 4.9 (IH, t, H 4); 4.7 (2H, s, H 18); 4.5 (2H, s, H 17); 3.7 (2H, d, H 3 J = 8.2); 5.6 (3Hi

s, OCH3); 2.3 (3H, s, CH3); m/z; 475(M''’); Anal.Calcd.for C27H26N206: C, 68.34; H, 5;42;

N, 5.90%. Found; C, 68.32; H, 5.44; N, 5.92%.

64


2-(2-Methoxy~4-{l-[2-(4-methylphenoxy)acetyl]-3-phenyl~4,S~dihydro~lH~5-pyrazolyl} phenoxy) acetic acid (XIV)

IR: (KBr) cm‘ :3167 (COOH), 1689 (C=0), 1560 (C=N), 1345 (C-N). ^H-NMR (DMSO-

dfi) ppm; 10.2 (IH, s, COOH); 7.02-8.11 (12H, m, H 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14);

6.2 (IH, dd, Hx, J = 5.7, 5.4 Hz); 4.3 (2H, s, H 16); 4.1 (2H, s, H 15); 3,8 (IH, dd, Hb, J = 9.3,

9.3 Hz); 3.5 (3H, s, OCH3); 3.2 (IH, dd, H a, J = 5.7, 5.4 Hz); 2.2 (3H, s, CHj); m/z:

475(M-'’); Anal.Calcd.for C27H26N2O6; C, 68.34; H, 5.42; N, 5.90%. Found: C, 68.32; H,

5.44; N, 5.92%.

2-{2-Methoxy-4-[l-(2-phenoxyacetyl)-3-phenyl-4,S-dihydro-lH-5-pyrazolyl]phenoxyJ

acetic acid (XV)

\OCHjCONHNH,

IR; (KBr) cm ^ 3175 (COOH), 1734 (C=0), 1559 (C=N), 1384 (C-N). *H-NMR (I>MSO-

dg) ppm; 10.1 (IH, s, COOH); 6.82-8.26 (13H, m, H 3 ,4 ,5 , 6, 7, 8, 9,10, M, 12, 13,14,15); 6.3 (IH, dd, Hx, J = 6.3, 6.0Hz);4.5 (2H, s, H 17);4.2 (2H, s, H 16); 3.9 (IH, dd, Hb. J

= 11,4, 11.4 Hz); 3.4 (3H, s, OCH3); 3.;1 (IH, dd, Ha. J = 6.0, 6.0 Hz); m/Z: 461(]Vr');

Anal.Calcd.for C26H24N2O6: C, 67.82; H, 5.25; N, 6.08%. Found: C, 67.84; H, 5.24; N,

6.06%. , ■ ■ . . ■ ■

65


2-{4-[l-(2-Hydroxybenzoyl)-3-phenyl-4,5-dihydro-JH-5-pyrazolyl]-2~methoxyphenoxy}

acetic acid (XVI)

IR: (KBr) cm'^ 3146 (COOH), 1694 (C=0), 1583 (C=N), 1378 (C-N). ^H-NMR (DMSO-

di) ppm: 10.5 (IH, s, COOH), 9.4 ( IH, s, OH); 6.82-8.02 (12H, m, H 5, 6, 7, 8, 9, 10, 11,

12, 13,14, 15, 16); 4.8 (IH, t, H 4); 4.6 (2H, s, H 17); 3.6 (2H, d, H 3); 3.3 (3H, s, OCHj);

m/z: 447(M^’); AnaI.Calcd.for CjsHzaNzO ; C, 67.26; H, 4.97; N, 6.27%. Found; C, 67.29;

H, 4.94; N, 6.2

2~{2-Methoxy-4'[3-phenyl-l-(2-phenylacetyl)-4,5'dihydro-lH-5-pyrazolyl]phenoxy} acetic acid (XVD)

o'-6 6,"CHj


dfi) ppm: lO.I (IH, s, COOH); 6.87-7.78 (13H, m, H 3, 4, 5, 6, 7, 8, 9, 10, II, 12, 13, 14,

15); 6.2 (IH, dd, H,. J = 5.7, 5.7 Hz); 4.3 (2H, s, H 17); 4.2 (2H, s, H 16);3.9 (IH, dd, Hb, J

= 10.5, 10.5 Hz); 3.5 (3H, s, OCH3); 3.2 (IH, dd, H a, J = 5.7, 5.7 Hz); m/z: 445(1VI ’);

Aml.Calcd.for C26H24N2O5: C, 70.26; H, 5.44; N, 6.30%. Found: C, 70.29; H, 5.45; N,

6,28%.

66


2-(2-Methoxy-4-{l'[2’{l-naphthyloxy)acetylj~3-phenyl-4,5-dihydro-lHS~pyrazolyl}

phenoxy) acetic acid (XVIII)

IR: (KBr) cm ‘: 3232 (COOH), 1691 (C=0), 1560 (C=N), 1367 (C-N). ^H-NMR (DMSO-

d<i) ppm: 9.9 (IH, s, COOH); 7.06-8.28 (15H, m, H 3, 4, 5, 6, 7, 8, 9,10,11, 12, 13,14, 15,16, 17); 6.3 (IH, dd, H,, J = 6,3,6.3 Hz); 4.7 (2H, s, H 19); 4.3 (2H, s, H 18); 3.5 (IH, dd, Hb,

J = 13.5, 13.5 Hz); 3.4 (3H, s, OCH3); 3.2 (IH, dd, Ha, J = 6.3, 6.3 Hz); m/z: 51 KM’' ’);

Anal.Calcd.for C30H25N2O6: C, 70.58; H, 5.13; N, 5.49%. Found; C, 70.59; H, 5.14; N, 5.48%,

2-(2-Methoxy-4-fl-[2-(2-naphthyloxy)acetylJ-3'phenyl-4,S-dihydro-lHS-pyrazolyl}

phenoxy) acetic acid (XIX)

IR: (KBr) cm'*: 3165 (COOH), 1688 (C=0 ), 1560 (C=N), 1376 (C-N). *H-NMR (DMSO- dft) ppm: 10.3 (IH, s, COOH); 7.20-8.37 (15H, ra, H 3, 4, 5, 6, 7, 8, 9, 10,M , 12,13, 14,

15,16,17); 6.3 (IH, dd, H,, J = 6.6,6.3 Hz); 4.4 (2H, s, H19); 4.2 (2H, s, H 18); 3.9 (IH, dd, Hb j = 12.3, 12.0 Hz); 3,8 (3H, s, OCH3); 3.2 (IH, dd, Ha, JW 6.3,6.3 Hz); n^^ Anal.Calcd.for C30H26N2O6: C, 70.58; H, 5.13; N, 5.49%. Found: C, 70.59; H, 5.14; N,

5.48%,

67


2-{4-[l-Benzfiyl~3'(4-chlorophenyl)-4,5‘dihydro-lH-5-pyrazjolyl]-2-methoxyphenoxy} acetic acid (XX)

(XX)

IR: (KBr) cm’ : 3143 (COOH), 1685 (C=0), 1559 (C=N), 1374 (C-N). ^H NMR (DMSO-

d«) ppm; 10,7 (IH, s, COOH); 8.3 (2H, s, H 4,5); 7.9 (IH, s, H 9); 7.7 (2H, d, H 7, 8, J =

6.3); 7.50-7.54 (3H, m, H 11, 12, 13); 7.4 (2H, s, H 3, 6); 6.86-7.02 (2H, d, H 10, 14, J =

6.6); 6.2 (IH, dd, J = 6.6, 6.6 Hz); 4.5 (2H, s, H 15); 3.9 (IH. dd, Hb, J = 11.1, 11.1 Hz);

3.6 (3H, s, OCH3); 3.2 (IH, dd, Ha, J = 5.7, 5.7 Hz); m/z: 466(M‘' ’); Anal.Calcd.for

CssHaiCJNzOs; C, 64.59; H, 4.55; N, 6.03%. Found: G, 64.56; H, 4.57; N, 6.02%.

2-{4-[l'-(2-Chlorobenzoyl)-3-(4-chlorophenyl)-4,5-dihydro-lH-5-pyramlyl]-2-methoxyphe

noxy} acetic acid (XXI)

' 'C H ,

CONHNH.Glacial CH4CQOH

IR: (KBr) cm'^ 3184 (COOH), 1694 (C=0), 1560 (C=N), 1377 (C-N). (DMSO-

dfi) ppm; 10.1 (IH, s, COOH), 7,7 (IH, d, H 15, J = 6.3); 7.4 (2H, .s, H 6, 7); 6,51-7.53 (8H,

m 5, 8,9,10,11, 12,13,14); 4.5 (IH, t, H 4); 4.1 (2H, s, H 16); 3.7 (IH, d, H 3, J = 5.7);

3.6 (3H, s, OCH3); in/z: 498(M-’);. Anal.Calcd.for C^HsoClaNjOs; C, 60.13; H, 4.04; N,

5.61%. Found; C, 60,16;H, 4.06;N, 5.63%

68


2-{4-ll~(4-Chlorobenzoyl)-3-{4-chlorophenyl)~4,5-dihydro-lH-5-pyrazolyl]~2-methoxyphenoxy} acetic acid (XXII)

IR: (KBr) cm"': 3163 (COOH), 1682 (C=0), 1557 (C=N), 1378 (C-N). *H-NMR (DMSO-

dfi) ppm: 10.0 (IH, s, COOH), 7.7 (2H, s, H 4, 5); 7.4 (2H, s, H 11, 12); 6.51-7.42 (7H, m,

3, 6, 7, 8, 9,10,13); 6.2 (IH, dd, H,, J = 5.7, 5.7 Hz); 4.3 (2H, s, H 14); 3.8 (IH, dd, H b , J =

10.5, 10.5 Hz); 3.5 (3H, s, OCH3); 3.2 (IH, dd, Ha. J = 5.7, 5.7 Hz); m/z; 498(M'');

Anal.Calcdior C25H20CI2N2O5; C, 60.13; H, 4.04; N, 5.61%. Found: C, 60.16; H, 4.06; N,

5.63%.

2-{4-[l-(4-Cromobenzoyl)-3-(4-chloropkenyl)-4,5'dikydro-lH-5-pyrazolyl]-2-methoxy

phenoxy} acetic acid (XXIII)

CONHNH;

(XXIII)

IR; (KBr) cm'^ 3168 (COOH), 1685 (C=0), 1559 (C=N), 1371 (C-N). *H-NMR (DMSO-

d6)ppm:11.8 (lH, s,eGOH); 7.9 (2H, s, H 4, 5);7.7 (2H,s,H 11, 12); 7,36-7.66 (4H, m,

H 3, 6, 10, 13); 7.1 (IH, s, H 9); 6.7 (2H, s, H 7, 8); 6.1 (IH, dd, H , J = 5.7, 5.7 Hz); 4.2

(2H, s, H 14); 3.8 (IH, dd, Hb. J = 12.0, 12.0 Hz); 16.{3H, s, OCH3); 3.3 (IH, dd, HU, J =

5.7, 5.4 Hz); rn/z: 544 (M^’); Anal.CaIcd.for GasHaoBrClNaOg: C, 55.22; H, 3.71; N, 5.15%.

Found: C, 55.24; H, 3.69; N, 5.17%.

69

Pyrazolmes Experimental

2-{4-[l-(4-Nitrobenzoyl)-3-(4~cMorophenyl)-4,S-dihydro-IH-S~pyrazoiyl]-2’methoxyphenoxyj acetic acid (XXIV)

■'CH, ' v ) ~

(XXIV)

IR: (KBr) cm *: 3178 (COOH), 1685 (C=0), 1559 (C=N), 1376 (C-N). *H-NMR (DMSO-

(Ifi) ppm: 10.0 (IH, s, COOH); 8.07-8.44 (1IH, m. H 3,4, 5 ,6 ,7, 8, 9, 10, 11,12, 13); 6,3

(]H, del H,. J = 6,3, 6.3 Hz); 4.5 (2H, s, H 14); 3.8 (IH, dd, Hb, J = 10.2, 10.2 Hz); 3.5 (3H,

s, OCH.,); 3.1 (IH, dd, Ha, J = 6.0, 6.0Hz); mJz: 51UM"-’); Anal.Calcd.for C25H2«C1N307; C,

58.89; H, 3.95; N, 8,24%. Found; C, 58.86; H, 3.99; N, 8.27%,

2-{4-ll-(4~Methylbenzoyl)-3-(4-chlorophenyl)'4j5'dihydro-lH-S'pyrazolylJ-2-methoxy

phenoxyj acetic acid (XXV)

; (XXV) -

IR; (KBr) cm'^ 3222 (COOH), 1682 (C=0), 1560 (C=N), 1374 (C-N). ‘H-NMR (DMSO-

d6)ppm: 10.2(1H, s, COOH);8.04(2H,s,H 4, 5); 7.7(1H,s ,H9); 7.3 (2H,d,H 7 ,8, J =

3.3); 7.03-7.74 (4H, m, 3, 6, 10, 13); 6.8 (2H, d, H I I, 12 J = 3.3); 6.2 (IH, dd, Hk. J = 6,3,

6.0 Hz); 4.2 (2H, s, H 14); 3.9 (IH, rid. Ha, 1= 12 0, 12.3 Hz); 3.6 (3H, s, OGH3); 3.2 (IH,

dd, Ha, j = 6.0, 6.3 Hz); 2.3 (3H, s, CHj); m/z: 480(M''’); Anal.Calcd.fbr C26H23GIN2O5: C,

65.20; H, 4.84; N, 5.85%. Found; C, 65.24; H, 4.88; N, 5.87%. ; ,

70


2-(2-Methoxy-4-{3-(4-chlorophenyl)-l-[2-(2~melhylphenoxy)acetyl]~4,5-dihydro~lH-S-pyrazolyljphenoxy) acetic acid (XXVI)

-OCHfiOWNM,

(XXVI)


dtf)ppm; !0.3 (IH, s, COOH); 8.1 (2H, s, 6, 7); 8.0(IH, s, 11); 7.21-8.03 (7H, ra, H 5, 8,9,

10,12, 13, 14); 7.1 (IH, s, 15); 4.9 (IH, t, H 4); 4.5 (IH, s, H 17); 4.1 (2H, s, H 16); 3.7 (IE,

d, H 3 i = 6.6); 3.6 (3H, s, OCH3); 2.3 (3H, s, CHO; m/z: 5!0(M^'); Anal.Calcd.for

C.THasClN.Of,; C 63.72: H, 4.95; N, 5.50%. Found: C, 63.74; H, 4.97; N, 5.52%.

2-(2-Methoxy'4-{3'(4-chlorophenyl)-l-[2-(4-methylphenoxy)acetyl]-4,5-dihydrO‘lH ‘5-pyra

zolyljphenoxy) acetic acid (XXVII)

CONHNH*

(XXVIl)

IR: (KBr) cm'^ 3237 (COOH), 1694 (C=0), 1560 (C=N), 1381 (C-N), H-NMR (DMSO-

ds) ppm: 9.9 (IH, s, COOH); 6.85-8.18 (IIH, m, H 3, 4, 5, 6, 7, 8; 9/lO, 11,12, 13); 6.3

(IH, dd, H,. J = 6.6, 6.6 Hz); 4.3 (2H, s, H 15); 4.2 (2H, s, H 14); 3.8 (IH, dd, Hb. J = 11.7,

11.7 Hz); 3.7 (3H, s, OCH3); 2,9 (IH, dd, Ha, J = 6.3, 6.6 Hz); 2.3 (3H, s, CH3); m/z:

51G(M"'); Anal.CalcdforC^yHasCINade: G, 63.72; H,4.95;:N, 5.50%. FoOTd;C, 63.74-H.

4.95; N, 5.53%. '

71


2-{2~Methoxy-4-[3-(4-chhrophenyl)-l~(2-phenoxyacetyl}-4,S-dihydro~lH-S-pyrazolyl]

phenoxy} acetic acid (XXVIII)

(xxvni)IR: (KBr) cm ^ 3158 (COOH), 1737 (C=0), 1598 (C=N), 1375 (C-N). ^H-NMR (DMSO-

dfi) ppm: ^H-NMR (DMSO-dg) ppm: 10.7 (IH, s, COOH); 8.1 ( 2H, s, H 4, 5); 7.09-8.18

(lOH, m, H 3, 6, 7, 8, 9, 10, 11,12, 13, 14); 6.2 (IH, dd, Hx, J = 6.3, 6.3 Hz); 4.2 (2H, s, H

16); 4.1 (2H, s, H 15); 3.9 (IH, dd, Hi,. J = 10,5, 10.5 Hz); 3.6 (3H, s, OCH3); 3.2 (IH, dd,

Ha, j 6.0, 6.3 H z ); ni/z: 496(M"’); Anal.Calcd.for C26H23CIN2O6; C, 63.10; H, 4.68; N,

5.66%. Found: C, 63.13; H, 4,69; N, 5.69%.

2-{4-[l-(2-Hydroxybenzoyl)-3-(4-chlorohenyl)-4,5-dihydro-lH-5-pyrazolyl]-2-methoxy

phenoxy} acetic acid (XXIX)

—CONHNH2

IR: (KBr) cm-\- 3188 (COOH), 1685 (0=0), 1559 (C=N), 1379 (C-N). *H-NMR (DMSO-

dfi) ppm:10.8 (IH, s, COOH), lO.l (IH, s, OH), 6.72-8.06 (IIH , m, H 5, 6,1, 8, 9, 10, 11,

12 , 13, 14, 15); 4.5 (IH, t, H 4); 4.1 (2H, s, H 16); 3.7 (2H, d, H, 3 J = 6 .6); 3.3 (3H,: s,

OCH3); m/z: 482(M"‘); Anal.Calcd.for C25H2, a N A : C, 62.44; H, 4-40; N, 5.83%. Rjund:;

C, 62.45; H, 4.43; N, 5.82%.

72


2-{2-Methoxy-4-[3~(4-chlorophenyl)~l-(2-phenyhicetyl)-4,5-dihydro-lB~5-pyrazolylJ

phenoxy} acetic acid (XXX)

'GH3

/== : { //

■CHXOMHNH.

(XXX)

IR: (KBr) cm'^:3201 (COOH), 1685 (C=0), 1561 (C=N), 1347 (C-N). ^H-NMR (DMSO-

d6)ppm : 10.2 ( I H , s, COOH); 8.1 (2H, s, H 4, 5); 7.78-8.09 (lOH, m,H 3, 6,7, 8, 9 ,1 0 ,1 1 ,

12,13, 14); 6.3 (IH, dd, H,, J = 6.6, 6.6 Hz); 4.2 (2H, s, H 16); 4,3 (2H, s, H 15), 3.9 (IH,

dd, H b . J = 10.5, 10.5 Hz); 3.6 (3H, s, OCH?); 3,2 (IH, dd, Ha. J 6.3, 6.6 Hz); m /z :

480(M^’); Anal.Calcd.for CaeHzaClNjOs: C, 65.20; H, 4.84; N, 5.85%. Found: C, 65.22; H,

4.83; N, 5.84%.

2-(2-Methoxy-4-{3-(4-chlor6phenyl)-l-[2-{l-naphthyloxy)acetyl]~4,S-dihydro-lH~5-

pyrazolyljphenoxy) acetic acid (XXXI)

-OCHXONHNH,Gtscial CHjCOOH

! Ha

IR: (KBr) cm"*: 3189 (COOH), 1682 (C=0), 1576 (G=N), 1378 (G-N).^H-NMR (DMSO-

d6)ppni:10.] (IH, s, COOH); 7.16(14H, m ,H 3,4, 5, 6,7, 8,9 ,10, 11,12, 13,14,15* 16);

6.2 (IH, dd, Hx, J = 6.0, 6.0 Hz); 4.7 (2H, s , H 18); 4.3 (2H, s , H 17); 3.7 (IH, dd, Hb. J -

12.0, 12.0 Hz); 3.6 (3H, s, OCH3); 3.3 (IH, dd, Ha, 6.3, 6.0 Hz); ra/z: 546(M-*-’);

Anal.Calcd.for CsoHasClNaOerC, 66.12; H, 4.62; N, 5.14%.:Found: C, 66.13; f t

5.J7%.

73


2-{4-[l-(2~Chlorobenzoyl)-3-(4-methoxyphenyl)-4,5‘dihydw-lH-S-pyrazolylf-2-methoxy

phenoxy} acetic acid (XXXIV)

1,

CONHNHjGfaciaf CHjCOOH


de) ppm; 10.5 (IH, s, COOH); 7.8 (IH, d, 15, J = 6.3); 7.3 (2H, s, H 6, 7); 6.81-7.47 (8H, m,

5, 8, 9, 10, 11, 12, 13, 14); 4.7 (IH, t, H 4); 4.2 (2H, s, H 16); 3.8 (2H, d, H 3, J = 6.6 Hz);

3.7 (6H, s, axOCHs); m/z: 496(M^^); Anal.Calcd.for C26H23CIN2O6: C, 63.10; H, 4.68; N,

5.66%. Found: C, 63.13; H, 4.69; N, 5.69%,

2~{4-[l-(4-Chlorobenzoyl)-3-(4-methoxyphenyl)-4,S-dihydro-lH-5-pyrazolyl]-2-methoxy

phenoxy} acetic acid (XXXV)

(XXXV)


dfi) ppm: 10.2 (1H, s, COOH); 7.7 (2H, s, II , 12); 7.42.-7J0 (2H, s, H 4, 5); 6.86-7.57 (7H,

m, 3, 6,1 , 8, 9, 10, 13); 6.3 (IH, dd, J = 6.3, 6 ,0Hz); 4.5 (2H, s, H 14); 3 .9 (IH , dd, Hb, J

= 12.0, 12.3 Hz); 3.6 (6H, s, 2XOCH3); 3.2 (IH, dd, Ha. J = 6.3, 6.3 H z); ra/z: 496(M^’);

Anal.CaIcd.for CaeHasClNjOe: C, 63.10; H, 4.68; N, 5.66%. Found: C, 63.13; H, 4:69; N,

5.69%. ■

75


2~{4-[l-(4-Bromobenzoyl)~3-(4-methoxyphenyl)-4,5-dihydro~lH-5~pyrazolyl]-2~methoxy phenoxy} acetic acid (XXXVI)

(XXXVI)

IR: (KBr) cm'^:3193 (COOH), 1767 (C=0), 1557 (C=N), 1374 (C-N). *H-NMR (I)MSO-

de) ppm: 11.2 (IH, s, COOH); 7.9 (2H, s, H 11, 12); 7.7 (2H, s, H 4, 5); 7.36-7.66 (4H, m. H

3, 6, 10, 13); 7.1 (IH, s, H 9); 6.7 (2H, s, H 7, 8); 6.1 (IH, dd, Hh. J = 6.3, 6.3 Hz); 4.6 (2H,

s, H 14); 3.8 (IH, dd, Hb, J = 12.3, 12.0 Hz); 3.6 (6H, s, 2XOCH3); 3.2 (IH, dd, Ha. J = 6.3,

6.3 Hz); m/z: 540(M-^’); Anal.Calcd.for CjeHssBrNjOg: C, 57.90; H, 4.30; N, 5.19%. Found:

C, 57.93; H, 4.33; N, 5.21%.

2-{2-Methoxy-4-[3-(4-methoxyphenyl)-l-(4-nitrobenzoyl)~4,5-dihydro-lH-5-pyrazoly}]

phenoxy) acetic acid (XXXVII)

(XXXVII)

IR : (KBr) cm'^ 3258 (COOH), 1653 (C=0), 1559 (C=N), 1379 (C-N).%-NMR (DMSO-

dfi) ppm:10.0 (IH, s, COOH); 7.07.8.32 (IIH , m, H 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13); 6,4

(IH, dd, Hx, J = 6.0, 6.0 Hz); 4.5 (2H, s, H 14); 3.8 (IH, dd, H b, J = 12.3,12.0 Hz); 3.6 (6H,

s, 2 X O C H 3 ); 3.3 ( I H , dd, H a , J = 5.7, 5.7 Hz); m/z: 506(M-"’); AnaI.Calcd.for C26H23N3O8:

C, 61.78; H, 4.59; N, 8.31%. Found: C, 61.74; H , 4.61; N, 8:33%.

76


2-{2-Methoxy~4’[3-(4-methoxyphenyl)-l-(4-methylbenzoyl)-4,5-dihydro-lH'5-pyrazolyl]

phenoxy} acetic acid (XXXVIII)

HO.

+ H3C -

TCH3

V. / CONHNH2

(XXXVIII)

IR: (KBr) cm‘ : 3232 (COOH), 1734 (C=0), 1559 (C=N), 1376 (C-N). ^H-NMR (DMSO-

dfi) ppm: 10.5 (IH, s, COOH); 7.9 (2H, s, H 4, 5); 7.8 (IH, s, H 9); 7.4 (2H, d, H 7, 8, J =

8.1 Hz); 7.03-7.74 (4H, m, H 3, 6, 10, 13); 6.8 (2H, s, H 11, 12); 6.2 (IH, dd, H , J = 5.7,

5.7 Hz); 4.5 (2H, s, H 14); 3.7 (IH, dd, Hb, J = 12.3, 12.0 Hz); 3.4 (6H, s, 2XOCH3); 3.2 (IH,

dd, Ha, j = 5.4, 5.6 Hz); 2.3 (3H, s, CH3); m/z: 475(M^’); Anal.Calcd.for C27H26N2O6: C,

68.34; H, 5.52; N, 5.90%. Found: C, 68.35; H, 5.51; N, 5.92%.

2~(2-Methoxy~4-{3-(4-methoxyphenyl)~l-[2-(2-methylphenoxy)acetyl]-4,5-dihydro~lH-5-

pyrazolyljphenoxy) acetic acid (XXXIX)

01CH,

(XXXIX)

IR: (KBr) cm‘ ; 3197 (COOH), 1741 (C=0), 1560 (C=N), 1376 (C-N). ^H-NMR (DMSO-

dfi) ppm: 10.4 (IH, s, COOH); 8.2 (2H, s, H 6, 7); 8.0 (IH, s, H 11); 7.21-8.05 (7H, m, H

5, 8, 9, 10, 12, 13, 14); 7.1 (IH, s, H 15); 4.9 (IH, t, H 4); 4.5 (2H, s, H 17); 4.1 (2H, s ,H

16); 3.7 (2H, d, H 3, J = 5.6 Hz); 3.6 (6H. s, 2xOCH.i); 2.2 (3H, s, CH3); m/z; 505(M-^');

Anal.Calcd.for CzgHzgNaOy: C, 66.66; H, 5.59; N, 5.55%. Found: C, 66.67; H, 5.56; N,

5.56%.

77


2-{2-Methoxy-4-{3-{4-methoxyphenyl)-l-[2-(4-methylphenoxy)acetyl]-4,S-dihydro-lH-5-pyrazolyljphenoxy) aceti cacid (XL)

Glacial CHjCOOH

(XL)\ H.C-

IR: (KBr) cm'^: 3234 (COOH), 1682 (C=0), 1560 (C=N), 1369 (C-N). *H-NMR (DMSO-

dfi) ppm:I0.7 (IH, s, COOH); 6.89-7.98 (IIH, m, H 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13); 6.2

(IH, dd, Hx, J = 6.3, 6.3 Hz); 4.6 (2H, s, H 15); 4.5 (2H, s, H 14); 3.9 (IH, dd, Hb. J = 12.0,

12.3 Hz); 3.6 (6H, s, 2XOCH3); 3.2 (IH, dd, Ha. J = 6.0, 6.3 Hz); 2.3 (3H, s, CH3); m/z:

505(M^’); Anal.Calcd.for CagHagNsO,: C, 66.66; H, 5.59; N, 5.55%. Found: C, 66.67; H,

5.56; N, 5.56%.

2-{2-Methoxy-4-[3-(4-methoxyphenyl)-l-(2-phenoxyacetyl)-4,S-dihydro-lH-5-pyrazolyl

Jphenoxy} acetic acid (XLI)

' r - ^ t s r x : \iHpCONHNH-

(XLI)

IR: (KBr) cm ' : 3162 (COOH), 1685 (C=0), 1567 (C=N), 1374 (G-N). ^H-NMR (DMSO-

dfi) ppm: 'H-NM R (DMSO-dg) ppm; 10,3 (IH, s, COOH); 8.0 ( 2H, s, H 4, 5); 7.07-8.11

(lOH, m, H 3, 6 , 7, 8, 9, 10, 11,12, 13, 14); 6.3 (IH, dd, H,, J = 6.6, 6.6 Hz); 4.5 (2H, s, H

16); 4.3 (2H, s, H 15); 3.8 (IH, dd, Hb, J = 11.1,11.1 Hz); 3.6 (6H, s, 2jcOCH3); 3,3 (IH, dd,

Ha, j = 5.7, 5.7 Hz); m/z: 491(M^‘); Anal.Calcd.for C27H26N2O7: C, 66.11; H, 5.34; N,

5.71%. Found: C, 66.13; H, 5.36- N, 5.73%.

78


2-{4-[l-(2-Hydroxybenzoyl)-3-(4-methoxyphenyl)-4,5-dihydro-lH-5-pyrazolyl]-2-methoxyphenoxyjacetic acid (XLII)

Ha

ICHV /

Q ada! CHjCOOH

IR: (KBr) cm’ : 3239 (COOH), 1694 (C=0), 1583 (C=N), 1376 (C-N). ^H-NMR (DMSO-

dfi) ppm: 10.8 (IH, s, COOH); 9.2 (IH, s, OH); 6.82-8.02 (IIH , m, H 5, 6, 7, 8, 9, 10, 11,

12, 13,14, 15); 4.6 (IH, t, H 4); 4.5 (2H, s, H 16); 3.8 (6H, s, 2xOCH3 ); 3.7 (2H, d, H 3, J =

5.7) m/z: 477(M^’); Anal.Calcd.for C26H24N2O7: C, 65.54; H, 5.08; N, 5.88%. Found: C,

65.55; H, 5.10; N, 5.89%.

2-{2-Methoxy~4-[3-(4-methoxyphenyl)-l-(2-phenylacetyl)-4,5-dihydro-lH-S-pyrazolyl]

phenoxy} acetic acid (XLIII)

c

C H ,

IR: (KBr) cm ^ 3193 (COOH), 1718 (C=0), 1564 (C=N), 1376(G-N). % -NM R (DMSO-

d«) ppm: 10.2 (IH, s, COOH); 8.0 (2H, s, H 4, 5); 8.09-7.74 (lOH, m, H 3, 6 , 7, 8, 9,10,

11, 12, 13, 14); 6.2 (IH, dd, H . J = 6.3, 6.0 Hz); 4.5 (2H, s, H 16); 4.3 (2H, s, H 15); 3.8

(IH, dd, Hb, J = 11.4, 11.4 Hz); 3.6 (6H, s, 2XOCH3); 3.2 (IH, dd, Ha, J = 6.0, 6.0 Hz); m/z:

475(M^'); Anal.Calcd.fbr C27H26N2O6: C, 68.34; H, 5.52; N, 5.90<%. Found: G, 68.35; H,

5.53; N, 5.89%,

79


2~(2-Methoxy-4-{3~(4-methoxyphenyl)-l-[2-(l-naphthyloxy}acetyl]-4,5-dihydro-lH-5- pyrazolyljphenoxy) acetic acid (XLIV)

'C H jC O N H N H ^

(XLIV)IR: (KBr) cm'^: 3168 (COOH), 1725 (C=0), 1558 (C=N), 1372 (C-N). ^H-NMR (DMSO-

dfi) ppm:10.3 (IH, s, COOH); 7.32-8.18 (14H, m, H 3,4, 5, 6, 7, 8, 9, 10,11, 12, 13, 14, 15,

16); 6.3 (IH, dd, J = 5.7, 5.7 Hz); 4.9 (2H, s, H 18); 4.5 (2H, s, H 17); 3.8 (6H, s,

2xOCH3); 3.4 (IH, dd, Hb. J = 10.5, 10.5 Hz); 3.2 (IH, dd, Ha, J = 5.7, 5.7 Hz); iti/z:

541(M^’); Anal.Calcd.for C31H28N2O7: C, 68 .88; H, 5.22; N, 5.18%. Found: C, 68.90; H,

5.23; N, 5.19%.

2-(2-Methoxy-4-{3-(4-methoxyphenyl)~l-[2-(2-naphthyloxy)acetyl]-4,S-dihydro-lH-5-

pyrazolyljphenoxy) acetic acid (XLV)

(XLV) ■IR ; (KBr) cm-\-3185 (COOH), 1720 (C=0), 1540 (C=N), 1375 (C-N).^H-NMR (DMSO-

dfi) ppmrlO.l (IH, s, COOH); 7.23-8.13 (14H, m, H 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13, 14,

15, 16); 6.2 (IH, dd, H , J = 6.6, 6.4 Hz); 4.6 (2H, s, H 18); 4.3 (2H, s, H 17); 3-7 (6H, s,

2XOCH3); 3.5 ( I H , dd, H b. J = 12.4, 12,4 Hz); 3.2 ( I H , dd, H a , J = 5.7, 5.7 Hz); m/z:

541(M-"^); Anal.Calcd.fbr C31H28N2O7; C, 68.88; H, 5.22; N, 5.18%. Bound: G, 68-90; H,

5.23; N, 5.19%.

80


2-{4-[l-BenzoyU3-(4-hydroxyphenyl)-4,5-dihydro-lH-5-pyrazolyl]-2-methoxyphenoxy}

acetic acid (XLVI)

(XL VI)

IR: (KBr) cm^: 3085 (COOH), 1686 (C=0), 1559 (C=N), 1378 (C-N). ^H-NMR (DMSO-

de) ppm: 10.4 (IH, s, COOH); 9.2 (IH, s, OH); 7.9 (IH, s, H 9); 7.8 (2H, d, H 7, 8, J = 5.7

Hz); 7.20-7.54 (7H, m, H 3, 6, 10, 11, 12,13, 14); 7.1 (2H, s, H 4, 5); 6.3 (IH, dd, Hx, J =

6.3, 6.3 Hz); 4.5 (2H, s, H 15); 3.8 (IH, dd, Hb, J = 13.5, 13.5 Hz); 3 J (3H, s, OCH3 ), 3.2

((IH, dd, Ha, j = 6.6, 6,0 Hz); ib/z: 447(M-"); Anal.Calcd.for C25H22N2O6; C, 67.26; H, 4.97;

N, 6.27%. Found: C, 67.28; H, 4.99; N, 6.30%.

2-{4-[l-(2-Chlorobenzoyl)-3-(4-hydroxyphenyl)-4,5’dihydro-lH‘5-pyrazolyl]-2-methoxy

phenoxy) acetic acid (XLVII)

"CH3 \ /CONHNHj

Glacial CHjCOOH

(XLVII)

IR; (KBr) cm'^ 3178 (COOH), 1717 (C=0), 1590 (C=N), 1335 (C-N). H-NMR (DMSO-

dfi) ppm: 10.0 (IH, s, COOH); 9.4 (IH, s, OH); 7.7 (IH, d, H 15, J = 5.7 Hz); 7.09-7.51

(8H, m, 5, 8, 9,10, 11, 12, 13,14); 6.4 (2H, s, H 6 , 7);4.8 (IH, t, H 4); 4.5 (2H, s, H 16);

3.7 (3H, s, OCH3); 3.2 (2H, d, H 3, J = 8.1 Hz); m/z: 482(M^’); A n a l.C ^ ^

C25H21CIN2O6: C, 62.44; H, 4.40; N, 5.83%. Found: C, 62.48; H, 4.44; N, 5.84%;

81


2-{4-[l-(4-Chlorobenzoyl)-3-(4-hydroxyphenyl)-4,5-dihydro-lH-5-pyrazolyl]-2~methoxy

phenoxyjacetic acid (XLVIII)

0-^"CH3 'OH OH

(XLVIII)

IR: (KBr) cm’ : 3166 (COOH), 1682 (C=0), 1560 (C=N), 1385 (C-N). ^H-NMR (DMSO-

dft) ppm: 10.1 (IH, s, COOH); 9.2 (IH, s, OH); 7.7 (2H, s, 11,12); 7.04-7.51 (7H, m, 3, 6,7 ,

8, 9,10, 13); 6.4 (2H, s, H 4,5); 6.3 (IH, dd, H., J = 6.3, 6.0 Hz); 4.5 (2H, s, H 14); 3.8 (IH,

dd, Hb, J = 9.3, 9.3 Hz); 3.7 (3H, s, OCH3); 3.1 ((IH, dd, Ha, J = 5.7, 5.7 Hz); m/z:

482(M'^’); Anal.Cakd.for C25H21CIN2O6: C, 62.44; H, 4.40; N, 5.83%. Found: C, 62.42; H,

4.44; N, 5.82%.

2~{4-[l-(4-Bromobenzoyl)-3-(4-hydroxyphenyl)-4,5-dihydro-lH-5-pyrazolyl]-2-methoxy

phenoxyj acetic acid (XLIX)

iHNHj

(XLIX)IR: (KBr) cm '^ 3088 (COOH), 1685 (C=0), 1559 (C=N), 1389 (C-N). 'H-NM R (DMSO-

dfi) ppm: 10.6 (IH, s, COOH); 9.8 ( IH, s, OH), 7.26-7.81(1 IH, m ,H 3 ,4 , 5 ,6 , 7, 8,9 ,1 0 ,

H , J2, 13); 6.4( lH,dd, Hx, J = 5.1, 5.4 Hz); 4.3 (2H, s , H 14); 3.9 (IH, dd.Hfi, J = 12.3,

12.3 Hz ); 3.6 (3H, s, OCH3); 3.2 (IH, dd, Ha. J = 5.4, 5.4 Hz); W z: 526(Jvr^);

Anal.Calcd.fbr CasHsiBrNzOftt C, 57.16; H, 4.03; N, 5.33%. Found: C, 57.17; H, 4-06; N,

5.36%. '

82


2-{2-Meihoxy~4-[3'(4~hydroxyphenyl)-l-{4-nitrobenzoyl)-4,5-dihydro-lH-5-pyrazolyl]

phenoxy} acetic acid (L)

:ONHNH,

(L)

IR: (KBr) cm'^ 3089 (COOH), 1690 (C=0), 1590 (C=N), 1382 (C-N). ^H-NMR (DMSO-

df,) ppm: 10.5 (IH, s, COOH); 9.6 (IH, s, OH); 7.26-7.88 (1 IH, m, H 3,4, 5 ,6 , 7, 8,9 ,1 0 ,

11,12, 13); 6.3 (IH, dd, H , J = 5.6, 5.6 Hz); 4.3 (2H, s, H 14); 3.7 (IH, dd, Hb, J = 11.3,

11.3 Hz); 3.6 (3H, s, OCH3); 3.2 (IH, dd, Ha. J = 6.3, 6.3 Hz); m/z: 492(M-^’);

Anal.Calcd.for C2.1H21N3O8 : C, 61.10; H, 4.31; N, 8.55%. Found: C, 61.11; H, 4.34; N,

8.56%.

2~{2-Methoxy-4-[3-(4-hydroxyphenyl)-l-(4-methylbenzoyl)-4,S~dihydro-lH~5~pyrazolyl]

phenoxy) acetic acid (LI)

+ H jC - ONHNHj

(LI)IR: (KBr) cm ^ 3187 (COOH), 1729 (C=0), 1556 (C=N), 1376 (C-N). ’H-NMR (DMSO-

dfi) ppm:10.3(lH , s, COOH); 9.8 (2H, s, OH); 8.0 (2H, s, H 10, 13); 7.8 (IH, s, H 9); 7,4

(2H, d, H 7, 8, J = 5.7 Hz); 7.3 (2H, d, H 3 ,6 , J = 4.5 Hz); 6.8 (2H, s, H 11,12); 6.7 (2H, s, H

4,5); 6.2 (IH, dd, Hx, J = 6.6, 6.6 Hz); 4.3 (2H, s, H 14); 3 J (1H, dd,HB. J = 11.4, lL 4 Hz);

3.4 (3H, s, OCH3); 2.9 (IH, dd, Ha. J = 6.3, 6.0 Hz); 2.2 (3H, s, CH3); m/z: 461 (M'^');


6.06%. ■■ ■ ■

83


2~(2-Methoxy-4-{3-(4-hydroxyphenyl)-l-[2-(2-methylphenoxy)acetyl]-4,S-dikydro-lH-5-

pyrazolyljphenoxy) acetic acid (LII)

^ ^ OCHjCONHNHj Glacial C^^COOH

IR: (KBr) cm \* 3375 (COOH), 1685 (C=0), 1541 (C=N), 1377 (C-N). ^H-NMR (DMSO-

de) ppmcJO.l (IH, s, COOH); 9.8 (IH, s, OH); 6.67-8.73 (IIH, m, H 5, 6, 7, 8, 9, 10, 11,

12, 13, 14, 15); 5.3 (IH, I, H 4); 4.6 (2H, s, H 17); 4.5 (2H, s, H 16); 3.8 (2H, d, H 3, J =

4.5 Hz); 3.7 (3H, s, OCH3); 2.3 (3H, s, CH3); mJz: 491(M-"'); Anal.Calcd.for C27H26N2O7: C,

66.1 ]; H. 5.34; N, 5.75%. Found: C, 66.13; H, 5.35; N, 5.77%.

2-(2-Methoxy-4'{3-(4-hydroxyphenyl)-l-[2-(4-methylphenoxy)acetylJ-4,5-dihydro-lH-5‘

pyrazolyljphenoxy) acetic acid (LIII)

4 H3C—^ ^ -OCH;CONHNH; Glacial CHaCOOH

IR: (KBr) cm'^ 3242 (COOH), 1695 (C=0), 1514 (C=N), 1379(C-N). %-NMR (DMSO-

dfi) ppm: 10.4 (IH, s, COOH); 9 .5 (lH ,s , OH)-6.78-8.68 (IIH, m ,H 3,4, S, 6, 7, 8, 9, TO,

11,12, 13); 6,3 (IH, dd, Hx, J = 5.7, 5.7 Hz); 4.5 (2H, s, H 15); 4.4 (2H, s, H 14); 3.:8 (1H,

dd, Hb, j = 10.5,10.5 Hz); 3.6 (3H, s, OCH3); 3.2 (IH, dd, Ha. J = 5.4, 5.4 Hz);: 2.2 (3H, s,

CH3); m/z: 491(M^'); Anal.Calcd.for C27H26N2O7: C, 66.11; H, 5.34; N, 5.75%. Found: C,

66.13; H, 5.35; N, 5.77%.

84


2-{2-Methoxy-4-[3-(4-hydroxyphenyl)-l~(2-phmoxyacetyl)-4,5-dihydro~lH-5-pyrazolyl]

phenoxyjacetic acid ( L I V )

OH

IR: (KBr) c m ’^ 3188 (C O O H ), 1696 (C = 0 ). 1557 (C==N), 1372 (C -N ). *H-NMR (D M S O -

dfi) p p m : ^ H -N M K (D M S O -d g ) p p m : 10.2 ( IH , s, C O O H ); 9,2 ( IH , s, O H ); 7.45-8.09

(lO H , m , H 3 , 6, 7, 8, 9, 10, 11, 12, 13, 14); 7.3 ( 2H , s, 4, 5); 6.4 ( IH , dd, Hx, J = 6.6, 6 .6

H z); 4.5 (2H , s, H 16); 4.3 (2H, s, H 15); 3.8 ( I H , dd, H g, J = 11.1, 11.1 H z); 3.6 (3H , s,

O C H 3); 2.9 ( IH , dd, H a, J = 5.7, 5.7 H z); mlz\ 477(M ^ ’ ); A n a l.C a lc d .fo r C26H24N2O7; C ,

65.54; H , 5.08; N , 5.88% . Found: C , 65.57; H, 5. 10; N , 5 .89% .

2-{4-[l-(2-Hydroxybenzoyl)-3-(4-hydroxyphenyl)-4,5-dihydro-lH-5-pyrazolylJ-2-meth

oxyphenoxy} acetic acid (LV)

OH

V /-CONHNH,

Glacial CHfOOH

I R : ( K B r ) c m ’^ 3220 (C O O H ), 1686 (C = 0 ), 1558 (C = N ), 1376 (C -N ). :^ H -N M R ( D M S O -

d 6 ) p p m : l L 8 (IH , s, C O O H ); 10.5 (2H , .s, 2x O H ); 6.90-7.88 (M H , m , H 5 , 6, 7 , 8, 9, 10,

11, 12, 13, 14, 15); 4.7 ( IH , t, H 4); 4.2 (2H , s, H 16); 3 .4 (3H ,s , O C H 3); 2.5 (2H , d ,H 3, J =

4.5 H z); m /z: 463(M-^'); A n a l.C a lc d .fo r C25H22N2O7: C , 64.93; H, 4 .80; N , 6 .069?;. F bim d: C ,

64.97; H , 4 .81; N , 6.08% ,

85


2-{2-Methoxy-4-[3-(4~hydroxyphenyl)-l-(2-phenylacetyl)-4,5-dihydrO‘lH~5-pyrazolyl]

phenoxy) acetic acid (LVI)

o.' C H ,

H.CONI-INH,


dfi) ppm:10.1 (IH, s, COOH); 8.4 (W , s, OH); 6.86-7.28 (12H, ni, H 3, 4, 5, 6, 7, 8, 9, 10,

11,12, 13, 14); 6.2 (IH, dd, J = 6.3, 6,3 Hz); 4.5 (2H, s, H 16), 4.2 (2H, s, H 15); 3.9 (IH,

dd, Hb, J = 12.3, 12.0 Hz); 3.7 (3H, s, OCHj); 3.5 (IH, dd, Ha, J = 5.6, 5.6 Hz); m/z

461(M^’); Anal.Calcd.for C26H24N2O6; C, 67.82; H, 5.25; N, 6,08%. Found: C, 67.84; H,

5,27; N, 6.10%.

2-(2-Methoxy-4~{3-(4-hydroxyphenyl)-l~[2-(l-uaphthyIoxy)acetyl]~4)5-dihydro-IH-5-

pyrazolyljphenoxy) acetic acid (LVII)

H O

iCHXONHNH;

: (LVII)IR: (KBr) cm'H 3089 (COOH), 1685 (C=0), 1559 (C=N), 1378 (C-N). *H-NMR (DMSO-

d6)ppm:10.3 (IH, s, C O O H ); 7.21-8.10 (14H, m, H 3, 4, 5, 6, 7, 8 ,9 ,10,11, 12,13,14,15,

16); 6.4 (IH, dd, Hx, J = 6.0, 6.0 Hz); 4.5 (2H, s, H 18); 4.3 (2H, s, H 17); 3.8 (IH, dd, Hb, J =

10.4, 10.4 Hz); 3.7 (3H, s, O C H 3); 3.5 (IH, dd, Ha. J = 5.7, 5.7 Hz);: m/z: 527(Ivr:');


5.30%. ■

86


2-(2-Methoxy-4-{3-(4-hydroxyphenyl)-I-[2-(2.naphthyloxy)acetyl]-4,5~dihydro-lH-S'pyrazolyljphenoxy) acetic acid (LVIII)

IR: (KBr) cm'^ 3088 (COOH), 1685 (C=0), 1559 (C=N), 1382 (C-N). ’H-NMR (DMSO-

dfi) ppm:10.6 (IH, s, COOH); 7.36-8.08 (14H, m, H 3, 4, 5, 6,7 , 8, 9, 10,11, 12, 13, 14, 15,

16); 6.3 (IH, dd, H,, J = 5.7, 5.7 Hz); 4.5 (2H, s, H 18); 4.3 (2H, s. H 17): 3.7 (IH, dd, Hb. J

= 12.0, 12.0 Hz); 3,6 (3H, s, OCH3); 3.2 (IH, dd, Ha. J = 5.7, 5.4 Hz): in/z; 527(M"');

Anal.Calcd.for C30H26N2O7: C, 6843; H, 4.98; N, 5,32%. Found: C, 68.44; H, 4.97; N,

5.30%.

2-{4-[l-Benzoyl-3-(2,4‘dihydroxyphenyl)-4,5-dihydro-lH-5-pyrazolyl]-2-methoxy

phenoxy} acetic acid (LIX)

HO. %

■'CH3

IR: (KBr) cm’*: 3245 (COOH), 1682 (G=0), 1563 (C=N), 1318 (C-N). ^H-NMR (DMSO-

d6)ppm : 11.4(1 H, s, COOH); 8.8 ( 2H, s, 2xOH); 7.9 (2H, .s, H 9,13); 7.9 (IH, s, H 8); 7.6

(2H, d, H 6 ,7); 7.50-7.54 (3H, m, H 12,13, 14); 7.4 (IH, d, H 7); 7.0 (IH, d,H 6); 6.8 (IH,

d, H 5); 4.6 (IH, t, H 4), 4.3 (2H, s, H 16); 3.9 (3H, s, OCHa) 2.5 (2H, d, H 3); m/z:

463(M-^’); Anal.Calcd.fbr; G25H22N2Q7 C, 64.93; H, 4.80; N, 6.06%. Found: C, 64.92; H,

4.81; N, 6.05%.

— _ _ _ _ _


2-{4-[l-(2~Chlorobenzoyl)-3-(2,4-dihydroxyphenyl)~4,S‘dihydro~lH'5~pymzolyl]~2-

methoxy phenoxy} acetic acid (LX)

(LX)

IR: (KBr) cm‘ :3190 (COOH), 1685 (C=0), 1545 (C=N), 1325 (C-N). ^H-NMR (DMSO-

de) ppm: 10.2 (IH, s, COOH); 9.4 ( 2H, s, 2xOH), 6.84-8.12 (lOH, m, 5, 6 , 7, 8, 9, 10, 11,

12, 13, 14); 4.8 (IH, t, H 4); 4.4 (IH, s, H 15); 3.6 (3H, s, OCH3); 2.5 (2H, d, H 3); mlr.

498(M^’); Anal.Calcd.for C23H21CIN2O7: C, 60.43; H, 4.26; N, 5.64%. Found: C, 60.44; H,

4.27; N, 5.62%.

2-{4-[l-(4-Chlorobenzoyl)-3-(2,4-dihydroxyphenyl)-4,5-dihydro~lH-5-pyrazolyl]-2-

methoxyphenoxy} acetic acid (LXI)

"CH3

IR: (K B r)cm ‘ 3048 (COOH), 1714 (G=0), 1555 (C=N), 1315 (C-N).'H-NMK (DMSO-

dg) ppm: 10.3 (IH, s, COOH); 9.9 ( 2H, s, 2xOH), 7.73-7.82 (lOH, m, 5, 6; ?, 8, 9, 10, 11,

12, 13, 14); 4.5 (IH, t, H 4); 4.3 (IH, s, H 15); 3.3 (3H, s, OCH3); 2.5 (2H, d, H 3); in/z

498(M^’); Anal.Calcd.fbr CjsHsjClNiOy: C, 60.43; H, 4.26; N, 5.64%. Fotmd: ;c, 60.45; H.

4.27; N, 5.62%.

88


2-{4-[l-(4-Bromobenzoyl)-3-(2,4-dihydroxyphenyl)-4,5-dihydro-lH-5-pyrazolylh2-

methoxy phenoxy} acetic acid (LXII)

(LXII)

IR: (KBr) cm’*: 3173 (COOH), 1654 (C=0), 1560 (C=N), 1317 (C-N). *H-NMR (DMSO-

dfi) ppm: 11.4 (IH, s, COOH); 9.7 (2H, s, 2xOH); 6.75-8.13 (lOH, m, 5, 6 , 7, 8, 9, 10, 11,

12, 13, 14); 4.6 (IH, t, H 4), 4.3 (IH, s, H 15); 3.8 (3H, s, OCH3), 2.5 (2H, d, H 3); m/z:

542(M''’); Anal.Calcd.for CasHaiBrNzO?; C, 55.47; H, 3.91; N, 5.17%. Found: C, 55.49; H.

3.93; N, 5.18%.

2~{4-[l-(4-Nitrobenzoyl)-3-(2,4-dihydroxyphenyl)-4,5-dihydro'lH-5'pyrazolyl]-2-meth

oxyphenoxy} acetic acid (LXIII)

(LXIII)

IR: (KBr) 3219 (COOH), 1740 (C=0), 1551 (C=N), 1381 (C-N). ^H-NMR (DMSO-

dfi)ppm: 10.4 (IH, s, COOH), 9.8 ( 2H, s, 2x0H), 8,01-8.03 (lOH, m, 5, 6, 7, 8, 9,10, IJ,

12, 13, 14); 4.7 (IH, t, H 4); 4.1 (IH, s, H 15); 3.9 (3H, s, OCH3); 2.5 (2H, d, H 3); tti/z:

508(M*’); AnalCalcd.for C25H2iN309: C, 59.17; H, 4.17; N, 8.28%. Found: C, 59.16; H,

4.18; N, 8.27%.

8^


2-{4-[3-(2,4-Dihydroxyphenyl)-l-(4-methylbenzoyl)-4,5-dihydro-lH-5-pyrazolyl]-2-

methoxy phenoxy } acetic acid (LXIV)

(LXIV)


de) ppm: 10.1 (IH, s, COOH); 9.0 ( 2H, s, 2xOH), 6.82-8.03 (lOH, m, 3 ,4 , 5, 6, 7, 8, 9, 10,

11, 12 ); 5.7 (IH, dd, H, J = 6.6, 6.3 Hz); 4.4 (IH, dd, Hb J = 12.0, 12.0 Hz); 4.1 (IH, s, H

13); 3.9 (IH, dd, Ha J = 6.3, 6.3 Hz); 3.8 (3H, s, OCH3); 2.3 (3H, s, C H 3); iWz: 477(M^’);

Anal.Calcd.for C26H24N2O7: C, 65.54; H, 5.08; N, 5.88%. Found; C, 65.53; H, 5.09; N,

5.90%.

2~(4-{3~(2,4-Dihydroxyphenyl}-l-[2~(2-methylphenoxy)acetyl]-4,5~dihydro-IH-5-pyra

zolylJ-2-methoxyphenoxy) acetic acid (LXV)

■ o ' ' I ' O'

OH

A-OCHjCONHNHj

Qiacffll CHgCOOH


dfi) ppm: ^H-NMR (DMSO-dg) ppm: 10.8 (IH, s, COOH); 9.4 (2H, s, 2xGH); 6.70-8.21

(10H,m, H 5,6, 7, 8 ,9 ,10 ,11 , 12, 13,14); 4.8 (IH, t, H 4); 4.3 (IH, s, H 16); 4.1(1H, s, H

15); 3.4 (3H, s, OCH3); 2.5 (2H, d, H 3); 2.3 (3H, s, CH3); m/z: 507(M''’); AnaLCalcd.fe^

C27H26N2O8: C, 64.02; H, 5.17; N, 5.53%. Found: C, 64.03; H, 5.17; N, 5,54%. :

90


2-(4-{3-(2,4~Dihydroxyphenyl)~l-[2-(4-meihylphenoxy)acetylJ-4y5-dihydro-lH-S-pyra

zolylj-2-methoxyphenoxy) acetic acid (LXVI)

(LXVI)

IR: (KBr) cm‘ : 3220 (COOH), 1680 (C=0), 1559 (C=N), 1378 (C-N). ^H-NMR (DMSO-

dfi) ppm: ^H-NMR (DMSO-de) ppm: 10.1 (IH, s, COOH); 9.0 (2H, s, 2xOH); 6.53-8.42

(lOH, m, H 5, 6, 7, 8, 9,10,11, 12,13, 14); 4.9 (IH, t, H 4); 4.4 (IH, s, H 16); 4.1 (IH, s, H

15); 3.3 (3H, s, OCH3); 2.5 (2H, d, H 3); 2.3 (3H, s, CH3); m/z: 507(M-'’); Anal.Calcd.for

C27H26N2O8: C, 64.02; H, 5.17; N, 5.53%. Found: C, 64.02; H, 5.17; N, 5,53%.

2-{4-[3-(2,4-Dihydroxyphenyl)-l-(2-phenoxyacetyl)-4,5-dihydro-lH-5-pyrazolyl]-2-

methoxy phenoxy} acetic acid (LXVII)

iHjCONHNHj

(LXVII)

IR; (KBr) cm'^ 3180 (COOH), 1692 (C=0), 1550 (C=N), 1342 (C-N). ^H-NMR (DMSO-

dfi) ppm: 10.3 (IH, s, COOH) , 8-7 ( 2H, s, 2xOH), 6.61-8.03 (11H, m, H 5, 6, 7, 8, 9, 10,

1 1 ,12, 13,14, 15); 4.6 (1H, t,H 4);4 .1 (IH, s, H 17); 3.9 (IH, s, H 16); 3.5 (3H, s, OCH3);

2.5 (2H, d, H 3); ra/z: 493(M^’); AnalCalcd.fbr C26H24N2O8; C, 63.41; H, 4.91 ; N, 5.69%.

FouBd: C, 63.40; H, 4.91; N, 5.70%.

91


2-{4-[3-(2,4~Dihydroxyphenyl)-l-(2-hydroxybenzoyl)-4,5-dihydro-lH-S-pymzolyl]-2-metho

xyphenoxy} acetic acid (LXVIII)

OH

Glacial CKUCOOH OONHNHg-------------HO

(LXVIII)

IR: (KBr) cm *: 3260 (COOH), 1740 (C=0), 1559 (C=N), 1386 (C-N). ^H-NMR (DMSO-

de) ppm: 10.1 (IH, s, COOH); 9.3 ( 3H, s, BxOH), 6.82-8.13 (lOH, m, H 5, 6, 7, 8, 9 , 10,

11, 12, 13, 14); 4.6 (IH, t, H 4); 4.2 (2H, s, H 15); 3.4 ( 3H, s, OCH3), 2.5 (2H, d, H 3);

m/z: 479(M""’); Anal.Calcd.for C25H22N2O8; C, 62.76; H, 4.63; N, 5.86%. Found; C, 62.77;

H, 4.64; N, 5.86%.

2- {4-[3-(2,4-Dihydroxyph enyl)-l-(2-phenylacetyl)-4,5-dihydro-IH-5-pyrazolyl]-2-meth

oxyphenoxy} acetic acid (LXIX)

H O ..

CH, 'OH

(LXIX)

IK: (KBr) crn'^ 3199 (COOH), 1654 (C=0), 1560 (C=N), 1317 (C-N). ’H-NMR (DMSO-

de) ppm: 10.5 (IH, s, COOH); 8.9 (2H, s, 2xOH); 6.81-8.30 (llH , m, 3, 4, 5 ,6, 7, 8, 9,10,

11, 12,13); 5.8 (IH, dd, H., J = 5.7,5.7 Hz); 4.7 (IH, dd,HB. J = 12.3, 12.3 Hz); 4.5 (2H, s,

H 15); 4.2 (2H, s, H 14); 3.9 (IH, dd, Ha, J = 6.0, 5,7 Hz); 3.6 ( 3H, s, OCH3); m/z:

477(M-''); Anal.Calcd.fbr C26H24N2O7: C, 65.54; H, 5.08; N, 5.88%. Found: C, 65.54; H,

5.09; N, 5.88%.

92


2-(4-{3-(2,4-Dihydroxyphenyl)-l-[2-(l-naphthyloxy)acetyl]-4,5-dihydro-lH-S-pyrazolyl}-

2-methoxyphenoxy) acetic acid (LXX)

(LXX)

IR: (KBr) cm '^ 3304 (COOH), 1760 (C=0), 1560 (C=N), 1380 (C-N). *H-NMR (DMSO-

de) ppm: 10.1 (IH, s, COOH); 8.2 (2H, s, 2xOH); 7.12-7.83 ( 13H, m, 5, 6 , 7, 8, 9, 10, 11,

12, 13, 14, 15, 16, 17); 4.8 (IH, t, H 4); 4.4 (2H, s, H 19); 4.1 (2H, s, H 18); 3.4 (3H, s,

OCH3); 2.8 (2H, d, H 3); 2.5 (2H, d, H 3); m/z: 543(M"^); Anal.Calcd.for C30H26N2O8: C,

66.41; H, 4.83; N, 5.16%. Found: C, 66.42; H, 4.83; N, 5.17%.

2-(4-{3-(2,4-Dihydmxyphenyl)-l-[2-(2-naphtkyloxy)acetyl]-4,5-dihydro-lH-5-pyrazolyl}~

2-methoxyphenoxy)acetic acid (LXXI)

Glacial CH3COOH

‘OCHgCONHNHg

IR: (KBr) cm-^: 3304 (COOH), 1760 (C=0), 1560 (C=N), 1380 (C-N). ^H-NMR (DMSO-

dfi) ppm: 10.1 (IH, s, COOH); 8.2 ( 2H, s, 2xOH); 7.1-7.8 (13H, m, 5, 6,7 , 8,9, 10,11,12,

13,14, 15, 16,17); 4.8 (IH, t, H 4); 4.5 (2H, s, H 19); 4.2 (2H, s, H 18); 3.4 ( 3H, s, OGH3);

2.8 (2H, d, H 3); 2.5 (2H, d, H 3); m/z: 543(M^’); Anal.Calcd.for G3oH26N208: G, 66.41; JH,

4.83; N, 5.16%. Found: C, 66.41; H, 4.83; N, 5.17%.

93

Oxadiazoles Experimental

Scheme-II

HO P '

r-C H O

CH3

" - m :0

KOH/CH,OHCH,

R'CONHNH, POCI,

(LXXII- CHI)

R =H,OCH3,OH,N02R’ =C6H5, /?-C]-QH4, />Br-QH4,/J-N02-C6H4,/7-CH3-C6H4.o-OH-QH<C6H5-

OCH2 .

94


General procedure for synthesis of 1 ,3 ,4-Oxadiazole derivatives (LXXII - XCIX)

To an equiraolar mixture (0.001 moles) of chalcone derivative (I, III, IV, and VI) and

appropriate acid hydrazide in 5 ml of phosphorus oxychloride (POQ 3) was added and the

reaction mixture was refluxed for 18-20 hour. After completion of reaction mixture was

poured onto crushed ice (20 gm) and neutralized witli aqueous sodium hydroxide solution.

The product (LXXII - XCIX) so obtained was filtered, washed with water and recrystalized

from methanol.

3-[3-Methoxy-4'(5~phenyl-ly 3 ,4-oxadiazol~2-ylmethoxy) phenyl]-l-phenyl-2-propen-l-

one (LXXII)

OCHs

CONHNHj

(LXXII)IR: (KBr) cm'^ 1654 (C=C), 1560 (C=N), 1167 (C-O-C). ^H-NMR (DMSO-de) ppm:

7.3-8.1 (13H,m,H 1, 2, 3, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15); 6.8 (IH, d, H 5 J = 12.9

Hz); 6.6 (IH, d, H 4 J = 12.6 Hz); 4.5 (2H, s, H 16); 3.7 (3H, s, OCH3); m/z: 413(M^');


6.80%.

3-{4-[5-(4~Chlorophenyl)-l, 3 ,4-oxadiazol-2-ylmethoxyJ-3-methoxyphenyl}-l''phenyl~2- propen-l-one (L X X n i)

ONHNHj

(LXXIII):IR: (KBr) cm'^: 1654 (C=C), 1560 (C=N), 1166 (C-O-C). ^H-NMR (DMSO-dg) ppm: 7.0-

8.3 (12H, m, H 1, 2, 3, 6, 7, 8, 9, 10, 11, 12, 13, 14); 6.8 (IH, d, H 5 J =7.8Hz); 6.5

(IH, d, H 4 J = 18.9 Hz); 4.5 (2H, s, H 15); 3.8 (3H, s, OCH3); m/z: 448(M-*^);

Anal.Calcd.fbr C25H]c>ClN204: C, 67.19; H, 4.29; N, 6.27%. Rmnd: C, 67,18; H, 4.30; N,

6.29%.

95


3-{4-[5-(4-Bromophenyl)-l, 3, 4-oxadiazol-2-ylmethoxy]-3-methoxyphenyl}-l-phenyl-2-

propen-l-one ih X n V )

C H ,

IR: (KBr) cm '^ 1654 (C=C), 1558 (C=N), 1168 (C-O-C). ^H-NMR (DMSO-dg) ppm: 7.1-

8.3(12H,m ,H 1, 2, 3, 6, 1, 8, 9,10,11,12,13, 14); 6.8 (IH, d ,H 5 J = 8.3 Hz); 6.6 (IH,

d, H 4 J = 14.4 Hz): 4.3 (2H, s, H 15); 3.7 (3H, s, OCH3); m/z: 492(M^*); Anal.Calcd.for

C25Hi9Bi-N204: C, 61.11; H, 3.90; N, 5.70%. Found: C, 61.13; H, 3.92; N, 5.72%.

3-{3-Methoxy-4-[5-(4-nitrophenyl)-l, 3, 4~oxadiazol-2-ylmethoxy]phenyl}-l-phenyl-2~ propen-l-one (LXXV)

+ 0|POCL

iONHNHj10

(LXXV)IR: (KBr) cm'*: 1654 (C=C), 1559 (C=N), 1167 (C-O-C). ^H-NMR (DM SO-4) ppm; 7.0-

8.2 (12H, m, H 1, 2, 3, 6, 7, 8, 9, 10, 11, 12, 13, 14); 6.7 (IH, d, H 5 J = 7.8 Hz); 6.4

(IH, d, H 4 J = 18.2 Hz); 4.5 (2H, s, H 15); 3.7 (3H, s, 0CH3);\m/z: 458(M'’’);

Anal,Calcd.for Ca^HiaNA,: C, 65.64; H, 4.19; N, 9.19%. Found: C, 65.66; H, 4.21; N,

9.20%.

3-{3-Methoxy-4-[5-(4-methylphenyl)-l, 3, 4'Oxadiazol~2-ylmethoxy]phenyl}-l-phenyl-2-

propen-l-one iUDLM)


IR: (KBr) cm'^ 1654 (C=C), 1560 (C=N), 1167 (C-O-C). ^H-NMR (DMSO-do) ppm; 7.1-

8.2 (12H ,m ,H 1, 2, 3, 6,7, 8, 9, 10, 11,12,13, 14); 6.8 (IH ,d, H5 J = 7 .2 Hz); 6.6 (IH,

d, H 4 J = 15.7 Hz); 4.5 (2H, s, H 15); 3,8 (3H, s, OCH3); 2.2 (3H, s, CH3); xn/z: 427(M^’);


6.59%.

3-{4-[5-(2-Hydroxyphenyl)'l, 3, 4-oxadiazol-2-ylmethoxy]-3-methoxyphenyl}-l-phenyl-2~

propen-I-one (LXXVU)

CH3

POCI,

“ CONHNHj

IR: (KBr) cm '^ 1654 (C=C), 1556 (C=N), 1166 (C-O-C). ^H-NMR (DMSO-dg) ppm: 9.1

(lH ,s,OH); 7.1-8.3(12H,m,H 1, 2, 3, 6, 7,8, 9, 10,11,12, 13,14); 6.7 (IH, d,H 5 J

= 6.4 Hz ); 6.5 (IH, d, H 4 J = 17.2 Hz); 4.6 (2H, s, H 15); 3.7 (3H, s, OCH3); in/z;

429(M^’); Anal.Calcd.foi* C23H20N2O5: C, 70.08; H, 4.71; N, 6.54%. Found: C, 70.09; H,

4.71; N, 6.56%.

3-[3-Methoxy-4-(S-phenoxymethyl-l, 3, 4-oxadiazol-2-ylmethoxy)phmyl]-hphenyl-2~ propen-l-one (LXXVIII)

" V '

(LXXVII)

HO •CHj

IR: (KBr) cm’ 1654 (C=C), 1560 (C=N), 1171 (C-O-C). ^H-NMR(DMS0-d6) ppm: 6.8

8 .2(13H ,m ,H l, 2, 3, 6, 7, 8, 9,10, 11,12,13,14, 15); 6 .6 (lH ,d ,H 5 J = 7.6H z); 6.2

(IH, d, H 4 J = 16.7 Hz); 4.7 (2H, s, H 17); 4.5 (2H, s, H 16); 3.8 (3H, s, OCH3); m/z:

443(M'^’); AnalCa]Gd.fbr C26H22N2O5: C, 70.58: H, 5.01; N, 6.33^. Found: C, 70.S ; H.

5.03; N, 6.36%.

97


l-(4~Methoxyphenyl)'3-[3-methoxy-4-(S-f)henyl-J, 3, 4-oxadiazol-2-ylmethoxy)phenyl]-2- propen-l-one (LXXIX)

I ,■CHg+ CONHNH;

POCI,

-CH3

(LXXIX)IR: (KBr) cm ^ 1654 (C=C), 1561 (C=N), J 157 (C-O-C). ‘H-NMR (DMSO-ds) ppm: 7.2-

8.0 (12H, m, H 1, 2, 3, 6, 7, 8, 9, 10, 11, 12, 13, 14); 7.1 (IH, d, H 5 J = 10,8Hz); 6.9

(IH, d, H 4 J =8.1 Hz); 4.5 (2H. s, H 15); 3.9 (6H, s, 2XOCH3); m/z: 443(M^’);


6.36%.

3-{4-[5-(4-Chlorophenyl)-l, 3, 4-oxadmzol-2-ylmethoxy]-3-methoxyphenyl}-l-(4-methoxy

phenyl)~2 -propen-l-one (LXXX)

POCI-

0

'CH3

+''O

ICH3

CONHNHr

1

(LXXX)IR; (KBr) cm'^: 1654 (C=C), 1559 (C=N), 1158 (G-O-C). ^H-NMR (BMSO-dg) ppm: 7.7-

8 .2 (9 H ,m ,H l, 2, 3, 6, 7, 8, 9, 10, 13); 7.1 (2H ,s,H 11, 12); 6.7 (IH, d, H 5 J =

lO.lHz); 6.6 (IH, d, H 4 J = 14.8Hz); 4.5 (2H, s, H 14); 3,8 (6H, s, 2xOCHj); m/z:

478(M'-’); Anal.Calcd.for C26H2,C1N:05: C 65.48; H, 4.44; N, 5.87%. Found: C, 65.49; H,

4.48; N, 5.86%.3~{4-[5-(4’Bromophenyl)'l,3,4-oxadiazol-2-ylmethoxy]-3-methoxyphenyl}-l-(4-methoxy

phenyl)-2-propen-l-one (LXXXI)

98


IR: (KBr) cm'h 1654 (C=C), 1561 (C=N), 1 ]57 (C-O-C). ^H-NMR (DMSO-ds) ppm: 7.7-

8.3 (9H, m, H 1, 2, 3, 6, 7, 8, 9, 10, 13); 7.0 (2H, s, H 11, 12); 6.6 (IH, d, H 5 J = 8.8

Hz); 6.4 (IH, d, H 4 J = 13.7 Hz); 4.5 (2H, s, H 14); 3.7 (6H, .s, 2xOCH.O; m/z; 522{M'"'};

Anai.Calcd.for CaeHsiBrNjOs: C, 59.90; H, 4.06; N, 5.37%. Found; C, 59.92; H, 4.08; N,

5.36%.

3-{3-Methoxy-4-[5-(4-nitrophenyl)-l, 3, 4-oxadiazoh2-ylmethoxy]phenyl}~l-(4-meihoxy

phenyl)-2-propen-l'one (LXXXII)

■CH,

(LXXXII)

IR: (KBr) cm ^ 1654 (C=C), 1556 (C=N), 1157 (C-O-C). ^H-NMR (DMSO-ds) ppm: 7.8-

8 .2 (9H ,m , H I, 2, 3, 6, 7, 8,9,10, 13); 7.1 (2H, s, H 11, 12); 6 .6 (lH ,d ,H 5 1=11.3

Hz); 6.4 (IH, d, H 4 J = 14.9 Hz); 4,6 (2H, s, H 14); 3.6 (6H, s, axOCH?); m/z: 488(M^’);

Anai.Calcd.for GseHziNsOy: C, 64.06; H, 4.34; N, 8.62%, Found: C, 64.03; H, 4,33; N,

8 .66%.

3-{3-Methoxy-4-[5~(4-methylphenyl)-l, 3, 4-oxadiazol-2-ylm ethoxyJphenyl}-l-(4-methoxy

phenyl)-2~propen-I-one (LXXXIII)

HO J H3C- -CONHNH2

(LXXXIII) :

IR: (KBr) cm'^ 1654 (C=C), 1560 (C=N), 1158 (C-O-C). ^H-NMR (DMSO-de) ppm: 7.2-

8.0 (1 IH, m, H I, 2, 3, 6, 7, 8, 9 ,10,11,12,13); 6.7 (IH, d, H 5 J = 8,1 Hz); 6.3 (IH, d,

H 4 J = 8.1 Hz); 4.4 (2H, s, H 14); 3.7 (6H, s, 2XOCH3); 2.3 (3H, s, CH3); m/z; 457(M^’);

AnalCalcd.for C27H24N2O5: C, 71.04; ;H, 5.30; N, 6.14%. Found: G, 71.03; H, 5.33; IS,

6.16%.

99


3-{4-[5-(2-Hydroxyphenyl)-l, 3, 4-QXadiazol-2-ylmethoxy]-3-meihoxypheny]}-l-(4-methoxy

phenyl)-2-propen-l-one (LXXXIV)

HO J CH,

POOL

+ ^ y — CONHNH,

CH,

10

(LXXXIV)

IR: (KBr) cm : 1654 (C=C), 1561 (C=N), 1158 (C-O-C). ^H-NMR (DMSO-de) ppm; 9.2

(IH, s, OH); 7.2-8.1 (IIH , m, H 1, 2, 3, 6, 7, 8, 9, 10, 11, 12, 13); 6,8 (IH, d, H 5 J =

7.3Hz); 6.5 (IH, d, H 4 J = 13.7Hz ); 4.7 (2H, s, H 14 ); 3.7 (6H, s, 2XOCH3); m/z:

459(M'’ ); Anal.Calcd.for C26H22N2O6: C, 68.11; H, 4.84; N, 6.11%. Found; C, 68.13; H,

4.83; N, 6.14%.

3-[3-Methoxy-4-(5-phenoxymethyl-l, 3, 4-oxadiazol-2~ylmethoxy)phenyl]-l-(4-m ethoxy

phenyl)-2-propen-l-one (LXXXV)

r fHOsJ 6. \ _ JCHa

POCIgIHgCONHNHs'

o

14- L

(LXXXV)

IR; (KBr) cm’*: 1654 (C=C), 1560 (G=N), 1157 (C-O-C). ’H-NMK (DMSO-de) ppm: 6.9-

7.9 (12H, m, H 1, 2, 3, 6, 7, 8, 9, 10,11, 12, 13, 14); 6.9 (IH, d, H 5 J = 8.3Hz ); 6.8

(IH, d, H 4 ; J = 17.4 Hz); 4.8 (2H, s, H 16); 4.4 (2H, s, H 15); 3.7 (6H, s, 2x001,); mfr.

473(M^’); Anal.Calcd.for C27H24N2O6: C, 68.63; H, 5.12; N, 5.93%. Found: C, 68.65; H,

5.13; N,5.94%.

100


l-(4-Hydroxypkenyl)-3-[3-methoxy-4-(5-phenyl-l, 3 ,4-oxadiazol-2-ylmethoxy) phenyl}-2-

propen-l-one (LXXXVI)

-CONHNHjPOCI,

(LXXXVI)IR; (KBr) cm"^: 1654 (C=C), 1559 (C=N), 1156 (C-O-C). ^H-NMR (DMSO-de) ppm: 9,2

(IH, s, OH); 7.3- 8.5 (12H, m, H 1, 2, 3, 6, 7,8, 9,10,11, 12,13,14); 7.2 (IH, d, H 5 J =

18.3Hz); 6.7 (IH, d, H 4 J =15 Hz); 4.4 (2H, s, H 15); 3.8 (3H, s, OCH3); 111/z; 429(M"');


6.54%.

3-{4-[5-(4-Chlorophenyl)-l, 3, 4-oxadiazol-2-ylmethoxy]-3-methoxyphenyl}-l-(4-hydroxy

phenyl)-2 -propen-l’0ne (LXXXVII)

'CK,+

"'OHCONHNHj

'OH

(LXXXVII)IR: (KBr) cm'^: 1654 (C=C), 1560 (C=N), 1155 (C-O-C). ^H-NMR (BMSO-d<i) ppm: 9.2

(lH ,s,O H );7.7-8.2(9H ,m , H l , 2, 3, 6, 7, 8, 9, 10, 13); 7.1-7.7 (2H, s, H 11, 12); 6.7-

6.8 (IH, d, H 5 J = 17.6Hz); 6.5 (IH, d, H 4 J = 14.7Hz); 4.5 (2H, s, H 14); 3.8 (3H, s,

OCH3); m/z: 464(M^'); Anal.Calcd.for C25H19CIN2O5: C, 64.87; H, 4.14; N, 6.05%. Found:

C, 64.85; H, 4.13; N, 6.07%.3~{4-[5-(4-Bromophenyl)-l, 3, 4-oxadiazol-2-ylmeihoxy]-3~methoxyphenyl}-l-(4-hydroxy

phenyl)-2-propen-l-one (LXXXVIII)


IM; (KBr) cm’ : 1654 (C=C), 1558 (C=N), 1156 (C-O-C). ^H-NMR (DMSO-d^) ppm: 9.4

(IH, s, OH); 7.7-8.2 (9H, m, H 1, 2, 3, 6, 7, 8, 9, 10,13); 7.1 (2H, s, H 11, 12); 6.7 (IH,

d, H 5 J = 15.4 Hz); 6.5 (IH, d, H 4 J = 11.8 Hz); 4.3 (2H, s, H 14); 3.7 (3H, s, OCH3);

m/z: SOBCM" ); Anal.Calcd.for C2sHj9BrN205: C, 59.19; H, 3.77; N. 5.22%. Found: C, 59.21;

H, 3.79; N, 5.24%.

l~(4-Hydroxypkenyl)-3-{3-methoxy-4-[5-(4-nitrophenyl)-l, 3, 4-oxadiazol~2-yl rnethoxy]

phenyl}~2-propen-l-one (LXXXIX)

V ■CHj

•CONHNH,POCI3

(LXXXIX)

IR: (KBr) cm : 1654 (C=C), 1560 (C=N), 1158 (C-O-C), ^H-NMR (DMSO-ds) ppm: 9.2

( IH, s, OH); 7.6-S.3 (9H, m, H 1, 2, 3, 6, 7, 8, 9, 10,13); 7.0 (2H. s, H 11, 12); 6.7 (IH,

d, H 5 J = 17.7 Hz); 6.5 (IH, d, H 4 J = 13,8 Hz); 4.4 (2H, s, H 14); 3.6 (3H, s, OCH3);

mJz: 474(M^’); Anal.Calcd.for CzsHi^NjO?: C. 63.42; H, 4.05; N, 8.88%. Found: C, 63.43;

H, 4.07; N, 8.91%.

l~(4-Hydroxypheityl)-3-{3-methoxy-4-[5-(4~meihylphenyl)-l, 3, 4~oxadiazol~2~yl rnethoxy]

phenyl}-2-propen-l~one (XC)

CONHNHg

: , (XC) ■'

IR: (KBr) cm’ ; 1654 (C=C), 1559 (C=N), 1156 (C-O-C). ^H-NMR (DMSO-de) ppm: 8.5

(IH, s, OH);7.1-8.3 (IIH , m, H 1, 2, 3, 6, 7. 8, % 10,11, 12,13); 7.0(1H, d, H 5 J = 8,1

Hz ); 6.8 (IH, d, H 4 J = 8.4 Hz); 4.4 (2H. s, H 14); 3.8 (3H, s, OCHa); 2.3 (3H, s, CH3);

m/z: 443(]Vf’); Anal.Calcd.fbr G26H22N2O5: C, 70.58; H, 5.01; N, 6.33%. Found: C, 70.57;

H, 5.03; N, 6.36%.

102


l-(4-Hydroxyphenyl)-3~{4-[5-(2-hydroxyphenyl)-l, 3, 4-oxadiazol-2-ylmethoxy]-3-methoxy

phenyl}-2-propen~l-one (XCI)

HO.

IR: (KBr) cm'^: 1654 (C=C), 1549 (C=N), 1155 (C-O-C). ^H-NMR (DMSO-dg) ppm: 10.8

(2H, s, 2xOH); 6.9-8.0 ( IIH , m, H 1, 2, 3, 6, 7, 8, 9, 10, 11, 12, 13); 6.7 (IH, d, H 5 J =

9.6Hz); 6.1 (IH, d, H 4 J = 5.4 Hz); 4.4 (2H, s, H 14); 3.7 (3H, s, OCH3); m/z: 445(M^‘);

Anal.Calcd.for C25H20N2O6: C, 67.56; H, 4.54; N, 6.30%. Found; C, 67.57; H, 4.57; N,

6.33%.

l~(4-Hydroxyphenyl)~3~[3~methoxy-4-(5~phenoxymethyl-l, 3, 4-oxadiazoU2-yl methoxy)

phenyl]-2-propen-l~one(KCll)

POCI,iHiCONHNHj -

p-16

12

(XCII)

IR: (KBr) cm'^: 1654 (C=C), 1559 (C=N), 1156 (C-O-C). ^H-NMR (DMSO-dg) ppm: 9.4

(IH, s,OH);7.0-8.7 (1 2 H ,m ,H l, 2, 3, 6 , 7. 8, 9, 10, 1 1 ,12, 13,14); 6.9 (IH, d, H 5 J -

15); 6.5 (IH, d, H 4 J = 13.5 Hz); 4.4 (2H, s, H 16); 4.2 (2H, s, H 15); 3.8 (3H, s, OCH3);

m/z; 459(M^’); Anal.Calcd.for C26H22N2O6: G, 68.11; H, 4.84; N, 6.11%. Found: C, 68.13;

H, 4.87; N, 6.13%

103


3-[3-Methoxy-4-(5-phenyl-l, 3, 4-oxadiazol-2-ylmethoxy) phenyl]-l-(4-nitrophenyl)-2-

propen-l-one (XCIII)

■GH3 \CONHNH,

(XCIII)IR: (KBr) cm'^: 1654 (C=C), 1560 (C=N), 1158 (C-O-C). (DMSO-d«) ppm: 7.4-

8.1 1, 2, 3, 6, 7, 8, 9, 10,11,12, 13, 14); 7.3 (IH, d, H 5 J = 8.1 Hz); 6.8

(IH, d, H 4 J = 8.4 Hz); 4.5 (2H, s, H 15); 3.8 ( 3H, s, OCH3); m/z: 458(M^’);


9.21%.

3-{4-[5-(4-Chlorophenyl)-l, 3, 4-oxadiazol-2-ylmethoxy]-3-methoxyphenyl}-l-(4-nitro

phenyl)-2-propen-l-one (XCIV)

'C B ,

+'"N02

-CONHNHj

(XCIV)IK: (KBr) cm '\-1654 (C=C), 1559 (C=N), 1159 (C-O-C). ^H-NMR (DMSO-dfi) ppm: 7.6-

8 .1 (9 H ,m ,H l, 2, 3, 6, 7, 8, 9, 10, 13); 7.5 (2H, s, H 11,12); 7.3 (IH, d, H 5 J = 8.1

Hz); 6.9 (IH, d, H 4 J = 8.4 Hz); 4.4 (2H, s, H 14); 3.8 (3H, s, OCH3); m/z: 493(M'");

Anal.Calcd.for CssHigCINsOe; C, 61.04; H, 3.69; N, 8.54%. Found: C, 61.06; H, 3.72; N,

8.55%.

3-{4-[5~(4~Bromophenyl)-l, 3, 4'Oxadiazot-2-ylmethoxy]-3-methoxyphenyl}’l-(4-nitro

phenyl)-2-propen-l-one (XCV)


IR: (KBr) cm ^ 1654 (C=C), 1561 (C=N), 1159 (C-O-C). ^H-NMR (DMSO-de) ppm: 7.2-

8 .5 (9H ,m ,H l, 2 , 3, 6, 7, 8, 9, 10, 13); 7.3 (2H, s, H 11,12); 6 .6 ( lH ,d ,H 5 J = 8.8

Hz ); 6.1 (IH, d, H 4 J = 8.3 Hz); 4.3 (2H, s, H 14); 3.7 (3H, s, OCH3); mJz: 537(M"');

Anal.Calcd.for CasHigBrNsOe; C, 55.19; H, 3.38; N, 7.87%. Found: C, 55.98; H, 3.36; N,

7.84%.

3-{3-Methoxy-4-[5-(4-nitrophenyl)-l, 3, 4-oxadiazol-2-ylmethoxy]phenyl]-l-(4-nitro

phenyl) -2-propen-1-one (XCVI)

■CONHNH,POCI,

(XCVI)

IR: (KBr) cm *: 1654 (C=C), 1556 (C=N), 1159 (C-O-C). ^H-NMR (DMSO-de) ppm: 7.4-

8.4 (9H, m, H 1, 2, 3, 6, 7, 8, 9, 10, 13); 7.2 (2H, s, H 11, 12); 6.7 (IH, d, H 5 J = 10.9

Hz); 6.4 (IH, d, H 4 J = 8.2 Hz); 4.4 (2H, s, H 14); 3.7 (3H, s, OCH3); m/z; 503 (M^‘);

AnaI.Calcd.for C25Hi8N40g: C, 59.76; H, 3.61; N, 11.15%. Found: C, 59.78; H, 3.63; N,

11.14%.

3-{3-Methoxy-4-[5-(4-methylphenyl)-l, 3, 4-oxadiazol-2-ylmethoxy]phenyl}-l-(4-nitro

phenyl)-2-propen-l-one (XCVII)

H jC - -CONHNH2

, (XCVII)

IR: (KBr) c m '\-1654 (C=C), 1559 (C=N), i l6 0 (C-OC). ^H-NMR (DMSO-ds) ppm: 7.1

( l lH ,m ,H l , 2, 3, 6, 7, 8, 9, 10, H , 12, 13); 6.7 (IH, d, H 5 J= 13.5Hz); 6.4 (IH, d, H

4 J = 9.7 Hz); 4.5 (2H, s, H 14); 3.8 (3H, s, OCH3); 2.3 ( 3H, s, CH3); myz: 472(M;'’);

Anal.Calcd.for C26H21N3O6: C, 66.24; H, 4.49; N, 8.91%. Found: C, 66.27; Hy 4.51; N,

8.93%. :

105


3.{4-[5'(2-ffydroxyphenyl)-I, 3, 4-oxadiazol-2-ylmethoxy]-3-methoxyphenyl}-l-{4~nitro

phenyl)-2-propen-l-one (XCVIII)

+''NOj

(XCVIII)

IR: (KBr) cm'': 1654 (C=C), 1560 (C=N), 1159 (C-O-C). ^H-NMR (DMSO-ds) ppm; 10.1

(lH ,s,O H );6 .9 -8 .5 (llH ,m ,H 1, 2, 3, 6, 7, 8, 9,10,11,12, 13); 6.8 (IH, d, H 5 J =

15.4 Hz); 6.1 (IH, d, H 4 J = 11.7 Hz); 4,3 (2H, s, H 14); 3.7 (3H, s, OCH3); m/z: 474(M''');


8.89%.

3-[3-Methoxy-4-(5-phenoxymethyl-l, 3, 4-oxadiazol~2-ylmethoxy)phenyl]-l-(4-nitro

phenyl)'2-propen~l-one (XCIX)

POCU

•CH3

(xax>:IR: (KBr) cm’*: 1654 (C=C), 1554 (C=N), 1160 (C-O-C). ^H-NMK (DMSO-de) ppm; 7.2-

8.5(12H, m ,H l, 2, 3, 6, 7, 8, 9,10,11,12, 13, 14); 6.7 (IH, d, H 5 J = 13.8 Hz ); 6.6

(IH, d, H 4 J = 10.4 Hz); 44 (2H, s, H 16); 4.2 (2H, s, H 15); 3.8 ( 3H, s, OCH3); m/z:

488(M-''); Anal.Calcd.for C26H21N3O7: C, 64.06; H, 4.34; N, 8.62%, Found: C, 64.08; H,

4.33; N, 8.65%. ,

106

Jsoxazolines Experimental

Scheme-Ill

C H ,CH3

+ R-CHONaOH

.OHCHj

C,H,OHCH3COOH

\v /

-OH

(C-CXH) (CXIII-CXXV)

General method for the preparation of compounds (C-CXII)

l-(4-Hydroxy-3-methyl-phenyl)-3-(mbstttutedphenyl)-2-Propen-l-one.

4-hydroxy-3-niethy] acetophenone (1.5017g, O.Olmmol) and the appropriate aldehyde

(O.OImmol), were dissolved in ethanol and sodium hydroxide (30%, 5mL) with 10ml of

petroleum ether was stirred under room temperature for 4 hour. The resulting solution was

allowed to stand overnight and then poured into ice-cold water and neutralized with HCl. The

solid which separated was filtered off, dried and purified from ethanol.

l-(4H ydroxy-3 ’-methyl‘phenyl)-3-(4’ methoxy phenyl)~2~propen-l-one (C)

CHj

HaCv-CHO

NaOH

CaHgOH

(C)

IR: (KBr) cm’’: 3200 (OH), 3042 (CH), 1686 (C=0). *H-NMR (DMSO-de) Ppm: 9.2 (IH,

s, OH): 7.2-7.9 (7H, m, aromatic); 6.S-6.9 (2xlH, d J = 7.5 Hz, 8.5 Hz, -CH=CH); 3.9 (3H,

s, OCH3); 2.2 (3H, s, CH3).

l-(4’~Hydroxy-3’-methyl-phenyl)~3-{4’^-chlorophenyl)-2-propen-l'one{Ct)

.OH

HaCs, -CHONaOH

GgHsOH

(Cl)

107

Isoxazolines Experimental

IR: (KBr) cm ': 3210 (OH), 3030 (CH), 1676 (C=0). ^H-NMR (DMSO-de) ppm; 9.2 (IH,

s, OH); 7.7-8.0 (7H, m, aromatic); 6.7-6.8 (2xlH, d J = 8.34 Hz, 6.79 Hz, -CH=CH); 2.2

(3H, s, CH3).

l-(4’-Hydroxy-3’-meihyI-phenyl)~3-(4”- dimethyl aminophenyl)-2-propen-l-one (CII)

H3C—N

CH3

H -.C

* //NaOH

CjHjOH

(CII)

IR: (KBr) c m 3200 (OH), 3040 (CH), 1680 (C=0). *H-NMR (DMSO-4) Ppm: 9.2 (IH,


(6H, s, N(2xCH3); 2.2(3H, s, CH3).

Hydroxy-3 ’-/«ethyl-phenyl)S- phenyl-2-propen~l -one (CIII)

CH,OH

-CHONaOH CH3

C2H5OH-O H

(CM)

IR: (KBr) cnr‘: 3210 (OH). 3042 (GH), 1680 (C=0). ^H-NMR (DMSO-dg) ppm: 9.2 (IH,

.s, OH); 7.7-8.2 (8H, m, ai'omatic); 6.8-7:4 (2xlH, d J = 8.28 Hz, 6.70 Hz, 'CH=CH); 2.2

(3H,s,CH3). '

l-(4 ’ Hydroxy-3’~methyl-phenyl)-3-(3’’ 4”- dimeihoxy phenyl)-2-propen~l-one (CTV)

lsoxazolin.es Experimental

IR: (KBr) cm‘ : 3232 (OH), 3046 (CH). 1680 (C=0). ^H-NMR (DMSO-dfi) ppm: 9.2

(IH, s, OH); 7.6-8.1 (6H, m, aromatic); 6.9-73 (2xlH, d J = 7.45 Hz, 7.29 Hz, -CH=CH);

3.9 (6H, s, 2xOCH3); 2.2 (3H, s, CH3).

1~(4^-Hydroxy~3ethyUphenyiy3-(34^\5^^-trimethoxyphenyl)-2-propen-l~me (CV)H3C--O p--CH3

CH3 CH,/

4- 0 -CHONaOH CH3

C2H5OH

CHa-OH

(CV)

IR: (KBr) cm'^: 3220 (OH), 3036 (CH), 1686 (C=0). ^H-NMR (DMSO-dg) ppm: 9.2 (IH,

s, OH); 7.7-8.1 (5H, m, aromatic); 6.9-1.5 (2xlH, d J = 7.55 Hz, 121 Hz, -CH=CH); 3.9

(9H, s, 3XOCH3); 2.2 (3H, s, CH3).

l- (4 ’-Hydroxy-3’~methyl-phenyl)-3-(4'’'-JlurophenyI)-2-propen-I-one (CVI)F

/ \OH

+ F -NaOH CHa

C2H5OH-OH

„(CVI) :

IR: (KBr) cm \- 3200 (OH), 3040 (CH), 1680 (C=0 ). *H-NMR (DMSO-dfi) ppm: 9.2 (IH,

s, OH); 7.7-S.2 (7H, m, aromatic); 6.9-7.S (2xlH, d J = 7.24 Hz, 7.29 Hz, -CH=CH); 2.2

(3H, s, CH3).

l-(4^-Hydroxy-3’-meihyl-phenyl)-3-(2'’''-chloro phenyl}-2-propen-l-om (CVII)

CH,

Cl

moH-C H O CgHgOH

:c':-

.. ■■■ . ■ ' 1: : ■■ ■■


IR: (KBr) cm'^: 3200 (OH), 3042 (CH). 1684 (C=0 ). ^H-NMR (DMS0-d6) ppm; 9.2 (IH,

s, OH); 7.6-8.0 (7H, m, aromatic); 6.9-15 (2aIH, d J = 8.35 Hz, 3.63 Hz, -CH=CH); 2.2

(3H, s, CH3).

l-(4 ’-Hydroxy-3^-methyl-phenyl)-3-(2’\ 6'‘’~dichlorophenyl)-2-propen-l-one (CVIII)

CH,

H3C.\ _ /

-CH OMaOH

C^HgOH

CHt

-OH

(CVIII)

IR: (KBr) cm *: 3210 (OH), 3040 (CH), 1670 (C=0). ‘H-NMR (DMSO-de) ppm: 9.2 (IH,


(3H, s, CH3).

l-(4^-Hydroxy-3’-methyl-phenyl)-3-(3'-nitrophenyl)~2-propen-l-one (CIX)

CH3O2N

NaOH

C2H5OH

(CIX)

IR: (KBr) cm’ : 3200 (OH), 3040 (GH), 1680 (C=0). ^H-NMR (DMSO-de) ppm: 9.2 (IH,

s, OH); 7.7-S.2 (7H, m, aromatic); 6.9-7.5 (2xlH, d J = 5.46 Hz, 16.3 Hz, -CH=CH); 2.2

(3 H ,s ,CH3>.


IR: (KBr) cm '^ 3200 (OH), 3040 (CH), 1680 (C=0). 'H-NMR (DMSO-df,) ppm: 9.2 (IH,

s, OH); 7.7-S.2 (6H, m, ai'oinatic); 6.4-7.4 (3H, m, furan); 6.S-6.9 (2xlH, d J =3.0 Hz, 8,36

Hz, -CH=CH); 2.2 (3H, s, CH3).

1 •(4’-Hydroxy-3’-methyl-phenyl)-3-(4^’-bromophenyl)~2-propen~l-one (CXI)Br

C H 3 \OH

+ Br~

V i-CHO

NaOH CHoC2H5OH

(CXI)

IR: (KBr) cm‘\* 3210 (OH), 3030 (CH), 1676 (C=0). 'H-NMR (DMS0-d6) ppm: 9.2 (IH,

s, OH); 7.7-8.0 (7H, m, aromatic); 6.8-7.1 (lHx2, d .1 = 8.23 Hz. 6.72 Hz, -CH=CH); 2.1

(3H, s, CHa).

l-(4’-Hydroxy~3’-methyl-phenyl)-3-(4-hydroxy-3”'methoxyphenyl)-2'propen-l-one

(CXII)HO 0 — C H 3

CH3

+ HO-

\ /-C H O

■ .(CXII)

IR: (KBr) cm'*: 3232 (OH), 3046 (CH), 1680 (C=0). ^H-NMR (»MSO-d«) ppm: 9.2- 9,3

(IH, s, 2xOH); 7.6-8.1 (6H, m, aromatic); 6.9-73 (2xlH, d J = 7.45 Hz, 7.29 Hz, -CH=CH);

3.9 (3H, s, OCH3); 2.2 (3H, s, GH3).

General method for the preparation of compounds (CXIII-CXXY)

Synthesis o f 4-[5-(substitutedphenyl)-4, 5-dihydro-34soxazolyl]-’2-methylphenol

To the solution of 0.002nioles of the appropriate(C-CXH) derivatives in i5m] of glacial

acetic acid 0.002moles hydroxylamine HCl was added and the le^ction roixture was reflu^d

for 15h and cooled. Excess of solvent was removed under induced pressure and the reaction


mixture was cooled, poured onto crushed ice (20gm). The product so obtained wiis filtered,

washed with water and recrystallized from methanol.

4-[5-(4-Methoxyphenyl)-4,5-dihydro-34soxazolyl]-2-methylphenol (CXIII)

(CXIII)

IR: (KBr) cm'^* 1628 (C=N), 1612 (C=C). ‘H-NMR {DMSO-d^) ppm: 6.7-7,2 (7H, m,

aromatic); 5.7-5.8 (IH, t, CH J = 6.4 Hz); 3.7 (3H, s, OCH3); 3.56-3.59 (2H, dd, CH. J =

6.4 Hz, J = 17 Hz); 2.3 (3H, s, CHj); m/z: 284(M^').

4-[5-(4~Chlorophenyl)-4, 5-dihydro-3-isoxazolyl]-2-methylphenol (CXIV)

IR : (KBr) c im \- 1596 (C=N). 1600 (G=C), 772 (C-Cl). ’H-NMK (DMSO-dfi) ppm; 6.7-

7.3 (7H, m, aromatic); 5.7-5.8 (lH, t, CH J = 6.4 Hz); 3.7 (3H, s, OCH3); 3.56-3.59 ( 2H, dd,

CH2 J = 6.4 Hz, J = 17 Hz); 2.3 (3H, s, CH3); m/z: 288(M- ').

4-[5-(4-Dimethylaminophenyl)-4,S-dihydro-3-isoxazolylJ-2-meihylphenol (CXV)

112

hoxazolines Experimental

IR: (KBr) cm'^: 1592 (C=N), 1600 (C=C). ^H-NMR (DMSO-dr,) ppm: 6.9-1.6 (7H. m,

aromatic); 5.7-5.S (IH, t, CH J = 6.4 Hz); 3.56-3.59 (2H, dd, CHa J = 6.4 Hz, J = 17 Hz):

2.4 (6H, s, 2x NH3); 2.3 (3H, s, CH3); m/z: 297(M"'^).

4~[5-Phenyl-4,5-dihydro-34soxazolyl]-2-meihylpheml(CKVT)

NHjOH.HCI

■OH CHjGOOH

(CXVI)

IR; (KBr) cm’ ' 1596 (C=N), 1608 (C=C). ^H-NMR (DMSO-4) ppm: 6.8-73 (8H, m,

aromatic); 5.7-5.S (IH, t, CH J = 6.4 Hz); 3.56-3.59 ( 2H, dd, CH2 J = 6.4 Hz, J = 17 Hz);

2.3 (3H, s, CH3); m/z: 254(M*’).

4-{5-(3,4~Dimethoxyphenyl)~4, 5~dihydro34soxazolyl]-2-methylphenol (CXVII)

IR: (KBr) cm-\* 1600 (C=N), 1622 (C=C).^H-NMR (DMSO-de) ppm: 6.1-12 (6H, m,

aromatic); 5.7-5.S (IH, t, CH J = 6.4 Hz); 3.7 (6H, s, 2XOCH3); 3.56-3.59 (2H, dd, CH. J =

6.4 Hz, / = 17 Hz); 2.3 (3H, s, CH3); m/z: 314(M''’).4'[5-(3, 4,5-Trimethoxyphenyl)-4, 5-dikydro-3-isoxazoIyl]-2'methylphenol (CXVIII)

H 3


IR: (KBr) cm '^ 1600 (C=N), 1618 (C=C). ^H-NMR (DMSO-d«) ppm: 6.7-7.2 (5H, an,

aromatic); 5.V-5.8 (IH, t, CH J = 6.4 Hz); 3.7 (9H, s, SxOCHs); 3.56-3.59 ( 2H, dd, CHz J

= 6 .4Hz, J = 1 7 Hz); 2.3(3H, s, CH3); m/z; 344(M"’).

4-[5‘{4-Flurophenyl)‘4,5-dihydro-34soxazolyl]-2-methylpheml (CXIX)F.

NHjOH.HCI

OH CH3COOH

(CXIX)

IR: (KBr) cm ^ 1600 (C=N), 1624 (C=C). ^H-NMR (DMSO-de) ppm: 6.1-13 (7H, m,

aromatic); 5.1-5.% (IH, t, CH J = 6.4 Hz); 3.56-3.59 ( 2H, dd, CH2 J = 6.4 Hz, J = 17 Hz);

2.3 (3H, s, CH3); m/z: 272(M^’).

4~[5-(2-Chlorophenyl)-4,5~dihydro-3-isoxazolyl]-2-methylphenol (CXX)

■OH CH3COOH

(CXX)

IR: (KBr) cm'*: 1600 (C=N), 1622 (C=C), 772 (G-Cl). ^H-NMR (DMSO-dg) ppm: 6.1-

7.3 (7H, m, aromatic); 5.7-5.S (IH, t, CH J = 6.4Hz); 3.56-3.59 ( 2H, dd, GHa J = 6-4 Hz,

J = 17 Hz); 2.3 (3H, s, CH3); m/z: 288(M^’).

4-[5-(2, 6-Dichlorophenyl)-4, 5-dihydro-3-isoxazolyl]‘2-methylphenol (CXXI)

■OH CH3COOH

(CXXI)

114


IR: (KBr) cm *: 1606 (C=N), 1608 (C=C), 111 (C-Cl). ^H-NMR (DMSO-d«) ppm: 6.7-

7.3 (6H, 111, aromatic); 5,7-5.8 (IH, t, CH J = 6.4 Hz); 3.56-3.59 (2H, dd, CH2 J = 6.4 Hz, J

= 17 Hz); 2.3 (3H, s, CH3); ni/z: 323(M"').

4-[5~(3-Nitrophenyl)-4, 5-dihydro-3-isoxazolyl]-2-methylphenol (CXXII)

NKOH.HCl

■OH CH,COOH

(CXXII)

IR: (KBr) cm'*: 1596 (C=N), 1600 (C=C). ^H-NMR (0MSO-ds) ppm: 6.8-8.1 (7H, m,

aromatic); 5.7-5.S (IH, t, CH J = 6 Hz); 3.56-3.59 ( 2H, dd, CH2 J = 6.4 Hz, J = 17 Hz);

2.3 (3H, .s, CHj), in/z; 299(M^').

4-[S-(2-Furyl}-4, S-dihydro-3-isoxazolyl]-2-methylphenol (CXXIII)

o0—N

CH3 NHjOH.HCI

CHjCOOH

(CXXIII)

IR: (KBr) cm *: 1606 (C=N), 1612 (C=C). *H-NMR (DMSO-dg) ppm: 6.S-7.4 (3H, m,

furan); 6.2-6.7 (3H, in, aromatic); 5.7~5.8 ( 1H, t, GH J = 6.4Hz); 3.56-3.59 ( 2H, dd, CH2 J

= 6.4 Hz, J = 17 Hz); 2.3 (3H, s, CH3); m/z: 244(M"’).

4-[5-(4~Bromophenyl)-4/5~dihydro-3-isoxazolyl]-2~methylphenol(CXXIY)

115

IR: (KBr) cm'^: 1602 (C=N), J6I0 (C=C), *H-NMR (DMSO-ds) ppm: 6.S-7.3 (7H, m,

aromatic); 5.7-5.S (IH, t, CH J = 6.4 Hz); 3.56-3.59 ( 2H, dd, CH2 J = 6.4 Hz, J = 17 Hz);

2.34 (3H, s, CH3);m/z; 333(M"’).

4’-[5-(4-Hydroxy-3~methoxyphenyl)-4^5-dihydrO‘-34soxazolyl]-2-methylphenol (CXXV)

Jsoxazolines_______________________________________________________Experimental

HO O— CH.

IR: (KBr) cni'^ 1600 (C=N), 1608 (C=C). *H-NMR (DMSO-de) ppm: 9.2- 9.7 (IH, s,

2xOH); 6.8-8.K 6H, m, aromatic); 5.7-5.8 (IH. t, CH J = 6 .4 H2); 3.9 (3H, s, OCH3); 3.56-

3.59 ( 2H, dd, CH2 J = 6.4 Hz, J = 17 Hz); 2.3 (3H, s, CH3); m/z: 300(M^').

116

Biological Consideration

DIURETIC ACTIVITY IN RATS {TJPSCHITZ TES7')

All in vivo experiinents were done following protocols approved by the CPCSEA, Janiia

Hamdard (Form No 421, Date of grant of permission: 18 Nov, 2007). Albino rats, 5 week

old, were obtained from Central Animal House Facility, Jamia Hamdard, New Delhi-130062.

RATIONALE: -

A method for testing diuretic activity in rats has been described by Lipschitz et.al (1943). The

test is based on water and sodium excretion in test animals and compared to rats treated with

a high dose of urea. Tlie “Lipschitz-value''’ is the quotient between excretion by test animals

and excretion by the urea control.

PROCEDURE:

Sixty healthy adult albino rats weighing 180-200 g were used. Each group was comprised of

six animals (n=6). They were housed in standai'd environmental conditions (temperature; 20-

25°C). The rats are fed with standard diet (Altromin® pellets) and water ad libitum. Fifteen

hours prior to the experiments food and water were withdrawn. Diiii'etic activity was

measured by collecting total excreted urine of rat kept in metabolic cage. The cages together

with the funnel and measuring cylinder used in the studies were coaled with liquid paraffin

before each experiment to facilitate the collection of urine with minimum loss. Each animal

was placed in metabolic cage provided with a wire me.sh bottom at and a funnel to collect the

urine. Stainless-steel sieves were placed in the funnel to retain feces and to allow the urine to

pass. Rats were placed in metabolic cages individually as soon as the treatments. Urine

excretion was recorded after 5 and 18h (Urine collected initially of 20min was discarded).

The test compounds were applied orally at a dose of 20mg per kg body weight in 5ml of

0.9% NaCl solution. Control group received 5ml of 0.9% NaCl solution per lOOOg body

weight. The test compounds are compared with two .standard diuretics Urea (Ig/kg body

weight in 5ml of 0.9% NaCl solution) and Frusemide (20mg/kg body weight in 5ml of 0.9%

NaCl solution). Animals were reused after two week washout period for another remaining

test compounds*.

MEASURNMENT OF URINE SODIUM POTASSIUM AND CHLORIDE LEV EL, ;

Estimation of sodium and potassium content of the urine samples treated with newly

synthesized compounds as well as other groups were done by using a lab model Mediflame

photometer. Chloride was estimated by titrating the urine by volhards method. Urinary

117

B iological Consideration

sodium, potassium and chloride content of the test groups were coinpared with that of control

and standard di’ug. The effect of different compounds 05 the sodium potassium and chloride

urinary excretion were calculated.

EVALUATION:

Urine volume excreted is recorded for each group. Results are expressed as the ‘%ipschitz-

value’\ i.e; the ratio T/U, in which T is the response of the test compound, and U, that of urea

treatment. Indices of 1.0 and more are regarded as a positive effect. With the potent diuretics,

Lipschitz- values of 2.0 and more can be found. Calculating this index foi- the 24 h (here

taking 18h) excretion period as well as for 5 h indicates the duration of the diuretic effect.

Similarly urine volume, quotients can be calculated for sodium excretion. Dose- response

curves can be established using various doses. Loop diuretics are characterized by a steep

dose- response curve. Saluretic drugs, like hydrochlorothiazide, sho ' Lipschitz- values

around 1.8, whereas loop diuretics (or high ceiling diuretics) like frusemide, bumetanide or

piretanide reach values of 4.0 and more.

Some other parameters like diuretic action and diuretic activity were also calculated. The

cumulative urine excreted during 5 h for each animal in the group is a measure of the diuretic

action for the given dose of drug. As the diuretic action is prone to variability, a pai'ameter

known as diuretic activity was calculated instead. To obtain the diuretic activity, the diuretic

action of the compound is compared to that of the standard drug^’

Total Urinary outputUrinary excretion = --------------------------------- X 100

Totalliquid intake

Diuretic action =

Diuretic activity =

Urinary excretion of treated group

Urinary excretion of control group

Diuretic action of treated group

Diuretic action of Standard group

118

Biological Con sideraiion

STATISTICAL ANALYSIS:

Each result is represented as the mean value ± S.E.M. (Standard En-or of Mean), where

number of replica (n) is 6. Statistically significant differences between treatment groups were

evaluated by analysis of variMce (ANOVA) followed by Dennett’s multiple comparison post

test. Dose-dependent effects were taken as significant differences. Probabilities less than

0.05 {P< 0.05) were taken as significant differences. P>0.05, the difference observed has no

significance i.e. occur commonly due to chance. P< 0.05, the difference observed is

significant and such difference is likely to occur due to chance®’’.

Antiviral activity

Antiviral activity assay

Confluent cell cultures in micro titer trays were inoculated with 100 CCIDjo (ICCIDjo

coiTesponding to the virus stock dilution that proved infective for 50% of the cell cultures).

After Ihour of virus adsorption to the cells, residual virus were removed and replaced by cell

culture medium (Eagle minimal essential medium) containing 3% foetal calf serum and

various concentrations of the test compounds. Viral cytopathogenicity was recorded as soon

as it reached completion in the untreated virus-infected cell cultures, i.e., at 1 to 2 days for

vesicular stomatitis; at 2 days for coxsackie and simplex types 1 and 2 and sindbis ; and 6 to

7 days for Reo and Para influenza viruses. The antiviral activity of the compounds is

expressed as the concentration required to inhibit viral cytopathogenicity by 50% (CC50) •

Cytotoxicity assays

Cytotoxicity was monitored by direct microscopical inspection of the cell monolayers which

had not been infected but were treated by the compounds at the same concentration as used in

the antiviral activity assays^^

Antimycobacterial activity

The primary screening was conducted at a concentration of 6.25mgymL (or molar equivalent

of highest molecular weight compound in a series of congeners against tuberculosis H37Rv

(ATCC27294) and INH resistant M. tuberculosis in the agar dilution technique and Bactec

Compound demonstrating at least 90% inhibition in the primary screen was re

examined at lower concentration (MIC) in broth micro dilution assay with almar blue. The

MIC was defined as the lowest concentration inhibiting ~ 99% of the inoculum. Concurrent

■ ' 119' . :• ■ ■

Biological Consideration

with the determination of MICs, compounds were tested for cytotoxicity (IC50) in VERO at

concentration equal to and greater than the MIC for M. tuberculosis H37Rv and INH

resistant M. tuberculosis after 72 h exposure. Viability was assessed on the basis of cellulai"

conversion of MTT in to a formazan product using the promega cell Titer 96 non radioactive

cell proliferation assay*^.

120

B iological Consideration

REFERENCES

1. Vogel H G, Drug discovery and Evaluation, II"'’ edn, 323.

2. Mukherjee P K, Business Horizons, 2002, 131.

3. Nedi T, Mekonnen N, Urga K, J Ethnopharmacol, 95, 2004, 57.

4. Jain S K, Mishi'a P, Indian J Chem, 43(B), 2004, 184.

5. Ratnasooriya W D, Pieris K PP, Sammaratunga U, Jayakodi } R A C , J

Ethnopharmacol, 91, 2004, 317.

6. Heira D M, Benjumea D, Abdala S, Luis H, Perez-Paz P, J Ethnopharmacol, 100,

2005, 205.

7. Nishijima K, Nishida H, Yamashita Y, Ito M, Onuki Y, Mizota M, Bur J Med Chem,

35, 2000, 227,

8. Clercq D E, Descamps J, Verhelst G, Walker R T, Jones A S, ToiTence P F, Shugar

D, J Infect Dis, 141,1980, 563.

9. Clercq D E, Holy A, Rosenberg I, Sakuma T, Balzarini J, Maudgal P C , Nature,

323,1986, 464.

10. Clercq D E, Antirnicroh Agents Chemother, 28, 1985, 84.

11. Pauwels R, Balzarini J, Baba M, Snoeck R, Schols D, Herdewijn P, Desmyter J, J

y irro lM eth ,2Q ,nm , 309.

12. Balzarini J, Naesens L, Slachmuylders J, Niphuis H, Rosenburg I, Holy A,

Schellekens H, Clercq D E, 5, AIDS, 1991, 21.

13. Collins L, Frazblau S G, Antimicrob Agents Chemother, 41,1996, 1004.

14. Heifets L B, Flory M A, Lindholm-Levy P J, Antimicrob Agents Chemother, 33,

1989, 1252.

15. Gunderson L L, Nissen- Meyer J, Spilsberg B, J Med Chem, 45, 2002, 13 83.

121

RESULTS & DISCUSSION

S y n th e s is o f p h e n o x y a c e tic a c id c h a lc o n e s (1 -V I)

Chalcones were prepared by reacting 2-(4-formyl-2-methoxypheBOXy) acetic acid with

appropriate acetophenone in the presence of base by conventional Claisen-Schmidt

condensation. The purity of the compounds was checked by TLC by using different ratio of

organic solvent. Spectral data (’H-NMR, IR) of all the synthesized compounds v^ere in full

agreement with the proposed structures, hi general, infra red spectra (IR) revealed COOH,

C=0 and C=C peak aimind 3171, 1682 and 1540 cm ’ respectively. In the Nuclear Magnetic

resonance spectra ('H-NMR) the signals of the respective protons of the prepared compounds

were verified on the basis of their chemical shifts, multiplicities and coupling constants. The

spectra showed a singlet at 8 10.2 ppm corresponding to COOH group; singlet at 8 3.7 ppm

con'esponding to methoxy group; doublet at 6 6.5-7.1 ppm corresponding to CH=CH proton;

coupling constant (J values) are within 7-13 Hz and multiplet at S 7.2-8.B ppm for ai'omatic

proton.

S y n th e s is o fp y r a z o l in e d e r iv a tiv e s ( V I I - L X X I )

Series-I (VII-XIX)

Reaction between newly synthesized chalcone (I) with appropriate acid hydrazide in glacial

acetic acid afforded titled pyrazoline (YII- XIX) (reaction time varied from 6-12 h).

Compounds were purified by recrystallization and column chromatography (Pertroleum:

hexane, 3:1). Both analytical and spectral data ('H-NMR, IR) of all the synthesized

compounds were in full agreement with the proposed structures. In general, infra red spectra

(IR) revealed COOH, C=N and C-N peak around 3174, 1560 and 1378 cm’’ respectively. In

the Nucleai’ Magnetic resonance spectra ('H-NMR) the signals of the respective protons of

the prepared compounds were verified on the basis of their chemical shifts, multiplicities and

coupling constants. The spectra showed double doublet as a usual pyrazoline pattern at 8 6.3

(H x ), 8 3.8 (Hb), and 8 3.2 (H a ) for all compounds of the series except compound VIII, XIII,

XVI (ortho substituted derivatives) where pyrazoline ring formation showed a characteristic

doublet and triplet for C-3 methylene and C-4 protons at a shift at 8 3.6 and 4.9 ppm

respectively. Singlet at 8 3.6 ppm corresponding to methoxy group; singlet at 8 9.4 ppm

corresponding to OH group, as in compound XVI; multiplet at 5 6.50-8.32 ppm for aromatic

proton; singlet at 8 2.3 ppm corresponding to CH3 group; singlet at 8 10.1-10.8 ppm

Synthesis________ ______________ ________________________________R esults & D iscussion

122

corresponding to COOH group. The elemental analysis results were within ± 0.4% of the

theoretical values.

Serles-II (XX-XXXII)

Reaction between newly synthesized chalcone (II) with appropriate acid hydrazide in glacial

acetic acid afforded titled pyrazoline (XX- XXXII) (reaction time varied from 6-12 h).

Compoimds were puiified by recrystallization and column, chromatography (Pertroleum;



(IR) revealed COOH, C=N and C-N peak at 3168, 1560 and 1378 cm’’ respectively. In the

Nuclear Magnetic resonance spectra ('H-NMR) the signals of the respective protons of the

prepared compounds were verified on the basis of their chemical shifts, multiplicities and


(H x ) , 5 3.8 (H b), and 6 3.2 (H a) for all compounds of the series except compound XXI,

XXVI and XXIX (ortho substituted derivatives) where pyrazoline ring formation showed a

characteristic doublet and triplet for C-3 methylene and C-4 protons at a shift 5 3.7 and 4.5

ppm respectively. Singlet at 6 3.6 ppm con-esponding to methoxy group; singlet at 6 10.1

ppm con’esponding to OH group, as in compound XXIX; multiplet at 8 6.85-8.44 ppm for

aromatic proton; singlet at 6 2.3 ppm corresponding to C H 3 group; singlet at 5 9.9-10.8 ppm


theoretical values.

Series-m (XXXIII- XLV)

Reaction between newly synthesized chalcone (III) with appropriate acid hydrazide in

glacial acetic acid afforded titled pyrazoline (XXXIII- XLV) (reaction time varied from 6-12

h). Compounds were purified by recrystaliization and column chromatography (Pertroleum:

hexane, 3:1). Both analytical and spectral data (^H-NMR, IR) of all the synthesized

compounds were in full agreement with the proposed structwes. In general, infra red spectra

(IR) revealed COOH, C=N and C-N peak at 3232, 1559 and 1374 cm"’ respectively. In the

Nuclear Magnetic resonance spectra (^H-NMR) the signals of the respective protons of the


coupling constants, The specti'a showed double doublet as a usual pyrazoline pattern at 8 6.2

(H x ) , 8 3.8 (H b) , and 8 3.2 (H a ) for all compounds of the series except compound XXXIV,

Synthesis______________________________ ___________________Results & Discussion

123

XXXIX, and XLII (ortho substituted derivatives) where pyrazoline ring formation showed a

chai'acteristic doublet and triplet for C-3 methylene and C-4 protons at a shift 5 3.7 and 4.7

ppm respectively. Singlet at 8 3.6 ppm corresponding to methoxy group; singlet at 6 9.2 ppm

corresponding to OH group, as in compound XLII; multiplet at 8 6.82-8.32 ppm for

aromatic proton; singlet at 5 2.3 ppm corresponding to CH3 group; singlet at 5 10.2-10.5 ppm


theoretical values.

Series-IV (XLVI-LVIII)

Reaction between newly synthesized chalcone (IV) with appropriate acid hydrazide in glacial

acetic acid afforded titled pyrazoline (XLVI- LVIII) (reaction time varied from 6-12 h).

Compounds were purified by recrystallization and colunm chromatography (Pertroleum:



(IR) revealed COOH, C=N and C-N peak at 3185, 1560 and 1378 cm'’ respectively. In the

Nuclear Magnetic resonance spectra (’H-NMR) the signals of the respective protons of the



(Hx), 5 3.8 (Hb), and 8 3.2 (Ha) for all compounds of the series except compound XLVII,

LII, and LV where pyrazoline ring formation showed a characteristic doublet and triplet for

C-3 methylene and C-4 protons at a shift 5 3.2 and 4.8 ppm respectively. Singlet at 8 3.7 ppm

coixesponding to methoxy group; singlet at 5 9.2-10.1 ppm corresponding to OH group,

multiplet at 5 6.67-8.73 ppm for aromatic proton; singlet at 5 2.2 ppm corresponding to C H 3 ;

singlet at 8 10-10.5 ppm corresponding to COOH group. The elemental analysis results were

within ± 0.4% of the theoretical values.

Series-V (LIX-LXXI)

Reaction between newly synthesized chalcone (V) with appropriate acid hydrazide in glacial

acetic acid afforded titled pyrazoline (LIX-LXXI) (reaction time varied from 6-12 h).

Compounds were purified by recrystallization and column chTomatography (Pertroleum:

hexane, 3:1). Both analytical and spectral data (’H-NMR, IR) of all the synthesized


(IR) revealed COOH, C=N and C-N peak at 3219, 1545 and 1325 cm'’ respectively. In the

Synthesis_______________________________ Results & Discussion

124

Synthesis_________________________________________________ R esults & D iscussion

Nuclear Magnetic resonance spectra (’H-NMR) the signals of the respective protons of the


coupling constants. The spectra showed a singlet at 5 10.2-10.8 ppm corresponding to the

COOH group. The pyrazoline ring formation showed a characteristic doublet and triplet for

C'3 methylene and C-4 protons at a shift 5 2,5 and 4.8 ppm respectively, a singlet at 5 3.6

ppm for methoxy gi'oup, a multiplet at 8 6.86-8.12 ppm for aromatic protons and a singlet at

8 9.4 ppm for OH protons. It was found interesting that only two compound of tlie series

LXIV and LXIX have shown usual pyrazoline splitting.

Synthesis o f o x a d ia zo le d e r iv a tiv e s (L X X I I - X C IX )

Series-I (LXXII- LXXVIII)

Oxadiazoles (LXXII- LXXVIII) were prepared by reacting chalcone (I) and appropriate

acid hydrazides in presence of phosphoius oxychloride (reaction time vaiied from 10-18 h).

The purity of the compounds was checked by TLC using different ratio of organic solvent

and melting point. Both analytical and spectral data (^H-NMR, IR) of all the synthesized


(IR) revealed C-C, C=N and C-O-C peak at 1654, 1560 and 1167 cm'’ respectively. In the

Nuclear Magnetic resonance spectra (*H-NMR) the signals of the respective protons of the


coupling constants. The specti’a showed a multiplet at 5 6.88-8.33 ppm corresponding to

aromatic proton; a singlet at 8 3.7 ppm for methoxy group. The elemental analysis results

were within ± 0.4% of the theoretical values.

Series-II (LXXIX- LXXXV)

Oxadiazoles (LXXIX- LXXXV) were prepared from chalcone (III) and appropriate acid

hydi azides in presence of phosphorus oxychloride (reaction time varied from 10-18 h). The

purity of the compounds was checked by TLC using different ratio of organic solvent and

melting point. Both analytical and spectral data (’H-NMR, IR) of all the synthesized


(IR) revealed C-C, C=N and G-O-C peak at 1654, 1560 and 1157 cm'* respectively. In the

Nucleai- Magnetic resonance spectra (^H-NMR) the signals of the respective protons of the


coupling constants. The spectra showed a multiplet at 5 6.96-8.31 ppm corresponding to

125

aromatic proton; a singlet at 5 33-3.9 ppm for methoxy group. The elemental analysis results


Series-Ill (LXXXVI- XCII)

Oxadiazoles (LXXXVI- XCII) were prepared from chalcone (IV) and appropriate acid

hydrazides in presence of phosphorus oxychloride (reaction time varied from 10-18 h). The

purity of the compounds was checked by TLC using different ratio of organic solvent and

melting point. Both analytical and spectral data ('H-NMR, IR) of all the synthesized


(IR) revealed C-C, C=N and C-O-C peak at 1654, 1560 and 1156 cm"’ respectively. In the

Nuclear* Magnetic resonance spectra (’H-NMR) the signals of the respective protons of the





Series-IV(XCIII-XCIX)

Oxadiazoles (XCIII - XCIX) were prepared from chalcone (VI) and appropriate acid

hydrazides in presence of phosphorus oxychloride (reaction time varied from 10-18 h). The

pui'ity of the compounds was checked by TLC using different ratio of organic solvent and

melting point. Both analytical and spectral data (’H-NMR, IR) of all the synthesized


(IR) revealed C-C, C=N and C-O-C peak at 1654, 1559 and 1159 cm'' respectively. In the

Nuclear Magnetic resonance spectra (^H-NMR) the signals of the respective protons of the





S y n th e s is o f C h a lc o n e d e r iv a tiv e s (C-CXJI)

Chalcones were prepared by reacting different substituted aromatic aldehydes with an

appropriate acetophenone in the presence of base by Claisen-Schmidt condensation. The

purity of the compounds was checked with TLC by using different ratio of organic solvent

and melting point. Spectral data (’H-NMR, IR) of all the synthesized compounds were in full

Syjtihesis___________________________________R esults & D iscussion

126

agreement with the proposed stiuctures. In general, infra red spectra (IR) revealed OH, C=H

and C=0 peak at 3200, 3040 and 1686 cm'' respectively. In the Nuclear Magnetic resonance

spectra (’H-NMR) the signals of the respective protons of the prepared compounds were

verified on the basis of their chemical shifts, multiplicities and coupling constants. The

spectra showed a singiet at singlet at 6 3.9 ppm corresponding to methoxy group; doublet at S

6.9-7.S ppm coitesponding to CH=:CH proton; coupling constant (J values) are within 6-8

Hz and multiplet at 5 6.9-7.5 ppm for aromatic proton; a singlet at 5 2.3 ppm corresponding

to methyl proton.

Synthesis o f I so x a z o lin e derivatives (C X H I-C X X V )

Reaction between synthesized chalcones (C-CXII) with hydroxyl amine HCI in glacial acetic

acid (reaction time varied from 9-12 h) afforded the titled isoxazolines (CXIII-CXXV) in

76-94% yield after recrystallization. Purity of compounds was checked by TLC and melting

point. Both analytical and spectral data (’H-NMR, IR) of all the synthesized compounds were

in full agreement with the proposed structures. In general, Infra Red spectra (IR) revealed,

OH, CH, G=N peaks at 3300, 3040, 1600, cm’’, respectively. The ’H-NMR spectra showed a

singlet at 6 2.3 ppm con-esponding to the methyl group; double doublet at 8 3.56-3.59 ppm

corresponding to the C-4 methylene group; a singlet at 6 3.9 ppm corresponding to the O C H 3

group; double doublet at 5 5.78-5.82 ppm corresponding to C-5 proton; a multiplet at 8 6.82-

8.12 ppm for the aromatic protons; and a singlet at d 9.7 ppm corresponding to the OH

proton.

Synthesis_______________________ ______ ________________________ R esu lts & Discussion

127

Diuretic activity

Selected compounds of pyrazoline series (Table la, Ib, Ic, Id and I^) were subjected for in-vivo

diuretic screening by standard Lipschitz method {1943) on ciJbiito rats at a dose of 20mg/kg

body weight using frusemide as a reference drug. Cuimiiative urine excreted during 0-5h and

5-18h for each group (6 albino rats) was measure of urinary excretion; data in Table-IV,

IVa, V and Va. During 0-5h compounds XXII, XXV. XXVII and XXVIII showed an

increase in cumulative urine output, whereas compound 2~(2-methox.y-4-f3-(4-chlorophenyl)

-1 -(2-phenoxyacetyl) -4,5-dihydrO'IH-5-pyrazolyij phenoxyj acetic acid (XXVIII) was

highly significant with urinary excretion of 247% with respect to control. Compound XXX,

XLI and LXVII lies in between control (98.40%) and standard frusemide (194.54%). During

5-18h the cumulative urine output of most of the compound was drastically increased with

comparison to the standard. Compound XXV, XXVII and XXVIII shows an increase in

urine output by almost one & half times to their 0-5h; Table IV and V. Among these 2-{4-

[l-(4-methylbenzoyl)-3-(4-chloropheny])'4,5-dihydro-]H-5-pyrazolyl]-2-methoxyphenoxy]

acetic acid (XXV) and 2-{2-methoxy-4~[3-(4-chlorophenyl)-l-(2-phenoxyacetyl)-4,5-

dihydro-lH-5-pyrazolyl] phenoxy)acetic acid (XXVIII) were highly significant 12.18±0.047

and 10.17±0.042 i.e. increased by 466.66% and 345.91%. Diuretic action of XXII, XXV,

XXVII and XXVIII was found to be 2.2, 2.2, 2.0 and 2.5 in comparison to 1.90 and 1.97 for

urea and frusemide respectively as shown in Table IV during 0-5h. Diuretic action in the

next 5-18h of study was increased by 3 to 4 fold as shown in Table V and it was 5.5, 9.3, 5.6

and 6.9 for XXII, XXV, XXVII and XXVHI. Diuretic activity of compounds XXV, XXVII

and XXVIII was significantly increased from 0-5h to 5-18h of study (Table-IV&V).

Lipschitz value during 0-5h and 5-18h of compound XXY, XXVII, XXVIII and LXVII was

significantly increased. Some of the compounds have Lipschitz value nearly equal to urea

(>1.0, means positive effects).

Compounds of pyi'azoline series (Tabic I.,, Ib, Ic.Ta and le) was also tested for excretion of

salt (Na" , K" , Cl') in urine in albino rat model. During 0-5h compounds XXII, XXVITand

XXVIII showed a significant increase in sodium excretion (p<0.05) i.e 2.82±0.003,

2.61 ±0.006, and 3.26±0.004 which was either similar or more than frusemide. XXII, XXVII

and XXVIII also show significant kaliuretic (excretion of potassium in urine) property

(p<0.05) i.e 1.55±0.01, 1.32+0.007, and 1.74±0.008, which are also more than the standard

Biological evaluation________________________________________ Results & Discussion

128

drug frusemide (L27+0.005). With regards to Na”/ ratio, it was observed that 2-{2~

methoxy-4-[3-(4-chlorophenyl)-1 -(2-phenylacetyi)-4,5-dihydro-1 H-5-pyrazolyl Jphenoxy)

acetic acid (XXX) exhibited stronger kaliuretic property with a ratio of (1.7). Table IVa

shows that compound 2-{2-methoxy-4-[3-(4-methoxyphenyI)-l-(2-phenoxyacetyl)-4,5-

dihydro-lH-5-pyrazolyl] phenoxy} acetic acid (XLI) and 2-{4-[3-(2,4-dihydroxyphenyl)-l-

(2-phenoxyacetyl)-4,5-dihydro-lH-5-pyrazoly]]-2-methoxyphenoxy] acetic acid (LXVII)

was potassium sparing (3.5, 3.4), while in rest of the compounds NaV K' ratio lies between

1.8-2.1 i.e. more kaliuretic. During period of 5-18h most of the compounds showed kahuretic

property; Table Va. Chloride excretion was also increased up to similar extent of sodium.

During 0-5h the ratio of Na'^/Cr for the compound 2-(2-raethoxy-4- {3-(4-chlorophenyl)-1 -[2-

(4-methylphenoxy)acetyI]-4,5-dihydro-lH-5-pyrazolyl)phenoxy)acetic acid (XXVII) was

calculated to be one, is least in the series which indicates that chloride excretion is more.

During next 5~18h chloride excretion of most of the compound does not change much.

In general compound XXII, XXV, XXVII and XXVIII had good diuretic potential. So it

was concluded that substituent with p-chlorobenzoyl, /7-methylbenzoyL yj-methyl

phenoxyacetyl and phenoxyacetyl at position I of pyrazoline moiety imparted good activity.

It was also observed that compound 2-{4-[]-(4-methylbenzoyl)-3-(4'Chloropheny])-4,5-

dihydro-lH-5-pyrazolyl]-2-methoxyphenoxy]acetic acid (XXV) with ;?-methy]benzoyl

substitution at position 1 and p-chlorophenyl substitution at position 3 of pyrazoline moiety

doubled the urinary excretion during 5-18h interval as compared to 0-5h of study.

Selected compound of (Table Ilg, Ilb, IIc, Ha ) oxadiazole series were also subjected for m-

vivo diuretic screening by same standard Lipschitz method (1943) on albino rats at a dose of

20 mg/kg body weight using frusemide as a reference drug. Cumulative urine excreted during

0-5h and 5-18h for each group (6 albino rats) was measure of urinary excretion. All the data

is presented in Table VI, Via, VII and Vila. In 0-5h, compound 3-13-methoxy-4-(5-

phenoxymethyl-1, 3 ,4-oxadiazol-2-ylmethoxy)phenyl]-l-phenyl'2-propen'l-one (LXXVIII)

showed an increase in cumulative urine output and was highly significant 6.56+0.010

(p<0.05) and increased by 280% with respect to control. In rest of the compounds cumulative

urine output (TabkVI) was less than standard frusemide 6.25±0.123 (p<0.05). During next

5-18h of study cumulative urine output of most of the compound was decreased except

compound LXXVIII (TableVII) which shows an increase in urinary output i.e.

B iological evaluation____________________________________________ R esu lts & Discussion

129

7.33±0.008(p<0.05) which was 333% with comparison to standard; frusemide

6.83±0.011(p<0.05) which was 248%.

During 0-5h of study diuretic action of compound LXXVIII was significantly increased (2.8)

as compared to frusemide (2.31) and urea (1.97) (TaWeVI). Rest of the compound of series

exhibited diuretic action less than standai'ds. Diuretic action (during 5-18h) of most of the

compounds of series was increased by ~ 2-4 fold as compared to 0-5h of study. Although

compound 3-[3-raethoxy-4-(5-phenoxymethyl-l, 3, 4-oxadiazo3-2-ylmethoxy) phenyl]-!-

phenyl-2-propen-1 -one (LXXVIII) was most potent with diuretic action of 6.3 (Table VII),

Lipschitz value showed that compound LXXVIII is more potent than urea as urinary output

was significantly increased during study 5-18h (TableVII); another compound of the series

3-{4-[5-(2-hydroxyphenyl)-l,3.4-oxadiazol-2-ylmethoxy]-3-methoxyphenyl}-l-(4-meihoxy

phenyl)-2-propen-1 -one (LXXXIV) has value (1.01), (TableVI) nearly equal to urea (>1,0,

means positive effects).

All compounds of oxadiazole series (Sheme-II) were further evaluated for their excretion of

salt (Na’j K'*', Cl') in urine in albino rat model. During 0-5h of study compounds LXXII,

LXXVIII, XCI, XCIV, XCVIII and XCIX showed a significant increase in sodium

excretion (p<0.05) i.e. 1.71±0.022, 2.79±0.020, 1.60±0,010, 1.81+0.018, 1.82±0.017, and

1.89+0.013 respectively which was more than frusemide (L46±0.013), but kaliuretic

property of these compounds was not significant except compound LXXVIII (1.55±0.014)

as shown in (Table V IJ. With regai'ds to Na'*' /K^ ratio, it was observed that coinpound

LXXVIII and XC were stronger Kaliuretic (1.8). From the study it was also concluded that

compound XCI, XCIV and XCVIII were excellent potassium sparing (3.0, 3.3, 3.9) while

rest of the compound were found moderate to good potassium sparing- During 5-18h of study

most of the compound inci*eases kaliuretic property except compound LXXVIII, XC and

XCIV (Table Vila). Chloride excretion was also increases almost in similar fashion as

sodium. The NaVCf ratio was least for compound LXXVIII (1.4) as shown in (Table Via)

for the duration of 0-5h. During 5-18h Chloride excretion tendency was not much increased

as in 0-5h o f study and Na' /CF ratio of compound LXXXIII (1.1) was minimum during 5-

18h of study (Table Vila). On the basis of activity exhibited by the compounds o f the series

a SAR was developed which indicates that oxadiazole ring with unsubstituted phenyl ring

showed maximum diuretic potential as in compound LXXVIH. On the other hand it was also

Biological evaluation _______________________________ R esu lts & D iscussion

130

observed that compound bearing electron withdrawing group in their phenyl ring was more

potent as compaied to compound having electron donating group in their phenyl ring as in

compound, LXXXIII, LXXXIV, LXXXV and XCIX respectively. Compound 3-!3-

methoxy-4-(5-phenoxymethyl-l,3,4-oxadia2ol-2-ylmethoxy) phenyl]-l-(4-nitrophenyl)-2-

propen-l-one(XCIX) having phenoxy substituent in the 5* position of oxadiazole and

electron withdrawing NO2 group in their phenyl ring shows more diuretic propensity as

compared to the compound like LXXXIII, LXXXIV and LXXXV was having -OCH3

electron donating group in the phenyl ring of oxadiazole.

Antiviral activity

The newly synthesized compounds XX-LXXI, (except XXVI & XXVIII) were evaluated

for their in vitro antiviral activity against Feline Corona Virus (FIPV) and Feline Herpes

Virus (in Crandell-Rees Feline Kidney; (CRFK) cell cultures), herpes simplex vii'us-l

(KOS), herpes simplex virus-2 (G), Vaccinia virus, Vesicular stomatitis virus, herpes simplex

virus-1 TK-KOS ACV* (in HEL cell cultures); Vesicular stomatitis virus, Coxsackie virus

B4, Respiratory syncytial virus (in HeLa cell cultures); Parainfluenza-3 virus, reovirus-1,

Sindbis virus, Coxsackie virus B4, Punta Toro virus (in Vero cell cultures). For each

compound, the Minimum Cytotoxic Concentration (MCC) [or 50% cytotoxic concentration

(CC50) for CRFK,] was determined. Ribavirin, Brivudin, Acyclovir, Ganciclovir, Dextran

sulfate (DS-5000) and (S)-DHFA were used as the reference compounds.

The results of the antiviral assays are shown in (Table-VIIIa-XId) against Cytotoxicity

towards uninfected host cells was determined under same conditions as antiviral activity i.e

microscopic evaluation of the cell moiphology of the confluent cell monolayer which either

had or had not been inoculated with virus. As the criterion for specific antiviral activity was

taken the inhibition of virus-induced cytopathogenicity at a concentration that was at least 5-

fold lower than the concentration required altering the morphology of the uninfected host

cells.

From the data obtained after the screening it was found that compound 2-{4“[l-(4-

bromobenzoyl)-3-(4-chlorophenyl)-4, 5-dihydro-lH-5-pyrazoIyl]-2'methoxyphenoxy] acetic

acid (XXIII) was active against all most all the selected strain of the viruses and compound

2-(2-methoxy-4- {3 -(4-chlorophenyl)-1 - [2-(2-naphthyloxy)acetyl]-4,5'dihydro-1H-5 pyrazol

yl)phenoxy)acetic acid (XXXII) was also shown good activity against most of the selected

Biological evaluation___________ _______________________ _____ Results & Discussion

131

strains [Viz: herpes simplex virus-1 (KOS), herpes simplex virus-2 (G), Vaccinia viius.

Vesicular stomatitis virus, herpes simplex virus-1 TK-KOS ACV (in HeL cell), Vesicular

stomatitis virus, Coxsackie viras B4, Respiratory syncytial virus (in HeLa cell cultures),

Pai’ainfluenza-3 virus, reovims-1, Sindbis virus, Coxsackie virus B4, Punta Toro virus (in

Vero cell cultures)] of vimses where as compound X X I I , XXIV & XXIX were found to be

potential candidates of the series as they shows good activity against few strains of

viruses(Table-VIIIa-VIIId)

It was also observed that among /?-chloroacetophenone derived pyi'azolines, presence of

electron withdrawing substituent at position 1 ( X X I I , XXIII & XXIV) enhances antiviral

activity. Moreover 2-hydroxyphenyl (XXIX) and 2-napthyloxyacetyl substituted (XXXII)

derivatives of the series were also potent up to certain extent (Table-VIIIa-d)*

The. data included in Table (IXa-d) indicates compound 2-(2-methoxy-4-{3-(4-

methoxyphenyl)-l-[2-( 1 -naphthyloxy)acetyl]-4,5-dihydro-lH-5-pyrazolyl} phenoxy) acetic

acid (XLIV) was active against almost all the selected strains of viruses but its cytotoxic

concentration was low as compare to standards. Therefore it can be considered potential

candidates of the series, where as compound 2'{2-methoxy-4-[3-(4-methoxyphenyl)-l-(2-

phenoxyacetyl)-4,5-dihydro-lH-5-pyrazolyI]phenoxy) acetic acid(XLI) was active against

herpes simplex virus-] (KOS), heipes simplex virus-2 (G), Vaccinia virus. Vesicular

stomatitis virus, herpes simplex virus-1 TK-KOS ACV^ (in HeL cell) strains of viruses,

similarly compound XLII & XLV were also active against herpes simplex virus-1 (KOS),

herpes simplex virus-2 (G), Vaccinia virus. Vesicular stomatitis virus, herpes simplex virus-1

TK-KOS ACV^ (in HeL cell). Vesicular stomatitis virus, Coxsackie virus B4, Respiratory

syncytial virus (in HeLa cell cultures), Parainfluenza-3 virus, reovirus-1, Sindbis virus,

Coxsackie virus B4, Punta Toro virus (in Vero cell cultures) virus strains respectively.

Among the pyrazolines synthesized from p-hydroxyacetophenones compound 2-{4-fl-(2-

hydroxybenzoyl)-3-(4-hydroxy phenyl)-4,5-dihydro-lH-5-pyrazolyl] -2-methoxy phenoxy)

acetic acid (LV) was the most potent compound against Felina Corona Virus, Felina Herpes

Virus(inCrandell-Rees Felina Kidney(CRFK) cell culture), Parainfluenza-B virus, reovirus-1,

Sindbis virus, Coxsackie virus B4, Punta Toro virus (in Vero cell cultures) virus strains

especially against Parainfluenza-3 virus as it was almost equipotent to standard Ribavirin

(Table Xa). Compound 2-(2-methoxy-4-{3-(4-hydroxyphenyl)-l-[2-(l-naphthyloxy) acetyl]-

B iological evaluation_________ ___________________________________ Results & Discussion

132

4,5-dihydro-lH-5'pyrazoly]}phenoxy) acetic acid (LVII) was also effective against most of

the viruses but it was toxic as compared to standards. Compound LI, H I , LIII, LIV were

active against herpes simplex vims-1 (KOS), herpes simplex virus-2 (G), Vaccinia virus,

Vesicular stomatitis virus, herpes simplex virus-1 TK-KOS ACV’’ (in HeL cell)viral strains

(Table Xb). Moreover compound 2-{2-methoxy-4-[3-(4'hydroxyphenyl)-l-(2-phenoxy

acetyl)-4,5-dihydro-lH-5-pyrazolyl]phenoxy}acetic acid (LIV) was also active against

Pai'ainfluenza-3 virus, reovinas-1, Sindbis virus, Coxsackie virus B4, Punta Toro virus (in

Vero cell cultures) viral strains(Table Xa).

According to activity observed by pyrazolines (LIX-LXXI); derivative LXXI were found

active against herpes simplex virus-1 (KOS), herpes simplex virus-2 (G), Vaccinia virus.

Vesicular stomatitis virus, herpes simplex virus-1 TK-KOS ACV^ (in HeL cell); (Table Xlb),

LXVII, LXVIII and LXXI against, Vesicular stomatitis virus, Coxsackie virus B4,

Respiratory syncytial virus (in HeLa cell cultures); (Table XIc). Whereas compound LXX

and LXXI were active against; Parainfluenza-3 virus, reovirus-1, Sindbis virus, Coxsackie

virus B4, Punta Toro virus (in Vero cell cultures). These data clearly indicate that compound

bearing hydroxyl analogue LXVIII and phenoxy acetic acid hydrazide analogues like

LXVII, LXX, and LXXI appears to be essential for the antiviral activity.

Antimycobacterial activity

The synthesized compounds (CXIII-CXXV) were tested for their in-vitro anti-mycobacterial

activity against MTB and INHR-MTB by using the agar dilution method and bactec 460 for

the determination of the Minimum Inhibitory Concentration (MIC). The MIC was defined as

the minimum concentration of compound require to inhibit ~99% of bacterial growth and

MIC’s of the compounds are reported in Table XII with the standard drug INH for

comparison.

Among the thirteen compounds synthesized, three compounds were found to be most active

compounds with MICs of less than IpM against MTB. In genera] compounds with halogen-

substituted phenyl group showed more activity. Among the synthesized compounds,

compounds 4[5-(4-bromophenyl)-4, 5-dihydro-3-isoxazolyl]-2'methylphenol (CXXIV) was

found to be the most active agent against MTB and INHR-MTB with MIC of 0.62 (aM.

Compounds with /?-chloro phenyl (CXTV) and o-chlorophenyl substituent (CXX) were also

found to be active against MTB with MIC of 0,83, and 0.72 |rM, respectively. Among these

B iological evaluation____________________________________________ R esu lts & Discussion

133

compounds that with the p-bromo phenyl substituent (CXXIV) was found to be 1 .12-fold

and 3.0-fold more active than INH against MTB aaid INHR-MTB, respectively. However

fluorophenyl and nitre phenyl substitutions produced moderate inhibitory activity against

MTB and INHR-MTB. On the other hand, the analogues with an electron donating group

(OCH3) p-methoxyphenyl (CXIII), 3, 4-dimethoxy phenyl (CXVII) and 3,4,5-trimethoxy

phenyl (CXVIII) exhibited relatively low inhibitory activity against MTB and INHR-MTB,

Among the newer derivatives, compound CXXIV showed a promising activity in-vitro. It is

conceivable that these derivatives showing anti-mycobacterial activity can be further

modified to exhibit better potency than the standard drugs.

Biological evaluation____________________ ____________________ Results & Discussion

134

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