CHALCONE - Shodhganga : a reservoir of Indian theses @ …shodhganga.inflibnet.ac.in/bitstream/10603/2520/8/08... · · 2012-05-31CHALCONE INTRODUCTION ... chalcone and its derivatives33-36

Chapter - I: Introduction

CHALCONE

INTRODUCTION

The chemistry of chalcones has generated intensive scientific studies

throughout the world. Especially interest has been focused on the synthesis and

biodynamic activities of chalcones. The name “Chalcones” was given by

Kostanecki and Tambor1. These compounds are also known as

benzalacetophenone or benzylidene acetophenone. In chalcones, two aromatic

rings are linked by an aliphatic three carbon chain. Chalcone bears a very good

synthon so that variety of novel heterocycles with good pharmaceutical profile

can be designed.

Chalcones are -unsaturated ketone containing the reactive keto-

ethylenic group –CO-CH=CH-. These are coloured compounds because of the

presence of the chromophore -CO-CH=CH-, which depends in the presence of

other auxochromes.

Different methods are available for the preparation of chalcones2-4.The

most convenient method is the Claisen-Schimdt condensation of equimolar

quantities of arylmethylketone with aryl aldehyde in the presence of alcoholic

alkali5.

Chalcones are used to synthesize several derivatives like cyanopyridines,

pyrazolines isoxazoles and pyrimidines having different heterocyclic ring

systems.6-9

1


N N

NH2

Ar Ar'

Pyrimidine

GuanidineAr C

O

CH

CH Ar'

NH2OH

NH2NH2

Malononitrile

N

CN

Ar'

Ar

Cyanopyridine

NNH

Ar Ar'

Pyrazoline

NO

Ar Ar'

Iso-oxazole

NOMENCLATRURE

Different methods of nomenclatures for chalcone were suggested at

different times. The following pattern has been adopted by “Chemical

Abstracts” published by American chemical society.

C CH CH

O

1

2 3

4

56

1'

2'3'

4'

5' 6'

(I)

The British Chemical Abstract and Journal of Chemical Society have

followed the following system.

2


C CH CH

O

1

23

4

5 6

1'

2' 3'

4'

5'6'(II)

SYNTHETIC METHODS OF PREPARING CHALCONES

CLAISEN-SCHMIDT REACTION

A variety of methods are available for the synthesis of chalcones, the

most convenient method is the one that involves the Claisen-Schmidt

condensation of equimolar quantities of a substituted acetophenone with

substituted aldehydes in the presence of aqueous alcoholic alkali.10-17 In the

Claisen-Schmidt reaction, the concentration of alkali used, usually ranges

between 10 and 60 %.18-19 The reaction is carried out at about 50 oC for 12-15

hours or at room temperature for one week. Under these conditions, the

Cannizaro reaction20 also takes place and thereby decreases the yield of the

desired product. To avoid the disproportionation of aldehyde in the above

reaction, the use of benzylidene-diacetate in place of aldehyde has been

recommended.21 (a)

C OHC

R

C

O

CH

CH

R'

R'R

+

:OH- -H2O

O

CH3

VARIOUS CONDENSING AGENTS USED IN SYNTHESIS OF CHALCONES

3


[1] Alkali

Alkali has been the most used condensing agents for synthesis of

chalcones. It is used as an aqueous solution of suitable concentration viz. 30 %,

40 %, 50 % and 70 %.

[2] Hydrochloric Acid

Dry hydrochloric gas in a suitable solvent like ethylacetate at 0 oC was

used as a condensing agent in a few syntheses of chalcones from aromatic

ketones. Methanolic solution of dry hydrochloric acid gas at 0 oC was also used

by Lyle, Paradis21 (b) and Marathey21 (c).

[3] Other Condensing Agents

Raval and Shah22 used phosphorous oxychloride as a condensing agent to

synthesize of chalcones. Szell and Sipos23 condensed 2-hydroxy-5-nitro-

acetophenone with benzaldehyde using anhydrous AlCl3. Kuroda, Matsukuma

and Nakasmura24 obtained chalcone by condensing acetophenone derived from

anisole and other polymethoxy benzenes with some methoxyaldehydes in

presence of anhydrous aluminium chloride.

Besides the above, other condensing agents used in synthesis of

chalcones have been,

(1) Amino acid 25

(2) Aqueous solution of borax 26

(3) Perchloric acid 27

(4) Piperidine 28

(5) Boron trifloride 29

(6) Alkali metal alkoxide 30

(7) Magnesium tert-butoxide 31

4


(8) Organocadmium compound 32

MECHANISM OF CHALCONE FORMATION

Kinetic studies have been reported for the base-catalyzed formation of

chalcone and its derivatives33-36. Two alternative mechanisms have been

advanced for the reaction of benzaldehyde with acetophenone in the presence

of a basic catalyst.

CH3COPh C2H5O CH2COPh C2H5OH

CH2COPh PhCHO Ph C CH2COPh

O

H

Ph C CH2COPh

O

H

H2O Ph C CH2COPh

OH

H

OH

Ph C CH2COPh

OH

H

Ph-CH=CHCOPh H2O

[I]

+

+

+

+

+

+

C2H5OPhCHO Ph C OC2H5

O

H

Ph C OC2H5

O

H

CH3COPh Ph C CH2COPh

OH

H

[II]

+

+

5


The formation of chalcone by the acid catalyzed condensation of

acetophenone and benzaldehyde has been studied.37, 38

The following mechanism seems to be operating

Ph C CH3

O

Ph C CH2

OH

+

Ph C

O

H Ph C

OH

H S[S=Solvent]

SH+

Ph C CH2

OH

Ph C H

OHTransition

+

Ph C

OH

CH2 CH Ph

OH

Ph C

OH

CH2 CH Ph

OH

Ph C

O

CH2 CH Ph

OH

Ph C

O

CH2 CH Ph

OH2

SH

S

+

++

Complex

S

+

+

+ +

+

+

Ph C

O

CH2 CH Ph

OH2

Ph C

O

CH CH Ph H2OH+

+

+ +

IMPORTANCE OF CHALCONES

(1) They have close relationship with flavones, aurones, tetralones and

aziridines.

6


(2) Chalcones and their derivatives find application as artificial sweeteners39-43,

scintillator44, polymerization catalyst 45-46, fluorescent whitening agent47,

organic brightening agent48-49, stabilizer against heat, visible light, ultraviolet

light and aging.50-54

(3) 3,2’,4’,6’-tetrahydroxy-4-propoxy-dihydrochalcone-4-β'-neohesperdoside55

has been used as synthetic sweetener and is 2200 times sweeter than

glucose.

(4) They contain a keto-ethylenic group and are therefore reactive towards

several reagents e.g. (a) phenyl hydrazine, (b) 2-amino thiophenol etc.

(5) The chalcones have been found useful in elucidating structure of natural

products like hemlock tannin56, cyanomaclurin57, ploretin58, eriodictyol and

homo eriodictyol59, naringenin60 etc.

METHODS OF SYNTHESIS

Carthamin (III), a red pigment was first obtained as red needles with

green iridescence using pyridine solvent from the flowers of cartharmus tinctoria

(safflower) by Kmetaka and Perkin61 and this was the first known example of

chalcone in nature.

OGC

OH

OHO

OHC

O

CH

CH

(III)

It isomerizes to a yellow compound isocarthamin (IV) on treatment with

dil. HCl as reported by Kuroda62.

7


OHC

O

CH

CH

(IV)

OHHO

OGC

OH

A variety of methods are available for the synthesis of chalcones. The

most convenient method is the one that involves the Claisen-Schmidt

condensation of equimolar quantities of substituted acetophenone with

substituted aldehydes in presence of aqueous alcoholic alkali.63-98

Venkatraman and Nagrajan99 prepared bis-chalcone (V, VI) from

dihydroxy-diacetylbenzene and anisaldehydes using alkali.

CH

CH C

O

OCH3 OH

C

O

OH

CH

CH

OCH3

(V)

CH

CH C

O

OH

C

O

OH

HC CHH3CO OCH3

(VI)

Several hydroxy-nitrochalcones were prepared using dry hydrogen

chloride gas100-102. Onoda and Sasaki103 used hydrochloric acid to synthesize

hydroxy-nitrochalcone (VII) from 2-hydroxy-5-nitroacetophenone and p-

anisaldehyde.

8


C

O

OH

CH

CH

NO2

OCH3

(VII)

The other condensing agents which have been employed are alkali metal

alkoxide104-105, magnesium-t-butoxide106, borax107, piperidine108, aluminium

chloride109, boron trifluoride110, amino acids111 and perchloric acid.112

Chalcones (X) were prepared by reaction of benzaldehyde (VIII) with

phosphonate carbanion (IX) derived from diethyl phenacyl phosphonate.113-116

CH

CH

C

(X)

CHO C

O

H2CP

OC2H5

C2H5O

O

(VIII) (IX)

+

O

Several workers117-119 prepared chalcones (XIV, XV) from ketones (XII,

XIII) and aromatic aldehyde (XI) in ethanol as energy transfer medium.

Ar1CH3 C

O

Ar1

(XII)

CHO Ar1 CH

CH C

O

CH

CH Ar1

(XIV)(XI)

OH

9


Ar1CH3 C

O

Ar2

(XIII)

CHO

(XI)

OHAr1 C

HCH C

O

Ar2

(XV)

Ar1 = C6H5, Ar2 = -R-C6H4

Mistry and Desai120 synthesized chalcone (XVI) using microwave technique.

H3CO C

Cl

ClCH

O

CH

(XVI)

Naik and Naik121 synthesized chalcone derivative from 2-hydroxy-3-

bromo-5-ethyl acetophenone.

RC CH

O

CH

OH

Br

C2H5C

O

OH

Br

C2H5 CH3

R-CHO

aq. KOH (40%)

The chalcones are associated with different biological activities like

insecticidal122, anticancer123, anti-inflammatory124, bactericidal125, fungicidal126,

antiviral127, antitumor128, antimalarial129 and antiulcer130. Literature shows that

lieochalcone and oxygenated chalcone has strong antileishmanial activity131-132.

It is reported that chalcones exhibited potent activity against human malarial

parasite133. Many workers have reported the different pharmaceutical activities

of chalcones and its derivatives134-137. The antibacterial activities of some

substituted chalcones have been studied by Modi et al138. De vincenzo et al139

10


reported anti-inflammatory activity of some chalcone derivatives. Aldose

reductase inhibitor activity of chalcone derivatives has also been reported by

Okuyama et al140, Toru et al141 reported anticancer activities of chalcones and

Ceo et al142 reports the chalcones as a-glucosidase inhibitors. Antiplasmodial

activity of ferrocenyl chalcones was reported by Xiang et al143. Bhatt and co-

workers reported cytotoxic properties of chalcones and their pyrazoles

derivatives.144

BIOLOGICAL IMPORTANCE

The presence of -unsaturated carbonyl system of chalcone makes it

biologically active145. They have shown antibacterial activity against S. aureus,

E. coli, C. albicans, T. utilis, S. sake, W. anomala and some other organisms146.

Devaux, Nuhrich and Dargelos147 synthesized some nitrofuryl chalcones

and tested for their antibacterial activity. Among all those derivatives the most

efficient was (XVII), which inhibited Staphylococcus landon at concentration 1

µg/ml.

OO2N C

HCH C

O

F

(XVII)

Some chalcones containing indole moiety (XVIII) were synthesized and

tested for antibacterial and antifungal activity by Dandia, Sehgal and Singh148.

11


NH

Ar

HC X

X

CH C

O

(XVIII)

where,Ar = Substituted phenyl

Chalcones incorporated with benzopyran moiety (XIX) were reported by

Hismat, El-Diwani and Melek149.

OH3C

OCH3

CH

O

CH

C

O

(XIX)

Salvie, Richard and John150 reported α-substituted chalcones. The α-

methyl compound (XX) was found to be the most active and tested for the

chemotherapy of leukemias.

OCH3

H3CO

OCH3

OCH3

OH

C

O

C

CH3

CH

(XX)

12


Heterocyclic substituted chalcones (XXI) were prepared by Bombardeli

and Valenti151. They reported that some of them were introduced for the

treatment of breast cancer, menopausal disorders and osteoporosis.

O

C

R

R1

O

O

CH

CH

Ar

(XXI)

Where, Ar = HeteroarylR = -OH, -OR', where R' = alkylR1= -H, -alkyl

Uenaka, Kawata, Nagai and Endoh152 synthesized β-hydroxy chalcones

(XXII). Compounds having fluoro substitution showed considerable activity

against Human Immuno Virus (HIV).

NHN

NC

O

HC C

CH3

R3

R1R2R4

Where,R1, R2, R3 = H, (un) substituted alkyl, alkoxy, halo

R4 = H, (un) substituted alkyl or aryl

(XXII)

Seele153 reported chalcone having heterocyclic moiety (XXIII) and

reported their insecticidal activity.

13


R C

O

C CH

Ar

Where,R, R1 = alkyl, phenyl, bi-phenyl, naphthyl, furyl

X = N, CH

H2C

N

X

(XXIII)

Some other biological activity of chalcone such as antiviral154, anti-

inflammatory155-156, prostaglandin binding157, antiulcer158, anti-tumor159,

cardiovascular160 and anti-cancer161 were also reported.

14


PYRIMIDINE

Pyrimidine nucleus exhibited remarkable pharmacological activities.

Literature indicates that compounds having pyrimidine nucleus have wide range

of therapeutic uses that include anti-inflammatory, antibacterial, anticancer,

antiviral, anti-HIV, antimalarial, antihypertensive, sedatives and hypnotics,

anticonvulsant and antihistaminic.

In medicinal chemistry pyrimidine derivatives have been very well known

for their therapeutic applications. The presence of a pyrimidine base in thymine,

cytosine and uracil, which are the essential binding blocks of nucleic acids, DNA

and RNA is one possible reason for their activity. The literature indicated that

compounds having pyrimidine nucleus possess broad range of biological

activities. Like 5-fluorouracil as anticancer; idoxuridine and trifluoridine as

antiviral; zidovudine and stavudine as antiHIV, trimethoprim, sulphamethiazine

and sulphadiazine as antibacterial; sulphadoxin as antimalarial and antibacterial;

minoxidil and prazosin as antihypertensive; barbiturates e.g. phenobarbitone as

sedative, hypnotics and anticonvulsant; propylthiouracil as antihyroid;

thionzylamine as H1-antihistamine; and toxoflavin and fervennuline as

antibiotics.

The replacement of two -CH units in benzene by nitrogen atoms gives

pyrimidines (I).

N N

(I)

15


Pyrimidines are considered to be 'important' if they occur naturally as

such or as part of a natural molecule from which the Pyrimidine can be obtained

easily; they are used as drugs; as agricultural chemicals.

During the last 160 years, many trivial names have been used for

pyrimidine and its derivatives, such as Miazine (I) and Cytosine (II) etc.

N NH

H2N

O

(II)

Preliminary IR spectra suggested that Pyrimidones (III) existed as

pyrimidinols (IV).162-163

N NH

O

(III)

N N

OH

(IV)

Similarly pyrimidine thiones (V) existed as pyrimidine thiols (VI).

N NH

S

(V)

N N

SH

(VI)

There are various methods for synthesis of pyrimidines; some of them are

described here.

16


1. Condensation of 1,1,3,3-tetraethoxy propane (VII) with thiourea in alcoholic

hydrochloric acid gave pyrimidine-2-(1H)-thione (VIII)164 and with N-methyl

urea under similar conditions gave 1-methyl pyrimidine-2-(1H)-one (IX)165.

CH(OEt)2

CH2

CH(OEt)2

(VII)

NH

N

N

N

NH2C

S

H2N NH2C

O

HNH3C

(VIII) (IX)

S O

CH3

2. Pyrimidone (XI) and pyrimidine thione (XII) have been prepared by heating

chalcone (X) with urea and thiourea respectively either with conc. HCl in

ethanol166 or with ethanol and Na-ethoxide167.

17


(X)

N NH

O

N NH

S

NH2C

O

H2N NH2C

S

H2N

(XI) (XII)

CH

C

O

R CH R'

R'R R R'

Most drugs in the pyrimidine series fall in to four categories; the

barbiturates, the sulphonamide; the antimicrobials and antitumor agents.

Barbituric acid was made conveniently from diethyl malonate and urea in

ethanolic sodium ethoxide168 and it has a variety of biological properties. Luminol

(R1 - Et, R2-Ph) (XIII) was prepared in 1904 but used as a long active CNS

depressant only from 1912 until the present day.

NH

NH

O

OO

R1

R2

(XIII)

Hyperthyroidism may be treated in several ways. One of these is

interference with the synthesis of the thyroid hormones, possibly or by removal

of iodine. Thiouracil (XIV) and thiobarbital (XV) are effective thyroid drugs.

Compound (XIV) is widely used probably because it has fewer side effects than

the others169.

18


NH

NH

NH

NH

O S

O

Et2

OR

O

(XV)(XIV)

Cytosine arabinoside (XVI) is established drug for the treatment of acute

leukemia's of childhood and adult granulocytic. It has also incidental antiviral

activity against herpes and herpes zaster types170.

O

CH3OH

CH3 HO

H3C

CH2OH N

N

NH2

CH3

(XVI)

El-Gaby, Adel-Hamide and Gharab171 prepared some new pyrimidine-2-

thiones (XVII). Some of these compounds were tested for in vitro anticancer

activity against Ehrlich Ascites Carcinoma Cells.

19


C2H5OOC

N NH

S

R CH3

(XVII)

where,R= 4-F-C6H4, 4-(F2)-C6H3, 1-Naphthyl

Wada and Yoshida172 prepared pyrimidine derivatives having general

structure (XVIII). They reported their use as herbicide which gave complete

control of Amaranthus retroflexus.

R2R1HCOOC

(XVIII)

N

N

N

N

OO

OCH3

OCH3

R2

R3

Several pyrazolo[3,4-d]pyrimidine derivatives were synthesized as

potential inhibitor of adenosine kinase by Cottom et al173. One of the compounds

(XIX) was found to display good anti-inflammatory activity.

N

N

NH2

N

N

I

OHO

HOOH

(XIX)

20


Lee et al174 synthesized and studied some 6-substituted pyridopyrimidine

analogous as potential AK inhibitors, led to the identification of 4-amino-5-(3-

bromophenyl)-7-(6-morpholinopyridin-3-yl)pyrido[2,3-d]-pyrimidine (XX, ABT-

702), a novel and potent non-nucleoside AK inhibitor with oral activity in animal

models of pain and inflammation The ABT-702 was further studied in details by

Boyle et al175 to evaluate its potential utility in chronic inflammation.

N

N N

N

N

O

Br

NH2

(XX)

Molina et al176 synthesized a number of pyrido[1,2-C] pyrimidines (XXI-

XXIII) and tested for effects on leukocyte function in vitro and anti-inflammatory

activity.

N N

COOC2H5

R

N

(XXI)

R=H, CH3, OCH3, F, Cl, Br

21


N N

COOC2H5

XX=O, S

(XXII)

N N

S

(XXIII)

Vidal et al177 have studied the effects of some hexahydroimidazo[1,2-

C]pyrimidine derivatives (XIV) on leukocyte functions in vitro and screened for

anti-inflammatory activity in two models of inflammation.

HN

N

HN

CH3

O2S

N

O

OOH3C

CH3

R

R=H, 4-Br, 4-F, 2-Cl

(XXIV)

22


Bruno et al178 reported the synthesis of some new 2,5-cycloamino-5H -

benzopyrano[4,3-d]pyrimidines (XXV) and screened them for anti-inflammatory,

analgesic and antipyretic activities and in vitro antiplatelet activity. All the

compounds failed to exhibit anti-inflammatory, analgesic and antipyretic

activities but they showed an interesting antiplatelet activity.

O NR'2

N N

NR2

NR2 & NR'2 = pyrrolo, piperidino, morpholino

(XXV)

Bahekar et al179 reported the synthesis of some [2-amino-6-(4-substituted

aryl)-4-(4-substituted phenyl)-1,6-dihydropyrimidin-5-yl]acetic acid derivatives

(XXVI) and evaluated for anti-inflammatory activity. Only few of them showed

remarkable anti-inflammatory activity.

N

NH

R

(XXVI)

R1

HOOCH2C

NH2

R1= Phenyl, 4-chloro phenyl, furfural, 4-methoxy phenyl,2-thiophene, 3-nicotine

23


Ferri et al180 synthesized some 2-tosylamino (XXVII-A) and 2-

tosyliminopyrimidine (XXVII-B) derivatives and studied their interference with

some leukocyte functions.

N

N

(XXVII -A)

NCH2 CONHR

Ts

N

N

CONHRCH2

N Ts

(XXVII -B)

where,R= H, C2H5, C6H5, 4-OH-C6H4, 2-4Cl2-C6H3, C6H5CH2CH2, 4-OH-C6H4CH2CH2

4-F-C6H4CH2CH2, 2-4-Cl2-C6H4CH2CH2

Jakubkiene et al181 reported the synthesis of some 5-(6-methyl-2-

substituted-4-pyrimidinyloxymethyl)-2,3-dihydro-1,3,4-oxadiazole-2-thiones

(XXVIII-A) and their 3-morpholinomethyl derivatives (XXVIII-B) and evaluated

them for anti-inflammatory activity. Most of the tested compounds were found

to be active and some of them were more active than acetylsalicylic acid.

N

N

NHN

OR

CH3

O CH2S

(XXVIII-A)

24


N

N

NN

OR

CH3

O CH2S

(XXVIII-B)

ON

R= thiomethyl, benzylamino, pyrrolidino, piperidino, morpholino

Bruno et al182 synthesized two different series N-methyl-N-pyrimidin-2-yl

glycine and N-5H-[1]benzopyrano[4,3-d]pyrimidin-2-yl substituted amino acids

and tested for anti-inflammatory activity. All the compounds showed significant

anti-inflammatory activity.

Sacchi et al183 synthesized a series of imidazo[1,2-a]pyrimidine 2-

carboxylic acid and 20 acetic acid analogs (XXIX-A-B) and tested them for anti-

inflammatory activity. Almost all the carboxylic acid derivatives showed a

remarkable anti-inflammatory activity.

N

N N

N

N N

CH2COOEt

Cl

H3C R1

R2

CH2COOH

(XXIX-A) (XXIX-B)

R1= OCH3, CH3

R2= OCH3, OC2H5

Abignente et al184 synthesized a group of imidazo[1,2-a]pyrimidine-2-

carboxylic acid esters, acids and amides. Some of them showed anti-

inflammatory activity, while almost all compounds displayed significant analgesic

activity.

25


Laneri et al185 reported the synthesis and anti-inflammatory activity of

some new 2-methylimidazo-[1,2-a]pyrimidine-3-carboxylic esters, acids and

amides. The compounds (XXX-XXXII) displayed maximum anti-inflammatory

activity.

N

N N

CH3

R2

R1

(XXX)

R1= OCH3, CH3, H

R2= OCH3, CH3, OC2H5

COOC2H5

N

N N

CH3

(XXXI)

CONH2

N

N N

CH3

(XXXII)

COOH

R1

R2R1, R2 = H

R1, R2 = CH3

26


2-AMINO PYRIMIDINE BASED ON CHALCONE

Pyrimidine derivatives are prepared in view of the fact that a number of

related compounds are known to be associated with biodynamic properties186.

Pyrimidine derivatives are reported to be prepared by condensing chalcone with

guanidine carbonate in methanol to give 2-Amino-dihydro pyrimidine187.

Recently condensation of chalcone with guanidine nitrate is also reported188.

Kadu and Doshi et al189 prepared 2-amino-pyrimidine by condensing 2-

hydroxy-4-benzo substituted chalcone and guanidine nitrate in ethanol in

presence of sodium hydroxide solution. There are few reports concerning

pyrimidine condensed with oxygen heterocycles190.

Amol et al191 reported the synthesis and antimicrobial activity of some

new 4-furyl-6-(4-substituted)-2-(OH)-pyrimidine (XXXIII) by reaction of sodium

nitrite and acetic acid with 2-Amino-4-furyl-6-(substituted)pyrimidine (XXXIV).

Almost all the compounds showed a remarkable antimicrobial activity.

O

N N

NH2

R

(XXXIV)

O

N N

OH

R

(XXXIII)

Nimavat and Joshi et al192 synthesized 2-amino-4-(3’-bromo phenyl)-6-

aryl-pyrimidine (XXXV) from 1-aryl-3-(3’-bromo phenyl)-2-propen-1-ones

27


(chalcone) and guanidine hydrochloride. All the synthesized compounds

screened for their antitubercular activity.

N N

Br

NH2

R

(XXXV)

28


QUINOLINE

INTRODUCTION

The synthesis of 4-hydroxyquinoline derivatives consists of a β-ketoester

with aryl amines and cyclisation of the acrylates or the crotonates.

Ethylacetoacetate and ethylbenzoylacetate were the first two β-

ketoesters, investigated for the synthesis of 2-and 4-hydroxyquinolines. These

hydroxyquinolines may carry a –OH group in either 2- or 4-position. Earlier

workers have shown that ethylacetoacetate and an aryl amine react at room

temperature in presence of catalyst to form ethyl-β-arylaminocrotonate or the

anil193-196 where as at higher temperatures (130-140 ºC) anilides are

produced.197-200

The anilides have also been prepared by refluxing the reactants for one

and half hour201. Houser and Reynolds202 employed different methods which

were more or less modified over the original Conrad-Limpach method.194

Coffey et al.196, Misani and Bogert203 have reported that aryl amines,

containing a nitro group, could not form anilides. However, three years later,

Kaslow and Stayner204 condensed p-nitroaniline with ethylacetoacetate to form

ethyl-β-(p-nitro-anilino)crotonate by refluxing ethylacetoacetate and p-nitro-

aniline dissolved in chloroform.

Backeberg205 obtained ethyl-β-(p-acetamidoanilino)-crotonate by heating

p-aminoacetanilide with ethylacetoacetate at 100 ºC for thirty minutes. Similarly,

the crotonate was obtained by refluxing the ester with p-aminoacetanilide in

methanol for 5 hours.204-206 Backeberg205, Kermack and Webster207 prepared and

cyclized ethyl-β-(m-acetamidoanilino)-crotonate. Conard and Limpach208

29


obtained ethyl-β-(1- and 2-naphthyl-amino)-crotonates by condensing

ethylacetoacetate with 1- and 2-naphthylamines.

Staskum and Israelstam209 obtained directly 2-phenyl-4-hydroxy-

quinolines from ethylbenzoylacetate and aryl amines using Polyphosphoric acid;

under these conditions a mixture, benzoylacetanilide and β-arylaminocinnamate

was also obtained. Mallams and Israelstam210 synthesized directly 4-

hydroxyquinaldines from ethylacetoacetate or its α-alkyl derivatives and

arylamines using polyphosphoric acid. It may be noted that they could not

cyclise by this method meta- or ortho-nitroanilines and ethylacetoacetate

directly. Desai and Desai211 however, found that acetoacetanilides could be

cyclised to 4-hydroxyquinaldines and also 2-hydroxy-lepidines by adjusting

temperature conditions. They also improved the yields of 4-hydroxyquinaldines

by the modification of the polyphosphoric acid method. They also modified the

procedure and were successful in cyclising o-nitroaniline or m-nitroaniline into 8-

nitro-4-hydroxyquinaldine and 7-nitro-4-hydroxyquinaldine directly, in very good

yield. Mehta and Desai212 refluxed a mixture of nitro-arylamine and

ethylacetoacetate in ethylacetate as solvent for two hours and the residue,

obtained after evaporation of the solvent was cyclised with polyphosphoric acid;

they have reported that the yields of 8-nitro, 7-nitro and 5-chloro-4-

hydroxyquinolines were higher.

Bangadiwala and Desai213 employed acetic anhydride and concentrated

sulphuric acid to cyclise anils of different β-ketoesters, such as ethyl-

acetoacetate, ethylbenzoylacetate, ethylacetylmalonate, ethylacetylcyanoacetate

and obtained 4-hydroxyquinolines.

Quinoline derivatives possess wide therapeutic activity, viz; antiseptic,

analgesic, trypanocidal, germicidal, amoebicidal, antitubercular, anthelmintic,

pyroplasmosis, schistomiasis, antiserotonin, cytokinin and antispasmodic.214-219

The recent researches in chemotherapy have revealed that sulfanilamide

and its derivatives have been found to possess definite bacteriostatic action

30


against various coccal infections. Basu and Das Gupta220 prepared some (4’-

amidobenzenesulfonyl)-aminoquinolines which are expected to have some

therapeutic importance since the replacement of one H-atom of sulfonamido

group of p-aminobenzenesulfonamide often widens the range of activity of the

drug221-223. Some 5,6 and 8-sulfonamidoquinolines have been synthesized224.

A large number of quinoline derivatives are the most effective and best

tolerated amoebicides known so far225-229. Among them, those quinoline moieties

with a methoxy or a methyl substituent (at position-8) are the most effective

one.

Maheshvari and Thaker230 synthesized 2-aryl/styryl-6-acetyl- quinolino-4-

yl-N2-phenyl/benzyl hydrazides and tested against bacteria, viz., E. coli, S.

aureus and M. tuberculosis.

A number of quinoline derivatives like vioform, chloroquin and intestopan

are well-known amoebicides231-232. Many substituted sulfonamides also exhibit

potent amoebicidal activity.233-238

Quinoline derivatives have been reported to possess various

pharmacological activity239-240. In view of this, quinolinoazetidinones,

thiazolidinones, triazolines and formazans have been synthesized and found to

be better cardiovascular agents241.

Urea derivatives of quinoline are used as analgesic and central nervous

system depressant and 8-aminoquinolines as antimalarial.242-243

With a view to synthesis biologically active compounds244, Patel and

Desai245 synthesized 2-(6’-methoxy-2’-styryl-4’-quinolin-oxy)-4-phenylureido-6-

arylthioureido-s-triazine (I).

31


N

N

N

N

H3CO

CH

CH

O

NHCONHR

NHCSNHR

(I)

Quinoline derivatives are drugs of therapeutic importance showing wide

spectrum of biological activities. Some work has been done on the synthesis and

screening of some N’-substituted quinoline derivatives. In view of this,

heterocyclic moiety has been incorporated in the N’-position of 6-methyl-4-

phenylquinolin-2(1H)-one246 to study the effect of N’-substitution on

antimicrobial activity.

Synthesis and biological screening of some azomethines and 2-

azitidinones247 of type (II) and (III) have been very recently reported.

N

OCH3

Cl

OCH3

NR

N

OCH3

Cl

OCH3 N

R

O

Cl

(II) (III)

Synthesis and antibacterial screening of 2-chloro-8-methylquinolin-3-yl-N-

(2’-phenyl-4’-arylidene-5’-oxoimidazolin-1’-yl) azomethines248 have been very

recently reported. A series of azetidinones249 bearing 2-chloroquinoline-3-

32


carboxaldehyde moiety have been synthesized and their antimicrobial activities

have been studied.

Synthesis of certain N-substituted-8-quinolinesulfonamides250 structurally

related to antimalarials was reported. Synthesis and properties of sulfonamides

of quinoline series251 had been reported. The chemistry of quinoline and p-

toluenesulfonamide has attracted special attention because of their therapeutic

properties252-253. Recently some sulfonamidoquinoline derivatives254 have been

found to possess enhanced antibacterial activity.

Some new sulfonamides of type (IV) have been prepared having

pharmaceutically important chloroquin moiety by condensing with different

carboxyaryl sulfonylchlorides. The products were screened for antimicrobial

activity255.

CH3

Cl

HC N NHSO2R

(IV)

Desai and Desai256 coupled o-, m-, p-cresols with diazotized sulfanilamide

and sulfathiazole and examined their antibacterial activity against different

organisms. 2,4-Dihydroxy-3-(p-azobenzenesulfamido)-quinoline derivatives257

had been prepared and screened for their antibacterial activity.

Some new sulfonamides like, N-arylsulfonamido-2-chloro-7-methoxy- and

8-methylquinolin-3-yl-azomethine258-259 have been synthesized and screened for

their antibacterial activity.

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45


PARTICULAR INTRODUCTION AND PRESENT WORK

Heterocycles are abundant in nature and are of great significance to life

because their structural subunits exist in many natural products such as

vitamins, hormones, antibiotics and alkaloids, as well as pharmaceuticals,

herbicides, dyes, and many more compounds1. Hence, they have attracted

considerable attention in the design of biologically active molecules.2

Some new Bis-thiazines (I) and Bis-pyrimidines (II) have been

synthesized from Bis-chalcone and screened for their antibacterial, antifungal

and anti-inflammatory activities.3

N S S N

OHHO

R R

(I)NH2NH2

N N N N

OHHO

R R

(II)NH2NH2

Where,R=H, 4-OMe, 4-Cl, 4-NO2, 4-Br, 2-Cl

46


K. M. Mahadevan et al4 reported a new method for the synthesis of

substituted benzofuran derivatives containing pyrimidine ring at 2 position (III).

This method is less time consuming and environmental friendly as compared to

the existing conventional method of synthesis.

N

N

O

R

NH2

(III)

Where,R= H, NO2, Cl, CH3, OCH3

M. Amir et al5 synthesized 4-(1H-indol-3-yl)-6-phenyl-1,2,3,4-

tetrahydropyrimidin-2-ones/ thiones as potent anti-inflammatory agent (IV, V).

NH

HN

NH RO

(IV)

NH

HN

NH RS

(V)

Several pyrimidine derivatives possess a broad spectrum of biological

effectiveness such as calcium channel blockers6, antitubercular7, anticancer7 and

antibacterial8.

Quinoline derivatives are also drugs of therapeutic importance showing a

wide spectrum of biological activities.

47


Some 2-aryl-4-carboxyquinoline-6-arsonic acids9 have been prepared and

screened for antibacterial activity. Some new 2-aryl-6,7-substituted quinolines10

of type (VI) and (VII) having 4-aminoantipyrine and 1,3,4-oxadiazole moiety

have been prepared and tested for antimicrobial activity.

N

N

N

CH2

R1

R2

R3

C6H5

(VI)

N R1

R2

R3

(VII)

CONH

C6H5

NN

CH3

O CH3

R1, R2, R3= methyl, methoxy, chloro, nitro

Some new 4-thiazolidinone derivatives of the type (VIII) bearing 8-

hydroxyquinoline moiety were prepared and screened for their antibacterial

activity11.

N

(VIII)X

NHC

SN

R

O

R =aryl, X= H/ CH3/ CH2COOH

HO

Very recently a number of substituted-4-hydroxy-3-(p-azobenzene-

sulfonamido)-2-phenylquinoline12, 4-[4-(2,6-disubstituted-quinolin-4-yl-amino)-2-

hydroxy-phenylazo]-sulfonamide13 and 4-hydroxy-3-(substituted arylazo)-2-

phenyl-6/7-substituted quinoline derivatives14 have been found to be active

against gram positive and gram negative bacteria.

48


Formazons are known to be useful agent in various diseases like viral and

bacterial infection and Parkinson diseases. A number of formazons have been

tested and reported as antibacterial15-17 and antitubercular agents.18

Some new N-p-acetylphenyl-α-arylazo-2-chloro-7-methoxyquinolin-3'-yl-

azomethines have been synthesized and screened for their antimicrobial

activities.19 All the compounds showed moderate activity.

A number of quinolinyl hydrazinobenzylidine azobenzenes(formazons)20-21

have been prepared and screened for antitubercular and antibacterial activity.

Several N-o-carboxyphenyl-α-aryl-azo-4-dimethyl-aminophenyl-azomethine

(formazones) have been synthesized and screened for antimicrobial activity.

Some of them showed good antibacterial activity.22

Some N'-substituted-[(2'-hydroxy-benzylidine)-amino-N2-4-phenyl-5-(aryl-

azo)-thiazoyl]-azobenzene (formazons) have been very recently reported and

screened for antibacterial activity against Gram positive and Gram negative

bacteria.23

In our efforts to discover new chemical pharmacophores which may be

responsible for the antibacterial as well as antifungal activity, we have described

our studies on the reaction of aromatic aldehyde with aromatic acetophenone to

form chalcone which were further reacted with guanidine nitrate to give 4,6-

diarylsubstituted-2-pyrimidinamine. These compounds were further coupled with

4-chloroquinoline derivative to get corresponding compound pyrimidine-quinoline

clubbed molecule.

Considering the versatile chemistry of cyanuric chloride24-26 and its

reactions with various nucleophiles such as amines, amino-sulfonamides,

alcohols, phenols, etc., the attempts were also made to couple 4-(3'-

bromophenyl)-6-(4-methoxyphenyl)pyrimidin-2-amine with cold brand reactive dyes.

49


Realizing the medicinal importance of 2-amino-pyrimidine, quinoline and

triazine derivatives it was considered worthwhile to incorporate these moieties.

It was therefore thought interesting to synthesize the title compounds with an

object of ascertaining whether they could augment the microbicidal efficacy.

The structures of the various synthesized compounds were assigned on

the basis of elemental analysis, IR and 1H NMR spectral data. These compounds

were also screened for antibacterial and antifungal activity. The research work is

scanned in Scheme 1 and Scheme-2.

50


COCH3 OHC+

KOH/ C2H5OHOH-

N N

NH2

(1) Conventional heating

(2) Heterocyclization

C2H5OH

40% NaOH

H2N C

NH

NH2

C

O

CH

CH

THF

Anhy. K2CO3NR3

R2

R1

Cl

NR3

R2

R1

N N

HN

R R'

R R'

R'R

R R'

Scheme-I

Ar y l acet ophenone Ar y l al d ehy d e

S ubs t i t ut ed chal cone

4,6 -Di ar y l subs t i t ut ed -2 -py r imi d i namine

Guani d i ne

4-C hl or oqu ino l i ne d er i v at i v e

N4-[ 4 ,6-D i ar y l subs t i t ut ed pheny l -2-py r i mi d i ny l ] -subs t i t ut ed -4-qui no l i nami ne

R= 2,4-(Cl)2-5-F, 4-Cl, 4-OCH3, 4-CH3

R'= 4'-F, 4'-Cl, 3'-NO2, 3'-Br

R1= -H, -CH3, R2 = -H, -Cl, -CH3, -OCH3, R3 = -H, -Cl

where

51


Scheme-I I

N N

NH2

Br

H3COCold brand reactive dye +

H2O + THF

NaHCO3

N N

NHBr

H3CO

Cold brand reactive dye

-HCl

4 -( 3 -br omopheny l ) -6 -( 4 -met hox y pheny l )py r i mi d i n -2 -ami ne

52

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CHALCONE - Shodhganga : a reservoir of Indian theses @ …shodhganga.inflibnet.ac.in/bitstream/10603/2520/8/08... · · 2012-05-31CHALCONE INTRODUCTION ... chalcone and its derivatives33-36