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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. n 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 #C$"C%&C%". These are coloured compounds because of the

presence of the chromophore "C$"C%&C%"! which depends in the presence of

other au'ochromes.

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

most convenient method is the Claisen")chimdt condensation of e*uimolar

*uantities of arylmethylketone with aryl aldehyde in the presence of alcoholic

alkali5.

Chalcones are used to synthesize several derivatives like cyanopyridines!

pyrazolines iso'azoles and pyrimidines having different heterocyclic ring

systems.6-9

+

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, ,

,%-

.r .r/

0yrimidine

1uanidine.r C

$

C%

C% .r/

,%-$%

,%-,%-

2alononitrile

,

C,

.r/

.r

Cyanopyridine

,

,%

.r .r/

0yrazoline

,

$

.r .r/

so"o'azole

NOMENC!TRURE

(ifferent methods of nomenclatures for chalcone were suggested at

different times. The following pattern has been adopted by Chemical

bstracts published by merican chemical society.

C CH CH

O

1

2 3

4

56

1'

2'3'

4'

5' 6'

(I)

The 3ritish Chemical bstract and 4ournal of Chemical )ociety have

followed the following system.

-

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C CH CH

O

1

23

4

5 6

1'

2' 3'

4'

5'6'

(II)

"#NT$ETIC MET$OD" O% &RE&!RIN' C$!CONE"

C!I"EN-"C$MIDT RE!CTION

variety of methods are available for the synthesis of chalcones! the

most convenient method is the one that involves the Claisen")chmidt

condensation of e*uimolar *uantities of a substituted acetophenone with

substituted aldehydes in the presence of a*ueous alcoholic alkali. 1(-1) n the

Claisen")chmidt reaction! the concentration of alkali used! usually ranges

between +5 and 65 7.1*-19The reaction is carried out at about 85 oC for +-"+8

hours or at room temperature for one week. 9nder these conditions! the

Cannizaro reaction2(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 $%C

:

C

$

C%

C%

:/

:/:

;

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.1/ !0a0i

lkali has been the most used condensing agents for synthesis of

chalcones. t is used as an a*ueous solution of suitable concentration viz. =5 7!

>5 7! 85 7 and ?5 7.

.2/ $droch0oric !cid

(ry hydrochloric gas in a suitable solvent like ethylacetate at 5 oC was

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

ketones. 2ethanolic solution of dry hydrochloric acid gas at 5 oC was also used

by @yle! 0aradis21 +3,and 2arathey21 +c,.

./ Other Condenin !ent

:aval and )hah22used phosphorous o'ychloride as a condensing agent to

synthesize of chalcones. )zell and )ipos2 condensed -"hydro'y"8"nitro"

acetophenone with benzaldehyde using anhydrous lCl=. Kuroda! 2atsukuma

and ,akasmura24obtained chalcone by condensing acetophenone derived from

anisole and other polymetho'y benzenes with some metho'yaldehydes in

presence of anhydrous aluminium chloride.

3esides the above! other condensing agents used in synthesis of

chalcones have been!

A+B mino acid 25

A-B *ueous solution of bora'

26

A=B 0erchloric acid 2)

A>B 0iperidine 2*

A8B 3oron trifloride 29

A6B lkali metal alko'ide (

A?B 2agnesium tert"buto'ide 1

>

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AB $rganocadmium compound 2

MEC$!NI"M O% C$!CONE %ORM!TION

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

chalcone and its derivatives-6. 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]

+

+

8

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The formation of chalcone by the acid catalyzed condensation of

acetophenone and benzaldehyde has been studied.)7 *

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

OH

Transition

+

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

+

+

+

Comle!

S

+

+

+ +

+

+

Ph C

O

CH2 CH Ph

OH2

Ph C

O

CH CH Ph H2OH+

+

+ +

IM&ORT!NCE O% C$!CONE"

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

aziridines.

6

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(2) Chalcones and their derivatives find application as artificial sweeteners9-4!

scintillator44! polymerization catalyst 45-46! fluorescent whitening agent4)!

organic brightening agent4*-49! stabilizer against heat! visible light! ultraviolet

light and aging.5(-54

(3) =!-D!>D!6D"tetrahydro'y">"propo'y"dihydrochalcone">"/"neohesperdoside55

has been used as synthetic sweetener and is --55 times sweeter than

glucose.

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

several reagents e.g. AaB phenyl hydrazine! AbB -"amino thiophenol etc.

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

products like hemlock tannin56! cyanomaclurin5)! ploretin5*! eriodictyol and

homo eriodictyol59! naringenin6(etc.

MET$OD" O% "#NT$E"I"

Carthamin AB! a red pigment was first obtained as red needles with

green iridescence using pyridine solvent from the flowers of cartharmus tinctoria

AsafflowerB by Kmetaka and 0erkin61 and this was the first known e'ample of

chalcone in nature.

$1C

$%

$%$

$%C

$

C%

C%

+III,

t isomerizes to a yellow compound isocarthamin AFB on treatment with

dil. %Cl as reported by Kuroda62.

?

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$%C

$

C%

C%

+I,

$%%$

$1C

$%

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

most convenient method is the one that involves the Claisen")chmidt

condensation of e*uimolar *uantities of substituted acetophenone with

substituted aldehydes in presence of a*ueous alcoholic alkali.6-9*

Fenkatraman and ,agraGan99 prepared bis"chalcone AF! FB from

dihydro'y"diacetylbenzene and anisaldehydes using alkali.

C%

C% C

$

$C%= $%

C

$

$%

C%

C%

$C%=

+,

C%

C% C

$

$%

C

$

$%

%C C%%=C$ $C%=

+-I,

)everal hydro'y"nitrochalcones were prepared using dry hydrogen

chloride gas1((-1(2. $noda and )asaki1( used hydrochloric acid to synthesize

hydro'y"nitrochalcone AFB from -"hydro'y"8"nitroacetophenone and p"

anisaldehyde.

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C

$

$%

C%

C%

,$-

$C%=

+II,

The other condensing agents which have been employed are alkali metal

alko'ide1(4-1(5! magnesium"t"buto'ide1(6! bora'1()! piperidine1(*! aluminium

chloride1(9! boron trifluoride11(! amino acids111and perchloric acid.112

Chalcones AHB were prepared by reaction of benzaldehyde AFB with

phosphonate carbanion AHB derived from diethyl phenacyl phosphonate.11-116

C%

C%

C

+8,

C%$ C

$

%-C0

$C-%8

C-%8$

O

(VIII) (IX)

+

$

)everal workers11)-119 prepared chalcones AHF! HFB from ketones AH!

HB and aromatic aldehyde AHB in ethanol as energy transfer medium.

r+C%= C

$

r+

+8II,

C%$ r+ C%

C% C

$

C%

C% r+

+8I,+8I,

$%

I

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r+C%= C

$

r-

+8III,

C%$

+8I,

$%r+ C

%C% C

$

r-

+8,

Ar1 = C6H5, Ar2 = -R-C6H4

2istry and (esai12(synthesized chalcone AHFB using microwave techni*ue.

%=C$ C

Cl

ClC%

$

C%

+8I,

,aik and ,aik121 synthesized chalcone derivative from -"hydro'y"="

bromo"8"ethyl acetophenone.

:C C%

$

C%

$%

3r

C-%8C

$

$%

3r

C-%8 C%=

:"C%$

a*. K$% A>57B

The chalcones are associated with different biological activities like

insecticidal122! anticancer12! anti"inflammatory124! bactericidal125! fungicidal126!

antiviral12)! antitumor12*! antimalarial129 and antiulcer1(. @iterature shows that

lieochalcone and o'ygenated chalcone has strong antileishmanial activity11-12.

t is reported that chalcones e'hibited potent activity against human malarial

parasite1. 2any workers have reported the different pharmaceutical activities

of chalcones and its derivatives14-1). The antibacterial activities of some

substituted chalcones have been studied by 2odi et al1*. (e vincenzo et al19

+5

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reported anti"inflammatory activity of some chalcone derivatives. ldose

reductase inhibitor activity of chalcone derivatives has also been reported by

$kuyama et al14(! Toru et al141 reported anticancer activities of chalcones and

Ceo et al142

reports the chalcones as a"glucosidase inhibitors. ntiplasmodialactivity of ferrocenyl chalcones was reported by Hiang et al14. 3hatt and co"

workers reported cytoto'ic properties of chalcones and their pyrazoles

derivatives.144

IOO'IC! IM&ORT!NCE

The presence of "unsaturated carbonyl system of chalcone makes it

biologically active145. They have shown antibacterial activity against ). aureus!

E. coli! C. albicans! T. utilis! ). sake! J. anomala and some other organisms146.

(evau'! ,uhrich and (argelos14) synthesized some nitrofuryl chalcones

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

efficient was AHFB! which inhibited )taphylococcus landon at concentration +

gLml.

$

$-, C%

C% C

$

M

+8II,

)ome chalcones containing indole moiety AHFB were synthesized and

tested for antibacterial and antifungal activity by (andia! )ehgal and )ingh14*.

++

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,%

r

%C H

H

C% C

$

+8III,

where!r & )ubstitute d phenyl

Chalcones incorporated with benzopyran moiety AHHB were reported by

%ismat! El"(iwani and 2elek149.

$

%=C

$C%=

C%

$

C%

C

$

+8I8,

)alvie! :ichard and 4ohn15( reported N"substituted chalcones. The N"

methyl compound AHHB was found to be the most active and tested for the

chemotherapy of leukemias.

$C%=

%=C$

$C%=

$C%=

$%

C

$

C

C%=

C%

+88,

+-

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%eterocyclic substituted chalcones AHHB were prepared by 3ombardeli

and Falenti151. They reported that some of them were introduced for the

treatment of breast cancer! menopausal disorders and osteoporosis.

$

C

:

:+

$

$

C%

C%

r

+88I,

Jhere! r & %eteroaryl: & "$%! "$:/! where :/ & alkyl:+& "%! "alkyl

9enaka! Kawata! ,agai and Endoh152 synthesized "hydro'y chalcones

AHHB. Compounds having fluoro substitution showed considerable activity

against %uman mmuno Firus A%FB.

,%,

,C

$

%C C

C%=

:=

:+:-:>

Jhere!

:+! :-! := & %! AunB substituted alkyl! alko'y! halo:> & %! AunB substituted alkyl or aryl

(XXII)

)eele15 reported chalcone having heterocyclic moiety AHHB and

reported their insecticidal activity.

+=

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: C

$

C C%

.r

Jhere!:! :+ & alkyl! phenyl! bi"phenyl! naphthyl! furyl

H & ,! C%

%-C

,

H

+88III,

)ome other biological activity of chalcone such as antiviral154! anti"

inflammatory155-156! prostaglandin binding15)! antiulcer15*! anti"tumor159!

cardiovascular16(and anti"cancer161were also reported.

+>

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PYRIMIDINE

0yrimidine nucleus e'hibited remarkable pharmacological activities.

@iterature indicates that compounds having pyrimidine nucleus have wide range

of therapeutic uses that include anti"inflammatory! antibacterial! anticancer!

antiviral! anti"%F! antimalarial! antihypertensive! sedatives and hypnotics!

anticonvulsant and antihistaminic.

n 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! (,

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

compounds having pyrimidine nucleus possess broad range of biological

activities. @ike 8"fluorouracil as anticancerO ido'uridine and trifluoridine as

antiviralO zidovudine and stavudine as anti%F! trimethoprim! sulphamethiazine

and sulphadiazine as antibacterialO sulphado'in as antimalarial and antibacterialO

mino'idil and prazosin as antihypertensiveO barbiturates e.g. phenobarbitone as

sedative! hypnotics and anticonvulsantO propylthiouracil as antihyroidO

thionzylamine as %+"antihistamineO and to'oflavin and fervennuline as

antibiotics.

The replacement of two "C% units in benzene by nitrogen atoms gives

pyrimidines AB.

N N

(I)

+8

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0yrimidines are considered to be /important/ if they occur naturally as

such or as part of a natural molecule from which the 0yrimidine can be obtained

easilyO they are used as drugsO as agricultural chemicals.

(uring the last +65 years! many trivial names have been used for

pyrimidine and its derivatives! such as 2iazine AB and Cytosine AB etc.

, ,%

%-,

$

+II,

0reliminary : spectra suggested that 0yrimidones AB e'isted as

pyrimidinols AFB.162-16

, ,%

$

+III,

, ,

$%

+I,

)imilarly pyrimidine thiones AFB e'isted as pyrimidine thiols AFB.

, ,%

)

+,

, ,

)%

+I,

There are various methods for synthesis of pyrimidinesO some of them are

described here.

+6

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1. Condensation of +!+!=!="tetraetho'y propane AFB with thiourea in alcoholic

hydrochloric acid gave pyrimidine"-"A+%B"thione AFB164and with ,"methyl

urea under similar conditions gave +"methyl pyrimidine"-"A+%B"one AHB165.

C%A$EtB-

C%-

C%A$EtB-

+II,

,%

,

,

,

,%-C

)

%-, ,%-C

$

%,%=C

+III, +I8,

) $

C%=

2. 0yrimidone AHB and pyrimidine thione AHB have been prepared by heating

chalcone AHB with urea and thiourea respectively either with conc. %Cl in

ethanol166or with ethanol and ,a"etho'ide16).

+?

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+8,

, ,%

$

, ,%

)

,%-C

$

%-, ,%-C

)

%-,

+8I, +8II,

C%

C

$

: C% :/

R'R R R'

2ost drugs in the pyrimidine series fall in to four categoriesO the

barbiturates! the sulphonamideO the antimicrobials and antitumor agents.

3arbituric acid was made conveniently from diethyl malonate and urea in

ethanolic sodium etho'ide16* and it has a variety of biological properties. @uminol

A:+ " Et! :-"0hB AHB was prepared in +I5> but used as a long active C,)

depressant only from +I+- until the present day.

,%

,%

$

$$

:+

:-

+8III,

%yperthyroidism may be treated in several ways. $ne of these is

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

of iodine. Thiouracil AHFB and thiobarbital AHFB are effective thyroid drugs.

Compound AHFB is widely used probably because it has fewer side effects than

the others169.

+

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NH

NH

NH

NH

O S

O

Et2

OR

O

(XV)(XIV)

Cytosine arabinoside AHFB is established drug for the treatment of acute

leukemia/s of childhood and adult granulocytic. t has also incidental antiviral

activity against herpes and herpes zaster types1)(.

$

C%=$%

C%= %$

%=C

C%-$% ,

,

,%-

C%=

(XVI)

El"1aby! del"%amide and 1harab1)1prepared some new pyrimidine"-"

thiones AHFB. )ome of these compounds were tested for in vitro anticancer

activity against Ehrlich scites CarcinomaCells.

+I

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C-%8$$C

, ,%

)

: C%=

(XVII)

where!:& >"M"C6%>! >"AM-B"C6%=! +",aphthyl

Jada and Poshida1)2 prepared pyrimidine derivatives having general

structure AHFB. They reported their use as herbicide which gave complete

control of maranthus retrofle'us.

:-:+%C$$C

(XVIII)

,

,

,

,

$$

$C%=

$C%=

:-

:=

)everal pyrazoloQ=!>"dRpyrimidine derivatives were synthesized as

potential inhibitor of adenosine kinase by Cottom et al1). $ne of the compounds

AHHB was found to display good anti"inflammatory activity.

,

,

,%-

,

,

$%$

%$

$%+8I8,

-5

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@ee et al1)4synthesized and studied some 6"substituted pyridopyrimidine

analogous as potential K inhibitors! led to the identification of >"amino"8"A="

bromophenylB"?"A6"morpholinopyridin"="ylBpyridoQ-!="dR"pyrimidine AHH! 3T"

?5-B! a novel and potent non"nucleoside K inhibitor with oral activity in animalmodels of pain and inflammation The 3T"?5- was further studied in details by

3oyle et al1)5to evaluate its potential utility in chronic inflammation.

,

, ,

,

,

$

3r

,%-

+88,

2olina et al1)6synthesized a number of pyridoQ+!-"CRpyrimidines AHH"

HHB and tested for effects on leukocyte function in vitro and anti"inflammatory

activity.

, ,

C$$C-%8

:

,

+88I,

:&%! C%=! $C%=! M! Cl! 3r

-+

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, ,

C$$C-%8

H

H&$! )

+88II,

, ,

)

+88III,

Fidal et al1))have studied the effects of some he'ahydroimidazoQ+!-"

CRpyrimidine derivatives AHFB on leukocyte functions in vitro and screened for

anti"inflammatory activity in two models of inflammation.

%,

,

%

,

C%=

$-)

,

$

$

$%=C

C%=

:

:&%! >"3r! >"M! -"Cl

+88I,

--

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3runo et al1)*reported the synthesis of some new -!8"cycloamino"8% "

benzopyranoQ>!="dRpyrimidines AHHFBand screened them for anti"inflammatory!

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

compounds failed to e'hibit anti"inflammatory! analgesic and antipyreticactivities but they showed an interesting antiplatelet activity.

$ ,:/-

, ,

,:-

,:- S ,:/-& pyrrolo! piperidino! morpholino

+88,

3ahekar et al1)9reported the synthesis of some Q-"amino"6"A>"substituted

arylB">"A>"substituted phenylB"+!6"dihydropyrimidin"8"ylRacetic acid derivativesAHHFB and evaluated for anti"inflammatory activity. $nly few of them showed

remarkable anti"inflammatory activity.

,

,%

:

+88I,

:+

%$$C%-C

,%-

:+& 0henyl! >"chloro phenyl! furfural! >"metho'y phenyl!-"thiophene! ="nicotine

-=

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Merri et al1*( synthesized some -"tosylamino AHHF"B and -"

tosyliminopyrimidine AHHF"3B derivatives and studied their interference with

some leukocyte functions.

,

,

+88II -!,

,

C%- C$,%:

Ts

,

,

C$,%:C%-

, Ts

+88II -9,

where!:& %! C

-%

8! C

6%

8! >"$%"C

6%

>! -">Cl

-"C

6%

=! C

6%

8C%

-C%

-! >"$%"C

6%

>C%

-C%

->"M"C6%>C%-C%-! -">"Cl-"C6%>C%-C%-

4akubkiene et al1*1 reported the synthesis of some 8"A6"methyl"-"

substituted">"pyrimidinylo'ymethylB"-!="dihydro"+!=!>"o'adiazole"-"thiones

AHHF"B and their ="morpholinomethyl derivatives AHHF"3B and evaluated

them for anti"inflammatory activity. 2ost of the tested compounds were found

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

,

,

,%,

$:

C%=

$ C%-)

+88III-!,

->

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,

,

,,

$:

C%=

$ C%- )

+88III-9,

$,

:& thiomethyl! benzylamino! pyrrolidino! piperidino! morpholino

3runo et al1*2synthesized two different series ,"methyl","pyrimidin"-"yl

glycine and ,"8%"Q+RbenzopyranoQ>!="dRpyrimidin"-"yl substituted amino acids

and tested for anti"inflammatory activity. ll the compounds showed significant

anti"inflammatory activity.

)acchi et al1* synthesized a series of imidazoQ+!-"aRpyrimidine -"

carbo'ylic acid and -5 acetic acid analogs AHHH""3B and tested them for anti"

inflammatory activity. lmost all the carbo'ylic acid derivatives showed a

remarkable anti"inflammatory activity.

,

, ,

,

, ,

C%-C$$Et

Cl

%=C :+

:-

C%-C$$%

+88I8-!, +88I8-9,

:+& $C%=! C%=

:-& $C%=! $C-%8

bignente et al1*4 synthesized a group of imidazoQ+!-"aRpyrimidine"-"

carbo'ylic acid esters! acids and amides. )ome of them showed anti"

inflammatory activity! while almost all compounds displayed significant analgesic

activity.

-8

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@aneri et al1*5 reported the synthesis and anti"inflammatory activity of

some new -"methylimidazo"Q+!-"aRpyrimidine"="carbo'ylic esters! acids and

amides. The compounds AHHH"HHHB displayed ma'imum anti"inflammatory

activity.

,

, ,

C%=

:-

:+

+888,

:+& $C%=! C%=! %

:-& $C%=! C%=! $C-%8

C$$C-%8

,

, ,

C%=

+888I,

C$,%-

,

, ,

C%=

+888II,

C$$%

:+

:- :+! :-& %

:+! :-& C%=

-6

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2-AMINO PYRIMIDINE BASED ON CHALCONE

0yrimidine derivatives are prepared in view of the fact that a number of

related compounds are known to be associated with biodynamic properties 1*6.

0yrimidine derivatives are reported to be prepared by condensing chalcone with

guanidine carbonate in methanol to give -"mino"dihydro pyrimidine1*).

:ecently condensation of chalcone with guanidine nitrate is also reported1**.

Kadu and (oshi et al1*9prepared -"amino"pyrimidine by condensing -"

hydro'y">"benzo substituted chalcone and guanidine nitrate in ethanol in

presence of sodium hydro'ide solution. There are few reports concerning

pyrimidine condensed with o'ygen heterocycles19(.

mol et al191 reported the synthesis and antimicrobial activity of some

new >"furyl"6"A>"substitutedB"-"A$%B"pyrimidine AHHHB by reaction of sodium

nitrite and acetic acid with -"mino">"furyl"6"AsubstitutedBpyrimidine AHHHFB.

lmost all the compounds showed a remarkable antimicrobial activity.

$

, ,

,%-

:

+888I,

$

, ,

$%

:

+888III,

,imavat and 4oshi et al192 synthesized -"amino">"A=D"bromo phenylB"6"

aryl"pyrimidine AHHHFB from +"aryl"="A=D"bromo phenylB"-"propen"+"ones

-?

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AchalconeB and guanidine hydrochloride. ll the synthesized compounds

screened for their antitubercular activity.

, ,

3r

,%-

:

+888,

-

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QUINOLINE

INTRODUCTION

The synthesis of >"hydro'y*uinoline derivatives consists of a "ketoester

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

Ethylacetoacetate and ethylbenzoylacetate were the first two "

ketoesters! investigated for the synthesis of -"and >"hydro'y*uinolines. These

hydro'y*uinolines may carry a #$% group in either -" or >"position. Earlier

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

temperature in presence of catalyst to form ethyl""arylaminocrotonate or the

anil19-196 where as at higher temperatures A+=5"+>5 CB anilides are

produced.19)-2((

The anilides have also been prepared by reflu'ing the reactants for oneand half hour2(1. %ouser and :eynolds2(2employed different methods which

were more or less modified over the original Conrad"@impach method.194

Coffey et al.196! 2isani and 3ogert2( have reported that aryl amines!

containing a nitro group! could not form anilides. %owever! three years later!

Kaslow and )tayner2(4condensed p"nitroaniline with ethylacetoacetate to form

ethyl""Ap"nitro"anilinoBcrotonate by reflu'ing ethylacetoacetate and p"nitro"

aniline dissolved in chloroform.

3ackeberg2(5obtained ethyl""Ap"acetamidoanilinoB"crotonate by heating

p"aminoacetanilide with ethylacetoacetate at +55 C for thirty minutes. )imilarly!

the crotonate was obtained by reflu'ing the ester with p"aminoacetanilide in

methanol for 8 hours.2(4-2(63ackeberg2(5! Kermack and Jebster2()prepared and

cyclized ethyl""Am"acetamidoanilinoB"crotonate. Conard and @impach2(*

-I

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obtained ethyl""A+" and -"naphthyl"aminoB"crotonates by condensing

ethylacetoacetate with +" and -"naphthylamines.

)taskum and sraelstam2(9 obtained directly -"phenyl">"hydro'y"

*uinolines from ethylbenzoylacetate and aryl amines using 0olyphosphoric acidO

under these conditions a mi'ture! benzoylacetanilide and "arylaminocinnamate

was also obtained. 2allams and sraelstam21( synthesized directly >"

hydro'y*uinaldines from ethylacetoacetate or its "alkyl derivatives and

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

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

directly. (esai and (esai

211

however! found that acetoacetanilides could becyclised to >"hydro'y*uinaldines and also -"hydro'y"lepidines by adGusting

temperature conditions. They also improved the yields of >"hydro'y*uinaldines

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

procedure and were successful in cyclising o"nitroaniline or m"nitroaniline into "

nitro">"hydro'y*uinaldine and ?"nitro">"hydro'y*uinaldine directly! in very good

yield. 2ehta and (esai212 reflu'ed a mi'ture 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 acidO

they have reported that the yields of "nitro! ?"nitro and 8"chloro">"

hydro'y*uinolines were higher.

3angadiwala and (esai21employed acetic anhydride and concentrated

sulphuric acid to cyclise anils of different "ketoesters! such as ethyl"

acetoacetate! ethylbenzoylacetate! ethylacetylmalonate! ethylacetylcyanoacetate

and obtained >"hydro'y*uinolines.

Uuinoline derivatives possess wide therapeutic activity! vizO antiseptic!

analgesic! trypanocidal! germicidal! amoebicidal! antitubercular! anthelmintic!

pyroplasmosis! schistomiasis! antiserotonin! cytokinin and antispasmodic214-219

The recent researches in chemotherapy have revealed that sulfanilamide

and its derivatives have been found to possess definite bacteriostatic action

=5

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against various coccal infections. 3asu and (as 1upta22( prepared some A>D"

amidobenzenesulfonylB"amino*uinolines which are e'pected to have some

therapeutic importance since the replacement of one %"atom of sulfonamido

group of p"aminobenzenesulfonamide often widens the range of activity of thedrug221-22. )ome 8!6 and "sulfonamido*uinolines have been synthesized224.

large number of *uinoline derivatives are the most effective and best

tolerated amoebicides known so far225-229. mong them! those *uinoline moieties

with a metho'y or a methyl substituent Aat position"B are the most effective

one.

2aheshvari and Thaker2(synthesized -"arylLstyryl"6"acetyl" *uinolino">"

yl",-"phenylLbenzyl hydrazides and tested against bacteria! viz.! E. coli! ).

aureusand 2. tuberculosis.

number of *uinoline derivatives like vioform! chloro*uin and intestopan

are well"known amoebicides21-22. 2any substituted sulfonamides also e'hibit

potent amoebicidal activity.2-2*

Uuinoline derivatives have been reported to possess various

pharmacological activity29-24(. n view of this! *uinolinoazetidinones!

thiazolidinones! triazolines and formazans have been synthesized and found to

be better cardiovascular agents241.

9rea derivatives of *uinoline are used as analgesic and central nervous

system depressant and "amino*uinolines as antimalarial.242-24

Jith a view to synthesis biologically active compounds244! 0atel and

(esai245 synthesized -"A6D"metho'y"-D"styryl">D"*uinolin"o'yB">"phenylureido"6"

arylthioureido"s"triazine AB.

=+

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,

,

,

,

%=C$

C%

C%

$

,%C$,%:

,%C),%:

AB

Uuinoline derivatives are drugs of therapeutic importance showing widespectrum of biological activities. )ome work has been done on the synthesis and

screening of some ,D"substituted *uinoline derivatives. n view of this!

heterocyclic moiety has been incorporated in the ,D"position of 6"methyl">"

phenyl*uinolin"-A+%B"one246 to study the effect of ,D"substitution on

antimicrobial activity.

)ynthesis and biological screening of some azomethines and -"

azitidinones24)of type AB and AB have been very recently reported.

,

$C% =

Cl

$C% =

,

:

,

$C%=

Cl

$C%= ,

:

$

Cl

+II, +III,

)ynthesis and antibacterial screening of -"chloro""methyl*uinolin"="yl","

A-D"phenyl">D"arylidene"8D"o'oimidazolin"+D"ylB azomethines24* have been very

recently reported. series of azetidinones249 bearing -"chloro*uinoline"="

=-

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carbo'aldehyde moiety have been synthesized and their antimicrobial activities

have been studied.

)ynthesis of certain ,"substituted""*uinolinesulfonamides25(structurally

related to antimalarials was reported. )ynthesis and properties of sulfonamides

of *uinoline series251 had been reported. The chemistry of *uinoline and p"

toluenesulfonamide has attracted special attention because of their therapeutic

properties252-25. :ecently some sulfonamido*uinoline derivatives254 have been

found to possess enhanced antibacterial activity.

)ome new sulfonamides of type AFB have been prepared having

pharmaceutically important chloro*uin moiety by condensing with different

carbo'yaryl sulfonylchlorides. The products were screened for antimicrobial

activity255.

C%=

Cl

%C , ,%)$-:

+I,

(esai and (esai256coupled o"! m"! p"cresols with diazotized sulfanilamide

and sulfathiazole and e'amined their antibacterial activity against different

organisms. -!>"(ihydro'y"="Ap"azobenzenesulfamidoB"*uinoline derivatives25)

had been prepared and screened for their antibacterial activity.

)ome new sulfonamides like! ,"arylsulfonamido"-"chloro"?"metho'y" and

"methyl*uinolin"="yl"azomethine25*-259have been synthesized and screened for

their antibacterial activity.

==

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[22+] A. J. Conan and -. J. Tro$, 4ed. !., 31, 18 (19*16 J. 4ed.

Chem., 6, )9 (19/9[228] %. !. ". Barton, &. S. inne00 and ". !. Senior, J. Chem. Soc., /) (19/*

[229] Von :ettinen, The Thera$e#tic -ents on the I#ino0ine >ro#$sL,

Chemica0 Cat. Co., Ae 3ork, 19))

[2)] J. 4. 4ahesh=ari and K. -. Thaker, J. nst. Chemists (ndia, 55, 189

(198)

[2)1] -.

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References

[2/+] B. ;. Kansara, !. !. Bhatt and -. ". ;arikh, J. nst. Chemists (ndia, 72,

8 (2

[2/8] . Bharma0 and !. ;arekh, J. nst. Chemists (ndia, 72, 111 (2

[2/9] A. J. %atta, ". C. Kh#nt and -. ". ;arikh, J. nst. Chemists (ndia, 72, 19(2

[2*] 4. -. Shaaban, !. 4. ". 50. 4o#a?i, 4. Kha0i?a, B#00. 9ac. ;harm. Cairo #@. . 4ehta and C. 4. %esai, J. So#th >#@.

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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 !" and Bis-pyrimidines !!" have been

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

and anti-inflammatory activities.3

N S S N

#HH#

$ $

(I)NH2NH2

% % % %

#HH#

$ $

(II)%H &%H&

'here,$(H, )-#*e, )-+l, )-%#&, )-Br, &-+l

)

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. *. *ahadevan et al4 reported a new method for the synthesis of

substituted benzofuran derivatives containing pyrimidine ring at & position !!!".

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

the existing conventional method of synthesis.

%

%

#

$

%H&

(III)

'here,$( H, %#&, +l, +H/, #+H/

*. 0mir et al5 synthesized )-1H-indol-/-yl"--phenyl-1,&,/,)-

tetrahydropyrimidin-&-ones2 thiones as potent anti-inflammatory agent !3, 3".

%H

H%

%H $#

(IV)

%H

H%

%H $S

(V)

Several pyrimidine derivatives possess a broad spectrum of biological

effectiveness such as calcium channel blockers6, antitubercular7, anticancer7and

antibacterial8.

4uinoline derivatives are also drugs of therapeutic importance showing a

wide spectrum of biological activities.

)5

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Some &-aryl-)-carboxy6uinoline--arsonic acids9have been prepared and

screened for antibacterial activity. Some new &-aryl-,5-substituted 6uinolines10

of type 3!" and 3!!" having )-aminoantipyrine and 1,/,)-oxadiazole moiety

have been prepared and tested for antimicrobial activity.

%

%

%

+H&

$1

$&

$/

+H7

(VI)

% $1

$&

$/

(VII)

+#%H

+H7

%

%

+H/

# +H/

$1, $&, $/( methyl, methoxy, chloro, nitro

Some new )-thiazolidinone derivatives of the type 3!!!" bearing 8-

hydroxy6uinoline moiety were prepared and screened for their antibacterial

activity11.

%

(VIII)9

%H+

S

%

$

#

$ (aryl, 9( H2 +H/2 +H&+##H

H#

3ery recently a number of substituted-)-hydroxy-/-p-azobenzene-

sulfonamido"-&-phenyl6uinoline12, )-:)-&,-disubstituted-6uinolin-)-yl-amino"-&-

hydroxy-phenylazo;-sulfonamide13 and )-hydroxy-/-substituted arylazo"-&-

phenyl-25-substituted 6uinoline derivatives

14

have been found to be activeagainst gram positive and gram negative bacteria.

)8

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-yl-

azomethines have been synthesized and screened for their antimicrobial

activities.190ll the compounds showed moderate activity.

0 number of 6uinolinyl hydrazinobenzylidine azobenzenesformazons"20-21

have been prepared and screened for antitubercular and antibacterial activity.

Several %-o-carboxyphenyl--aryl-azo-)-dimethyl-aminophenyl-azomethine

formazones" have been synthesized and screened for antimicrobial activity.

Some of them showed good antibacterial activity.22

Some %>-substituted-:&>-hydroxy-benzylidine"-amino-%&-)-phenyl-7-aryl-

azo"-thiazoyl;-azobenzene formazons" have been very recently reported and

screened for antibacterial activity against ?ram positive and ?ram negative

bacteria.23

!n 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 ),-

diarylsubstituted-&-pyrimidinamine. hese compounds were further coupled with

)-chloro6uinoline derivative to get corresponding compound pyrimidine-6uinoline

clubbed molecule.

+onsidering 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 )-/>-

bromophenyl"--)-methoxyphenyl"pyrimidin-&-aminewith cold brand reactive dyes.

)@

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$ealizing the medicinal importance of &-amino-pyrimidine, 6uinoline and

triazine derivatives it was considered worthwhile to incorporate these moieties.

!t was therefore thought interesting to synthesize the title compounds with an

obAect of ascertaining whether they could augment the microbicidal efficacy.

he structures of the various synthesized compounds were assigned on

the basis of elemental analysis, !$ and 1H %*$ spectral data. hese compounds

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

scanned in Scheme 1 and Scheme-&.

7

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+#+H/ #H+C

-#H2 +&H7#H#H-

% %

%H&

1" +onventional heating

&" Heterocyclization

+&H7#H

)BD %a#H

H&% +

%H

%H&

+

#

+H

+H

H

$ $>

$>$

$ $>

heme-I

0r y l ac et o ph en on e 0r y l al d eh y d e

S u b s t i t u t e d c h a l c o n e

) , - E i a r y l s u b s t i t u t e d - & -p y r i m i d i na m i n e

? u a n i d i n e

) - + h l o r o 6 u i n o l i n e d e r i v a t i v e

% ) - : ) , - Ei a r y l s u b s t i t u t e d p he ny l - & -p y r i mi d i n y l ; - s ubs t i t u t e d - )- 6u i n o l i n a mi n e

$( &,)-+l"&-7-( )>--+l, />-%#&, />-Br

$1( -H, -+H/, $& ( -H, -+l, -+H/, -#+H/, $/ ( -H, -+l

where

71

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heme-II

% %

%H&

Br

H/+#+old brand reactive dye C

H C .H

(#$$5)

[=] K. 0. 0ahade7an, . K. Prakash, 8. . An/nak/!ar, 0. '. K/!arasa!y, .

P.'andeshara22a and . ;. ;heri&ara, 1ndian +. he!.,45 B, 16441>$3

(#$$6)

[?] 0. A!ir and ;. A. +a7ed,Acta Phar!a, 58, =6>=>> (#$$5)

[6] (a) K. ;. Atal, . . Ro7nyak, ;. 8. Ki!ball and ;. 0oreland, +. 0ed. he!.,

33, #6#4 (144$) (b) K. ;. Atal, . '. ;anson, ;. 0oreland, 8. 0. Floyd

and ;. *. ] K. ;. 'i!a7at, K. H. Po2at, ;. C. 9asoya and H. ;. +oshi, 1ndian +. Heterocyclic

he!., 12, #1> (#$$3)

[5] (a) K. 9ashi and H. . 'aik,Asian +. he!.,17,#=$ (#$$?) (b) R. 9yas, P. .

ho/dhary, H. ;har!a and . C. 9er!a, 1ndian +. Heterocyclic he!.,17,

#3> (#$$5) () P. . har/cha and H. . 'aik, Asian +. he!., 11, 1??3

(1444)

[4] 8. +. hatt, . . Ka!dar and A. R. Parikh, +. 1nst. he!ists (1ndia),56, #33

(145=)

?3

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References

[1$] R. R. Cakhani and A. R. Parikh, +. 1nst. he!ists (1ndia), 59, #3$ (145>)

[11] H. ;. +oshi and A. R. Parikh, +. 1nst. he!ists (1ndia), 62, ##, #?1 (144$)

[1#] ;. A. ;hah, Ph. 8. -hesis, 9. '. ;o/th /@. (#$$$)

[14] R. . Kh/nt, '. +. 8atta and A.R. Parikh, +. 1nst. he!ists (1ndia), 74 (1),

15(#$$#)

[#$] +. 0achhi% R. ;hetty, . 0. 8esai, 8. Patel and H. 8. +oshi, +. 1nst. he!ists

(1ndia), 74 (2), 65>$ (#$$#)

[#1] +. 0achhi, 8. Patel, . 0. 8esai, P. 8esai and H. 8. +oshi, +. 1nst. he!ists

(1ndia), 74 (3), 11$11# (#$$#)

[##] '. Rao, A. 'arendra ab/, . o2inath and . Ra!an, +. 1nst. he!ists

(1ndia), 76 (1), 1$ (#$$=)

[#3] . 0. 8esai, 8. Patel, 8. 8esai and H.8. +oshi, +. 1nst. he!ists (1ndia), 76

(3), 4= (#$$=)

[#=] 9. ara@, C. P/ccetti, . Fasolis, +. . Din/!, +. C. 0ontero, A. ;cozzafa7a, 8.

9/llo, A. nnocenti, . -. ;/2/ran, ioor&. 0ed. he!. Cett. 14, ?=#>

(#$$=)

[#?] . F. 8EAlelio, H. +. Dhite, +. :r&. he!.24, 6=3 (14?4)

[#6] K. 8esai, 8. Patel, 0/llakhan, . 0. 8esai, A. . 0ehta, +. 1nst. he!ists

(1ndia), 71 (3), 43 (1444)

08_chapter 1

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