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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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Chapter - I: Introduction
, ,
,%-
.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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Chapter - I: Introduction
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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Chapter - I: Introduction
.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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Chapter - I: Introduction
AB $rganocadmium compound 2
MEC$!NI"M O% C$!CONE %ORM!TION
Kinetic studies have been reported for the base"catalyzed formation of
chalcone and its derivatives-6. Two alternative mechanisms have been
advanced for the reaction of benzaldehyde with acetophenone in the presence
of a basic catalyst.
CH3COPh C2H5O
CH2COPh C2H5OH
CH2COPh PhCHO Ph C CH2COPh
O
H
Ph C CH2COPh
O
H
H2O Ph C CH2COPh
OH
H
OH
Ph C CH2COPh
OH
H
Ph-CH=CHCOPh H2O
[I]
+
+
+
+
+
+
C2H5OPhCHO Ph C OC2H5
O
H
Ph C OC2H5
O
H
CH3COPh Ph C CH2COPh
OH
H
[II]
+
+
8
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Chapter - I: Introduction
The formation of chalcone by the acid catalyzed condensation of
acetophenone and benzaldehyde has been studied.)7 *
The following mechanism seems to be operating
Ph C CH3
O
Ph C CH2
OH
+
Ph C
O
H Ph C
OH
H S
[S=Solvent]
SH+
Ph C CH2
OH
Ph C H
OH
Transition
+
Ph C
OH
CH2 CH Ph
OH
Ph C
OH
CH2 CH Ph
OH
Ph C
O
CH2 CH Ph
OH
Ph C
O
CH2 CH Ph
OH2
SH
S
+
+
+
Comle!
S
+
+
+ +
+
+
Ph C
O
CH2 CH Ph
OH2
Ph C
O
CH CH Ph H2OH+
+
+ +
IM&ORT!NCE O% C$!CONE"
(1) They have close relationship with flavones! aurones! tetralones and
aziridines.
6
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Chapter - I: Introduction
(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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Chapter - I: Introduction
$%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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Chapter - I: Introduction
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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Chapter - I: Introduction
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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Chapter - I: Introduction
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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Chapter - I: Introduction
,%
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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Chapter - I: Introduction
%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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Chapter - I: Introduction
: 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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Chapter - I: Introduction
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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Chapter - I: Introduction
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,
, ,
$%
+I,
)imilarly pyrimidine thiones AFB e'isted as pyrimidine thiols AFB.
, ,%
)
+,
, ,
)%
+I,
There are various methods for synthesis of pyrimidinesO some of them are
described here.
+6
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Chapter - I: Introduction
1. Condensation of +!+!=!="tetraetho'y propane AFB with thiourea in alcoholic
hydrochloric acid gave pyrimidine"-"A+%B"thione AFB164and with ,"methyl
urea under similar conditions gave +"methyl pyrimidine"-"A+%B"one AHB165.
C%A$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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Chapter - I: Introduction
+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.
,%
,%
$
$$
:+
:-
+8III,
%yperthyroidism may be treated in several ways. $ne of these is
interference with the synthesis of the thyroid hormones! possibly or by removal
of iodine. Thiouracil AHFB and thiobarbital AHFB are effective thyroid drugs.
Compound AHFB is widely used probably because it has fewer side effects than
the others169.
+
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Chapter - I: Introduction
NH
NH
NH
NH
O S
O
Et2
OR
O
(XV)(XIV)
Cytosine arabinoside AHFB is established drug for the treatment of acute
leukemia/s of childhood and adult granulocytic. t has also incidental antiviral
activity against herpes and herpes zaster types1)(.
$
C%=$%
C%= %$
%=C
C%-$% ,
,
,%-
C%=
(XVI)
El"1aby! del"%amide and 1harab1)1prepared some new pyrimidine"-"
thiones AHFB. )ome of these compounds were tested for in vitro anticancer
activity against Ehrlich scites CarcinomaCells.
+I
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Chapter - I: Introduction
C-%8$$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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Chapter - I: Introduction
@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$$C-%8
:
,
+88I,
:&%! C%=! $C%=! M! Cl! 3r
-+
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Chapter - I: Introduction
, ,
C$$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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Chapter - I: Introduction
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,
:+
%$$C%-C
,%-
:+& 0henyl! >"chloro phenyl! furfural! >"metho'y phenyl!-"thiophene! ="nicotine
-=
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Chapter - I: Introduction
Merri et al1*( synthesized some -"tosylamino AHHF"B and -"
tosyliminopyrimidine AHHF"3B derivatives and studied their interference with
some leukocyte functions.
,
,
+88II -!,
,
C%- C$,%:
Ts
,
,
C$,%:C%-
, Ts
+88II -9,
where!:& %! C
-%
8! C
6%
8! >"$%"C
6%
>! -">Cl
-"C
6%
=! C
6%
8C%
-C%
-! >"$%"C
6%
>C%
-C%
->"M"C6%>C%-C%-! -">"Cl-"C6%>C%-C%-
4akubkiene et al1*1 reported the synthesis of some 8"A6"methyl"-"
substituted">"pyrimidinylo'ymethylB"-!="dihydro"+!=!>"o'adiazole"-"thiones
AHHF"B and their ="morpholinomethyl derivatives AHHF"3B and evaluated
them for anti"inflammatory activity. 2ost of the tested compounds were found
to be active and some of them were more active than acetylsalicylic acid.
,
,
,%,
$:
C%=
$ C%-)
+88III-!,
->
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Chapter - I: Introduction
,
,
,,
$:
C%=
$ C%- )
+88III-9,
$,
:& thiomethyl! benzylamino! pyrrolidino! piperidino! morpholino
3runo et al1*2synthesized two different series ,"methyl","pyrimidin"-"yl
glycine and ,"8%"Q+RbenzopyranoQ>!="dRpyrimidin"-"yl substituted amino acids
and tested for anti"inflammatory activity. ll the compounds showed significant
anti"inflammatory activity.
)acchi et al1* synthesized a series of imidazoQ+!-"aRpyrimidine -"
carbo'ylic acid and -5 acetic acid analogs AHHH""3B and tested them for anti"
inflammatory activity. lmost all the carbo'ylic acid derivatives showed a
remarkable anti"inflammatory activity.
,
, ,
,
, ,
C%-C$$Et
Cl
%=C :+
:-
C%-C$$%
+88I8-!, +88I8-9,
:+& $C%=! C%=
:-& $C%=! $C-%8
bignente et al1*4 synthesized a group of imidazoQ+!-"aRpyrimidine"-"
carbo'ylic acid esters! acids and amides. )ome of them showed anti"
inflammatory activity! while almost all compounds displayed significant analgesic
activity.
-8
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Chapter - I: Introduction
@aneri et al1*5 reported the synthesis and anti"inflammatory activity of
some new -"methylimidazo"Q+!-"aRpyrimidine"="carbo'ylic esters! acids and
amides. The compounds AHHH"HHHB displayed ma'imum anti"inflammatory
activity.
,
, ,
C%=
:-
:+
+888,
:+& $C%=! C%=! %
:-& $C%=! C%=! $C-%8
C$$C-%8
,
, ,
C%=
+888I,
C$,%-
,
, ,
C%=
+888II,
C$$%
:+
:- :+! :-& %
:+! :-& C%=
-6
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Chapter - I: Introduction
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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Chapter - I: Introduction
AchalconeB and guanidine hydrochloride. ll the synthesized compounds
screened for their antitubercular activity.
, ,
3r
,%-
:
+888,
-
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Chapter - I: Introduction
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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Chapter - I: Introduction
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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Chapter - I: Introduction
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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Chapter - I: Introduction
,
,
,
,
%=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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Chapter - I: Introduction
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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[21] 4a00ams and srae0stam, ibid, 29, )*/8 (19/
[211] %esai and %esai, nd. J. o? Chem.,5, 1+ (19+
[212] -. >. 4ehta and C. 4. %esai, J. So#th >#@. r#t', %e#t. 4ed. &och., 68, 19)+ (19)2
[22)] %omak, Khin, &och., 16, 1/2 (19)+
[22/] >. J#ne@a, K. Aaran and J. "a, J. nd. Chem. Soc., 17, /9* (19/
/)
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References
[22*] J. !. :sbond, J. Chem. Soc., 18*) (19*
[22] J. !. B#rckha0ter and &. !. 5derton, J. -m. Chem. Soc., 73, /8)8 (19*1
[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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Chapter - I: Introduction
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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Chapter - I: Introduction
. *. *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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Chapter - I: Introduction
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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Chapter - I: Introduction
-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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Chapter - I: Introduction
$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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Chapter - I: Introduction
+#+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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Chapter - I: Introduction
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> (#$$5) () P. . har/cha and H. . 'aik, Asian +. he!., 11, 1??3
(1444)
[4] 8. +. hatt, . . Ka!dar and A. R. Parikh, +. 1nst. he!ists (1ndia),56, #33
(145=)
?3
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[1$] R. R. Cakhani and A. R. Parikh, +. 1nst. he!ists (1ndia), 59, #3$ (145>)
[11] H. ;. +oshi and A. R. Parikh, +. 1nst. he!ists (1ndia), 62, ##, #?1 (144$)
[1#] ;. A. ;hah, Ph. 8. -hesis, 9. '. ;o/th /@. (#$$$)
[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)