HGFH

Synthesis, Characterization & Biological Evaluation of Some Substituted Cinnoline Derivatives
OBJECTIVES
Cinnoline are the six membered heterocyclic compound having two heteroatoms in the
ring. The review of literature showed that cinnoline derivatives were found to elicit many
pharmacological actions like anti-hypertensive, antithrombotic, antihistamine, antileukemic, CNS
activity, anti tumor, antibacterial and antisecretory activity.
Similarly mida!ole and "yra!ole moieties are well known for their therapeutic values.
Combination of two biologically active moieties in one molecule might result in an overall
enhanced biological activity.
Study is aimed to synthesi!e some cinnoline derivatives from substituted anilines and these
substituted cinnolines are further condensed with mida!ole and "yra!ole moieties respectively
and further evaluating these substituted cinnoline derivatives for biological activity.
#. Synthesis of new series of substituted cinnoline derivatives condensed with imida!ole and
"yra!ole $oieties.
%. Characteri!ation of newly synthesi!ed compounds by analytical and spectral methods vi!.,
& spectra, N$& spectra and $ass spectra.
'. Screening for the (ntibacterial, (ntifungal and (nthelmintic activity of the newly
synthesi!ed compounds.
# ) " a g e
INTRODUCTION
The approach to the practice of medicinal chemistry has developed extensively involving
synthesis of new organic compounds based on modification of naturally available compounds of
biological interest. The present work deals with the synthesis and evaluation of substituted
cinnoline derivatives.
Cinnolines are the six-membered heterocyclic compounds having two hetero atoms in the
ring. They are also called as #,%- ben!odia!ines or ben!opyrida!ine or #,%- dia!anaphthalene or
phenodia!ine
#
. *+
1
2
3
4 5
6
7
8
N
N
The ,en!odia!ines are reactive by virtue of the presence of a ben!ene ring and the
electrophilic attack takes place in this ring
%
.
Cinnoline derivatives particularly amino cinnolines play vital role in pharmaceutical
practice owing to their wide biological activities like bactericidal activity.
Thus, the basis of our research programme was centered around the fact that certain
structural units present in known biological active compounds are also found in other compounds
which similar properties and also by affecting structural variation and modifying molecular
structure, the relationship in respect to chemical structure and biological activity could be better
explored. Several physico-chemical parameters are said to be associated with this phenomenon.
,oth steric and electronic factors are claimed to be prime determinates in the variation in
biological activity
'
. (pparently an example where the discovery of cinoxacin by -.(. -hite in
#./0 showed good antibacterial activity, by keeping the same thing in mind 1.2oga et al 3. $ed.
% ) " a g e
*+
Chem in #.40 synthesi!ed norfloxacin*+ with one nitrogen less in the structure which showed
better activity than cinoxacin*+, later after studying molecular and receptor properties. ,ayer
pharmaceuticals *5ermany+ replaced ethyl group with cyclopropyl and patented it as
ciprofloxacin*.6+
N
N
COOH
O
O
O
N
N
N
F
C
2
H
5

COOH
O
Cinoxacin Norfloxacin
N
N
F COOH
O
N
Ciprofloxacin
n the present work substituted anilines were dia!oti!ed and the dia!oti!ed aniline is
reacted with active methylene compound, such as cyanoacetamide through 3app- klingemann
reaction.
Then the substituted aryl hydro!ono *cyano+ acetamide in the 7-form voluntarily undergoes
intramolecular 8riedel Craft9s reaction in chloroben!ene in presence of aluminium chloride leading
to substituted :- amino cinnoline '- carboxamide.
Three main approaches have been explored for the synthesis of cinnolines. The first approach
made use of the condensation between the ;-nitrogen atom of a chain of two or more carbon
atoms, and these chains being oriented in the ortho positions of ben!ene ring *6+
' ) " a g e
<
*+
*+
*6+
N
C
C
N
N
N
n the second approach the chain of two nitrogen atom is increased by one carbon atom which
condenses with the carbon atom of a second chain in the orthoposition to build up the heterocyclic
ring. *6+
N
C
N
C
N
N
The third approach the carbon atom of a chain containing two nitrogen and two carbon atom reacts
with the hydrogen in the ortho position of the aromatic ring *6 + to yield cinnoline
derivatives*6+.
N
C
N
C
N
N
"ossible mechanism for these three synthetic approaches to the cinnoline structure have been put
forward by various workers
=11,13,17,19,26>
although not supported by experimental evidences. The first
two approaches are believed to possess the common feature of electrophilic attack by dia!onium
cation on carbon ? carbon center of unsaturation *@+ as below.
: ) " a g e
A
<
<
B
C
<
<
A
A
A
*6+
*6+
*6+ *6+
N N
C
C
N
N
C C
N
N
D ) " a g e
Imidazole

Properie!
$olecular formula C
'
1
:
N
%
$olar mass E4.0// gFmol
(ppearance white or pale yellow solid
Gensity #.%' gFcm
'
, solid
$elting point 4.-.# HC *'E%-'E: 2+
,oiling point %DE HC *D%. 2+
Solubility in water miscible
*@+
Imidazole is an organic compound with the formula C
'
1
:
N
%
. This aromatic heterocyclic is a
dia!ole and is classified as an alkaloid. mida!ole refers to the parent compound whereas
imida!oles are a class of heterocycle with similar ring structure but varying substituents. This ring
system is present in important biological building blocks such as histidine, and the related
hormone histamine. mida!ole can serve as a base and as a weak acid. $any drugs contain an
imida!ole ring, such as antifungal drugs and nitroimida!ole,
Guring the past decade, imida!ole derivatives have occupied a uniIue place in the field of
medicinal chemistry. They have wide range of biological activities. They are well known
analgesics, anti-inflammatory, antiparasitic, anthelmintic, platelet aggregation inhibitors and
antiepileptic agents. mida!ole can be found in many other drugs such as dacarba!ine,
metronida!ole, cimetidine, fluma!enil, thyroliberin, methima!ole, pilocarpine and etomidate which
are used as antineoplastic antibiotic, antiulcerative, ben!odia!epine antagonist, prohormone,
antihyperthyroid, muscarinic receptor..
Sr#$#re a%d properie! & mida!ole is a D-membered planar ring, which is soluble in water and
other polar solvents. t exists in two eIuivalent tautomeric forms because the hydrogen atom can
be located on either of the two nitrogen atoms. mida!ole is a highly polar compound, as evidenced
by a calculated dipole of '.E#G, and is entirely soluble in water. The compound is classified as
aromatic due to the presence of a sextet of J-electrons, consisting of a pair of electrons from the
protonated nitrogen atom and one from each of the remaining four atoms of the ring.
Some resonance structures of imida!ole are shown belowK
E ) " a g e
Preparaio%
mida!ole can be formed in a vapor phase reaction. The reaction occurs with formamide,
ethylenediamine, and hydrogen over platinum on alumina, and it must take place between ':0 and
:40 HC. This forms a very pure imida!ole product.
/ ) " a g e
P'arma$e#i$al deri(ai(e!
mida!ole skeleton is present in many important pharmaceuticals. Synthetic imida!oles are
present in many fungicides and antifungal, antiproto!oal, and antihypertensive medications
#
.
mida!ole is important precursor of the theophylline molecule, found in tea leaves and coffee
beans, which stimulates the central nervous system
'#
. t is present in the anticancer medication
mercaptopurine, which combats leukemia by interfering with GN( activities) The substituted
imida!ole derivatives are valuable in treatment of many systemic fungal infections. mida!oles
belong to the class of (!ole antifungals, which includes 2etocona!ole, $icona!ole, and
Clotrima!ole.
P*R+,O-E
"yra!ole is the organic compound with the formula C
'
1
'
N
%
1. t is a heterocycle characteri!ed by a
D-membered ring of three carbon atoms and two adLacent nitrogen centres. "yra!oles are also the
class of compounds that have the ring C
'
N
%
with adLacent nitrogen centres.
P.razole
Properie!
$olecular formula C
'
1
:
N
%
$olar mass E4.04 g mol
M#
$elting point
EE?/0 HC
,oiling point
#4E?#44 HC
4 ) " a g e
(cidity *pK
a
+ #:.0
,asicity *pK
b
+ %.D
Preparation and reactions.
"yra!oles are synthesi!ed by the reaction of <,A-unsaturated aldehydes with hydrazine and
subseIuent dehydrogenation.
Substituted pyra!oles are prepared by condensation of #,'-diketones with hydra!ine. 8or example,
acetylacetone and hydra!ine gives ',D-dimethylpyra!ole.
C1
'
C*N+C1
%
C*N+C1
'
O N
%
1
:
P *C1
'
+
%
C
'
1N
%
1 O % 1
%
N
ccurrence and uses
Celecoxib, a pyra!ole derivative used as an analgesic. n medicine, derivatives of pyra!oles are
used for their analgesic, anti-inflammatory, antipyretic, antiarrhythmic, tranIuili!ing, muscle
relaxing, psychoanaleptic, anticonvulsant, monoamineoxidase inhibiting, antidiabetic and
antibacterial activities. n #.D., the first natural pyra!ole, #-pyra!olyl-alanine, was isolated from
seeds of watermelons.
. ) " a g e
REVIE/ O0 -ITER+TURE&
Though no cinnoline derivative occur in nature it is observed that considerable interest in
attached to the chemotherapeutic activity of cinnoline derivatives.
V) Vo%) Ri$'er

112233 prepared cinnoline derivatives*:+by the dia!oti!ation of o-aminoaryl
propiolic acids*#+ or o-amino aryl acetylenes followed by hydration and cycli!ation.
N
N
OH
COOH
R
H
2
O
70
260
N
N R
OH
R
NH
2
C C-COOH
HONO
Hcl
R
C C-COOH
N
2
+
Cl-
Solle a%d Be$4er,119253 reported that N-substituted isatin derivatives, obtained through reaction
between substituted phenyl hydra!ones and oxalyl chloride gave '-phenyl cinnoline :-carboxylic
acid derivatives*D+ on treatment with alkali, these on decarboxylation gave corresponding '-phenyl
cinnolines. The reaction evidently, proceeds through the opening of the heterocyclic ring of isatin
derivatives of the intermediate keto acid structure, the structural reIuirement of the second
approach for the synthesis of cinnolines.
N
N
R
COOH
C
6
H
5

#0 ) " a g e
*#+ *%+ *'+
*:+
*D+
0)6)S $#rd a%d /) 6ep7or', 119823 found that bis *:-amino E- cinnolyl+ guanidine
dimethiodide *E+ had a chemotherapeutic index of the same order of antrycide methyl sulphate
and the compound had been designated as
N
N
NH-C-NH
CH
3
I
NH
2
N
N
CH
3
I-
NH
2

NH
*E+
Ra.mo%d N) Ca!le e al, 119893 prepared :-mercapto cinnolines * /+ E,/-dimethoxy :-
mercaptocinnoline *4+ and a number of alkyl and heterocyclic derivatives by the action of thiourea
on :-chloro cinnoline. These compounds have been prepared for antitumor screening.
N
N
SH
N
N
H
3
CO
H
3
CO
SH
*/+ *4+
6arma% S) -o7rie, 119663 prepared '-"henyl-:-dialkyl aminoalkoxy cinnolines *.+ and ', *: ?
dialkyl amino alkoxy phenyl+ cinnolines. (nd they were screened for hypotensive and antibiotic
activity.
N
N
OR
C
6
H
5

*.+
## ) " a g e
T'eodor a%d 'i! $o97or4er!

119693 reported the preparation of #,%-matonyl, #,%-dihydro
cinnolines *#0+
N
N
R
O
O
R
1
-here &Q"h, Tolyl *#0+
&
#
Q"ropyl, sopropyl, so(myl, ,utyl
&
%
Q&'Q1
These compounds have been reported to have anti inflammatory , antipyretic and analgesic
activity.
+%!le.

1197:3 prepared a number of #-alkyl-E, /-methylene dioxy ?:-*#1+ oxocinnolin-'-
carboxylic acids. *## +
N
N
O
O
O
R
R
1

*##+
-here &Q$e, "ropyl, so-"ropyl, C1
%
C1
%
N1, C1
%
-C1QC1
%
&
#
Q7t, CN, and CNN1
#% ) " a g e
These compounds and their salts were found to be active against mycoplasm a
gallicepticum, 7-coli, salmonella dublim, vibrocoli etc.
;a%%er C)B a%d pa%di U);, 119213 synthesi!ed cinnoline derivatives by reaction of ;-amino- <,
; -. unsaturated esters and amides with aryl dia!onium salts.
N
N R'
C-R
O
& &
#
N7t N$e *7thyl /-methoxy cinnoline-'-carboxylate+
S$'mid a%d $o97or4er 119253 have synthesi!ed various :-*#1+ oxo cinnoline '-carboxylic acid
derivatives*#:+ as useful synthons for pharmaceuticals by cycli!ing phenyl hydra!ones in presence
of an organic carboxylic acid anhydride with a friedel craft9s catalyst. "henyl hydro!ones in acetic
anhydride*#'+ was treated with pocl
'
and the mixture was stirred and warmed to 4D-.0c and for
#D minutes at #00-#0Dc to give in E/R yield.
NH
N
N
N
O
R
C
R
HOOC
*#'+ *#:+
-here &QCN
%
1
#' ) " a g e
*#%+
Na<ara=a% e al

119263 synthesi!ed :, E, /, 4 tetrahydro ? D-*#1+ cinnolinones *#E+ by the reaction
of substituted dimedones *#D+ with hydra!ines. (nd they have been screened for CNS depressant
activity.
OH
O R
2
R
1
R
O
R
R
3
NHNH
2 +
N
N
O R
2
R
1
R
R
3

R
*#D+ *#E+
-here a &Q$e, &
#
Q"h, &
%
Q1 ,&
'
Q1
b &Q$e,&
#
Q"h , &
%
Q1, &
'
Q*C1
%
+
%
N$e
%
0#!$o, Ra>>aello e al, 119223 prepared # alkyl-'- carboxy-:-cinnolones*#/+, and screened for
antibacterial activity.
N
N
R
2

CO
2
H
O
R
R
1
&
#
&
#
Q1
&&
#
QNC1
%
N
&
%
Qalkyl
#: ) " a g e
*#/+
?)S) +@@ad. e al, 119933 prepared '-acetyl, E-sulphonyl-#1 cinnoline, :-one derivatives*#4+ by
the intramolecular cyclisation of the corresponding hydra!ones with (lcl
'
. They have been
screened for antibacterial activity.
N
N
H
O
COCH
3
RO
2
S
Sa%$za4 + e al, 119953 synthesi!ed N
%-
substituted cinnoline derivatives by alkylation of :-
hydroxy cinnolines using ethyl bromo acetate. Several of the compounds were tested for their
effect on central nevrous system.
Sa%$za4 + a%d Pa4#l!4a /, 119973 synthesi!ed some :-amino, '-cinnoline carboxylic acid
derivatives vi! *#, '- oxa!ino *D,:-c+ cinnolines and pyrimido *D,:-c+ cinnolines by condensation
of E,/,4 substituted :-amino, '-cinnoline carboxylic acids with acid anhydrides. These were
screened for CNS activity.
Sa%$za4 +, e a,119923 synthesi!ed some :-amino, '-cinnoline carboxylic acid derivatives vi!
*pyrimido *D,:-c+ cinnolines and tria!epino */,E-c+ cinnoline. Some of the synthesi!ed compounds
were screened for their effect on CNS.
S#@@a<'a 6, +@adia 6+, a%d Jo$'e% - 119993 prepared %,:-disubstituted thia!oles and
reported antitumor activity by performing assay on human cell lines.
+mer +)?) e al

,12:::3 prepared %-amino :-phenyl pyrido *',%-c+ cinnoline '-carbonitrile by
condensation reactions of *:-amino cinnolin '-yl+ phenyl methanone and :-amino '-cinnoline
carbonitrile*#.+ (nd above analogs exhibited antibacterial activity.
#D ) " a g e
*#4+
N
N
N
NH
2

CN
Ph
Bar@ara !e>a S4a, e al ,12::33 synthesi!ed %, /- dihydro-'1-diben!o *de, h+ cinnoline ', /-
dione derivatives. (nd screened for antileukemic activity.
S'a!'i4a% R paa% e al, 12::53 synthesi!ed some fluoro cinnoline #1-:-one '-phenyl
imida!o*%,#-b+thia!ole*%/+ and pyra!olo =:,'-c> fluoro cinnoline*%E+ and they were screened for
antibacterial and antifungal activities.
N
N
H
O
F
HN
COCH
3

R
R=H, Cl
N
N
F
Cl
N
N
CH
3
R
R=H
NO
2

O
2
N
F
Cl
N
N
H
O
N
N
S
Ph
Irad.a% ?+ e al) 12::73 reported potent anti-tumor activity in some amino imida!ole
compounds.
D#a S 12:1:3 Synthesi!ed a series of %-substituted-:,D-diphenyl imida!oles by refluxing ben!il
with different substituted aldehydes and screened for anthelmintic activity. The compounds
showed significant anthelmintic activity compared to the standard drugs.
#E ) " a g e
*%D+ *%E+
*%/+
Pri.adar!i%i P 12:123 prepareds new substituted pyra!oles from o-hydroxyacetophenone and
cinnamic acids as starting material through#,'-diketones as intermediates. These intermediates on
reaction with hydra!ines in alkaline media produce pyra!oles. The antimicrobial activity of
synthesi!ed pyra!oles. n the most cases having Chloro substitution on the styryl ring was found
to be more efficient.
Bal@i + 119923 synthesi!ed thirty-six novel pyra!ole derivatives and studied their antiproliferative
activity in human ovarian adenocarcinoma (%/40 cells, human lung carcinoma (D:. cells, and
8our of these substances found potent against cancer.
#/ ) " a g e
I% 'e pre!e% Re!ear$' 7or4 'e >i(e S#@!i#ed Ci%%oli%e !erie!
7ere !.%'e!ized i% 7'i$' $i%%oli%e moie. 7a! $o%de%!ed 7i'
Imidazole a%d P.razole moie. !eparael.)

T'e >ollo7i%< me'odolo<. 7a! #!ed >or S.%'e!i! &
S$'eme I
#4 ) " a g e
SC6E?E 9 I
1 0i<) 1 & SC6E?E A I 3
SUBSTITUTED CINNO-INE I?ID+,O-E DERIV+TIVES 111a9 e3
SUBSTITUTED CINNO-INE P*R+,O-E DERIV+TIVES 112a9 e 3
#. ) " a g e
1) Preparaio% o> !#@!i#ed '.drazo%o 1$.a%o3 a$eamide& 15a 9e3
BR & a Q %-$e, @ Q '- Chloro, $ Q %- 8luoro, d Q %,' di Chloro, e Q '- Nitro C
The substituted aniline *0.#.D mole+ was dissolved in a mixture of conc 1Cl */.Dml+ and water
*/.Dml+ and cooled to 0H to DH c in an ice bath. To this a cold saturated solution of sodium nitrite
*0.#.mole+ was added slowly. Soon after the addition, the fumes of nitrous acid were liberated, a
pinch of sulphamic acid F thiourea was added, stirred till the fumes were ceased. The dia!onium
salt thus formed was filtered in to a cooled solution of cyano acetamide *0.#.D mole+ in water
*'D0ml+,#0 gm C1
'
CNNNa and #D ml alcohol. The mixture was kept for stirring up to E hrs at
room temperatureS the solid was collected and recrystalli!ed from methanol.
2) S.%'e!i! o> !#@!i#ed a%ili%e 59ami%o $i%%oli%e 39$ar@oDamide& 18a 9e3
To the anhydrous (lCl
'
*0.###mole+ the chloroben!ene #D0ml was added and nitrogen gas was
passed for half an hour. This mixture was added to the substituted phenyl hydra!ono cyano
acetamide then nitrogen was passed for #0 min, the mixture was then refluxed for %hrs. t was
cooled, dilute 1Cl *%0ml+ was added to it. t was then heated on water bath cooled, filtered,
washed twice with dilute NaN1 solution and filtered. The product was recrystalli!ed from
methanol, water #0K#.
3) 1a3 Preparaio% o> !#@!i#ed 59129ami%o imidazole3 9$i%%oli%e 939$ar@oDamide 111a9e3 &
The substituted :-amino cinnoline-'-carboxamide 18a9e3 and %-Chloro imida!ole 173 in G$8 will
be refluxed for %hrs, and poured in to crushed ice. The precipitate obtained will be filtered, dried
and recrystalli!ed in methanol.
1@3 Preparaio% o> !#@!i#ed 59189ami%o9p.razole39$i%%oli%e 939$ar@oDamide 112a9e3 & The
substituted :-amino cinnoline-'-carboxamide 18a9e3 and D-chloro pyra!oline 123 in G$8 will be
refluxed for % hrs, and poured in to crushed ice. The precipitate obtained will be filtered, dried and
re crystalli!ed in methanol)
%0 ) " a g e
?ET6ODO-OE* & BIO-OEIC+- +CTIVITIES
1) +%i@a$erial a$i(i. !#die!
The newly synthesi!ed different series of substituted cinnoline derivatives in the present
investigations were tested for their antibacterial activities.
Ee%eral Pro$ed#re
+) Di!4 di>>#!io% me'od
$odified 2irby-,auer method was used for the evaluation of microbial sensitivity of the
synthesi!ed compounds. Circular paper disks were impregnated with the specific amount of test
compounds and were placed on suitable agar medium *$uller 1inton agar+, which was inoculated
with the test organism. (fter incubation the petri dishes were observed for growth of inhibition
!one around the disk. ( ThaloU or Vone of inhibition forms, where concentration of the diffused
molecule is sufficient to inhibit microbial growth. The diameter of !one of inhibition is directly
proportional to antimicrobial activity of the compound. The diameter of !one of inhibition was
compared with that of standard antibiotics.
B) ?IC 1?i%im#m I%'i@ior. Co%$e%raio%3
$C of the synthesi!ed compounds were determined by tube dilution techniIues. Serial
dilution of the substance under examination was placed into culture tubes containing suitable
medium and inoculated with the test organism. (fter incubation, the minimum concentration of
test compound that inhibited the growth of the organism was observed.
C#li(aio% o> mi$roor<a%i!m
The cultures were obtained from Gepartment of ,W$, 6&, !atnagar. The following
bacterial cultures were used for the study.
%# ) " a g e
#. ,acillus subtilis - 5ram positive bacteria
%. Staphylococcus aureous - 5ram positive bacteria
'. 7scherichia coli - 5ram negative bacteria
:. "seudomonas aeruginosa - 5ram negative bacteria
The bacterial cultures were sub-cultured in the Nutrient broth medium and incubated under aerobic
conditions at '/C for %: hrs. These cultures were used for the test.
Preparaio% o> paper di!4!
"aper disk of E mm diameter and % mm thickness were used for the test. These disks were
found to absorb 0.0% ml of the solvent *G$8+. These disks were sterili!ed by autoclaving #%#C
*#D lbs psig+ for #D minutes. (ll the samples were tested at D0 g level. To obtain this sample
solution containing %D00 gFml *%D mgF#0ml+ were prepared in sterile G$8 and 0.% ml each of the
solution was added into bottle containing #0 disks. Gisk containing #0 gFdisk of norfloxacin was
taken as standard. (ll the solutions were prepared using aseptic precautions.
Preparaio% o> %#rie% a<ar & The composition of nutrient agar isK
I%<redie%! F#a%i.
,eef extract #0 gm
"eptone #0 gm
Sodium chloride 0D gm
(gar %0 gm
"urified water #000 ml
The media was prepared by dissolving the specified Iuantities of the dehydrated medium in
purified water by heating on a water bath and were dispensed in %0 ml volume into test tubes. The
%% ) " a g e
p1 /.% 0.%
test tubes were closed with cotton plugs and were sterili!ed by autoclaving at #%#C *#D lbs psig+
for #D minutes. The contents of the tubes were poured aseptically into sterile "etri dish and
allowed to solidify. These sterili!ed media were used to subculture the bacteria cultures.
Pro$ed#re
7ach "etri dish containing nutrient agar medium was inoculated with one bacterial culture
by spreading the suspension of the organism with a sterile cotton swab. 7ach plate was divided
into six eIual positions along the diameter. 7ach portion was used to place one disk. 8our disk of
each sample was placed on four portions, two disks were placed one each with Norfloxacin disk
and a disk impregnated with the solvent.
(ll plates were kept in the refrigerator for '0 minutes to allow the diffusion of sample to
the surrounding agar medium. The "etri dishes were incubated at '/C for #4 hrs. Giameter of the
!one of inhibition was measured and the average diameter for each sample was calculated. The
diameter obtained for the test samples were compared with that produced by standard Norfloxacin.
B) Deermi%aio% o> ?IC @. #@e dil#io% e$'%iG#e&
Preparaio% o> %#rie% @ro'n KThe composition of the media is K
I%<redie%! F#a%i.
,eef extract #0 gm
"eptone #0 gm
NaCl D gm
"urifier water #000 ml
The media were prepared by dissolving the specified Iuantities of dehydrated medium *1i-media+
in purified water. The medium was distributed as :-ml Iuantities into test tubes. The tubes were
closed with cotton plugs and sterili!ed by autoclaving at #%#C *#D lbs psig+ #D minutes.
%' ) " a g e
p1 /.% 0.%
Pro$ed#re
(ll the synthesi!ed compounds were dissolved separately to prepare a stock solution
containing #000 gFml of G$8. '% mg of different synthesi!ed compounds were dissolved in % ml
of the G$8 and # ml of this solution was aseptically transferred to the sterile nutrient broth
medium and made up to #E ml with sterile nutrient media, thus # ml of the resulted solution gives
#000 gFml. # ml of the above solution was transferred to # ml of G$8 to give half the
concentration of first.
Thus successive concentrations like %D0, #%D, E%.D and so were prepared in a similar manner upto
E dilutions from sixth one ml of the solution is discarded. The tubes were mixed well after each
addition. (ll the tubes were inoculated with one loopful of one of the test organism. The process
was repeated with different test organisms. ( positive control and a negative control were also
prepared to confirm the nutritive property and sterility, respectively of the prepared medium. The
tubes were incubated at '/C for %: hours. The presence or absence of growth of organism was
observed after incubation.
Concentration of the test compound in the dilutions prepared is as follows.
Dil#io% # % ' : D E
Conc. gFml #000 D00 %D0 #%D E%.D '#.%D
2) +%i 0#%<al +$i(i. S#die!
The (ntifungal activity of newly synthesi!ed compounds was studied against two fungal
organisms.
Aspergillus niger
%: ) " a g e
Candida albicans
The fungal cultures were inoculated into Sabouraud9s broth and incubated under aerobic
conditions at %DC for :4 hours.
C#li(aio% o> mi$roor<a%i!m!
The cultures were obtained from the Gepartment of ,W$, 6&, !atnagar . The following fungal
cultures were used for the study.
Aspergillus niger
Candida albicans
The fungal cultures were sub cultured in Sabouraud9s broth medium and incubated under aerobic
condition at %DC for :4 hrs. These cultures were used for the test.
Preparaio% o> paper di!4
"aper disk of E mm diameter and % mm thickness was used for the test. These disks were found to
absorb 0.0% ml of the solvent *G$8+. These disks were sterili!ed by autoclaving at #%#C *#Dlbs
psig+ for #D minutes. (ll the samples were tested at D0g level. To obtain this sample solution
containing %D00 gFml *%D mgF#0 ml+ were prepared in sterile G$8 and 0.% ml each of the
solution was added into bottle containing #0 disks. Gisk containing %D gFdisk of griseofulvin was
taken as standard. (ll the solutions were prepared using aseptic precautions.
Preparaio% o> Sa@o#ra#dH! a<ar media
Composition of Sabouraud9s agar isK
I%<redie%! F#a%i.
Gextrose %0 gm
%D ) " a g e
"eptone #0 gm
(gar %0 gm
-ater #000 ml
p1 D.: 0.%
in purified water. The media was distributed :-ml Iuantities into test tubes. The tubes were closed
with cotton plug and sterili!ed by autoclaving at #%#C *#D lbs psig+ #D minutes.
Pro$ed#re & 7ach "etri dish containing nutrient agar medium was inoculated with one bacterial
culture by spreading the suspension of the organism with a sterile cotton swab. 7ach plate was
divided into six eIual positions along the diameter. 7ach portion was used to place one disk. 8our
disk of each sample was placed on four portions, two disks were placed, one each with
griseofulvin disk and a disk impregnated with the solvent.
(ll plates were kept in the refrigerator for '0 minutes to allow the diffusion of sample to
the surrounding agar medium. The "etri dishes were incubated at %DC for :4 hrs. Giameter of the
!one of inhibition was measured and the average diameter for each sample was calculated. The
diameter obtained for the test samples were compared with that produced by standard griseofulvin.
%E ) " a g e
B) Deermi%aio% o> ?IC @. T#@e dil#io% e$'%iG#e)
Preparaio% o> Sa@o#ra#dH! deDro!e media
Composition of the media isK
I%<redie%! F#a%i.
"eptone #0 gm
Gextrose %0 gm
-ater #000 ml
in purified water. The medium was distributed :-ml Iuantities into test tubes. The tubes were
closed with cotton plug and sterili!ed by autoclaving at #%#C *#D lbs psig+ for #D minutes.
Pro$ed#re & (ll the synthesi!ed compounds were dissolved separately to prepare a stock solution
containing #000 gFml of G$8. '% mg of different synthesi!ed compounds were dissolved in % ml
of the G$8 and # ml of this solution was aseptically transferred to the sterile nutrient broth
medium and made up to #E ml with sterile nutrient media, thus # ml of the resulted solution gives
#000 gFml. # ml of the above solution was transferred to # ml of G$8 to give half the
concentration of first. Thus successive concentrations like %D0, #%D, E%.D and so were prepared in a
similar manner upto E dilutions from sixth one ml of the solution are discarded.
The tubes were mixed well after each addition. (ll the tubes were inoculated with one
loopful of one the test organism. The process was repeated with different test organism. ( positive
control and a negative control were also prepared to confirm the nutritive property and sterility,
respectively of the prepared medium. The tubes were incubated at %DC for :4 hours. The presence
or absence of growth of organism was observed after incubation.
%/ ) " a g e
p1 D.: 0.%
Concentration of the test compound in the dilutions prepared is as follows.
Gilution # % ' : D E
Conc. *gFml+ #000 D00 %D0 #%D E%.D '#.%D
derivatives in order to check their effects on normal animals.
Daa a%al.!i!
The data were subLected to analysis of variance *(NN6(+ as per statistical methods using S"SS
*#..E+ software package.
3) +%i'elmi%i$ +$i(i. S#die!
Xiterature Survey revealed that there is no report available regarding anthelmintic activity of
substituted cinnoline derivatives. n the present work the substituted cinnoline derivatives were
evaluated for anthelmintic activity by following method.
/orm! Colle$io% a%d +#'e%i$aio%&
ndian earthworms *"heretima posthuma+ were collected from the waterlogged areas of soil and
identified at ndian 6eterinary &esearch nstitute, !atnagar and were utili!ed for in-vitro
anthelminthic assay as per standard protocol *5arg and (tal, #.E'+
%4 ) " a g e
Preparaio% o> Te! Sample&
Suspensions of samples were prepared by triturating the samples with #%.DR tween 40 and
distilled water and the resultant mixture stirred using a mechanical stirrer for '0 minutes. The
resulting suspensions were used for the activity studies. The suspensions were diluted to contain
#00 mg in D0 ml of the test samples. Standard drug mebenda!ole was also be prepared with the
same concentration in a similar way.
+%'elmi%i$ +!!a.&
The anthelmintic assay was carried out as per the method of 5arg and (tal, *#.E'+ with minor
modifications. The assay was performed on adult ndian earthworm *"heretima posthuma+ due to it
anatomical and physiological resemblance with the intestinal roundworm of man and animal. 8ive
earthworms of similar si!es were placed in a "etri plate of : inches diameter containing D0 ml of
suspension of the test standard drug mebenda!ole at room temperature. (nother set of five
earthworms were kept as control in D0 ml suspension of distilled water and #%.DR tween 40. D0
ml each of suspension of the test compounds were added into separate "etri plates containing five
earthworms in each. The time reIuired for the paralysis and death of the worms was noted. The
death time was ascertained by placing the earthworms in warm water at D0
o
C, which stimulated the
movement if the worms were alive.
%. ) " a g e
RESU-TS
+)1 EDperime%al
The synthesis of substituted cinnoline sulphanomide derivatives by the described above
method remitted in products with good yield.
+)1)1 Preparaio% o> !#@!i#ed p'e%.l '.drazo%o 1$.a%o3 a$eamide) & 5 1a A e3
Commo% >or @o' 'e !erie! i)e) 111a A e3 I 121 a Ae3
t was prepared by dia!oti!ation of substituted aniline and followed interaction with
cyanoacetamide through the 3app-2lingemann reaction.
Ta@le & +)1)1 P'.!i$al daa o> !#@!i#ed p'e%.l '.drazo%o 1$.a%o3 a$eamide&
Sl)
No)
Compo#%d
No
P'.!i$al %a#re ?)P1J$3 *ield 1K3
# G
a
Creamish -hite
amorphous powder
#/:H-#/DHC 40.#%R
% G
b
,rown amorphous powder #E/H-#E4HC E/.D0R
' G
c
Nrange amorphous powder #:4H-#D0HC E:.DER
: G
d
Creamish -hite
amorphous powder
#40H-#4%HC EE.4'R
D Ge Nrange amorphous powder #::H-#:EHC 4#.%ER
'0 ) " a g e
C)No) D
a
& O9?e'.l p'e%.l '.drazo%o1$.a%o3 a$eamide)
N = N
CH
CN
CONH
2
CH
3
"hysical State K Creamish -hite
amorphous powder
$olecular formula K C
#0
1
#0
N
:
N
$olecular weight K %0%.00
$elting point K #/DHC
"ercentage yield K 40.#%R
C)No) D
@
& ?9C'loro p'e%.l '.drazo%o1$.a%o3 a$eamide)
N=N
CH
CN
CONH
2

Cl
"hysical State K ,rown amorphous powder
.
1
/
ClN
:
N
$olecular weight K %%%.D0
$elting point K #E4HC
"ercentage yield K E/.D0R
'# ) " a g e
C)No) D
$
& O9 >l#oro p'e%.l '.drazo%o1$.a%o3 a$eamide)
N=N
CH
CN
CONH
2

F
"hysical State K Nrange amorphous powder
.
1
/
8N
:
N
$olecular weight K %0E.00
$elting point K #D0HC
"ercentage yield K E:.DER
C)No) D
d
& 2,39di9C'loro p'e%.l '.drazo%o1$.a%o3 a$eamide)
N=N
CH
CN
CONH
2

Cl
Cl
"hysical State K Creamish -hite
amorphous powder
.
1
E
Cl
%
N
:
N
$olecular weight K %D/.0
$elting point K #4%HC
"ercentage yield K EE.4'R
'% ) " a g e
C)No) D
e
& ?9Niro p'e%.l '.drazo%o 1$.a%o3 a$eamide)
"hysical State K Nrange amorphous powder
.
1
/
N
D
N
'

$olecular weight K %''.00
$elting point K #:EHC
"ercentage yield K 4#.%ER
+)1)2 Preparaio% o> !#@!i#ed 59ami%o $i%%oli%e9 39$ar@oDamide& 8 1a A e3
Commo% >or @o' 'e !erie! i)e) 111a A e3 I 121 a Ae3
Substituted phenyl hydra!ono *cyano+ acetamide voluntarily undergoes intra molecular
friedelcrafts reaction in chloroben!ene in presence of (lCl
'
leading to substituted :-amino
cinnoline-'-carboxamide.
Ta@le& +)1)2) P'.!i$al daa o> !#@!i#ed 59ami%o $i%%oli%e939 $ar@oDamide&
Sl)
No)
Compo#%d No P'.!i$al %a#re ?)P 1J$3 *ield 1K3
# GS
a
Gark -hite powder %%'-%%DHC /:.%%R
% GS
b
Gark ,rown powder %%%-%%:HC E#.EDR
' GS
c
Gark 5reen powder %#/-%#.HC D..E#R
: GS
d
Gark Creamish powder %%D-%%EHC E4./'R
D GS
e
Gark Nrange powder %#:H-%#DHC /D.#:R
C)No) DS
a
& 29?e'.l959ami%o 39$ar@oDamide $i%%oli%e&
'' ) " a g e
N
N
CONH
2
NH
2
CH
3
"hysical State K Gark -hite powder
#0
1
#0
N
:
N
$olecular weight K %0%.00
$elting point K %%DHC
"ercentage yield K /:.%%R
C)No) DS
@
& 79C'loro 59ami%o $i%%oli%e 39$ar@oDamide&
N
N
NH
2
CONH
2

Cl
"hysical State K Gark ,rown powder
.
1
/
ClN
:
N
$olecular weight K %%%.D0
$elting point K %%:HC
"ercentage yield K E#.EDR
C)No) DS
$
& 29>l#oro 59ami%o $i%%oli%e 39$ar@oDamide&
N
N
F
NH
2
CONH
2
"hysical State K Gark 5reen "owder
.
1
/
8N
:
N
$olecular weight K %0E.00
': ) " a g e
$elting point K %#.HC
"ercentage yield K D..E#R
C)No) DS
d
& 7, 29Di9C'loro 59ami%o $i%%oli%e 39$ar@oDamide&
N
N
Cl
NH
2
CONH
2
Cl
"hysical State K Gark Creamish powder
.
1
E
Cl
%
N
:
N
$olecular weight K %D/.0
$elting point K %%EHC
"ercentage yield K E4.E'R
'D ) " a g e
C)No) DS
e
& 79Niro 59ami%o $i%%oli%e 939$ar@oDamide&
"hysical State K Gark Nrange powder
.
1
/
N
D
N
'
$olecular weight K %''.00
$elting point K %#DHC
"ercentage yield K /D.#:R
'E ) " a g e
ELPERI?ENT+- RESU-TS O0 SC6E?E 1 11a A= 3
The synthesis of substituted cinnoline imida!ole derivatives by the described above method
remitted in products with good yield.
Ta@le & 1):) P'.!i$al daa o> !#@!i#ed 59129ami%o9Imidazole3 Ci%%oli%e93Car@oDamide
deri(ai(e! &111a A=3
Compo#%d Name
Comp)
No)
P'.!i$al %a#re ?)P1JC3
*ield
1K3
4-methyl- :*%-amino-imida!ole+
cinnoline-'-carboxamide
11DSD
a
"ale white crystals %/4-%40HC E0.#%R
/ chloro- :*%-amino- imida!ole+
11DSD
@
5reen - brown crystals %E%-%E:HC ED.E:R
4-8luoro- :*%-amino- imida!ole+
11DSD
$
"ale red crystals %%:-%':HC E#./0R
/,4-Gi-chloro-:*%-amino- imida!ole+
11DSD
d
5reenish crystals '0%-'0:HC E0.#%R
/- Nitro - :*%-amino- imida!ole+
11DSD
e
"ale orange Crystals %':-%'EHC DD.E/R
'/ ) " a g e
RESU-TS O0 BIO-OEIC+- EV+-U+TION 1SC6E?E 11a9=3
1)1 +%i@a$erial a$i(i. !#die!
1)1 1+3 Di!4 Di>>#!io% ?e'od
Ta@le& 1)1) 1+3 Daa >or a%i@a$erial a$i(iie! o> !.%'e!ized $ompo#%d!
Sl)No)
Compo#%d No
Diameer o> zo%e o> i%'i@iio% 1mm3
P. aeruginosa
E. coli B.subtilis S. aureus
0#
##GSGa
#' #: #/ #'
0% ##GSGb
%# %# %0 #.
0' ##GSGc
#4 #. #/ %0
0: ##GSGd
%0 %0 #. %0
0D ##GSGe
#% #' #/ #:
0E
0/
Norfloxacin
*#0Yg+
G$8
%#
0
%'
0
%:
0
%%
0
(ll the synthesi!ed substituted Cinnoline imida!ole derivatives were tested at D0Yg level and
shown moderate to good antibacterial activity, among the tested compounds 11DSD@, 11DSD$
a%d 11DSDd showed significant activity. The compounds ##GSGa and ##GSGd showed
moderate activity in comparison with the standard drug norfloxacin.
1)1 1B3 ?IC 1?i%im#m I%'i@ior. Co%$e%raio%3
'4 ) " a g e
Ta@le& 1)1 1B3 Daa o> ?IC >or a%i9@a$erial a$i(i.
Sl)No)
Compd)No)
S.aureus B.subtilis E.coli P.aeruglnosa

Dil#io% 1 2 3 5 8 6 1 2 3 5 8 6 1 2 3 5 8 6 1 2 3 5 8 6
0# ##GSGa
- O O O O O - - O O O O - - O O O O - O O O O O
0% ##GSGb - - - - - O - - - - O O - - - - O O - - - - O O
0' ##GSGc - - - - O O - - - - - O - - - - O O - - - - O O
0:
0D
##GSGd
##GSGe
-
-
-
-
-
O
-
O
O
O
O
O
-
-
-
-
-
-
-
O
-
O
O
O
-
-
-
-
-
-
-
O
-
O
O
O
-
-
-
-
-
O
-
O
O
O
O
O
0E Norfloxacin - - - - - - - - - - O O - - - - - O - - - - O O
0/ Ove control O O O O O O O O O O O O O O O O O O O O O O O O
04 -ve control - - - - - - - - - - - - - - - - - - - - - - - -
ZO9 ndicates presence of growth and Z?9 indicates absence of growth
The concentration of derivatives in different dilution is given belowK
7valuation of antibacterial activity was carried out for all the newly synthesi!ed substituted
cinnoline thia!ole derivatives. (ll compounds showed moderate to good antibacterial activity.
Gerivatives like 11DSD@, 11DSD$, a%d 11DSDd showed higher activity than all. These
compounds can be subLected to further studies for toxicity.
1)2 +%i 0#%<al +$i(i. S#die!
1)2 1+3 Di!4 di>>#!io% me'od
Ta@le& 1)2 1+3 Daa >or a%i>#%<al a$i(i. o> !.%'e!ized $ompo#%d!
Sl) No) Compo#%d No)
'. ) " a g e
C. albicans
!. niger
#. ##GSGa #E #:
%. ##GSGb %# #.
'. ##GSGc #D #'
..
#0.
##GSGd
##GSGe
%#
#'
%0
#E
##. 5riseofulvin *%DYg+ %' %:
#%. G$8 0 0
(ll the Substituted Cinnoline imida!ole derivatives were tested at D0Yg level. 8rom the
anti-fungal activity studies it is evident that the synthesi!ed compounds showed moderate to good
anti-fungal activity. (mong the tested compounds 11DSD@ a%d 111DSDd have shown good
activity against C. albicans and (.niger.
Ta@le& 1)2 1B3 Daa o> ?IC >or a%i>#%<al a$i(i.)
Sl)No) Pre!e%$e or a@!e%$e o> <ro7'
:0 ) " a g e
Compo#%d
N
o
)
C. albicans
!. niger
Dil#io%
1 2 3 5 8 6 1 2 3 5 8 6
0# ##GSGa - - O O O O - - O O O O
0% ##GSGb - - - - - O - - - - O O
0' ##GSGc - - - - O O - - - O O O
0:
0D
##GSGd
##GSGe
-
-
-
-
-
O
-
O
O
O
O
O
-
-
-
-
-
O
-
O
O
O
O
O
0E Ove control O O O O O O O O O O O O
0/ -ve control - - - - - - - - - - - -
ZO9 ndicate presence of growth Z?9 indicate absence of growth
Dil#io% # % ' : D E
Conc. gFml #000 D00 %D0 #%D E%.D '#.%D
(ll the Synthesi!ed compounds have shown anti-fungal activity to a certain extent. (mong the
tested compounds 11DSD@ and 11DSDd have shown good activity against C. albicans and
(.niger. while other compounds show moderate activity.
:# ) " a g e
1)3 & +%'elmi%i$ a$i(i. o> !#@!i#ed Ci%%oli%e imidazole deri(ai(e!
Ta@le & 1)3
Te! Sample! Co%$e%raio%
1m<3
?ea% paral.!i%< ime
1mi%3 MS)E)
?ea% dea' ime
1mi%3 M S)E.
Control - No effect No effect
$ebenda!ole #00 :.#0[0.'E D.'E[0.'%
##GSGa #00 D.#:[0.##\ D.D.[0.%D\\\
##GSGb #00 :.#.[0/E\\ D.''[0.'%\\
##GSGc #00 :.%4[0.'#\\ D.:.[0.%%\\\
##GSGd #00 :.%#[0D0\\\ D.'D[0.:D\\
##GSGe #00 :.DD[0./#\ E.#%[0.#'\\
*Table ,+
ZS.7.9 represents Standard 7rror. 6alues are significantly different from reference standard
*$ebenda!ole+ + \p]0.0DS \\ p] 0.0#, \\\ p] 0.00#.
7valuation of anthelmintic activity for substituted cinnoline imida!ole derivatives exhibits potent
anthelmintic activity against earthworm (Pheretima posthuma) *Table #.'+. The two derivatives
11DSD@, a%d 11DSDd3 not only demonstrated significantly shorter paraly!ing time, but also
caused death of worms in significantly shorter time as compared to reference drug *$ebenda!ole+,
while other derivatives showed partial activity.
RESU-TS O0 SC6E?E 1 12a A= 3
:% ) " a g e
Ta@le & 2): P'.!i$al daa o> !#@!i#ed 591989ami%o9p.razole3 Ci%%oli%e939Car@oDamide
deri(ai(e!& 112a A=3
Compo#%d Name Com) No P'.!i$al %a#re ?)P1JC3
*ield
1K3
4-methyl- :-*-D-amino- pyra!ole+ cinnoline-
'-carboxamide
12DST
a
white crystals %%#-
%%%HC
E/.:0R
/ chloro- :*-D-amino-pyra!ole+ cinnoline-'-
carboxamide
12DST
@
^ellow ,rown
crys.
%%E-
%%4HC
E:.40R
4-8luoro- :*-D-amino-pyra!ole+ cinnoline-
'-carboxamide
12DST
$
5renish yellow
crys
#.4-
%00HC
E0.4#R
/,4-Gi-chloro-:*-D-amino-pyra!ole+
12DST
d
Creamish white
cryst
%ED-
%E/HC
/#.#%R
/- Nitro- :*-D-amino-pyra!ole+ cinnoline-'-
carboxamide
12DST
e
"ale yellow
Crystals
#/4-
#40HC
D4./#R
RESU-TS O0 BIO-OEIC+- EV+-U+TION 1SC6E?E A12a9= 3
2)1 +%i@a$erial a$i(i. !#die!
:' ) " a g e
2)1 1+3 Di!4 Di>>#!io% ?e'od
Ta@le& 2)1) 1+3 Daa >or a%i@a$erial a$i(iie! o> !.%'e!ized $ompo#%d!
Sl)No)
Compo#%d No
P. aeruginosa
E. coli B.subtilis S. aureus
0#
#%GSTa
#: #: #% #:
0% #%GSTb
#. #. %0 #.
0' #%GSTc
#% #' #/ ##
0: #%GSTd
#. %0 #. %#
0D #%GSTe
#D #: #' #:
0E
0/
Norfloxacin
*#0Yg+
G$8
%#
0
%'
0
%:
0
%%
0
(ll the synthesi!ed substituted cinnoline pyr!ole derivatives were tested at D0Yg level and shown
moderate to good antibacterial activity, among the tested compounds 12DST@ a%d 12DSTd
showed significant activity. The compounds #%GSTa and #%GSTc, #%GSTe showed moderate
activity in comparison with the standard drug norfloxacin.
Ta@le& 2)1 1B3 Daa o> ?IC >or a%i9@a$erial a$i(i.
:: ) " a g e
Sl)No)
Compd)No)
S.aureus B.subtilis E.coli P.aeruglnosa

Dil#io% 1 2 3 5 8 6 1 2 3 5 8 6 1 2 3 5 8 6 1 2 3 5 8 6
0# #%GSTa - - - O O O - - - O O O - - - - O O - - O O O O
0% #%GSTb - - - - O O - - - - - O - - - - O O - - - - O O
0' #%GSTc - - - - - O - - - - O O - - - - O O - - - - - O
0:
0D
#%GSTd
#%GSTe
-
-
-
-
-
O
O
O
O
O
O
O
-
-
-
-
-
-
O
-
O
O
O
O
-
-
-
-
-
-
-
O
O
O
O
O
-
-
-
-
-
-
-
O
O
O
O
O
0E Norfloxacin - - - - - - - - - - O O - - - - O O - - - O O O
0/ Ove control O O O O O O O O O O O O O O O O O O O O O O O O
04 -ve control
- - - - - - - - - - - - - - - - - - - - - - - -
ZO9 ndicates presence of growth and Z?9 indicates absence of growth
Dil#io% # % ' : D E
Conc. gFml #000 D00 %D0 #%D E%.D '#.%D
7valuation of antibacterial activity was carried out for all the newly synthesi!ed substituted
cinnoline pyr!ole derivatives. (ll compounds showed moderate to good antibacterial activity.
Gerivatives like 12DST@ a%d 12DST$ showed higher activity than all. These compounds can be
subLected to further studies for toxicity.
2)2 +%i 0#%<al +$i(i. S#die!
2)2 1+3 Di!4 di>>#!io% me'od
Ta@le& 2)2 1+3 Daa >or a%i>#%<al a$i(i. o> !.%'e!ized $ompo#%d!
Sl) No) Compo#%d No)
C. albicans
!. niger
#. #%GSTa #/ #D
:D ) " a g e
%. #%GSTb %0 %#
'. #%GSTc %0 %%
:.
D.
#%GSTd
#%GSTe
#.
#:
%0
#D
E. 5riseofulvin *%DYg+ %' %:
/. G$8 0 0
(ll the derivatives were tested at D0Yg level. 8rom the anti-fungal activity studies it is
evident that the synthesi!ed compounds showed moderate to good anti-fungal activity. (mong the
tested compounds 12DST$, 12DSTd a%d 12DST@ have shown good activity against C. albicans
and (.niger.
Ta@le& 2)2 1B3 Daa o> ?IC >or a%i>#%<al a$i(i.)
Sl)No) Pre!e%$e or a@!e%$e o> <ro7'
:E ) " a g e
Compo#%d
N
o
)
C. albicans
!. niger
Dil#io%
1 2 3 5 8 6 1 2 3 5 8 6
0# #%GSTa - - O O O O - - O O O O
0% #%GSTb - - - - O O - - - - O O
0' #%GSTc - - - - O O - - - - O O
0:
0D
#%GSTd
#%GSTe
-
-
-
O
O
O
O
O
O
O
O
O
-
-
-
-
O
O
O
O
O
O
O
O
0E Ove control O O O O O O O O O O O O
0/ -ve control - - - - - - - - - - - -
ZO9 ndicate presence of growth Z?9 indicate absence of growth
Dil#io% # % ' : D E
Conc. gFml #000 D00 %D0 #%D E%.D '#.%D
(ll the Synthesi!ed compounds have shown anti-fungal activity to a certain extent. (mong the
tested compounds 12DST@ a%d 12DST$ have shown good activity against C. albicans and
(.niger. while other compounds show moderate-activity.
2)3& +%'elmi%i$ a$i(i. o> !#@!i#ed Ci%%oli%e p.razole deri(ai(e!
Ta@le & 2)3 &
Te! Sample! Co%$e%raio%
1m<3
?ea% paral.!i%< ime
1mi%3 MS)E)
?ea% dea' ime
1mi%3 M S)E)
Control - No effect No effect
:/ ) " a g e
$ebenda!ole #00 :.#%[0.#E D.'0[0.:0
#%GSTa #00 D.#.[0.D%\\ D.D4[0.:#\
#%GSTb #00 :.%E[0.'.\ D.%4[0#'\
#%GSTc #00 :.D.[0.%0\\ D.:#[0.4%\\
#%GSTd #00 :.%:[0.:'\\ D.%E[0./#\\
#%GSTe #00 D.D%[0.D0\ E.::[0.##\\
ZS.7.9 represents Standard 7rror. 6alues are significantly different from reference standard
*$ebenda!ole+ \p]0.0DS \\ p] 0.0#, \\\ p] 0.00#.
7valuation of anthelmintic activity for substituted cinnoline pyr!ole derivatives exhibits potent
anthelmintic activity against earthworm (Pheretima posthuma). The two derivatives 112DST@ I
12DSTd3 demonstrated significant activity almost similar to reference drug *$ebenda!ole+, while
other derivatives showed partial activity.
Re!#l! C'ara$erizaio%
The characteri!ation reIuires the identification of molecular frame work, the nature of
functional groups that are present and their location within the skeletal structure and finally the
establishment of any stereo chemical relationships, which might exist.
The problem of characteri!ation of organic compounds has been revolutioni!ed by the
progressive adoption of the wide range of spectroscopic techniIues, which are now available.
:4 ) " a g e
These have been applied extensively in the preparative section to confirm the structure of the
expected products. The same were applied in present work to confirm the structure of newly
synthesi!ed compounds.
n the present work the representative products were characteri!ed by their infrared *&+
spectra, proton magnetic resonance *"$&+ spectra and mass spectra. Some intermediates were
characteri!ed by measuring their melting point and comparing with literature value, wherever
possible.
The & spectra were recorded by NCNX7TT-$"(CT-:008T-& S"7CT&N
"1NTN$7T7& using a thin film supported on 2,r pellets.
The "$& spectra were recorded on 37NX-3$S G-'00 *'00 $1!+ N$& spectro meter. (ll
spectra were obtained in Geuturated $ethanol and chemical shift values are reported as values in
ppm relative to T$S * Q 0+ as internal standard.
$ass spectra were recorded on 37NX S@#0% $S System operating at /0 ev.
T'e IR, N?R a%d ?+SS !pe$ra o> o%e Compo#%d >rom ea$' Serie! i! <i(e% i% >i<#re 3)1 o
5)3 >or 'e repre!e%ai(e $ompo#%d!)
SPECTR+- 0E+TURES &
Sample 11DSDd &
:. ) " a g e
C)No) 11DSD
d
N 7,29Di9$'loro951929ami%o9 imidazole3 $i%%oli%e939$ar@oDamide
IR 1;Br3 i% $m
-#
10i< 3)13
"eak at ':EE.# cm
-#
corresponds to N1 stretching
"eak at '':#.D cm
-#
corresponds to asymmetric N1
%
group.
"eak at '%'E.% cm
-#
corresponds to C1 stretching.
"eak at #E/#.. cm
-#
corresponds to C Q N stretching.
"eak at #D00.E cm
-#
corresponds to aromatic C Q C stretching.
"eak at #E/#.. cm
-#
"eak at #%04 - #E/# cm
-#
corresponds to imida!ole
6
1
9N?R O i% ppm 10i< 3)23
C 4.#0 ? 4.%D *%1, d, of cinnolines+
C /.D# ? /.E/ *:1, d, mida!ole+
C #:.## *#1, s, of N1+
C #0.'D *%1, s, of CNN1%+
C 4.4 *#1, d, of N1 mida!ole+
?a!! i% mPz 10i< 3)33
$olecular ion peak at mF! Q '%D m1! is because of molecular formula
C
#%
1
#0
Cl
%
N
E
N. ,ase peak is at mF! Q #D: m1!. 8ragment ion peak is observed at
mF! Q %D/ because of C
##
1
04
Cl
%
NS
,
mF! Q %:# because of C
.
1
:
Cl
%
N
'
N, mF! Q .4 because of
C
:
1
4
N
'.
D0 ) " a g e
Sample 12DSTd &
C)No) 12DST
d
N 7,29Di9$'loro951989ami%o9 p.razole3 $i%%oli%e939$ar@oDamide
IR 1;Br3 i% $m
-#
10i< 5)13
"eak at ':4#.4 cm
-#
corresponds to N1 stretching
"eak at ''E'.# cm
-#
corresponds to asymmetric N1
%
group.
"eak at '%%#.4 cm
-#
corresponds to C1 stretching.
"eak at #E''.0 cm
-#
"eak at #:/D.' cm
-#
corresponds to aromatic C Q C stretching.
"eak at #/%D.D cm
-#
"eak at #### - #E'' cm
-#
corresponds to pyra!ole
6
1
9N?R O i% ppm 10i< 5)23
C /.'D ? /.D' *%1, d, of cinnolines+
C E.:D ? E.E# *%1, d, pyra!ole+
C #'.E0 *#1, s, of N1+
C #0.ED *%1, s, of CNN1%+
C 4.# *#1, d, of N1 pyra!ole+
?a!! i% mPz 10i< 5)33
$olecular ion peak at mF! Q '%' m1! is because of molecular formula
C
#%
1
4
Cl
%
N
E
N. ,ase peak is at mF! Q #D% m1!. 8ragment ion peak is observed at
mF! Q %DE because of C
##
1
E
Cl
%
NS
,
mF! Q %:% because of C
.
1
:
Cl
%
N
'
N, mF! Q ./ because of
C
:
1
4
N
'.
D# ) " a g e
D% ) " a g e
D' ) " a g e
D: ) " a g e
DD ) " a g e
S"##!$%
DE ) " a g e
n both substituted cinnoline series, the compounds which are halogen mainly
Chloro W 8luoro substituted *"N2 CNX&7G ,(&S+ are showed potent
antibacterial and (ntifungal activity than other compounds. 7specially
Chloro Substituted Compounds Showed more potent antimicrobial activity in
both the Series.
f we compare both the series then it is found that Substituted cinnoline
imida!ole compounds are more potent in antibacterial activity in comparision
to Substituted cinnoline pyra!ole Compounds.
f we compare both the series then it is found that Substituted cinnoline
pyra!ole compounds are more potent in antifungal activity in comparision to
Substituted crinoline imida!ole Compounds.
The "resent Studies Suggested $ainly Chloro Substituted cinnoline
Gerivatives for potent antimicrobial activity in future.
f we compare anthelmintic results among both substituted cinnoline series
then we can say that both the Subsituted cinnoline series are almost eIually
potent. 8urther halogen especially Chloro substituted compounds were found
be more potent among all the compounds in both the series.
The Chloro Substituted compounds from substituted cinnoline imida!ole as
well as substituted cinnoline thia!ole series showed potent anthelmintic
D/ ) " a g e
activity i.e less paraly!ing and death time in earthworms even with the
standard drug $ebenda!ole.
The Chloro Substituted compounds showed delayed paraly!ing time in
comparison to standard drug but even less death time when compared to
standard drug, this might be due to the reason that these derivatives reIuired
more time for absorption and once when they absorbed they produced
anthelmintic action rapidly due to this they reIuire more time for paraly!ing
the worms rather than death.
8urther, it would be suggested that these derivatives reIuire improvement in
their physicochemical properties in order to get good absorption properties
and then further evaluated for shorter paraly!ing time in worms.
D4 ) " a g e
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Synthesis, Characterization & Biological Evaluation of Some Substituted Cinnoline Derivatives

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