Synthesis anti-inflammatory and anticancer activity evaluation of some pyrazole and oxadiazole derivatives

Article abstract of DOI:10.1007/s00044-011-9850-7

Pyrazole derivatives IIa-l have been synthesized by condensation of chalcones Ia-f with hydrazine hydrate and phenyl hydrazine under microwave irradiation in good yields. Oxadiazole derivatives IVa-f have been synthesized by condensation of N'-hydroxypico

Full text of DOI:10.1007/s00044-011-9850-7

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2012) 21:3043–3052
DOI 10.1007/s00044-011-9850-7
ORIGINAL RESEARCH
Synthesis anti-inflammatory and anticancer activity evaluation
of some pyrazole and oxadiazole derivatives
•
Sham M. Sondhi Sandeep Kumar
•
•
Nikhil Kumar Partha Roy
Received: 19 August 2011 / Accepted: 25 October 2011 / Published online: 6 November 2011
Ó Springer Science+Business Media, LLC 2011
Abstract Pyrazole derivatives IIa–l have been synthe-
sized by condensation of chalcones Ia–f with hydrazine
hydrate and phenyl hydrazine under microwave irradiation
in good yields. Oxadiazole derivatives IVa–f have been
synthesized by condensation of N0-hydroxypicolinami-
dine, N0-hydroxy isonicotinamidine, N0-hydroxypyrazine-
2-carboxamidine with 2,5 dimethoxybenzaldehyde and
3-methoxy-4-hydroxy benzaldehyde, respectively. Struc-
tures assigned to IIa–l and IVa–f are fully supported by
correct spectral and analytical data. All compounds
(IIa–l & IVa–f) have been screened for anti-inflammatory
and anticancer activities. Compounds IIj, IIk, and IVb
exhibited good anti-inflammatory activity, while, IIa, c, j,
and IVd showed better anticancer activity against four and
three cancer cell lines, respectively.
Pyrazole and oxadiazole derivatives have been reported to
exhibit anti-inflammatory (Burguete et al., 2007; Abdellatif
et al., 2008; Bala et al., 2010; Sahoo et al., 2011), anti-
cancer (Markwalder et al., 2004; Lv et al., 2010; Zheng
et al., 2010; Ziedan et al., 2010; Abu-Zaied et al., 2011),
antiviral (El-Sabbagh et al., 2009; Veerasamy et al., 2010),
antiasthmatic (Crespo et al., 2000; Sun et al., 2006), anti-
malarial (Severina et al., 2002; Cunico et al., 2006; Zareef
et al., 2007; Mishra et al., 2008), antimicrobial (Katade
et al., 2008; Narwade et al., 2008; Khalil, 2009; Abdel-
Wahab et al., 2009; Bakht et al., 2010; El-Enany et al.,
2010; Manjunatha et al., 2010), and antibacterial (Liu
et al., 2008, 2010; Flipo et al., 2011) activities. Cancer and
inflammatory diseases are widely prevalent throughout the
world and as a matter of concern; studies in these area are
well documented (Iniguez et al., 2010; Chavan and More,
2011; Kumar et al., 2011; Zhang et al., 2011). The treat-
ment of inflammation using various drugs are available in
the market but these drugs have serious side effects such as
dyspepsia, gastroduodenal ulcer, and gastritis bleeding
(Sondhi et al., 2007) and hence cannot be used for long
time continuously. Prolonged inflammation can cause
various types of cancer such as colon, cervix, and breast
cancer (Harris et al., 2008; Harris, 2009). Limited numbers
of anticancer drugs are available in the market and there is
an urgent need to develop safe and cost effective anticancer
agents (Settimoa et al., 1998) and anti-inflammatory drugs
(Cheng et al., 2008; Chandra et al., 2010). Motivated by
wide range of biological activities exhibited by pyrazole
and oxadiazole derivatives and in continuation of our
efforts in search of potent anticancer and anti-inflammatory
agents (Sondhi et al., 2009, 2010a, b, c) we have synthe-
sized a number of pyrazole and oxadiazole derivatives and
screened them for anti-inflammatory and anticancer activ-
ities which we wish to report in this article.
Keywords Pyrazole derivatives ꢀ
Oxadiazole derivatives ꢀ Anticancer ꢀ
Anti-inflammatory activity
Introduction
Pyrazole and oxadiazole derivatives form an important
class of compounds possessing wide range of biological
activities (Koryakova et al., 2008; Shen et al., 2009).
S. M. Sondhi (&) ꢀ S. Kumar
Department of Chemistry, Indian Institute
of Technology-Roorkee, Roorkee 247667, UK, India
e-mail: sondifcy@iitr.ernet.in
N. Kumar ꢀ P. Roy
Department of Biotechnology, Indian Institute
of Technology-Roorkee, Roorkee 247667, UK, India
123

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Med Chem Res (2012) 21:3043–3052
Results and discussion
condensation product IIg, which was crystallized from
chloroform: MeOH (8:2) to give pure 2-[5-(2,5-dime-
thoxyphenyl)-1-phenyl-4,5-dihydro-1H-pyrazol-3yl] pyri-
dine (IIg; Scheme 1) in good yield. Spectral and analytical
data of IIg reported in experimental section of this article
fully support the structure assigned to it. Similarly con-
densation of Ib–f with phenyl hydrazine gave condensation
products IIh–l (Scheme 1), respectively. Power level,
irradiation time, solvent of crystallization, yield, mp,
spectral and analytical data of IIh–l reported in experi-
mental section of this article fully support the structures
assigned to them.
N0-Hydroxypicolinamidine, (IIIa, Scheme 2), N0-hydroxy-
isonicotinamidine (IIIb, Scheme 2), and N0-hydroxy-pyr-
azine-2-carboxamidine (IIIc, Scheme 2) have been synthesized
by following reaction procedure reported in literature
(Katarzyna, 2009). Equimolar ratio of N0-hydroxypicoli-
namidine (IIIa, Scheme 2) and 2,5-dimethoxybenzaldehyde
were mixed together thoroughly and subjected to microwave
irradiation at a power level of 450 W for 3 min. Thin layer
chromatography (TLC) of reaction mixture showed the
presence of starting materials, so the reaction contents were
further irradiated for 4 min and progress of reaction was
monitored by TLC, which showed the absence of starting
materials. From this observation it is inferred that irradiation
Chalcone derivatives Ia–f (Scheme 1) were synthesized by
condensation of 2-acetyl pyridine, 3-acetyl pyridine,
4-acetyl pyridine with 2,5-dimethoxybenzaldehyde, and
4-(dimethyl amino) benzaldehyde as reported in literature
(Efange et al., 2001; Sunduru et al., 2006). 3-(2,5-Dime-
thoxyphenyl)-1-pyridin-2-yl-propenone (Ia; Scheme 1) on
condensation with hydrazine hydrate under microwave
irradiation for 3 min and at a power level of 180 W gave
condensation product IIa (Scheme 1). This product was
purified by crystallization from chloroform to give pure
2-[5-(2,5-dimethoxyphenyl)-4,5-dihydro-1H-pyrazol-3yl]
pyridine (IIa; Scheme 1) in good yield. Spectral and ana-
lytical data of IIa reported in experimental section of this
article fully support the structure assigned to it. Similarly
chalcone derivatives Ib–f on condensation with hydrazine
hydrate gave corresponding products IIb–f. Irradiation
time, power level, solvent of crystallization, yield, melting
point (mp), spectral and analytical data of IIb–f reported in
experimental section of this article is in full agreement with
structures assigned to them. Condensation of 3-(2,5-dime-
thoxyphenyl)-1-pyridin 2-yl-propenone (Ia; Scheme 1)
with phenyl hydrazine in equimolar ratio, under micro-
wave irradiation for 3 min (power level 450 W) gave
Scheme 1 Synthesis of
pyrazole derivatives
R1
N
O
C
R1NHNH2H2O
N
Z
C C R
H H
Z
MW, 3 min, 180W
Y X
X
Y X
R
Ia-f
Y
IIa-l
Z
R
X
Y
Z
R
R1
OCH3
OCH3
Ia
Ib
N
CH
N
CH
IIa
N
CH CH
H
H
OCH3
OCH3
OCH3
OCH3
H3CO
H3CO
CH
CH
N
IIb CH
N
CH
N
H3CO
H3CO
H3CO
H3CO
Ic
Id
Ie
If
CH
N
CH
CH
N
IIc CH CH
IId
IIe CH
IIf CH CH
IIg
IIh CH
IIi CH CH
IIj
IIk CH
IIl CH CH
H
H
CH
CH
N
N CH CH
NMe2
NMe2
NMe2
NMe2
NMe2
CH
CH
N
CH
N
H
NMe2
OCH3
CH
H
N
CH CH
Ph
Ph
Ph
OCH3
OCH3
H3CO
H3CO
H3CO
N
CH
N
N
CH CH
NMe2 Ph
NMe2
NMe2
N
CH
N
Ph
Ph
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Med Chem Res (2012) 21:3043–3052
3045
Scheme 2 Synthesis of
oxadiazole derivatives
RCHO
R
Z
NH2
Z
N
N
MW 450W
Y
Y
O
7 min
X
NOH
X
IIIa-c
IVa-f
X
Y
Z
X
Y
Z
R
OCH3
OCH3
OCH3
IIIa
N
CH
N
CH
CH
N
IVa
N
CH
N
CH
CH
N
H3CO
H3CO
H3CO
IIIb CH
IVb CH
IIIc
N
CH
IVc
IVd
IVe
IVf
N
CH
CH
N
OCH3
OH
OCH3
OH
OCH3
N
CH
CH
N
CH
N
CH
OH
Table 1 Anti-inflammatory
and in vitro anticancer activity
of compounds IIa–l and IVa–f
Compd.
no.
Anti-inflammatory
activity (%) at 50 mg/kg p.o.
Anticancer activity at a concentration of 1 3 10-5
M
Lung
NCI H-522
Ovary
PA1
Breast
T47D
Colon
HCT-15
Liver
HepG2
IIa
IIb
IIc
IId
IIe
IIf
15
15
13
18
22
0
28
40
24
34
25
28
16
32
29
26
20
32
23
10
23
48
25
20
–
25
31
24
21
36
26
18
32
31
16
20
24
25
19
26
30
32
20
–
26
13
19
03
15
21
12
22
37
41
33
07
37
25
41
33
34
35
–
10
04
28
05
06
03
09
07
05
12
01
06
05
02
07
03
05
01
–
23
34
34
29
35
29
20
26
32
24
32
35
33
27
17
39
13
20
–
IIg
IIh
IIi
27
24
18
35
34
32
28
35
11
24
14
26
39
–
IIj
IIk
IIl
IVa
IVb
IVc
IVd
IVe
IVf
a
CYC-PHO Cyclophospamide
b
CYC-HEXI Cycloheximide
c
Ibuprofen
aCYC-PHO
bCYC-HEXI
c5-FU
5-FU 5-Flurouracil
04
13
24
04
51
10
18
09
05
05
03
08
14
05
18
Bold value represent,
compounds showing good anti-
inflammatory and anticancer
activity
–
for 3 ? 4 min is required for completion of reaction to give
condensation product IVa. Compound IVa was further
purified by crystallization from methanol to give pure
2-[5-(2,5-dimethoxyphenyl)-[1,2,4] oxadiazol-3-yl] pyri-
dine (IVa, Scheme 2) in good yield. Spectral and analytical
data of IVa reported in experimental section of this article is
in full agreement with structure assigned to it. Similarly
condensation of IIIb and IIIc with 2,5-dimethoxybenzal-
dehyde and IIIa, b, c with 3-methoxy-4-hydroxy benzalde-
hyde gave IVb, c and IVd–f (Scheme 2), respectively.
Power level, irradiation time, solvent of crystallization,
yield, mp, spectral and analytical data of IVb–f reported in
123

3046
Med Chem Res (2012) 21:3043–3052
experimental section of this article fully support the struc-
tures assigned to them.
Lung NCl H-522
Ovary PA1
Breast T47D
Colon HCT-15
Liver HepG2
60
50
40
30
20
10
0
All the compounds were also prepared by using micro-
wave reactor model CEM DISCOVER No 908010. Reac-
tion temperature for IIa–f, IIg–l, and IVa–f was 85, 110,
and 160°C and irradiation time was 3, 5, and 5 min,
respectively.
Since over-expression of cox-2 and prostaglandin cas-
cade are involved in carcinogenesis (Brown and DuBois,
2005; Grosch et al., 2006; Harris 2009), non steroidal anti-
inflammatory drugs (selective or non selective cox-2
inhibitors) exhibit strong potential for chemoprevention of
cancer (Xiao et al., 2006; Harris et al., 2007, 2008). In
view of above information from literature it is considered
worth while to evaluate newly synthesized compounds for
anti-inflammatory and anticancer activities.
IVa
Ivb
Ivc
Ivd
Ive
Ivf
S1
S2
S3
Compounds
In vitro anticancer activity (Monks et al., 1991; Skehan
et al., 1990) evaluation of compounds IIa–l and IVa–f was
carried out against five human cancer cell lines consisting
of lung (NCI H-522), ovary (PA1), breast (T47D), colon
(HCT-15), and liver (HepG2). Percentage (%) growth
inhibition of compounds IIa–l and IVa–f against various
cancer cell lines was determined at a concentration of
10 lM and results are summarized in Table 1. Graphical
representations of these results are shown in Figs. 1 and 2,
respectively.
Fig. 2 Graphical representation of anticancer activity of compounds
IVa–j and S1 (CYC-PHO), S2 (CYC-HEXI C), and S3 (5-FU) against
five human cancer cell lines
ibuprofen exhibited 39% anti-inflammatory activity at
50 mg/kg p.o. Compounds IIa, c, j exhibited good anti-
cancer activity against four cancer cell lines i.e., lung (NCI
H-522), breast (T47D), colon (HCT-15), liver (HepG2),
and IVd against three cancer cell lines i.e., lung (NCI
H-522), breast (T47D), liver (HepG2).
Anti-inflammatory activity (Winter et al., 1962) evalu-
ation of IIa–l and IVa–f was carried out using carrageenan
induced paw edema assay and results are summarized in
the Table 1. A look at the Table 1 indicates that com-
pounds IIj, IIk, and IVb exhibited 35, 34, and 35% anti-
inflammatory activity respectively, whereas standard drug
Conclusion
A number of pyrazole and oxadiazole derivatives IIa–l and
IVa–f have been synthesized and screened for anti-
inflammatory and anticancer activities. Compounds IIj,
IIk, and IVb exhibited good anti-inflammatory activity and
IIa, c, j, and IVd exhibited good anticancer activity against
various cancer cell lines screened.
60
Lung NCl H-522
Ovary PA1
Breast T47D
Colon HCT-15
Liver HepG2
50
40
30
20
10
0
Experimental
Chemistry
Microwave oven model M197DL (Samsung) and micro-
wave reactor model CEM DISCOVER model NO 908010
were used for microwave irradiation. Mp were determined
on a JSGW apparatus and are uncorrected. IR spectra were
1
recorded using a Perkin Elmer 1600 FT spectrometer. H
and 13C NMR spectra were recorded on a Bruker WH-500
spectrometer at a ca 5–15% (w/v) solution in DMSO-d6,
CDCl3, and D2O. GC–MS was recorded on Perkin Elmer
Clarus 500 gas chromatograph where built in MS detector
was used. Elemental analysis was carried out on a Vario
IIa IIb IIc IId IIe IIf IIg IIh IIi IIj IIk IIl S1 S2 S3
Compounds
Fig. 1 Graphical representation of anticancer activity of compounds
IIa–l and S1 (CYC-PHO), S2 (CYC-HEXI C), and S3 (5-FU) against
five human cancer cell lines
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Med Chem Res (2012) 21:3043–3052
3047
EL III elementor. TLC was performed on silica gel G for
TLC (Merck) and spots were visualized by iodine vapor or
by irradiation with ultraviolet light (short wave length,
254 nm).
1H, J = 10.5 and 16.5 Hz, one H of CH2), 3.748 (s, 3H,
OCH3), 3.809 (s, 3H, OCH3), 5.226–5.267 (t, 1H,
J = 10.5 Hz, CH), 6.179 (bs, 1H, NH), 6.755–6.819 (m,
2H, Ar), 7.025–7.031 (d, 1H, J = 3 Hz, Ar), 7.117–7.214
(m, 1H, Ar), 7.649–7.683 (m, 1H, Ar), 7.950–7.966 (d, 1H,
J = 8 Hz, Ar), 8.560–8.570 (m, 1H, Ar), 13C NMR
(125 MHz, CDCl3) d: 43.3 (C), 49.8 (C), 55.8 (C), 56.1
(C), 111.4 (C), 111.9 (C), 113.4 (C), 114.4 (C), 120.1 (C),
122.6 (C), 136.8 (C), 148.3 (C), 148.5 (C), 151.0 (C) and
153.7 (C) GC–MS: m/z 283, (M?, 20%). Anal. Calcd for
C16H17N3O2: C 67.83, H 6.05, N 14.83; Found C 67.64, H
6.09, N 14.79.
General procedure for synthesis of pyrazole derivatives
Synthesis of 2-[5-(2,5-dimethoxyphenyl)-4,5-dihydro-
1H-pyrazol-3-yl]-pyridine (IIa)
(i) 3-(2,5-Dimethoxyphenyl)-1-pyridin-2-yl-propenone (0.269
g; 1 mmol) and hydrazine hydrated (0.060 g;
1.2 mmol) were mixed together to make a homoge-
neous mixture and then this reaction mixture was
subjected to microwave irradiation for 3 min at a
power level of 180 W. Progress of reaction was
monitored by TLC. TLC of reaction mixture showed
formation of a new product and absence of starting
materials. This crude product was crystallized from
chloroform to give pure product IIa in quantitative
yield
4-[5-(2,5-dimethoxyphenyl)-4,5-dihydro-1H-pyrazol-3-yl]-
pyridine (IIc) Irradiation time: 3 min, power level:
180 W, solvent of crystallization: CHCl3, yield-82%, mp:
115°C: IR (KBr) vmax 3,412(NH), 1,590, 1,531 (Ar) cm-1
.
1H NMR (500 MHz, CDCl3) d: 3.095–3.148 (dd, 1H,
J = 9.5 and 16.5 Hz, one H of CH2), 3.614–3.669 (dd, 1H,
J = 10.5 and 17 Hz, one H of CH2), 3.749 (s, 3H, CH3),
3.810 (s, 3H, CH3), 5.228–5.268 (t, 1H, J = 10 Hz, CH),
6.167 (bs, 1H, NH), 6.762–6.780 (m, 1H, Ar), 6.803–6.820
(d, 1H, J = 8.5 Hz, Ar), 7.026–7.032 (d, 1H, J = 3 Hz,
Ar), 7.658–7.669 (d, 2H, J = 5.5 Hz, Ar), 8.348–8.360 (d,
2H, J = 6 Hz, Ar), 13C NMR (125 MHz, CDCl3) d: 43.4
(C), 49.9 (C), 55.7 (C), 56.1 (C), 111.4 (C), 111.9 (C),
113.1 (C), 113.5 (C), 114.4 (C), 120.2 (C), 122.7 (C),
136.9 (C), 148.3 (C), 149.0 (C), 151.1 (C) and 153.8
(C) GC–MS: m/z 283, (M?, 20%). Anal. Calcd for
C16H17N3O2: C 67.83, H 6.05, N 14.83; Found C 67.77, H
6.09, N 14.89.
(ii) 3-(2,5-Dimethoxyphenyl)-1-pyridin-2-yl-propenone(0.269
g; 1 mmol) and hydrazine hydrated (0.060 g;
1.2 mmol) were mixed together to make a homoge-
neous mixture. This homogeneous mixture was
subjected to microwave irradiation at 85°C for
3 min. TLC of reaction mixture show absence of
starting materials. Crude product so obtained was
purified by crystallization from chloroform to give
pure product IIa in quantitative yield
Yield-83%, mp: 114°C: IR (KBr) vmax 3,140 (NH) 1,587,
1
1,489 (Ar) cm-1. H NMR (500 MHz, CDCl3) d: 3.121–
3.175 (dd, 1H, J = 10 and 17 Hz, one H of CH2),
3.641–3.696 (dd, 1H, J = 10 and 17 Hz, one H of CH2),
3.776 (s, 3H, OCH3), 3.836 (s, 3H, OCH3), 5.254–5.295
(t, 1H, J = 10 Hz, CH), 6.207 (bs, 1H, NH), 6.789–6.806
(m, 1H, Ar), 6.829–6.847 (d, 1H, J = 9 Hz, Ar),
7.053–7.059 (d, 1H, J = 3 Hz, Ar), 7.205–7.232 (m, 1H,
Ar), 7.711–7.979 (m, 1H, Ar), 7.978–7.994 (d, 1H,
J = 8 Hz, Ar), 8.588–8.596 (m, 1H, Ar), 13C NMR
(125 MHz, CDCl3) d: 43.1 (C), 49.7 (C), 55.6 (C), 55.9
(C), 111.3 (C), 111.8 (C), 113.0 (C), 113.4 (C), 114.3 (C),
120.0 (C), 122.5 (C), 136.7 (C), 148.2 (C), 148.4 (C), 150.9
(C) and 153.4 (C) GC–MS: m/z 283, (M?, 5%). Anal.
Calcd for C16H17N3O2: C 67.83, H 6.05, N 14.83; Found C
67.55, H 6.12, N 14.78.
N ,N-dimethyl-4[3-(pyridin-2-yl)-4,5-dihydro-1H-pyrazol-
5-yl] benzenamine (IId) Irradiation time: 3 min, power
level: 180 W, solvent of crystallization: CHCl3, yield-81%,
mp: 121°C: IR (KBr) vmax 3,414(NH), 1,587, 1,490 (Ar)
1
cm-1. H NMR (500 MHz, MHz, CDCl3) d: 2.900 (s, 6H,
2 9 CH3), 3.212–3.263 (dd, 1H, J = 8 and 17.5 Hz, one H
of CH2), 3.535–3.591 (dd, 1H, J = 11 and 17 Hz, one H of
CH2), 4.876–4.914 (t, 1H, J = 10 Hz, CH), 6.050 (bs, 1H,
NH), 6.594–6.612 (d, 3H, J = 9 Hz, Ar), 7.213–7.227 (d,
2H, J = 7 Hz, Ar), 7.652–7.691 (m, 1H, Ar), 7.951–7.967
(d, 1H, J = 8 Hz, Ar), 8.560–8.570 (d, 1H, J = 5 Hz, Ar),
13C NMR (125 MHz, CDCl3) d: 40.5 (C), 50.6 (C), 112.8
(C), 112.9 (C), 123.6 (C), 127.1(C), 128.9 (C), 129.9 (C),
133.0 (C), 147.2 (C), 148.3 (C), 149.3 (C), 150.4 (C) and
154.5 (C) GC–MS: m/z 266, (M?, 90%). Anal. Calcd for
C16H18N4: C 72.15, H 6.81, N 21.04; Found C 72.29, H
6.84, N 21.11.
3-[5-(2,5-dimethoxyphenyl)-4,5-dihydro-1H-pyrazol-3-yl]-
pyridine (IIb) Irradiation time: 3 min, power level:
180 W, solvent of crystallization: CHCl3, yield-84%, mp:
118°C: IR (KBr) vmax 3,314(NH), 1,587, 1,487 (Ar) cm-1
.
N,N-dimethyl-4[3-(pyridin-3-yl)-4,5-dihydro-1H-pyrazol-
5-yl] benzenamine (IIe) Irradiation time: 3 min,
power level: 180 W, solvent of crystallization: CHCl3,
1H NMR (500 MHz, MHz, CDCl3) d: 3.094–3.147 (dd,
1H, J = 9.5 and 16.5 Hz, one H of CH2), 3.613–3.668 (dd,
123

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Med Chem Res (2012) 21:3043–3052
3-[5-(2,5-dimethoxyphenyl)-1-phenyl-4,5-dihydro-1H-pyr-
azol-3-yl]-pyridine (IIh) Irradiation time: 3 min, power
level: 450 W, solvent of crystallization: CHCl3: MeOH
(8:2), yield-81%, mp: 183°C: IR (KBr) vmax 3,444 (NH),
1,625, 1,575, 1,524, 1,497 (Ar) cm-1. 1H NMR (500 MHz,
CDCl3) d: 3.17–3.22 (dd, 1H, J = 10 and 20 Hz, one H of
CH2), 3.61 (s, 3H, CH3), 3.88 (s, 3H, CH3), 3.95–4.01 (dd,
1H, J = 15 and 20 Hz, one H of CH2), 5.58–5.63 (dd, 1H,
J = 10 and 20 Hz, CH), 6.68–6.69 (d, 1H, J = 5 Hz, Ar),
6.72–6.74 (m, 1H, Ar), 6.79–6.82 (t, 1H, J = 7.5 Hz, Ar),
6.84–6.86 (d, 1H, J = 10 Hz, Ar), 7.07–7.09 (m, 2H, Ar),
7.18–7.22 (m, 2H, Ar), 7.66–7.67 (d, 1H, J = 5 Hz, Ar),
8.35–8.36 (d, 1H, J = 5 Hz, Ar), 8.53–8.55 (t, 2H,
J = 5 Hz, Ar), 13C NMR (125 MHz, CDCl3) d: 43.8 (C),
49.7 (C), 55.5 (C), 111.9 (C), 112.9 (C), 123.8 (C), 127.5
(C), 129.0 (C), 129.9 (C), 133.0 (C), 148.2 (C), 149.3 (C),
152.1 (C), 152.9 (C), 154.3 (C) and 155.4 (C) GC–MS: m/z
359, (M?, 5%). Anal. Calcd for C22H21N3O2: C 73.52, H
5.89, N 11.69; Found C 73.62, H 5.82, N 11.74.
yield-80%, mp: 119°C: IR (KBr) vmax 3,316 (NH), 1,591,
1
1,569, 1,488 cm-1. H NMR (500 MHz, CDCl3) d: 2.931
(s, 6H, 2 9 CH3), 3.214–3.264 (dd, 1H, J = 8 and 17 Hz,
one H of CH2), 3.537–3.592 (dd, 1H, J = 10.5 and 17 Hz,
one H of CH2), 4.877–4.915 (t, 1H, J = 10 Hz, CH), 6.051
(bs, 1H, NH), 6.688–6.712 (m, 2H, Ar), 7.183–7.232 (m,
3H, Ar), 7.658–7.692 (m, 1H, Ar), 7.952–7.968 (d, 1H,
J = 8 Hz, Ar), 8.562–8.571 (d, 1H, J = 4.5 Hz, Ar), 13C
NMR (125 MHz, CDCl3) d: 40.4 (C), 50.5 (C), 111.6 (C),
112.2 (C), 112.7 (C), 123.4 (C), 126.9 (C), 128.8 (C), 129.8
(C), 132.9 (C), 147.1 (C), 148.2 (C), 149.2 (C), 150.3
(C) and 155.4 (C) GC–MS: m/z 266, (M?, 85%). Anal.
Calcd for C16H18N4: C 72.15, H 6.81, N 21.04; Found C
72.25, H 6.83, N 21.08.
N,N-dimethyl-4[3-(pyridin-4-yl)-4,5-dihydro-1H-pyrazol-
5-yl] benzenamine (IIf) Irradiation time: 3 min, power
level: 180 W, solvent of crystallization: CHCl3, yield-81%,
mp: 128°C: IR (KBr) vmax 3,384(NH), 1,639, 1,580, 1,535,
1,478 (Ar) cm-1 1H NMR (500 MHz, 2.930 (s, 6H,
.
4-[5-(2,5-dimethoxyphenyl)-1-phenyl-4,5-dihydro-1H-pyrazol-
3-yl]-pyridine (IIi) Irradiation time: 3 min, power level:
450 W, solvent of crystallization: CHCl3: MeOH (8:2),
yield: 77%, mp: 187°C: IR (KBr) vmax 3,429 (NH), 1,628,
2 9 CH3), 3.216–3.266 (dd, 1H, J = 8 and 17 Hz, one H
of CH2), 3.541–3.596 (dd, 1H, J = 10.5 and 17 Hz, one H
of CH2), 4.879–4.918 (q, 1H, J = 7 and 10 Hz, CH), 6.147
(bs, 1H, NH), 6.690–6.715 (d, 2H, J = 12 Hz, Ar),
7.184–7.213 (dd, 2H, J = 1.5 and 8 Hz, Ar), 7.657–7.668
(d, 2H, J = 5.5 Hz, Ar), 8.349–8.361 (d, 2H, J = 6.5 Hz,
Ar), 13C NMR (125 MHz, CDCl3) d: 40.2 (C), 50.4 (C),
111.5 (C), 112.5 (C), 123.3 (C), 126.9 (C), 128.6 (C), 129.7
(C), 132.7 (C), 148.1 (C), 149.0 (C), 149.6 (C), 150.1
(C) and 154.2 (C) GC–MS: m/z 266, (M?, 90%). Anal.
Calcd for C16H18N4: C 72.15, H 6.81, N 21.04; Found C
72.31, H 6.78, N 21.07.
1
1,585, 1,509 (Ar) cm-1. H NMR (500 MHz, CDCl3) d:
3.18–3.22 (dd, 1H, J = 5 and 10 Hz, one H of CH2), 3.61 (s,
3H, CH3), 3.88 (s, 3H, CH3), 3.95–4.01 (dd, 1H, J = 15 and
20 Hz, one H of CH2), 5.60–5.64 (dd, 1H, J = 10 and 15 Hz,
CH), 6.68–6.69 (d, 1H, J = 5 Hz, Ar), 6.72–6.74 (m, 1H,
Ar), 6.79–6.82 (t, 1H, J = 7.5 Hz, Ar), 6.84–6.86 (d, 1H,
J = 10 Hz, Ar), 7.07–7.09 (m, 2H, Ar), 7.18–7.22 (m, 2H,
Ar), 7.66–7.67 (d, 2H, J = 5 Hz, Ar), 8.35–8.36 (d, 2H,
J = 5 Hz, Ar), 13C NMR (125 MHz, CDCl3) d: 44.1 (C),
49.6 (C), 55.3 (C), 111.7 (C), 112.3 (C), 112.8 (C), 112.9 (C),
123.8 (C), 127.7 (C), 129.0 (C), 129.8 (C), 133.0 (C), 149.3
(C), 152.2 (C), 152.9 (C), 154.4 (C) and 155.4 (C) GC–MS:
m/z 359, (M?, 20%). Anal. Calcd for C22H21N3O2: C 73.52,
H 5.89, N 11.69; Found C 73.49, H 5.85, N 11.62.
2-[5-(2,5-dimethoxyphenyl)-1-phenyl-4,5-dihydro-1H-pyr-
azol-3-yl]-pyridine (IIg) Irradiation time: 3 min, power
level: 450 W, solvent of crystallization: CHCl3: MeOH
(8:2), yield-77%, mp: 173°C: IR (KBr) vmax 3,382(NH),
1
1,601, 1,485 (Ar) cm-1. H NMR (500 MHz, CDCl3) d:
3.200–3.250 (dd, 1H, J = 7 and 18 Hz, one H of CH2),
3.645 (s, 3H, CH3), 3.922 (s, 3H, CH3), 3.979–4.041 (dd,
1H, J = 13 and 18.5 Hz, one H of CH2), 5.630–5.668 (dd,
1H, J = 6.5 and 12.5 Hz, CH), 6.707–6.713 (d, 1H,
J = 3 Hz, Ar), 6.744–6.768 (m, 1H, Ar), 6.818–6.847 (t,
1H, J = 9.5 Hz, Ar), 6.878–6.887 (d, 1H, J = 4.5 Hz, Ar),
7.077–7.099 (m, 2H, Ar), 7.148–7.243 (m, 3H, Ar),
7.691–7.725 (m, 1H, Ar), 8.139–8.161 (m, 1H, Ar),
8.550–8.557 (m, 1H, Ar), 13C NMR (125 MHz, CDCl3) d:
43.7 (C), 49.7 (C), 55.6 (C), 111.7 (C), 112.3 (C), 112.8
(C), 123.6 (C), 127.1 (C), 128.9 (C), 129.1 (C), 129.9 (C),
133.0 (C), 148.3 (C), 149.3 (C), 152.1 (C), 152.9 (C), 154.3
(C) and 155.5 (C) GC–MS: m/z 359, (M?, 5%). Anal.
Calcd for C22H21N3O2: C 73.52, H 5.89, N 11.69; Found C
73.68, H 5.76, N 11.78.
N,N-dimethyl-4[1-phenyl-3-(pyridin-2-yl)-4,5-dihydro-1H-
pyrazol-5-yl] benzenamine (IIj) Irradiation time: 3 min,
power level: 450 W, solvent of crystallization: CHCl3:
MeOH (8:2), yield: 79%, mp: 183°C: IR (KBr) vmax 3,315
(NH), 1,587, 1,487, 1,442 (Ar) cm-1. 1H NMR (500 MHz,
CDCl3) d: 2.968 (s, 6H, 2 9 CH3), 3.070–3.118 (dd, 1H,
J = 7 and 17 Hz, one H of CH2), 3.792–3.852 (dd, 1H, J =
12.5 and 17 Hz, one H of CH2), 5.342–5.381 (dd, 1H, J = 7
and 12.5 Hz, CH), 6.826–6.839 (t, 1H, J = 3 Hz, Ar),
6.956–6.973 (d, 2H, J = 8.5 Hz, Ar), 7.062–7.081 (dd, 2H,
J = 1 and 7.5 Hz, Ar), 7.165–7.217 (m, 4H, Ar), 7.542–
7.569 (m, 1H, Ar), 8.295–8.323 (m, 1H, Ar), 8.533–8.546
(dd, 1H, J = 1.5 and 5 Hz, Ar), 8.859–8.862 (d, 1H,
J = 1.5 Hz, Ar), 13C NMR (125 MHz, CDCl3) d: 40.6 (C),
123

Med Chem Res (2012) 21:3043–3052
3049
1.2 mmol) were mixed together to give a homoge-
neous mixture and then this reaction mixture was
subjected to microwave irradiation for 3 min at a
power level of 450 W. TLC of reaction mixture
showed the presence of starting materials so reaction
contents were further irradiated for 4 min and progress
of reaction was monitored by TLC, which showed the
absence of starting materials. From this observation it
is inferred that irradiation for 3 ? 4 min is required
for completion of reaction to give condensation
product IVa. Compound IVa was further purified by
crystallization from methanol to give pure 2-[5-(2,
5-dimethoxyphenyl)-[1,2,4] oxadiazol-3-yl] pyridine
(IVa, Scheme 2) in good yield
42.8 (C), 50.5 (C), 111.7 (C), 113.1 (C), 113.4 (C), 119.4 (C),
123.5 (C), 126.6 (C), 128.8 (C), 130.7 (C), 132.8 (C), 143.2
(C), 144.2 (C), 146.2 (C), 148.3 (C), 149.7 (C), 152.1 (C) and
156.3 (C) GC–MS: m/z 342, (M?, 60%) Anal. Calcd for
C22H22N4: C 77.16, H 6.48, N 16.36; Found C 77.27, H 6.44,
N 16.41.
N,N-dimethyl-4[1-phenyl-3-(pyridin-3-yl)-4,5-dihydro-1H-
pyrazol-5-yl] benzenamine (IIk) Irradiation time: 3 min,
power level: 450 W, solvent of crystallization: CHCl3:
MeOH (8:2), yield: 76%, mp: 191°C: IR (KBr) vmax 3,386
(NH), 1,622, 1,595, 1,495 (Ar) cm-1. 1H NMR (500 MHz,
CDCl3) d: 2.92 (s, 6H, 2 9 CH3), 3.09–3.13 (dd, 1H, J = 5
and 15 Hz, one H of CH2), 3.74–3.79 (dd, 1H, J = 5 and
15 Hz, one H of CH2), 5.24–5.28 (dd, 1H, J = 5 and
10 Hz, CH), 6.70–6.72 (m, 2H, Ar), 6.78–6.81 (m, 1H, Ar),
7.09–7.11 (m, 2H, Ar), 7.15–7.20 (m, 4H, Ar), 7.66–7.67
(d, 1H, J = 5 Hz, Ar), 8.35–8.36 (d, 1H, J = 5 Hz, Ar),
8.53–8.55 (t, 2H, J = 5 Hz, Ar), 13C NMR (125 MHz,
CDCl3) d: 40.6 (C), 42.8 (C), 50.5 (C), 113.0 (C), 113.1
(C), 119.4 (C), 123.5 (C), 126.6 (C), 128.8 (C), 129.2 (C),
130.7 (C), 132.8 (C), 143.2 (C), 144.2 (C), 146.2 (C), 148.3
(C), 149.7 (C), 153.2 (C) and 155.3 (C) GC–MS: m/z 342,
(M?, 55%) Anal. Calcd for C22H22N4: C 77.16, H 6.48, N
16.36; Found C 77.23, H 6.49, N 16.44.
(ii) N0-hydroxypicolinamidine (IIIa, Scheme 2), (0.269 g;
1 mmol) and 2,5-dimethoxybenzaldehyde (0.060 g;
1.2 mmol) were mixed together to make a homoge-
neous mixture. This homogeneous mixture was sub-
jected to microwave irradiation at 160°C for 5 min.
TLC of reaction mixture shows the absence of starting
materials. This crude product was crystallized from
methanol to give pure product IVa in good yield
Yield: 77%, mp: 211°C: IR (KBr) vmax 1,587, 1,489, (Ar)
1
cm-1. H NMR (500 MHz, DMSO-d6) d: 3.748 (s, 3H,
OCH3), 3.869 (s, 3H, OCH3), 7.164–7.194 (q, 2H, J = 3.5
and 5.5 Hz, Ar), 7.247–7.272 (dd, 1H, J = 3 and 9 Hz,
Ar), 7.723–7.750 (m, 1H, Ar), 8.015–8.072 (m, 2H, Ar),
8.747–8.758 (dd, 1H, J = 1 and 4.5 Hz, Ar), 13C NMR
(125 MHz, CDCl3) d: 55.6 (C), 56.0 (C), 110.3 (C), 113.2
(C), 117.1 (C), 123.3 (C), 124.7 (C), 126.9 (C), 128.4 (C),
133.8 (C), 136.9 (C), 150.9 (C), 153.4 (C), 156.4 (C) and
156.5 (C) GC–MS: m/z 283, (M? 45%) Anal. Calcd for
C15H13N3O3: C 63.60, H 4.60, N 15.19; Found C 63.67, H
4.69, N 14.89.
N,N-dimethyl-4[1-phenyl-3-(pyridin-4-yl)-4,5-dihydro-1H-
pyrazol-5-yl] benzenamine (IIl) Irradiation time: 3 min,
power level: 450 W, solvent of crystallization: CHCl3:
MeOH (8:2), yield: 76%, mp: 197°C: IR (KBr) vmax
3,387(NH), 1,632, 1,593, 1,539 (Ar) cm-1 1H NMR
.
(500 MHz, CDCl3) d: 2.92 (s, 6H, 2 9 CH3), 3.08–3.13
(dd, 1H, J = 5 and 20 Hz, one H of CH2), 3.75–3.79 (dd,
1H, J = 10 and 15 Hz, one H of CH2), 5.24–5.28 (dd, 1H,
J = 5 and 10 Hz, CH), 6.70–6.72 (m, 2H, Ar), 6.78–6.81
(t, 1H, J = 7.5 Hz, Ar), 7.09–7.11 (m, 2H, Ar), 7.15–7.20
(m, 4H, Ar), 7.66–7.67 (d, 2H, J = 5 Hz, Ar), 8.35–8.36
(d, 2H, J = 5 Hz, Ar), 13C NMR (125 MHz, CDCl3) d:
40.8 (C), 42.9 (C), 50.6 (C), 112.8 (C), 113.2 (C), 113.6
(C), 119.6 (C), 123.7 (C), 126.8 (C), 128.9 (C), 129.9 (C),
130.8 (C), 132.9 (C), 143.4 (C), 144.4 (C), 146.3 (C), 148.4
(C), 149.8 (C), 152.5 (C) and 155.8 (C) GC–MS: m/z 342,
(M?, 58%) Anal. Calcd for C22H22N4: C 77.16, H 6.48, N
16.36; Found C 77.11, H 6.51, N 16.34.
4-[5-(2,5-dimethoxyphenyl)-[1,2,4]oxadiazol-3-yl]-pyr-
idine (IVb) Irradiation time: 7 min, power level: 450 W,
solvent of crystallization: MeOH, yield: 76%, mp: 237°C:
1
IR (KBr) vmax 2,921 (CH3), 1,585, 1,462 (Ar) cm-1. H
NMR (500 MHz, DMSO-d6) d: 3.751 (s, 3H, OCH3), 3.873
(s, 3H, OCH3), 7.169–7.203 (q, 2H, J = 3.5 and 8 Hz, Ar),
7.255–7.280 (q, 1H, J = 3.5 and 9.5 Hz, Ar), 7.865–7.876
(d, 2H, J = 6 Hz, Ar), 8.839–8.851 (d, 2H, J = 6 Hz, Ar),
13C NMR (125 MHz, CDCl3) d: 56.7 (C), 57.0 (C), 111.2
(C), 114.2 (C), 117.2 (C), 121.3 (C), 124.3 (C), 125.7 (C),
126.1 (C), 151.6 (C), 154.4 (C), 156.4 (C) and 157.5 (C),
GC–MS: m/z 283, (M? 85%) Anal. Calcd for C15H13N3O3:
C 63.60, H 4.60, N 15.19; Found C 63.54, H 4.67, N 14.97.
General procedure for synthesis of oxadiazole derivatives
(IVa–f)
Synthesis of 2-[5-(2,5-dimethoxyphenyl)-[1,2,4]oxadiazol-
3-yl]-pyridine (IVa)
2-[5-(2,5-dimethoxyphenyl)-[1,2,4]oxadiazol-3-yl]-pyrazine
(IVc) Irradiation time: 7 min, power level: 450 W,
solvent of crystallization: MeOH, yield: 78%, mp: 196°C:
(i) N0-hydroxypicolinamidine (IIIa, Scheme 2), (0.269 g;
1 mmol) and 2,5-dimethoxybenzaldehyde (0.060 g;
123

3050
Med Chem Res (2012) 21:3043–3052
IR (KBr) vmax 1,575, 1,447 (Ar) cm-1
.
1H NMR (500
OH), 13C NMR (125 MHz, CDCl3) d: 55.9 (C), 108.7 (C),
114.3 (C), 115.1 (C), 127.3 (C), 129.6 (C), 130.8 (C), 145.3
(C), 147.1 (C), 147.2 (C), 148.1 (C), 151.6 (C) and 156.8
(C) GC–MS: m/z 270, (M? 10%) Anal. Calcd for
C13H10N4O3: C 57.78, H 3.73, N 20.73; Found C 57.72, H
3.76, N 20.67.
MHz, DMSO-d6) d: 3.749 (s, 3H, OCH3), 3.877 (s, 3H,
OCH3), 7.165–7.195 (q, 2H, J = 3.5 and 5.5 Hz, Ar),
7.247–7.272 (q, 1H, J = 3 and 9 Hz, Ar), 8.864–8.871 (t,
1H, J = 2 Hz, Ar), 8.970–8.975 (d, 1H, J = 2.5 Hz, Ar),
9.225–9.228 (d, 1H, J = 1.5 Hz, Ar), 13C NMR (125 MHz,
CDCl3) d: 55.7 (C), 56.0 (C), 110.3 (C), 113.2 (C), 115.2
(C), 123.3 (C), 124.7 (C), 130.9 (C), 145.4 (C), 147.3 (C),
148.2 (C), 153.4 (C), 155.4 (C) and 156.6 (C) GC–MS: m/z
285, (M?10%) Anal. Calcd for C14H12N4O3: C 59.15, H
4.23, N 19.71; Found C 59.28, H 4.19, N 19.67.
Pharmacology
In vitro cytotoxicity against human cancer cell lines (Monks
et al., 1991; Skehan et al., 1990) The human cancer cell
lines procured from National Cancer Institute, Frederick,
U.S.A. were used in present study. Cells were grown in
tissue culture flasks in complete growth medium (RPMI-
1640 medium with 2 mM glutamine, pH 7.4 supplemented
with 10% fetal bovine serum, 100 lg/ml streptomycin and
100 units/ml penicillin) in a carbon dioxide incubator
(37°C, 5% CO2, 90% RH). The cells at subconfluent stage
were harvested from the flask by treatment with trypsin
(0.05% in PBS (pH 7.4) containing 0.02% EDTA). Cells
with viability of more than 98%, as determined by trypan
blue exclusion, were used for determination of cytotoxicity.
The cell suspension of 1 9 105 cells/ml was prepared in
complete growth medium.
2-methoxy-4-[3-(pyridin-2-yl)-[1,2,4]oxadiazol-5-yl]-phe-
nol (IVd) Irradiation time: 7 min, power level: 450 W,
solvent of crystallization: MeOH, yield: 79%, mp: 247°C:
IR (KBr) vmax 3,425 (OH), 1,626, 1,578, 1,525 (Ar) cm-1
.
1H NMR (500 MHz, DMSO-d6) d: 3.843 (s, 3H, OCH3),
6.954–6.970 (d, 1H, J = 8 Hz, Ar), 7.387–7.415 (t, 1H,
J = 12.5 Hz, Ar), 7.428–7.430 (d, 1H, J = 1 Hz, Ar),
7.723–7.750 (m, 1H, Ar), 8.015–8.072 (m, 2H, Ar),
8.747–8.758 (dd, 1H, J = 1 and 4.5 Hz, Ar), 10.254 (bs,
1H, OH), 13C NMR (125 MHz, CDCl3) d: 55.9 (C), 108.7
(C), 114.3 (C), 116.9 (C), 126.9 (C), 127.3 (C), 128.4 (C),
129.6 (C), 133.7 (C), 136.9 (C), 147.1 (C), 150.9 (C), 151.7
(C), 156.8 (C), GC–MS: m/z 269, (M? 55%) Anal. Calcd
for C14H11N3O3: C 62.45, H 4.09, N 15.65; Found C 62.41,
H 4.15, N 15.69.
Stock 4 9 10-2 M compound solutions were prepared
in DMSO. The stock solutions were serially diluted with
complete growth medium containing 50 lg/ml of genta-
mycin to obtained working test solution of required
concentrations.
2-methoxy-4-[3-(pyridin-4-y)l-[1,2,4]oxadiazol-5-yl]-phe-
nol (IVe) Irradiation time: 7 min, power level: 450 W,
solvent of crystallization: MeOH, yield: 81%, mp: 253°C:
In vitro cytotoxicity against various human cancer cell
lines was determined (Monks et al., 1991) using 96-well
tissue culture plates. The 100 ll of cell suspension was
added to each well of the 96-well tissue culture plates. The
cells were allowed to grow in CO2 incubator (37°C, 5%
CO2, 90% RH) for 24 h. The test materials in complete
growth medium (100 ll) were added after 24 h incubation
to the wells containing cell suspension. The plates were
further incubated for 48 h (37°C in an atmosphere of 5%
CO2 and 90% relative humidity) in a carbon dioxide
incubator after addition of test material and then the cell
growth was stopped by gently layering trichloroacetic acid
(50% TCA, 50 ll) on top of the medium in all the wells.
The plates were incubated at 4°C for one hour to fix the
cells attached to the bottom of the wells. The liquid of all
the wells was gently pipetted out and discarded. The plates
were washed five times with distilled water to remove
TCA, growth medium low molecular weight metabolites,
serum proteins etc. and air dried. Cell growth was mea-
sured by staining with sulforhodamine B dye (Skehan
et al., 1990). The adsorbed dye was dissolved in Tris–HCl
buffer (100 ll, 0.01 M, pH 10.4) and plates were gently
stirred for 10 min on a mechanical stirrer. The optical
density (OD) was recorded on ELISA reader at 540 nm.
IR (KBr) vmax 3,425 (OH), 1,578, 1,525 (Ar) cm-1. H
1
NMR (500 MHz, DMSO-d6) d: 3.837 (s, 3H, OCH3),
6.948–6.965 (d, 1H, J = 8.5 Hz, Ar), 7.382–7.385 (d, 1H,
J = 1.5 Hz, Ar), 7.407–7.427 (dd, 1H, J = 2 and 8 Hz,
Ar), 7.860–7.872 (dd, 2H, J = 1.5 and 4.5 Hz, Ar),
8.837–8.849 (dd, 2H, J = 1.5 and 4 Hz, Ar), 10.245 (bs,
1H, OH), 13C NMR (125 MHz, CDCl3) d: 55.9 (C), 108.7
(C), 114.4 (C), 116.2 (C), 120.4 (C), 125.2 (C), 127.4 (C),
129.6 (C), 147.2 (C), 150.5 (C), 151.8 (C) and 156.8
(C) GC–MS: m/z 269, (M?60%) Anal. Calcd for
C14H11N3O3: C 62.45, H 4.09, N 15.65; Found C 62.48, H
4.10, N 15.67.
2-methoxy-4-[3-(pyrazin-2-yl)-[1,2,4]oxadiazol-5-yl]-phe-
nol (IVf) Irradiation time: 7 min, power level: 450 W,
solvent of crystallization: MeOH, yield: 77%, mp: 235°C:
IR (KBr) vmax 3,312 (OH), 1,612, 1,590, 1,532, (Ar) cm-1
.
1H NMR (500 MHz, DMSO-d6) d: 3.840 (s, 3H, OCH3),
6.953–6.969 (d, 1H, J = 8 Hz, Ar), 7.386 (s, 1H, Ar),
7.411–7.430 (dd, 1H, J = 1.5 and 8 Hz, Ar), 8.864–8.871
(t, 1H, J = 2 Hz, Ar), 8.970–8.975 (d, 1H, J = 2.5 Hz,
Ar), 9.225–9.228 (d, 1H, J = 1.5 Hz, Ar), 10.253 (bs, 1H,
123

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edema inhibition test was used on albino rats of Charles
Foster by adopting the method of Winter et al. Groups of
five animals of both sexes (body weight 120–160 g),
excluding pregnant females, were given a dose of test
compound. 30 min later, 0.20 ml of 1% freshly prepared
carrageenan suspension in 0.9% NaCl solution was injected
subcutaneously into the planter aponeurosis of the hind
paw and the volume was measured by a water plethys-
mometer apparatus and then measured again 1–3 h later.
The mean increase of paw volume at each interval was
compared with that of control group (five rats treated with
carrageenan but not with test compound) at the same
intervals and percent inhibition value calculated by the
formula given below.
%antiꢁinflammatoryactivity ¼ ½1 ꢁ Dt=Dcꢂ ꢃ 100ꢂ
Dt and Dc are paw volumes of edema in tested and control
groups, respectively. Compounds IIa–l and IVa–f were
screened for anti-inflammatory activity and results are
summarized in Table 1.
El-Enany M, El-Meligie SEM, Abdou NA, El-Nassan HB (2010)
Synthesis and antimicrobial activity of some 3,5-diaryl-4,
5-dihydropyrazole derivatives. Orient J Chem 26:1265–1270
El-Sabbagh OI, Baraka MM, Ibrahim SM, Pannecouque C, Andrei G,
Snoeck R, Balzarini J, Rashad AA (2009) Synthesis and antiviral
activity of new pyrazole and thiazole derivatives. Eur J Med
Chem 44:3746–3753
Acknowledgments We are thankful to technical staff of the
Chemistry Department, I. I. T. Roorkee, for spectroscopic studies and
elemental analysis and to Mr Rakesh Kumar (Integral Biosciences
Ltd, Noida) for helping to use microwave reactor. Mr. Sandeep
Kumar is thankful to MHRD New Delhi for financial assistance.
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