Synthesis and pharmacological evaluation of some novel 2-pyrazolines bearing benzenesulfonamide as anti-inflammatory and blood glucose lowering agents

Article abstract of DOI:10.1007/s00044-012-0130-y

A series of novel pyrazolines (2a-l) bearing benzenesulfonamide moiety were synthesized by condensing appropriate chalcone (1a-l) with 4- hydrazinobenzenesulfonamide hydrochloride. Structure of all novel synthesized compounds was characterized on basis of

Full text of DOI:10.1007/s00044-012-0130-y

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2013) 22:1378–1385
DOI 10.1007/s00044-012-0130-y
ORIGINAL RESEARCH
Synthesis and pharmacological evaluation of some novel
2-pyrazolines bearing benzenesulfonamide as anti-inflammatory
and blood glucose lowering agents
•
Syed Ovais Rafia Bashir Shafiya Yaseen
•
•
•
Pooja Rathore Mohammed Samim
•
Kalim Javed
Received: 16 December 2011 / Accepted: 25 May 2012 / Published online: 17 June 2012
Ó Springer Science+Business Media, LLC 2012
Abstract A series of novel pyrazolines (2a–l) bearing
benzenesulfonamide moiety were synthesized by con-
densing appropriate chalcone (1a–l) with 4-hydrazino-
benzenesulfonamide hydrochloride. Structure of all novel
synthesized compounds was characterized on basis of
elemental analysis data and spectral data (IR, 1HNMR,
MS). Compounds (2a–l) were screened for in vivo anti-
inflammatory action in carrageenan-induced rat paw edema
model and blood glucose lowering action in glucose fed
hyperglycemic normal rats. Compounds 2a, 2e, and 2l
showed significant anti-inflammatory action (more than
75 %) at 5 h and also showed superior gastrointestinal
safety profiles as compared to celecoxib. One compound
(2i) was found to exhibit significant blood glucose lowering
activity.
acid. There are at least two mammalian COX isoforms (Xie
et al., 1991; Kujubu et al., 1991). COX-2 is induced in
response to pro-inflammatory conditions, while COX-1 is
constitutive and responsible for the maintenance of physi-
ological homeostasis, such as gastrointestinal integrity and
renal function. Traditional NSAIDs such as aspirin, indo-
methacin, and diclofenac are nonselective inhibitors and
are associated with gastric ulceration, bleeding, and renal
function suppression (Vane and Botting, 1998). Generally,
prostacyclin and thromboxane normally balance each oth-
er’s opposing effects.
Several selective inhibitors of COX-2 were shown to
possess anti-inflammatory activity with little or no gastric
side effects (Dannhardt and Kiefer, 2001). By far the
greatest amount of research in the COX-2 area has been
performed in the preparation and evaluation of carbocyclic
or heterocyclic ring system bearing two vicinal aryl moi-
eties. During the last few years a large number of com-
pounds have been developed as potential candidates
(Fig. 1). The introduction of COX-2 inhibitors, such as
celecoxib, rofecoxib, and valdecoxib in the 1990s was
viewed as a milestone triumph over human suffering of
pain and inflammation with little or no damage to the
gastric mucosa (Flower, 2003). Unfortunately, rofecoxib
(Vioxx) was withdrawn from the market in the fall of 2004
after clinical reports of its linkage to elevated risk of car-
diac stroke (Abramson and Greenberg, 2008).
Keywords Pyrazoline ꢀ Sulfonamide ꢀ
Anti-inflammatory ꢀ Anti-hyperglyceamic
Introduction
Nonsteroidal anti-inflammatory drugs (NSAIDs) are
widely used for the treatment of pain, fever, and inflam-
mation. Conventional NSAIDs act as nonselective inhibi-
tors of cyclooxygenase (COX) enzymes, which catalyze
the formation of prostaglandins (PGs) from arachidonic
Among the highly marketed COX-2 inhibitors that
comprise the pyrazole nucleus, celecoxib is the one which
is treated as a safe anti-inflammatory and analgesic agent.
It is considered as a typical model of the diaryl heterocyclic
template that is known to selectively inhibit the COX-2
enzyme. Some other examples of pyrazole derivatives as
NSAIDs are mefobutazone, ramifenazone, famprofazone
(Reynold, 1993; Amir and Kumar, 2005; Gursoy et al.,
S. Ovais ꢀ R. Bashir ꢀ S. Yaseen ꢀ P. Rathore ꢀ M. Samim ꢀ
K. Javed (&)
Department of Chemistry, Faculty of Science, Jamia Hamdard
(Hamdard University), New Delhi 110 062, India
e-mail: kjavedchem@yahoo.co.in; kjaved@jamiahamdard.ac.in
123

Med Chem Res (2013) 22:1378–1385
1379
O
Fig. 1 Some potent COX-
inhibitors
O
O
H3C
O
H3C
H3C
H N
2
S
S
S
S
O
O
O
O
S
N
N
CF
Br
3
O
O
H C
3
F
F
DuP-697
SC-57666
Rofecoxib
Celecoxib
O
H2N
S
F
N
N
O
O
O
O
CH3
Na+
N-
CH3
CH3
N
O
S
O
S
H3C
O
O
H2N
O
Valdecoxib
JTE-522
Parecoxib Sodium
O
CH3
S
O
N
N
F3C
F
SC-58125
2000; Kumar et al., 2003). But due to serious adverse
effects such as bone marrow depression (Inman, 1977),
water and salt retention and carcinogenesis (Leonard,
1953), the use of pyrazole derivatives is limited. This
limitation has led to the investigation of new pyrazole
derivatives with more potent activity and less toxicity.
Motivated by aforesaid findings, and pursuing our
studies on pyrazoline moiety (Rathish et al., 2009; Bashir
et al., 2011). Some novel pyrazoline derivatives were
synthesized by replacing pyrazole moiety with a dihydro-
pyrazole nucleus linked in C3 and C5 with phenyl group
and evaluated for anti-inflammatory activity.
Experimental
Melting points were determined by open capillary tubes and
are uncorrected. Purity of the compounds was checked on
TLC plates (silica gel G) which were visualized by exposing
to iodine vapors. Infrared (IR) spectra were recorded (in
KBr) on a BIO-RAD FTS-135 spectrophotometer and
1HNMR spectra were recorded on a Bruker Spectrospin DPX
400 MHz spectrometer using deuterated DMSO as solvent
and tetramethyl silane (TMS) as an internal standard.
Chemical shifts are given in d (ppm) scale and coupling
constants (J values) are expressed in Hz. Mass spectra (MS)
were recorded on ESI Q-TOF Water. Elemental analysis was
carried out on CHNS Elementar (Vario EL III).
Recently pyrazolines have also been reported as dipep-
tidyl peptidase-IV (DP-IV) inhibitors (Ahn et al., 2004).
Inhibition of DP-IV increases the level of circulating glu-
cagon-like peptidase-1 (GLP-1) and thus, increases insulin
secretion (Pospisilik et al., 2002; Sudre et al., 2002) which
could ameliorate hyperglycemia in type 2 diabetes. It gave
us immense confidence to evaluate the anti-hyperglycemic
effect of these synthesized compounds.
General procedure for the synthesis of chalcones (1a–l)
To a cold solution (below 10 °C) of 1-(3-hydroxy-phenyl)-
ethanone (0.01 mol) and desired aromatic aldehyde
(0.01 mol) in ethanol (20 ml) was added a chilled solution of
123

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Med Chem Res (2013) 22:1378–1385
sodium hydroxide (10 ml of 30 % solution). The reaction
mixture was covered with a layer of petroleum ether
(60–80 °C) and left at room temperature for a period of 12 h.
It was poured on crushed ice (100 ml) and acidified with
concentrated HCl. The product obtained was filtered, washed
with water and dried residue was crystallized from
chloroform.
J = 8.4 Hz, H-300, H-500), 7.08–7.19 (3H, m, H-20, H-50,
H-60), 7.24 (2H, d, J = 8.4 Hz, H-200, H-600), 7.38 (2H, d,
J = 8.4 Hz, H-3, H-5), 7.56 (2H, d, J = 8.4 Hz, H-2, H-6),
9.56 (1H, s, OH). ESI–MS (m/z): 427 [M?], 426 [M?-1],
428 [M??1], 429 [M??2], 430 [M??3]. CHNS analysis: C:
59.01 (58.99), H: 4.21 (4.24), N: 9.83 (9.82), S: 7.49 (7.49).
Molecular formula: C21H18ClN3O3S.
General procedure for the preparation of pyrazolines
4-[3-(3-Hydroxy-phenyl)-5-(4-methoxy-phenyl)-4,5-
(2a–l)
dihydro-pyrazol-1-yl]-benzenesulfonamide (2c)
A mixture of appropriate chalcone (1a–l) (0.01 mol) and
4-hydrazinobenzenesulfonamide hydrochloride (0.01 mol)
in ethanol (95 %) (20–150 ml) was refluxed for 6–12 h. The
reaction mixture was concentrated to a small volume and left
at room temperature when a solid mass separated out, which
were filtered, dried and crystallized from appropriate
solvent.
This compound was obtained as light brown crystals when
recrystallized from methanol in 27 % yield, m.p.
131–133 °C, Rf = 0.69, (toluene:ethyl acetate:formic acid,
7.5:2:0.5). IR tmax (KBr): 3390 cm-1 and 3256 cm-1
(NH2), 1592 cm-1 (C=N), 1307 cm-1 and 1149 cm-1
1
(SO2N\). HNMR (400 MHz, DMSO, d): 3.06 [1H, dd,
J = 4.8 Hz, J = 17.6 Hz, H-4 trans (pyrazoline)], 3.67
(3H, s, OCH3), 3.87 [1H, dd, J = 12 Hz, J = 17.6 Hz, H-4
cis (pyrazoline)], 5.54 [1H, dd, J = 4.8 Hz, J = 11.6 Hz,
H-5 (pyrazoline)], 6.78 (1H, d, J = 7.6 Hz, H-40), 6.86
(2H, d, J = 8.8 Hz, H-3, H-5), 6.97 (2H, s, SO2 NH2), 7.03
(2H, d, J = 8.8 Hz, H-2, H-6), 7.12–7.15 (3H, m, H-20
H-300, H-500), 7.20–7.22 (2H, m, H-50, H-60), 7.55 (2H, d,
J = 8.8 Hz, H-200, H-600), 9.52 (1H, s, OH). ESI–MS (m/z):
423 [M?], 422 [M?-1], 424 [M??1]. CHNS analysis: C:
62.41 (62.40), H: 4.96 (5.00), N: 9.92 (9.92), S: 7.56 (7.57).
Molecular formula: C22H21N3O4S.
4-[3-(3-Hydroxy-phenyl)-5-phenyl-4,5-dihydro-
pyrazol-1-yl]-benzenesulfonamide (2a)
This compound was obtained as light brown crystals when
recrystallized from methanol in 35 % yield, m.p.
141–143 °C, Rf = 0.51, (toluene:ethyl acetate:formic acid,
7.5:2:0.5). IR tmax (KBr): 3404 cm-1 and 3270 cm-1
(NH2), 1591 cm-1 (C=N), 1306 cm-1 and 1144 cm-1
1
(SO2N\). HNMR (400 MHz, DMSO, d): 3.13 [1H, dd,
J = 5.6 Hz, J = 16.8 Hz, H-4 trans (pyrazoline)], 3.92
[1H, dd, J = 12.4 Hz, J = 17.6 Hz, H-4 cis (pyrazoline)],
5.59 [1H, dd, J = 4.8 Hz, J = 12.0 Hz, H-5 (pyrazoline)],
6.79 (1H, d, H-40, J = 7.6 Hz), 6.97 (2H, s, SO2NH2), 7.02
(2H, d, J = 8.8 Hz, H-300, H-500), 7.14 (1H, d, J = 6.8 Hz,
H-60), 7.21–7.33 (7H, m, H-20, H-50, H-2, H-3, H-4, H-5,
H-6), 7.55 (2H, d, J = 8.4 Hz, H-200, H-600), 9.56 (1H, s,
OH). ESI–MS (m/z): 393 [M?], 392 [M?-1], 394
[M??1]. CHNS analysis: found (calculated): C: 64.10
(64.12), H: 4.87 (4.83), N: 10.68 (10.68), S: 8.14 (8.15).
Molecular formula: C21H19N3O3S.
4-[3-(3-Hydroxy-phenyl)-5-p-tolyl-4,5-dihydro-
pyrazol-1-yl]-benzenesulfonamide (2d)
This compound was obtained as yellow crystals when re-
crystallized from methanol in 29 % yield, m.p. 158–160 °C,
Rf = 0.85, (toluene:ethyl acetate:formic acid, 7.5:2:0.5). IR
t
max (KBr): 3371 cm-1 and 3278 cm-1 (NH2), 1591 cm-1
(C=N), 1327 cm-1 and 1146 cm-1 (SO2N\). 1HNMR
(400 MHz, DMSO, d): 2.20 (3H, s, CH3), 3.10–3.14 [1H, m,
H-4 trans (pyrazoline)], 3.85–3.92 [1H, m, H-4 cis (pyraz-
oline)], 5.53–5.56 [1H, m, H-5 (pyrazoline)], 6.78 (1H, d,
J = 7.2 Hz, H-40), 6.97 (2H, s, SO2 NH2), 7.01 (2H, d,
J = 8.8 Hz, H-300, H-500), 7.11–7.21 (7H, m, H-200, H-600,
H-20, H-50, H-60, H-3, H-5), 7.54 (2H, d, J = 8.8 Hz, H-2,
H-6), 9.58 (1H, s, OH). ESI–MS (m/z): 407 [M?], 406 [M?-
1], 408 [M??1], 409 [M??2]. CHNS analysis: C: 64.86
(64.85), H: 5.16 (5.19), N: 10.32 (10.31), S: 7.86 (7.87).
Molecular formula: C22H21N3O3S.
4-[5-(4-Chloro-phenyl)-3-(3-hydroxy-phenyl)-4,5-
dihydro-pyrazol-1-yl]-benzenesulfonamide (2b)
This compound was obtained as yellow crystals when re-
crystallized from methanol in 55 % yield, m.p. 84–86 °C,
Rf = 0.69, (toluene:ethyl acetate:formic acid, 7.5:2:0.5). IR
t
max (KBr): 3471 cm-1 and 3304 cm-1 (NH2), 1592 cm-1
(C=N), 1326 cm-1 and 1148 cm-1 (SO2N\). 1HNMR
(400 MHz, DMSO, d): 3.12 [1H, dd, J = 5.2 Hz, J =
18.8 Hz, H-4 trans (pyrazoline)], 3.92 [1H, dd, J = 12 Hz,
J = 17.2 Hz, H-4 cis (pyrazoline)], 5.63 [1H, dd,
J = 4.4 Hz, J = 7.2 Hz, H-5 (pyrazoline)], 6.79 (1H, d,
J = 7.6 Hz, H-40), 6.98 (2H, s, SO2NH2), 7.02 (2H, d,
4-[5-(4-Hydroxy-phenyl)-3-(3-hydroxy-phenyl)-4,5-
dihydro-pyrazol-1-yl]-benzenesulfonamide (2e)
This compound was obtained as brown crystals when re-
crystallized from methanol in 27 % yield, m.p.
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Med Chem Res (2013) 22:1378–1385
1381
151–153 °C, Rf = 0.58, (toluene:ethyl acetate:formic acid,
7.5:2:0.5). IR tmax (KBr): 3351 cm-1 and 3252 cm-1
(NH2), 1591 cm-1 (C=N), 1326 cm-1 and 1136 cm-1
analysis: C: 61.62 (61.60), H: 4.64 (4.68), N: 10.27 (10.26),
S: 7.82 (7.83). Molecular formula: C21H19N3O4S.
1
(SO2N\). HNMR (400 MHz, DMSO, d): 3.02–3.14 [1H,
4-[5-(3,4-Dimethoxy-phenyl)-3-(3-hydroxy-phenyl)-
m, H-4 trans (pyrazoline)], 3.81–3.88 [1H, m, H-4 cis
(pyrazoline)], 5.46 [1H, dd, J = 4.8 Hz, J = 11.6 Hz, H-5
(pyrazoline)], 6.67 (2H, d, J = 8.4 Hz, H-3, H-5), 6.78
(1H, d, J = 7.6 Hz, H-40), 6.96 (2H, s, SO2NH2),
7.01–7.03 (4H, m, H-300, H-500, H-2, H-6), 7.14 (1H, d,
J = 7.2 Hz, H-6), 7.19–7.20 (2H, m, H-20, H-60), 7.54 (2H,
d, J = 8.8 Hz, H-200, H-600), 9.37 (1H, s, OH), 9.55 (1H, s,
OH). ESI–MS (m/z): 409 [M?], 408 [M?-1], 410
[M??1], 411 [M??1]. CHNS analysis: C: 61.61 (61.60),
H: 4.65 (4.68), N: 10.26 (10.26), S: 7.82 (7.83). Molecular
formula: C21H19N3O4S.
4,5-dihydro-pyrazol-1-yl]-benzenesulfonamide (2h)
This compound was obtained as yellow crystals when re-
crystallized from methanol in 47 % yield, m.p.
217–219 °C, Rf = 0.45, (toluene:ethyl acetate:formic acid,
7.5:2:0.5). IR tmax (KBr): 3403 cm-1 and 3277 cm-1
(NH2), 1593 cm-1 (C=N), 1331 cm-1 and 1154 cm-1
1
(SO2N\). HNMR (300 MHz, DMSO, d): 3.11 [1H, dd,
J = 12.3 Hz, J = 17.4 Hz, H-4 trans (pyrazoline)], 3.69
(3H, s, OCH3 at C-3), 3.72 (3H, s, OCH3 at C-4), 3.88 [1H,
dd, J = 8.4 Hz, J = 14.8 Hz, H-4 cis (pyrazoline)], 5.52
[1H, dd, J = 6.0 Hz, J = 15.2 Hz, H-5 (pyrazoline)], 6.67
(1H, d, J = 8.4 Hz, H-40), 6.81 (1H, d, J = 8.4 Hz, H-5),
6.88 (1H, d, J = 8.4 Hz, H-6), 6.93 (1H, s, H-2), 7.02 (2H,
s, SO2NH2), 7.07 (2H, d, J = 8.7 Hz, H-300, H-500),
7.16–7.26 (3H, m, H-20, H-50, H-60), 7.59 (2H, d,
J = 8.7 Hz, H-200, H-600), 9.61(1H, s, OH). ESI–MS (m/z):
453 [M?], 452 [M?-1], 454 [M??1]. CHNS analysis: C:
60.92 (60.91), H: 5.07 (5.11), N: 9.27 (9.27), S: 7.06 (7.07).
Molecular formula: C23H23N3O5S.
4-[5-(2-Chloro-phenyl)-3-(3-hydroxy-phenyl)-4,5-
dihydro-pyrazol-1-yl]-benzenesulfoamide (2f)
This compound was obtained as brown crystals when re-
crystallized from methanol in 43 % yield, m.p. 258–260 °C,
Rf = 0.84, (toluene:ethyl acetate:formic acid, 7.5:2:0.5). IR
t
max (KBr): 3348 cm-1 and 3284 cm-1 (NH2), 1592 cm-1
(C=N), 1329 cm-1 and 1148 cm-1 (SO2N\). 1HNMR
(400 MHz, DMSO, d): 3.12 [1H, dd, J = 11.6 Hz,
J = 16.4 Hz, H-4 trans (pyrazoline)], 4.02 [1H, dd,
J = 12.8 Hz, J = 17.6 Hz, H-4 cis (pyrazoline)], 5.78 [1H,
dd, J = 8.4 Hz, J = 12 Hz, H-5 (pyrazoline)], 6.79 (1H, d,
J = 7.6 Hz, H-40), 6.93–6.99 (5H, m, H-200, H-600, SO2NH2,
H-60), 7.15 (1H, J = 7.6 Hz, H-3), 7.16–7.31 (4H, m, H-20,
H-50, H-4, H-5), 7.54 (1H, d, J = 7.6 Hz, H-6), 7.60 (2H, d,
J = 7.6 Hz, H-300, H-500), 9.56 (1H, s, OH). ESI–MS (m/z):
428 [M??1], 429 [M??2], 430 [M??3]. CHNS analysis: C:
59.01 (58.98), H: 4.22 (4.24), N: 9.83 (9.82), S: 7.49 (7.49).
Molecular formula: C21H18ClN3O3S.
4-[3-(3-Hydroxy-phenyl)-5-(3,4,5-trimethoxy-phenyl)-
4,5-dihydro-pyrazol-1-yl]-benzenesulfonamide (2i)
This compound was obtained as yellow crystals when
recrystallized from methanol in 44 % yield, m.p. 269–
270 °C, Rf = 0.38, (toluene:ethyl acetate:formic acid,
7.5:2:0.5). IR tmax (KBr): 3390 cm-1 and 3299 cm-1 (NH2),
1591 cm-1 (C=N), 1329 cm-1 and 1138 cm-1 (SO2N\).
1HNMR (400 MHz, DMSO, d): 3.13-3.14 [1H, m, H-4 trans
(pyrazoline)], 3.59 (3H, s, OCH3), 3.66 (6H, s, 2xOCH3), 3.88
[1H, dd, J = 17.6 Hz, J = 28.4 Hz, H-4 cis (pyrazoline)],
5.45 [1H, dd, J = 6.8 Hz, J = 12.8 Hz, H-5 (pyrazoline)],
6.55 (2H, s, SO2NH2), 6.79 (1H, d, J = 7.6 Hz, H-40), 7.00
(2H, s, H-2, H-6), 7.06 (2H, d, J = 8.8 Hz, H-300, H- 500),
7.15 (1H, d, J = 7.2 Hz, H-50), 7.21–7.23 (2H, m, H-20,
H-60), 7.59 (2H, d, J = 8.8 Hz, H-200, H-600), 9.57 (1H, s,
OH). ESI–MS (m/z): 483 [M?], 482 [M?-1], 484 [M??1].
CHNS analysis: C: 59.62 (59.61), H: 5.17 (5.21), N: 8.69
(8.68), S: 6.63 (6.62). Molecular formula: C24H25N3O6S.
4-[5-(2-Hydroxy-phenyl)-3-(3-hydroxy-phenyl)-4,5-
dihydro-pyrazol-1-yl]-benzenesulfonamide (2g)
This compound was obtained as brown crystals when re-
crystallized from chloroform in 32 % yield, m.p.
249–250 °C, Rf = 0.55, (toluene:ethyl acetate:formic acid,
7.5:2:0.5). IR tmax (KBr): 3348 cm-1 and 3234 cm-1
(NH2), 1591 cm-1 (C=N), 1305 cm-1 and 1135 cm-1
1
(SO2N\). HNMR (400 MHz, DMSO, d): 3.02 [1H, dd,
J = 4.6 Hz, J = 12.0 Hz, H-4 trans (pyrazoline)], 3.88
[1H, dd, J = 12 Hz, J = 17.2 Hz H-4 cis (pyrazoline)],
5.68 [1H, dd, J = 4.4 Hz, J = 11.2 Hz, H-5 (pyrazoline)],
6.66 (1H, d, J = 7.2 Hz, H-40), 6.79 (2H, s, SO2NH2), 6.86
(1H, d, J = 8.0 Hz, H-3), 7.02–7.20 (8H, m, H-20, H-30,
H-50, H-4, H-5, H-6, H-200, H-600), 7.56 (2H, d, J = 8.0 Hz,
H-300, H-500), 9.69 (1H, s, OH), 9.88 (1H, s, OH). ESI–MS
(m/z): 409 [M?], 408 [M?-1], 410 [M??1]. CHNS
4-[3-(3-Hydroxy-phenyl)-5-styryl-4,5-dihydro-pyrazol-
1-yl]-benzenesulfonamide (2J)
This compound was obtained as brown crystals when
recrystallized from methanol in 29 % yield, m.p. 228–
229 °C, Rf = 0.67, (toluene:ethyl acetate:formic acid,
7.5:0 2:0.5). IR tmax (KBr): 3308 cm-1 and 3240 cm-1
(NH2), 1591 cm-1 (C=N), 1326 cm-1 and 1143 cm-1
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Med Chem Res (2013) 22:1378–1385
(SO2N\).1HNMR (400 MHz, DMSO, d): 3.14–3.20 [1H,
m, H-4 trans (pyrazoline)], 3.70 [1H, dd, J = 11.6 Hz,
J = 17.2 Hz, H-4 cis (pyrazoline)], 5.19-5.20 [1H, m, H-5
(pyrazoline)], 6.27 (1H, m, H-50), 6.63 (1H, d,
J = 15.6 Hz, b-H), 6.79 (1H, d, J = 7.6 Hz, H-40), 6.98
(2H, s, SO2NH2), 7.15–7.28 (7H, m, H-3, H-4, H-a, H-300,
H-500, H-20, H-60), 7.39 (2H, d, J = 6.8 Hz, H-2, H-6), 7.62
(2H, d, J = 6.8 Hz, H-200, H-600), 9.55 (1H, s, OH). ESI–
MS (m/z): 419 [M?], 420 [M??1], 421 [M??2]. CHNS
analysis: C: 65.87 (65.85), H: 5.03 (5.05), N: 10.05 (10.02),
S: 7.66 (7.64). Molecular formula: C23H21N3O3S.
Biological activities
All the experiments were carried out in albino rats of
Wistar strain (either sex) were procured from Central
Animal House of Jamia Hamdard, New Delhi (Registration
no. 173/CPCSEA). The experiments were performed in
accordance with the guidelines for the care and use of
laboratory animals, laid down by the Committee for the
Purpose of Control and Supervision of Experiments in
Animals (CPCSEA), Ministry of Social Justice and
Empowerment, Govt. of India, Jan. 2000. Animals descri-
bed as fasted were deprived of food for at least 16 h but
allowed free access to water. CMC (1 % w/v) in distilled
water was used as vehicle for dosing in all the experiments.
All treatments were given orally.
4-[5-Furan-2-yl-3-(3-hydroxy-phenyl)-4,5-dihydro-
pyrazol-1-yl]-benzenesulfonamide (2k)
This compound was obtained as reddish brown crystals when
recrystallized from methanol in 37 % yield, m.p.
259–260 °C, Rf = 0.60, (toluene:ethyl acetate:formic acid,
7.5:2:0.5). IR tmax (KBr): 3340 cm-1 and 3250 cm-1 (NH2),
1592 cm-1 (C=N), 1329 cm-1 and 1145 cm-1 (SO2N\).
1HNMR (400 MHz, DMSO, d): 3.13–3.14 [1H, m, H-4 trans
(pyrazoline)], 3.77 [1H, dd, J = 13.6 Hz, J = 18.8 Hz, H-4
cis (pyrazoline)], 5.72 [1H, dd, J = 4.4 Hz, J = 12 Hz, H-5
(pyrazoline)], 6.36 [1H, d, J = 2.8 Hz, (H-4 furan)], 6.45
[1H, d, J = 2.8 Hz, H-5 (furan)], 6.80 (1H, d, J = 7.6 Hz,
H-40), 7.01 (2H, s, SO2NH2), 7.16–7.25 (5H, m, H-20, H-50,
H-60, H-200, H-600), 7.53 (1H, s, H-2), 7.60 (2H, d,
J = 8.8 Hz, H-300, H-500), 9.58 (1H, s, OH). ESI–MS (m/z):
383[M?], 384 [M??1], 385 [M??2]. CHNS analysis: C:
59.54 (59.52), H: 4.43 (4.47), N: 10.97 (10.97), S: 8.35
(8.36). Molecular formula: C19H17N3O4S.
Anti-inflammatory activity
Carrageenan-induced hind paw edema method was used for
evaluating anti-inflammatory activity (Winter et al., 1962).
Fasted rats were divided into fourteen groups of 6 animals
each. One group of rats, which served as control was given
vehicle only (10 ml/kg), while animals of group II were
given celecoxib 0.05 mmol/kg suspended in the vehicle and
served as standard. Test compounds (2a–l) (0.05 mmol/kg)
suspended in vehicle (10 ml/kg) were administered to
respective groups. After 30 min, all animals were injected
with 0.1 ml of 1 % carrageenan solution (prepared in normal
saline) in the subplantar aponeurosis of left hind paw to
induce inflammation and the volume of injected paw was
measured by using plethysmometer immediately (at 0 h).
The paw volume was again measured after 3 and 5 h (Table
1). The average paw volume in a group of treated rats was
compared with vehicle (control group) and the percentage
inhibition of edema was calculated by using the formula
4-[5-Anthracen-9-yl-3-(3-hyroxy-pheyl)-4,5-dihydro-
pyrazol-1-yl]-benzenesulfonamide (2l)
Percent inhibition ¼ ð1 ꢁ Vt=VcÞ ꢂ 100
where Vt is the mean paw volume of the test drug treated
rats and Vc is the mean paw volume of the control.
This compound was obtained as yellow crystals when re-
crystallized from methanol in 27 % yield, m.p. 265–266 °C,
Rf = 0.77, (toluene:ethyl acetate:formic acid, 7.5:2:0.5). IR
t
max (KBr): 3382 cm-1 and 3277 cm-1 (NH2), 1588 cm-1
(C=N), 1314 cm-1 and 1145 cm-1 (SO2N\). 1HNMR
(300 MHz, DMSO, d): 3.07–3.14 [1H, m, H-4 trans (pyr-
azoline)], 3.46 [1H, dd, J = 13.8 Hz, J = 7.5 Hz, H-4 cis
(pyrazoline)], 4.19–4.27 [1H, m, H-5 (pyrazoline)],
6.76–6.94 (4H, m, H-200, H-600, SO2NH2), 7.25–7.41 (7H, m,
H-3/H-6, H-20, H-60, H-300, H-5 00, H- 40, H-50), 7.62 (1H, t,
H-7/H-2), 7.72 (1H, t, H-7/H-2), 7.93 (1H, d, J = 6.6 Hz,
H-5/H-4), 8.08 (1H, d, J = 5.4 Hz, H-5/H-4), 8.19 (1H, d,
J = 6.0 Hz, H-8/H-1), 8.66 (1H, s, H-10), 8.79 (1H, d,
J = 7.2 Hz, H-8/H-1), 9.63 (1H, s, OH). ESI–MS (m/z): 493
[M?], 492 [M?-1], 494 [M??1], 495 [M??2]. CHNS
analysis: C: 70.56 (70.57), H: 4.68 (4.70), N: 8.50 (18.51), S:
6.51 (6.50). Molecular formula: C29H23N3O3S.
Ulcerogenic activity
Acute gastric ulcerogenic effect of the compounds 2a, 2e,
and 2l were evaluated in Albino Wistar rats (Daidone et al.,
1994). Albino wistar rats (150–220 g) were fasted over
24 h and where randomly allotted into five groups of six
animals each. Group I served as control and was admin-
istered vehicle 10 ml/kg (CMC 1 % w/v in distilled water)
orally. Group II served as standard and was administered
orally celecoxib (0.15 mmol/kg i.e., three times the dose
given in anti-inflammatory activity) suspended in vehicle.
Group III, IV, and V were administered orally compounds
2a, 2e, and 2l (0.15 mmol/kg) suspended in vehicle,
123

Med Chem Res (2013) 22:1378–1385
1383
respectively. They were sacrificed under deep anesthesia
after 6 h of dosing. Their stomach were removed and
opened through greater curvature for examining lesions or
bleedings. Compounds 2a, 2e, and 2l showed no ulcers.
Table 1 Anti-inflammatory activity of tested compounds using car-
rageenan-induced hind paw edema in rats
Treatment Increase in paw volume ml SEM after carrageenan
(0.05 mol/kg) administration
3 h
5 h
Effect of synthesized compounds (2a–l) on oral glucose
tolerance in normal rats
Vehicle
0.416 0.04
0.450 0.04
Celecoxib
0.1 0.02*** (75.9)
0.26 0.01** (35.8)
0.33 0.01 (19.2)
0.08 0.02*** (82.2)
0.10 0.03*** (77.7)
0.21 0.02*** (51.8)
0.16 0.03*** (62.9)
0.15 0.02*** (66.0)
0.10 0.02*** (77.7)
0.13 0.04*** (70.3)
0.2 0.02*** (55.5)
0.15 0.01*** (66.7)
0.11 0.05*** (74.4)
0.18 0.02** (59.2)
0.31 0.01*** (29.6)
0.10 0.02*** (77.7)
2a
2b
2c
2d
2e
2f
Fasted albino rats (150–200 g) were classified into fourteen
groups of six animals each. Animals of group I received only
vehicle (10 ml/kg) to serve as control, while animals of group II
were given gliclazide 0.05 mmol/kg suspended in the vehicle
and served as standard. The test compounds (2a–l) in the dose
of 0.05 mmol/kg suspended in the vehicle were administered to
respective groups. All the animals were given glucose (3 g/kg,
p.o.) 30 min after dosing. Blood samples were collected from
retro-orbital plexus (under mild anesthesia) just before and
60 min after the glucose loading, and blood glucose levels were
measured with an auto analyzer AccuCheck Advantage II
glucose kit (Table 2).
0.15 0.03*** (64.7)
0.15 0.04*** (64.7)
0.15 0.21*** (64.7)
0.28 0.04*** (32.6)
0.26 0.02** (35.4)
0.18 0.02*** (55.9)
0.20 0.04*** (51.9)
0.25 0.02** (39.9)
0.26 0.02*** (35.8)
0.16 0.03*** (59.8)
2g
2h
2i
2j
2k
2l
Values are presented as mean SEM (n = 6); values in parentheses
represent percent inhibitions
***
Results and discussion
** P \ 0.01,
followed by Dunnett’s test)
P \ 0.001 compared to control (one-way ANOVA
Chemistry
The synthetic route used to synthesize title compounds
(2a–l) is outlined in Scheme 1. Chalcones required for the
synthesis of pyrazolines were synthesized through modified
reported method (Ansari et al., 2008) Structures of 2-pyr-
azolines (as given in scheme) were established on the basis
of spectral (IR, NMR, and Mass) and CHNS analyses data.
The IR spectra showed absorption bands in the region
1588–1593 cm-1 corresponding to C=N stretching bands
because of ring closure. Also, infrared spectra revealed
NH2 peak at 3403–3256 cm-1 and for SO2NH2 peak at
resemblance with celecoxib because of this reason celecoxib
was used as reference standard in this study. All the deriva-
tives exhibited varying degree of anti-inflammatory activity
(19.2–64.7 % at 3 h and 29.6–77.7 % at 5 h) (Table 1).
Among these compound 2e showed maximum activity
(64.7 % at 3 h and 77.7 % at 5 h).
With regard to SAR we observed that replacement of
benzenoid ring with heterocyclic ring (2k) causes
remarkable reduction in the activity at both time points (3
and 5 h). Introduction of Cl atom at ortho or para position
(C-2 or C-4) leads to decrease in the activity (2a vs 2b, 2a
vs 2f) at both time points. On the other hand introduction of
OCH3 or CH3 at C-4 leads to significant increase in the
activity at 3 h but reduce the activity at 5 h (2a vs 2c, 2a vs
2d). It is interesting to note that introduction of more than
one methoxyl group in the 5-phenyl ring of pyrazoline
causes enhancement in the activity at 5 h and slight
reduction in the activity at 3 h (2c vs 2h, 2h vs 2i).
Introduction of hydroxyl at C-4 causes an enhancement of
the activity at 3 h (2a vs 2e) but when the same group is
introduced at ortho position (C-2), it diminishes the activity
at 5 h (2a vs 2g).
1305–1331 cm-1 and 1154–1135 cm-1
.
In the 1HNMR spectra of 2-pyrazolines, the three
hydrogen atoms attached to the C-4 and C-5 carbon atoms
of the heterocyclic ring gave an ABX spin system. Mea-
sured chemical shift and coupling constant values (cf.
‘Experimental’ section) equivocally prove the 2-pyrazoline
structure. The protons of the SO2NH2 group were observed
at 6.76–7.02 ppm generally as a sharp peak. The hydroxyl
and aromatic protons were observed at expected ppms.
Elemental analysis (C, H, N, and S) data were within
0.4 % of the theoretical values.
Anti-inflammatory activity
Ulcerogenic activity
Anti-inflammatory activity of synthesized compounds was
evaluated by using carrageenan-induced rat hind paw edema
method. Synthesized compounds (2a–l) have structural
Ulcerogenic activity of the compounds 2a, 2e, and 2l was
recorded at dose of 0.15 mmol/kg and compared with
123

1384
Med Chem Res (2013) 22:1378–1385
Scheme 1 Synthesis is of
pyrazo lines bearing
O
O
benzenesulfonamide moiety. 1a,
2a; Ar = phenyl. 1b, 2b;
Ar = 4-chlorophenyl. 1c, 2c;
Ar = 4-methoxyphenyl. 1d, 2d;
Ar = 4-methylphenyl. 1e, 2e;
Ar = 4-hydroxyphenyl. 1f, 2f;
Ar = 2-chlorophenyl. 1g, 2g;
Ar = 2-hydroxyphenyl. 1h, 2h;
Ar = 3,4-dimethoxyphenyl. 1i,
2i; Ar = 3,4,5-
CH3
NaOH
Ar
ArCHO
+
OH
OH
Chalcones (1a-l)
HN NH HCl
2
trimethoxyphenyl. 1j, 2j;
Ar = ethylenephenyl. 1k, 2k;
Ar = furyl (C-2). 1l, 2l;
H
H
O
S O
HO
Ar = anthryl (C-9)
NH
2
N
Ar
N
Reflux in EtOH, 8 - 12 h
H
O S O
NH
2
Pyrazolines (2a-l)
Table 2 Effect of synthesized compounds on oral glucose tolerance
in normal rats
Blood glucose lowering activity
Treatment
(0.05 mol/Kg)
Blood glucose level (mg/dl)
All the synthesized compounds were evaluated for sugar
lowering activity in glucose fed hyperglycemic normal rats.
Only compound (2i) was found to exhibit significant blood
glucose lowering activity. It has been observed that as the
number of methoxyl groups are increased in the 5-phenyl
of pyrazoline, the activity enhances gradually (2a vs 2c, 2c
vs 2h, 2h vs 2i).
0 min
60 min
Control
74.0 3.92
63.67 2.51
78.3 0.05
74.6 1.14
70 1.28
126.50 3.80
85.83 2.72
126.3 2.44
134.0 2.17
116.5 1.31
138.6 2.37
121 1.23
121 1.12
133 3.89
111 1.17
94.6 0.80*
131 1.71
133 1.86
136.6 0.87
Gliclazide
2a
2b
2c
2d
2e
2f
75.3 2.10
78.0 0.88
75 1.78
Conclusion
The present study describes the synthesis of novel 2-pyr-
azolines bearing benzenesulfonamide moiety (2a–l). These
synthesized compounds were evaluated for anti-inflam-
matory action in carrageenan-induced rat paw edema
model and blood glucose lowering action in glucose fed
hyperglycemic normal rats. Compounds 2a, 2e, and 2l
showed significant anti-inflammatory action at 5 h (more
than 75 %) and proved to have superior gastrointestinal
safety profiles as compared to standard drug celecoxib. The
compound (2i) showed significant blood glucose lowering
effect when compared to the standard drug gliclazide.
2g
2h
2i
77.3 1.01
76.6 1.47
76.0 1.58
75 1.52
2j
2k
2l
74.3 1.00
76.3 1.12
Values are presented as mean SEM (n = 6)
* P \ 0.001 compared to control (one-way ANOVA followed by
Dunnett’s test)
reference drug celecoxib (0.15 mmol/kg). All three active
compounds were generally found safe from the point of
view of ulcer induction.
Acknowledgments One of the authors, Syed Ovais is thankful to
HNF for awarding a fellowship.
123

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1385
Kujubu DA, Fletcher BS, Varnum BC, Lim RW, Herschman HR
(1991) TIS10, a phorbol ester tumor promoter inducible mRNA
from Swiss 3T3 cells, encodes a novel prostaglandin synthase/
cyclooxygenase homologue. J Biol Chem 266:12866–12872
Kumar S, Sharma K, Bajaj D, Bansal S, Sharma K, Archana K,
Saxena S, Lata B, Gupta VK, Srivastava (2003) Synthesis and
anti-inflammatory, analgesic, ulcerogenic and cyclooxygenase
activities of novel quinazolinyl-D2-pyrazolines. Indian J Chem,
Sect B: Org Chem Incl Med Chem 42(8):1979–1984
References
Abramson SB, Greenberg JD (2008) Are NSAIDs and selective
cyclo-oxygenase 2 inhibitors associated with increased risk of
myocardial infarction? Nat Clin Pract Rheumatol 4(4):182–183
Ahn JH, Kim HM, Jung SH, Kang SK, Kim KR, Rhee SD, Yang SD,
Cheon HG, Kim SS (2004) Synthesis and DP-IV inhibition of
cyano-pyrazoline derivatives as potent anti-diabetic agents.
Bioorg Med Chem Lett 14(17):4461–4465
Amir M, Kumar S (2005) Synthesis and anti-inflammatory, analgesic,
ulcerogenic and lipid peroxidation activities of 3,5-dimethyl
pyrazoles, 3-methyl pyrazol-5-ones and 3,5-disubstituted pyraz-
olines. Indian J Chem, Sect B: Org Chem Incl Med Chem
44B(12):2532–2537
Ansari LF, Iftikhar F, Ihsan-ul-Haq, Mirza B, Baseer M, Rashid U
(2008) Solid-phase synthesis and biological evaluation of a
parallel library of 2,3-dihydro-1,5-benzothiazepines. Bioorg Med
Chem 16:7691–7697 (and references cited there in)
Bashir R, Ovais S, Yaseen S, Hamid H, Alam MS, Samim M, Singh
S, Javed K (2011) Synthesis of some new 1,3,5-trisubstituted
pyrazolines bearing benzenesulfonamide as anticancer and anti-
inflammatory agents. Bioorg Med Chem Lett 21:4301–4305
Daidone G, Maggio B, Raffa D, Plescia S, Bajardi ML, Caruso A,
Cutuli VMC, Amico-Roxas M (1994) Synthesis and pharmaco-
logical study of ethyl 1-methyl-5-[2-substituted-4-oxo-3(4H)-
quinazolinyl]-1H-pyrazole-4-acetates. Eur
29(9):707
Dannhardt G, Kiefer W (2001) Cyclooxygenase inhibitors—current
status and future prospects. Eur J Med Chem 36(2):109–126
Flower RJ (2003) The development of COX2 inhibitors. Nat Rev
Drug Discov 2(3):179–191
Gursoy S, Demirayak G, Capan K, Erol K, Vural (2000) Synthesis
and preliminary evaluation of new 5-pyrazolinone derivatives as
analgesic agents. Eur J Med Chem 35(3):359–364
Inman WH (1977) Study of fatal bone marrow depression with special
reference to phenylbutazone and oxyphenbutazone. Br Med J
1(6075):1500–1505
Leonard JC (1953) Toxic effects of phenylbutazone with special
reference to disorders of the blood. Br Med J 13(4823):1311–
1313
Pospisilik JA, Stafford SG, Demuth HU, Brownsey R, Parkhouse W,
Finegood DT, McIntosh CH, Pederson RA (2002) Long-term
treatment with the dipeptidyl peptidase IV inhibitor P32/98
causes sustained improvements in glucose tolerance, insulin
sensitivity, hyperinsulinemia, and beta-cell glucose responsive-
ness in VDF (fa/fa) Zucker rats. Diabetes 51(4):943–950
Rathish IG, Javed K, Ahmad S, Bano S, Alam MS, Pillai KK, Singh
S, Bagchi V (2009) Synthesis and antiinflammatory activity of
some new 1,3,5-trisubstituted pyrazolines bearing benzenesul-
fonamide. Bioorg Med Chem Lett 19:255–258
Reynold JEFF (ed) (1993) The extra pharmacopia, 30th edn.
Pharmaceutical Press, Martindale, p 1
Sudre B, Broqua P, White RB, Ashworth D, Evans DM, Haigh R, Junien
JL, Aubert ML (2002) Chronic inhibition of circulating dipeptidyl
peptidase IV by FE 999011 delays the occurrence of diabetes in
male zucker diabetic fatty rats. Diabetes 51(5):1461–1469
Vane JR, Botting RM (1998) Anti-inflammatory drugs and their
mechanism of action. Inflamm Res 47:78–87
Winter CA, Risley EA, Nuss GW (1962) Carrageenin-induced edema
in hind paw of the rat as an assay for antiinflammatory drugs.
Proc Soc Exp Biol Med 111:544–547
Xie WL, Chipman JG, Robertson DL, Erikson RL, Simmons DL
(1991) Expression of a mitogen-responsive gene encoding
prostaglandin synthase is regulated by mRNA splicing. Proc
Natl Acad Sci USA 88(7):2692–2696
J
Med Chem
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