Synthesis and antiinflammatory activity of some new 1,3,5-trisubstituted pyrazolines bearing benzene sulfonamide

Article abstract of DOI:10.1016/j.bmcl.2008.10.105

Nineteen new 2-pyrazoline bearing benzenesulfonamide derivatives were synthesized by condensing chalcones with 4-hydrazinonbenzenesulfonamide hydrochloride. Their chemical structures were proved by means of IR, ¹H NMR, ¹³C NMR, mass spectroscopic and elemental analyses data. These compounds were tested at dose of 20 mg/kg for their anti-inflammatory activity in carrageenan-induced rat paw edema model and volume of paw edema was measured at 0, 3 and 5 h. Two compounds 3k and 3l were found to be more active than celecoxib throughout the study (at 3 and 5 h). While two other compounds 3m and 3n showed more potent activity than celecoxib at 5 h. They are devoid of ulcerogenic potential when administered orally at a dose of 60 mg/kg. Compounds (3k-m) showed COX-1 and COX-2 inhibitory activity at 0.05 μM.

Full text of DOI:10.1016/j.bmcl.2008.10.105

Bioorganic & Medicinal Chemistry Letters 19 (2009) 255–258
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and antiinflammatory activity of some new 1,3,5-trisubstituted
pyrazolines bearing benzene sulfonamide
a
a
a
b
I. G. Rathish a, Kalim Javed a, , Shamim Ahmad , Sameena Bano , M. S. Alam , K. K. Pillai ,
*
Surender Singh c, Vivek Bagchi d
a Department of Chemistry, Faculty of Science, Jamia Hamdard (Hamdard University), New Delhi 110 062, India
b Department of Pharmacology, Faculty of Pharmacy, Jamia Hamdard (Hamdard University), New Delhi 110 062, India
c Department of Pharmacology, All India Institute of Medical Sciences, New Delhi 110 029, India
d Department of Chemistry, Indian Institute of Technology, New Delhi 110 016, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Nineteen new 2-pyrazoline bearing benzenesulfonamide derivatives were synthesized by condensing
chalcones with 4-hydrazinonbenzenesulfonamide hydrochloride. Their chemical structures were proved
by means of IR, 1H NMR, 13C NMR, mass spectroscopic and elemental analyses data. These compounds
were tested at dose of 20 mg/kg for their anti-inflammatory activity in carrageenan-induced rat paw
edema model and volume of paw edema was measured at 0, 3 and 5 h. Two compounds 3k and 3l were
found to be more active than celecoxib throughout the study (at 3 and 5 h). While two other compounds
3m and 3n showed more potent activity than celecoxib at 5 h. They are devoid of ulcerogenic potential
when administered orally at a dose of 60 mg/kg. Compounds (3k–m) showed COX-1 and COX-2 inhibi-
Received 27 February 2008
Revised 11 October 2008
Accepted 20 October 2008
Available online 30 October 2008
Keywords:
2-Pyrazolines
Celecoxib
Anti-inflammatory activity
COX-1
tory activity at 0.05 lM.
Ó 2008 Elsevier Ltd. All rights reserved.
COX-2
Cyclooxygenases (COXs) are key enzymes in the synthesis of
prostaglandin H2 which is a precursor for the biosynthesis of
prostaglandins, thromboxanes, and prostacyclins.1 COX enzymes
exist in two isoforms: cyclooxygenase-1 (COX-1) and cyclooxy-
genase-2 (COX-2).2 The COX-1 enzyme is constitutively ex-
pressed and is critical for protection of gastric mucosa, platelet
aggregation, and renal blood flow whereas the COX-2 enzyme
is inducible and expressed during inflammation, pain, and onco-
genesis.3 Since COX-2 is involved in inflammation and pain, mol-
ecules that inhibit it’s enzymatic activity would be of
therapeutic value. Many non-steroidal anti-inflammatory drugs
(NSAIDs) were found to interact with these enzymes and inhibit
their enzymatic activity.4 These molecules include aspirin and
indomethacin which are non-selective and inhibit both COX-1
and COX-2. Aspirin inhibits COX-1 more strongly than COX-24
and inhibition of COX-1 by aspirin reduces the production of
PGE2 and PGI2 which has an adverse ulcerogenic effect.5 For this
reason, in recent years, selective COX-2 inhibitors, that achieve
the same anti-inflammatory efficacy as traditional NSAIDs but
minimize the risk of unwanted side effects, have been devel-
oped. However, clinical studies have suggested that selective
COX-2 inhibitors could cause typical COX-mediated side effects
such as gastrointestinal injury, increased systemic blood pres-
sure, and hypersensitivity.6 Furthermore, concerns have been
raised about the cardiovascular safety of selective COX-2 inhib-
itors and some of them, like VioxxÒ or BextraÒ, have been with-
drawn from the market.
In our quest for synthesis of novel NSAID with similar or greater
efficacy than other NSAIDs and with little or no gastric side effects,
we synthesized a series of 2-pyrazoline-bearing benzene sulfon-
amide moiety and evaluated their ability to inhibit carrageenan-
induced paw edema in rats and COX-1 and COX-2 enzyme
in vitro using recombinant enzymes.
The synthetic route used to synthesize title compounds is
outlined in Scheme 1. The aromatic ketones (1a, 1b, 1c, and
1d) required for the synthesis of chalcones were obtained
through reported methods7,8 or purchased from Loba chemie
Pvt. Ltd. The intermediate chalcones (2a–s) were prepared by
base catalyzed Claisen–Schmidt condensation of the aromatic
ketones with different aromatic aldehydes.8,9 Finally 3,5-diaryl-
2-pyrazolines bearing benzene sulfonamide moiety (3a–s) were
obtained by the condensation of appropriate chalcones and
4-hydrazinobenzenesulfonamide hydrochloride in ethanol. The
chemical structures of these compounds were determined on
the basis of spectral data analysis; such as IR, 1H NMR, 13C
NMR, and Mass spectral data.10
* Corresponding author. Tel.: +91 11 26059688.
E-mail addresses: kjavedchem@yahoo.co.in, kjaved@jamiahamdard.ac.in
(K. Javed).
0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.10.105

256
I. G. Rathish et al. / Bioorg. Med. Chem. Lett. 19 (2009) 255–258
Table 2
R
CH
R3
3
R3
In vitro COX-1 and COX-2 enzyme inhibition assay data for test compounds 3k–n.
i or ii
R
+
O
OHC
Test compounds
% Inhibition (0.05 lm)
1a-d
O
2a-s
iii
COX-1
COX-2
3k
3l
3m
3n
30.04
60.90
73.25
58.84
38.57
50.00
85.71
42.85
H
R
H
R3
N
N
tent than celecoxcib throughout the study. The other two pyrazo-
lines (3m and 3n) showed more potent anti-inflammatory
activity than celecoxcib at 5th hour.
SO NH
2
2
Pyrazoline derivatives (3k–n) showing anti-inflammatory
activity greater than celecoxib were evaluated for acute gastric
ulcerogenic effect in Wistar rats. Six hours after the treatment
at a dose of 60 mg/kg bw (three times of the dose) they were
sacrificed under deep ether anesthesia and their stomachs were
removed and opened through great curvature for examining
lesions or bleedings. These compounds did not cause any gastric
ulceration.
Compounds (3k–n) were tested for their ability to inhibit
COX-1 and COX-2. Cyclooxygenase activity of ovine COX-1 and
COX-2 was assayed using COX inhibitory screening assay kit
(Cayman chemicals) by method of Gierse et al.12 All assays were
3a-s
CH
3
2
1
R
R
Where R =
,
O
O
OH
1a, 2a-g, 3a-g; R1 = OH, R2 = OCH3
1b, 2h-o, 3h-o; R1 = R2 = OCH3
1c, 2p, 2q, 3p, 3q; R1 = OH, R2 = H
1d, 2r, 2s, 3r, 3s
Scheme 1. Reagent and conditions: (i) 30% aq NaOH, EtOH, 0–5 °C, 12 h; (ii)
piperidine, EtOH, reflux 2–3 h; (iii) 4-hydrazinobenzenesulfonamide hydrochloride,
EtOH, reflux 12–18 h.
conducted in duplicate at a concentration of 0.05 lM of test
compounds (3k–n). All four compounds inhibit both the COX-1
and COX-2 (Table 2).
In summary four derivatives (3k–n) out of novel nineteen syn-
thesized compounds exert potent anti-inflammatory activity that
is mainly related to the inhibition of COX-1 and COX-2. They
(3k–n) did not cause any gastric ulceration and these may possibly
be used as lead compounds for developing new anti-inflammatory
agents.
Crystallographic data for compound 3k has been deposited with
Cambridge Crystallographic Data Centre as supplementary publi-
cation number CCDC 703851. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
http://www.ccdc.cam.ac.uk/data_request/cif.
Anti-inflammatory activity was evaluated using the well-
known carrageenan-induced rat paw edema.11 Overnight fasted
Wistar rats (16 h) of either sex weighing 150–175 g were divided
into groups of six animals each. Test compounds (20 mg/kg bw)
and celecoxib (20 mg/kg) were administered orally. 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 and the volume of paw was measured by using plethys-
mometer at 0, 3, and 5 h post-carrageenan treatment. All pyrazo-
line derivatives except 3b, 3c, and 3f showed significant activity
(Table 1). Two pyrazolines (3k and 3l) were found to be more po-
Table 1
Results of anti-inflammatory effect of 2-pyrazoline derivatives against carrageenan induced rat paw edema model in rats.
Test compounds
Treatment
Increase in paw volume ml SEM after carrageenan administration
5 h
3 h
Control
Celecoxib
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
0.75 0.0026
0.75 0.0045
0.15 0.0031 (79.5%)
0.55 0.0023 (27%)
0.68 0.0036 (9%)
0.75 0.0022 (0%)
0.30 0.0033 (60%)
0.5 0.0023 (33.3%)
0.75 0.0021 (0%)
0.53 0.0040 (28.6%)
0.57 0.0021 (26.3%)
0.56 0.0021 (25%)
0.38 0.0021 (49.3%)
0.13 0.0031 (83.3%)
0.15 0.0040 (79.6%)
0.23 0.0021 (70%)
0.23 0.0026 (68.8%)
0.55 0.0042 (26.6%)
0.38 0.0038 (50.0%)
0.36 0.0021 (52.0%)
0.60 0.0026 (20.0%)
0.60 0.0026 (20.0%)
0.45 0.0031 (40%)
0.47 0.0023 (37.3%)
0.65 0.0040 (13%)
0.75 0.0021 (0%)
0.48 0.0036 (35.3%)
0.69 0.0031 (8.3%)
0.75 0.0031 (0%)
0.40 0.0021 (46.3%)
0.40 0.0034 (46.3%)
0.7 0.0040 (6.6%)
0.67 0.0026 (10.6%)
0.18 0.0026 (76.6%)
0.15 0.0021 (79.6%)
0.25 0.0022 (66.5%)
0.32 0.0021 (57.6%)
0.71 0.0033 (5.3%)
0.44 0.0031 (41.3%)
0.67 0.0022 (10.6%)
0.67 0.0033 (10.6%)
0.52 0.0033 (30.6%)
R
R
R
R
R
1 = OH, R2 = OCH3, R3 = 4-OCH3
1 = OH, R2 = OCH3, R3 = 3,4-(OCH3)2
1 = OH, R2 = OCH3, R3 = H
1 = OH, R2 = OCH3, R3 = 2-Cl
1 = OH, R2 = OCH3, R3 = 3-OH
R1 = OH, R2 = OCH3, R3 = 3,4,5-(OCH3)2
R
R
R
R
R
R
1 = OH, R2 = OCH3, R3 = 4-Cl
1 = R2 = OCH3, R3 = 2-Cl
1 = R2 = OCH3, R3 = 4-Cl
1 = R2 = OCH3, R3 = 4-OCH3
1 = R2 = OCH3, R3 = 3,4,5-(OCH3)2
1 = R2 = OCH3, R3 = 4-N,N(CH3)2
R1 = R2 = OCH3, R3 = H
R
R
R
R
R
R
1 = R2 = OCH3, R3 = 3-NO2
1 = R2 = OCH3, R3 = 3-OH
1 = OH, R2 = H, R3 = 4-OCH3
1 = OH, R2 = H, R3 = 3,4-(OCH3)2
3 = 4-OCH3
3q
3r
3s
3 = 3-OH

I. G. Rathish et al. / Bioorg. Med. Chem. Lett. 19 (2009) 255–258
257
J = 8.7 Hz, Ar-H), 10.68 (1H, s, phenolic OH); 13C NMR (75 MHz, CDCl3,d, ppm):
43.75 (CH2 of pyrazoline), 54.94 (O-CH3), 55.66 (2 x O-CH3), 60.20 (O-CH3),
62.08 (CH of pyrazoline), 136.3 (Ar C-O-C), 151.6 (C=N of pyrazoline), 153.45 (2
x Ar C-O-C), 158.48 (Ar C-OH), 161.75 (Ar C-O-C); FAB-MS (m/z): 513 [M+], 514
Acknowledgment
Thanks are due to SAIF, CDRI, Lucknow, for providing Mass
spectra.
[M+1]. 3 g) m.p. 216 °C; yield 15%; IR (t
max, cmÀ1, KBr): 3392 (OH), 3321 &
3286 (NH2), 1595 (C=N), 1335 & 1156 (SO2N<); 1H NMR (300 MHz, DMSO-d6, d,
ppm): 3.78 (3H, s, OCH3), 4.05 [1H, m, H-4 cis (pyrazoline)], 5.59 [1H, m, H-5
(pyrazoline)], 6.56 (2H, s, SO2NH2), 6.96–7.62 (11 H, m, Ar-H); 13C NMR
(75 MHz, DMSO-d6, d, ppm): 44.05 (CH2 of pyrazoline), 55.40 (O-CH3), 60.41
(CH of pyrazoline), 152.0 (C=N of pyrazoline), 158.04 (Ar C-OH), 161.79 (Ar C-
O-C); FAB-MS (m/z): 457 [M+], 459 [M+2], 409, 391. 3 h) m.p. 216 °C; yield
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2008.10.105.
42%; IR (t
max, cmÀ1, KBr): 3379 & 3254 (NH2), 1599 (C=N), 1338 & 1147
(SO2N<); 1H NMR (300 MHz, DMSO-d6, d, ppm): 3.15 [1H, dd, J = 5.3, 18.4 Hz,
H-4 trans (pyrazoline)], 3.78 (3H, s, OCH3), 3.79 (3H, s, OCH3), 4.05 [1H, dd,
J = 12.1, 18.3 Hz, H-4 cis (pyrazoline)], 5.63 [1H, dd, J = 5.2, 12.0 Hz, H-5
(pyrazoline)], 6.53 (2H, m, Ar-H), 6.89 (4H, m, SO2NH2 and Ar-H), 7.01 (1H, d,
J = 6.65 Hz, Ar-H), 7.21 (2H, m, Ar-H), 7.45 (1H, d, J = 7.51 Hz, Ar-H) 7.59 (2H, d,
J = 8.7 Hz, Ar-H), 7.87 (1H, d, J = 8.6 Hz, Ar-H); 13C NMR (75 MHz, DMSO-d6, d,
ppm): 44.89 (CH2 of pyrazoline), 55.43 (O-CH3), 55.74 (O-CH3), 59.58 (CH of
pyrazoline), 149.06 (C=N of pyrazoline), 158.87 (Ar C-O-C), 161.89 (Ar C-O-C);
FAB-MS (m/z): 471 [M+], 473 [M+2], 460, 455, 443, 428. 3i) m.p. 110 °C, yield
References and notes
1. Hamberg, M.; Samuelsson, B. Proc. Natl. Acad. Sci. U.S.A. 1973, 70, 899.
2. Fu, J. Y.; Masferrer, J. L.; Seibert, K.; Raz, A.; Needleman, P. J. Biol. Chem. 1990,
265, 16737.
3. Smith, W. L.; DeWitt, D. L. Adv. Immunol. 1996, 62, 167; Herschman, H. R.
Biochim. Biophys. Acta 1996, 1299, 125.
4. Meade, E. A.; Smith, W. L.; DeWitt, D. L. J. Biol. Chem. 1993, 268, 6610.
5. Allison, M. C.; Howatson, A. G.; Torrance, C. J.; Lee, F. D.; Russell, R. I. G. N. Engl. J.
Med. 1992, 327, 749.
6. De Gaetano, G.; Donati, M. B.; Cerletti, C. Trends Pharmacol. Sci. 2003, 24, 245.
7. Ahluwalia, V. K.; Bhagat, P.; Aggarwal, R.; Chandra, R. Intermediates in Organic
Synthesis; I.K. International Pvt. Ltd.: New Delhi, Bangalore, Mumbai, 2005. pp.
116–117.
26%; IR (t
max, cmÀ1, KBr): 3381 & 3262 (NH2), 1592 (C=N), 1332 & 1156
(SO2N<); 1H NMR (300 MHz, CDCl3, d, ppm): 3.29 [1H, dd, J = 5.8, 18.2 Hz, H-4
trans (pyrazoline)], 3.79 (3H, s, OCH3), 3.85 (3H, s, OCH3), 4.00 [1H, dd, J = 12.1,
18.2 Hz, H-4 cis (pyrazoline)], 4.61 (2H, s, SO2NH2), 5.22 [1H, dd, J = 5.8,
12.0 Hz, H-5 (pyrazoline)], 6.46 (1H, d, J = 2.0 Hz, Ar-H), 6.57 (1H, dd, J = 2.0 Hz,
8.7 Hz, Ar-H), 7.0 (2H, d, J = 8.8 Hz, Ar-H), 7.19 (2H, d, J = 8.3 Hz, Ar-H), 7.31
(2H, d, J = 8.3 Hz, Ar-H), 7.68 (2H, d, J = 8.8 Hz, Ar-H), 7.95 (1H, d, J = 8.6 Hz, Ar-
H); 13C NMR (75 MHz, CDCl3, d, ppm): 46.75 (CH2 of pyrazoline), 55.42 (2 x O-
CH3), 62.68 (CH of pyrazoline), 149.50 (C=N of pyrazoline), 159.02 (Ar C-O-C),
162.19 (Ar C-O-C); FAB-MS (m/z): 471 [M+], 475 [M+4], 473 [M+2], 470 [M-1],
8. Khan, M. S. Y.; Sharma, P. Indian J. Chem. 1993, 32B, 374.
9. Andotra, C. S.; Khajuria, J.; Singh, G. B.; Singh, S. J. Indian Chem. Soc. 1993, 70,
266.
10. Spectral data: Compound 3a: Mp 220 °C; 35% yield; IR (t
max, cmÀ1, KBr): 3351
457 and 441. 3j) m.p. 122 °C; yield 20%; IR (t
max, cmÀ1, KBr): 3367 & 3272
and 3265 (NH2), 1596 (C@N), 1339 and 1156 (SO2N<); 1H NMR (300 MHz,
CDCl3, d, ppm): 3.27 [1H, dd, J = 5.9, 17.3 Hz, H-4 trans (pyrazoline)], 3.78 (3H,
s, OCH3), 3.84 (3H, s, OCH3), 3.94 [1H, dd, J = 12.0, 17.2 Hz, H-4 cis (pyrazoline)],
4.60 (2H, s, SO2NH2), 5.25 [1H, dd, J = 5.8, 11.9 Hz, H-5 (pyrazoline)], 6.49 (1H,
dd, J = 1.8, 8.6 Hz, Ar-H), 6.60 (1H, d, J = 1.8 Hz, Ar-H), 6.88 (2H, d, J = 8.5 Hz, Ar-
H), 6.95 (2H, d, J = 8.7 Hz, Ar-H), 7.06 (1H, d, J = 1.8 Hz, 8.7 Hz, Ar-H), 7.18 (2H,
d, J = 8.5 Hz, Ar-H), d 7.71 (2H, d, J = 8.7 Hz, Ar-H), 10.65 (1H, s, phenolic OH);
13C NMR (75 MHz, CDCl3, d, ppm): 43.83 (CH2 of pyrazoline), 54.98 (O-CH3),
55.11 (O-CH3), 61.21 (CH of pyrazoline), 151.60 (C@N of pyrazoline), 158.66
(Ar C-OH), 159.0 (Ar CAOAC), 161.90 (Ar CAOAC); FAB-MS (m/z): 453 [M+],
(NH2), 1596 (C=N), 1336 & 1156 (SO2N<); 1H NMR (300 MHz, CDCl3,d, ppm):
3.31 [1H, dd, J = 5.8, 18.1 Hz, H-4 trans (pyrazoline)], 3.77 (3H, s, OCH3), 3.79
(3H, s, OCH3), 3.85 (3H, s, OCH3), 3.97 [1H, dd, J = 12.0, 18.2 Hz, H-4 cis
(pyrazoline)], 4.61 (2H, s, SO2NH2), 5.20 [1H, dd, J = 5.8, 11.9 Hz, H-5
(pyrazoline)], 6.45 (1H, s, Ar-H), 6.56 (1H, d, J = 7.8 Hz, Ar-H), 6.85 (2H, d,
J = 8.6 Hz, Ar-H), 7.04 (2H, d, J = 8.4 Hz, Ar-H), 7.17 (2H, d, J = 8.1 Hz, Ar-H), 7.65
(2H, d, J = 8.4 Hz, Ar-H), 7.95 (1H, d, J = 8.3 Hz, Ar-H); 13C NMR (75 MHz, CDCl3,
d): 46.94 (CH2 of pyrazoline), 55.40 (3 x O-CH3), 62.85 (CH of pyrazoline),
149.60 (C=N of pyrazoline), 159.04 (Ar C-O-C), 162.07 (Ar C-O-C), FAB-MS (m/
z): 467[M+], 469 [M+2], 451, 436, 387, 360. 3k) m.p. 160 °C; yield 47%; IR
454 [M+1]. Compound 3b: Mp 210 °C; yield 30%; IR (t
max, cmÀ1, KBr): 3319 and
(t
max, cmÀ1, KBr): 3299 & 3086 (NH2), 1592 (C=N), 1321 & 1143 (SO2N<); 1H
3253 (NH2), 1599 (C@N), 1338 and 1155 (SO2N<); 1H NMR (300 MHz, CDCl3, d,
ppm): 3.28 [1H, dd, J = 6.4, 17.4 Hz, H-4 trans (pyrazoline)], 3.83 (3H, s, OCH3),
3.84 (3H, s, OCH3), 3.86 (3H, s, OCH3), 3.97 [1H, dd, J = 12.0, 17.3 Hz, H-4 cis
(pyrazoline)], 5.22 [1H, dd, J = 6.5, 11.9 Hz, H-5 (pyrazoline)], 5.72 (2H, s,
SO2NH2), 6.50 (1H, dd, J = 1.8 Hz, 8.5 Hz, Ar-H), 6.61 (1H, d, J = 1.8 Hz, Ar-H),
6.75 (1H, s, Ar-H), 6.84 (2H, s, Ar-H), 6.95 (2H, d, J = 8.7 Hz, Ar-H), 7.08 (1H, d,
J = 8.6 Hz, Ar-H), 7.72 (2H, d, J = 8.7 Hz, Ar-H), 10.69 (1H, s, phenolic OH); 13C
NMR (75 MHz, CDCl3, d, ppm): 43.30 (CH2 of pyrazoline), 54.52 (OACH3), 55.03
(O-CH3), 61.05 (CH of pyrazoline), 147.77 (Ar C-O-C), 148.76 (Ar C-O-C), 151.16
(C=N of pyrazoline), 158.0 (Ar C-OH), 161.23 (Ar C-O-C); FAB-MS (m/z): 483
NMR (300 MHz, DMSO-d6, d, ppm): 3.17 [1H, m, H-4 trans (pyrazoline)], 3.79
(3H, s, OCH3), 3.81 (3H, s, OCH3), 3.98 [1H, m, H-4 cis (pyrazoline)], 5.40 [1H, m,
H-5 (pyrazoline)], 6.62 (2H, s, SO2NH2), 7.00-7.34 (9H, m, Ar-H), 7.55 (2H, d,
J = 8.3 Hz, Ar-H), 7.85 (1H, d, J = 8.2 Hz, Ar-H); 13C NMR (75 MHz, DMSO-d6, d,
ppm): 46.40 (CH2 of pyrazoline), 55.45 (O-CH3), 55.72 (O-CH3), 62.08 (CH of
pyrazoline), 148.92 (C=N of pyrazoline), 158.89 (Ar C-O-C), 161.84 (Ar C-O-C);
FAB-MS (m/z): 437[M+], 439 [M+2]. 3l) m.p. 220 °C; yield 48%; IR ( max, cmÀ1
t ,
KBr): 3329 & 3235 (NH2), 1594 (C=N), 1338 & 1157 (SO2N<); 1H NMR (300
MHz, CDCl3, d, ppm): 3.31 [1H, dd, J = 6.5, 18.2 Hz, H-4 trans (pyrazoline)],
3.81-3.82 (12H, s, 4xOCH3), 3.86 (3H, s, OCH3), 4.00 [1H, dd, J = 11.9, 18.0 Hz, H-
4 cis (pyrazoline)], 5.14 [1H, dd, J = 6.6, 11.8 Hz, H-5 (pyrazoline)], 6.11 (2H, s,
SO2NH2), 6.48 (3H, s, Ar-H), 6.57 (1H, d, J = 8.6 Hz, Ar-H), 7.04 (2H, d, J = 8.3 Hz,
Ar-H), 7.69 (2H, d, J = 8.3 Hz, Ar-H), 7.94 (1H, d, J = 8.6 Hz, Ar-H); 13C NMR
(75 MHz, CDCl3, d, ppm): 46.48 (CH2 of pyrazoline), 55.01 (2 x O-CH3), 55.69 (2
x O-CH3), 60.24 (O-CH3), 63.47 (CH of pyrazoline), 137.40 (Ar C-O-C), 148.95
(C=N of pyrazoline), 153.34 (2 x Ar C-O-C), 158.58 (Ar C-O-C), 161.75 (Ar C-O-
C); FAB-MS (m/z): 527[M+], 529 [M+2], 512, 495, 463, 447. 3m) m.p. 204 °C;
[M+], 484 [M+1]. 3c) m.p. 238 °C; yield 28%; IR ( max, cmÀ1, KBr): 3392 & 3282
t
(NH2), 1595 (C=N), 1333 & 1153 (SO2N<); 1H NMR (300 MHz, CDCl3, d, ppm):
3.30 [1H, dd, J = 5.9, 17.4 Hz, H-4 trans (pyrazoline)], 3.84 (3H, s, OCH3), 4.05
[1H, dd, J = 12.0, 17.4 Hz, H-4 cis (pyrazoline)], 5.33 [1H, dd, J = 5.9, 12.0 Hz, H-5
(pyrazoline)], 6.37 (2H, s, SO2NH2), 6.49 (1H, dd, J = 1.8 Hz, 8.5 Hz, Ar-H), 6.58
(1H, d, J = J = 1.8 Hz, Ar-H), 6.92 (2H, d, J = 8.6 Hz, Ar-H), 7.10 (1H, d, J = 8.6 Hz,
Ar-H), 7.27-7.36 (5H, m, Ar-H), 7.71 (2H, d, J = 8.6 Hz, Ar-H), 10.66 (1H, s,
phenolic OH); 13C NMR (75 MHz, CDCl3, d, ppm): 44.01 (CH2 of pyrazoline),
55.16(O-CH3), 61.06 (CH of pyrazoline), 151.85 (C=N of pyrazoline), 158.08 (Ar
C-OH), 161.64 (Ar C-O-C); FAB-MS (m/z): 423 [M+], 424 [M+1]. 3d) m.p.
yield 37%; IR (t
max, cmÀ1, KBr): 3342 & 3282 (NH2), 1593 (C=N), 1534 & 1350
(NO2), 1321 & 1158 (SO2N<); 1H NMR (300 MHz, CDCl3, d, ppm): 3.32 [1H, dd,
J = 5.7, 18.3 Hz, H-4 trans (pyrazoline)], 3.81 (3H, s, OCH3), 3.86 (3H, s, OCH3),
4.09 [1H, dd, J = 12.4, 18.2 Hz, H-4 cis (pyrazoline)], 5.39 [1H, dd, J = 5.7,
12.2 Hz, H-5 (pyrazoline)], 5.89 (2H, s, SO2NH2), 6.46 (1H, s, Ar-H), 6.58 (1H, d,
J = 8.5 Hz, Ar-H), 7.00 (2H, d, J = 8.5 Hz, Ar-H), 7.56 (2H, m, Ar-H), 7.69 (2H, d,
J = 8.5 Hz, Ar-H), 7.97 (1H, d, J = 8.6 Hz, Ar-H), 8.14 (2H, m, Ar-H); 13C NMR
(75 MHz, CDCl3, d, ppm): 45.80 (CH2 of pyrazoline), 55.46 (2 x O-CH3), 61.64
(CH of pyrazoline), 147.91 (Ar C-NO2), 148.24 (C=N of pyrazoline), 158.2 (Ar C-
O-C), 162.42 (Ar C-O-C); FAB-MS (m/z): 482 [M+], 484 [M+2], 460. 3n) m.p.
220 °C; yield 25%; IR (t
max, cmÀ1, KBr): 3386 & 3284 (NH2), 1597 (C=N), 1332
& 1149 (SO2N<); 1H NMR (300 MHz, DMSO-d6, d, ppm): 3.22 [1H, dd, J = 5.2,
17.0 Hz, H-4 trans (pyrazoline)], 3.84 (3H, s, OCH3), 4.12 [1H, dd, J = 13.0,
17.4 Hz, H-4 cis (pyrazoline)], 5.66 [1H, dd, J = 5.5, 12.3 Hz, H-5 (pyrazoline)],
6.36 (2H, s, SO2NH2), 6.49 (1H, dd, J = 1.8 Hz, J = 8.6 Hz, Ar-H), 6.58 (1H, s, Ar-
H), 6.86 (2H, d, J = 7.8 Hz, Ar-H), 7.10–7.49 (5H, m, Ar-H), 7.74 (2H, d, J = 7.7 Hz,
Ar-H), 10.61 (1H, s, phenolic OH); 13C NMR (75 MHz, DMSO-d6, d, ppm): 43.00
(CH2 of pyrazoline), 55.39 (O-CH3), 58.82 (CH of pyrazoline), 152.06 (C=N of
pyrazoline), 158.01 (Ar C-OH), 161.80 (Ar C-O-C); FAB-MS (m/z): 457 [M+], 459
192 °C; 52% yield; IR (t
max, cmÀ1, KBr): 3318, 3158 & 3069 [NH2 and N(CH3)2],
1594 (C=N), 1338 & 1157 (SO2N<); 1H NMR (300 MHz, CDCl3, d, ppm): 2.96
(6H, s, 2xCH3), 3.17 [1H, dd, J = 4.7, 18.2 Hz, H-4 trans (pyrazoline)], 3.79 (3H, s,
OCH3), 3.82 (3H, s, OCH3), 3.95 [1H, dd, J = 11.9, 18.1 Hz, H-4 cis (pyrazoline)],
5.48 [1H, m, H-5 (pyrazoline)], 6.62-7.22 (10H, m, Ar-H and SO2NH2), 7.55 (2H,
d, J = 8.7 Hz, Ar-H), 7.87 (1H, d, J = 9.2 Hz, Ar-H); 13C NMR (75 MHz, CDCl3, d,
ppm): 44.42 [N(CH3)2] of pyrazoline), 46.16 (CH2 of pyrazoline), 55.39 (O-CH3),
55.69 (O-CH3), 61.26 (CH of pyrazoline), 148.8 (C=N of pyrazoline), 158.8 (Ar C-
O-C), 161.78 (Ar C-O-C); FAB-MS (m/z): 480 [M+]. 3o) m.p. 138 °C; yield 32%;
[M+2], 461[M+4], 425, 391. 3e) m.p. 236 °C; yield 60%; IR (t
max, cmÀ1, KBr):
3302 & 3196 (NH2), 1596 (C=N), 1342 & 1154 (SO2N<); 1H NMR (300 MHz,
DMSO-d6, d, ppm): 3.78 (3H, s, OCH3), 4.02 [1H, dd, J = 12.1, 17.7 Hz, H-4 cis
(pyrazoline)], 5.48 [1H, dd, J = 4.8, 11.9 Hz, H-5 (pyrazoline)], 6.52–7.62 (13 H,
m, Ar-H and SO2NH2), 9.45 (1 H, brs, phenolic OH), 10.48 (1 H, brs, phenolic
OH); 13C NMR (75 MHz, DMSO-d6, d, ppm): 44.09 (CH2 of pyrazoline), 55.36
(O-CH3), 61.0 (CH of pyrazoline), 152.07 (C=N of pyrazoline), 158.0 (2 x Ar C-
OH), 161.73 (Ar C-O-C); FAB-MS (m/z): 441 [M+2], 439 [M+], 427, 391, 359,
IR (t
max, cmÀ1, KBr): 3486 (OH), 3281 & 3107 (NH2), 1591 (C=N), 1324 & 1143
346. 3f) m.p. 194 °C; yield 27%; IR (t
max, cmÀ1, KBr): 1594 (C=N), 1334 & 1159
(SO2N<); 1H NMR (300 MHz, DMSO-d6, d, ppm): 3.17 [1H, dd, J = 4.7, 18.2 Hz,
H-4 trans (pyrazoline)], 3.80 (3H, s, OCH3), 3.82 (3H, s, OCH3), 3.95 [1H, dd,
J = 11.9, 18.2 Hz, H-4 cis (pyrazoline)], 5.40 [1H, dd, J = 4.7, 11.8 Hz, H-5
(pyrazoline)], 6.59–6.70 (5H, m, Ar-H and SO2NH2), 6.98–7.16 (5H, m, Ar-H),
7.56 (2H, d, J = 8.6 Hz, Ar-H), 7.86 (1H, d, J = 9.2 Hz, Ar-H), 9.44 (1H, s, phenolic
OH); 13C NMR (75 MHz, DMSO-d6, d, ppm): 46.33 (CH2 of pyrazoline), 55.44
(SO2N<); 1H NMR (300 MHz, CDCl3, d, ppm): 3.29 [1H, dd, J = 7.0, 17.6 Hz, H-4
trans (pyrazoline)], 3.75 (9H, s, 3xOCH3), 3.85 (3H, s, OCH3), 4.01 [1H, dd,
J = 12.0, 17.7 Hz, H-4 cis (pyrazoline)], 5.20 [1H, dd, J = 7.1, 11.9 Hz, H-5
(pyrazoline)], 6.39 (2H, s, SO2NH2), 6.50 (3H, m, Ar-H), 6.58 (1H, d, J = 2.4 Hz,
Ar-H), 6.95 (2H, d, J = 8.8 Hz, Ar-H), 7.10 (1H, d, J = 8.6 Hz, Ar-H), 7.24 (2H, d,

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(O-CH3), 55.74 (O-CH3), 61.98 (CH of pyrazoline), 148.90 (C=N of pyrazoline),
157.86 (Ar C-O-C), 158.86 (Ar C -O-C), 161.79 (Ar C-O-C); FAB-MS (m/z): 453
max, cmÀ1, KBr): 3381 & 3271 (NH2),
[1H, dd, J = 12.4, 18.9 Hz, H-4 cis (pyrazoline)], 5.31 [1H, dd, J = 6.4, 12.2 Hz, H-
5 (pyrazoline)], 5.92 (2H, s, SO2NH2), 6.10 (1H, s, coumarin-H), 6.87 (2H, d,
J = 8.3 Hz, Ar-H), 6.95 (2H, d, J = 8.6 Hz, Ar-H), 7.02 (1H, d, J = 8.8 Hz, coumarin-
H), 7.19 (2H, d, J = 8.3 Hz, Ar-H), 7.52 (1H, d, J = 8.8 Hz, H- coumarin-H ‘), 7.73
(2H, d, J = 8.6 Hz, Ar-H), 12.07 (1H, s, phenolic OH); 13C NMR (75 MHz, DMSO-
d6, d, ppm): 18.45 (CH3), 46.99 (CH2 of pyrazoline), 55.07 (O-CH3), 60.89 (CH
of pyrazoline), 153.84 (C=N of pyrazoline), 158.72 (Ar C-O-C), 159.41 (C=O of
coumarin), 159.87 (Ar C-OH); FAB-MS (m/z): 505 [M+], 507 [M+2], 489, 460.
[M+]. 3p) m.p. 218 °C; yield 51%; IR (
t
1593 (C=N), 1331 & 1151 (SO2N<); 1H NMR (300 MHz, CDCl3,d, ppm): 3.31 [1H,
dd, J = 5.7, 17.4 Hz, H-4 trans (pyrazoline)], 3.79 (3H, s, OCH3), 4.01 [1H, dd,
J = 12.0, 17.4 Hz, H-4 cis (pyrazoline)], 5.33 [1H, dd, J = 5.8, 11.9 Hz, H-5
(pyrazoline)], 6.21 (2H, s, SO2NH2), 6.86-7.21 (9H, m, Ar-H), 7.44 (2H, m, Ar-H),
7.72 (2H, d, J = 8.3 Hz, Ar-H), 10.53 (1H, s, phenolic OH); 13C NMR (75 MHz,
CDCl3, d, ppm): 43.41 (CH2 of pyrazoline), 54.67 (O-CH3), 61.10 (CH of
pyrazoline), 151.17 (C=N of pyrazoline), 156.48 (Ar C-OH), 158.68 (Ar C-O-C);
3s) m.p. 208 °C, yield 61%. IR (tmax, , KBr): 3256, 1729 (C=O of
cmÀ1
coumarin), 1593 (C=N), 1329 & 1156 (SO2N<); 1H NMR (300 MHz, DMSO-d6,
d, ppm): 2.43 (3H, s, CH3), 3.81 [1H, dd, J = 6.2, 18.9 Hz, H-4 trans (pyrazoline)],
4.47 [1H, dd, J = 12.4, 18.9 Hz, H-4 cis (pyrazoline)], 5.29 [1H, dd, J = 6.3,
12.2 Hz, H-5 (pyrazoline)], 6.10 (1H, s, coumarin-H), 6.27 (2H, s, SO2NH2), 6.74
(3H, m, Ar-H), 6.96 (2H, d, J = 8.63 Hz, Ar-H), 7.03 (1H, d, J = 8.89 Hz, coumarin-
H), 7.16 (1H, m, Ar-H), 7.54 (1H, d, J = 8.83 Hz, coumarin-H), 7.74 (2H, d,
J = 8.62 Hz, Ar-H), 9.07 (1H, s, phenolic OH), 12.07 (1H, s, phenolic OH); 13C
NMR (75 MHz, DMSO-d6, d, ppm): 18.43 (CH3), 46.92 (CH2 of pyrazoline),
61.21 (CH of pyrazoline), 153.76 (C=N of pyrazoline), 157.89 (Ar C-OH), 159.32
(C=O of coumarin), 159.83 (Ar C-OH); FAB-MS (m/z): 491 [M+], 493 [M+2],
489, 411.
FAB-MS (m/z): 423 [M+]. 3q) m.p. 184 °C; yield 47%; IR ( max, cmÀ1, KBr):
t
3338 & 3251 (NH2), 1596 (C=N), 1332 & 1147 (SO2N<); 1H NMR (300 MHz,
CDCl3, d, ppm): 3.33 [1H, dd, J = 5.8, 17.3 Hz, H-4 trans (pyrazoline)], 3.83 (3H,
s, OCH3), 3.85 (3H, s, OCH3), 4.05 [1H, dd, J = 12.0, 17.4 Hz, H-4 cis (pyrazoline)],
5.32 [1H, dd, J = 5.8, 11.9 Hz, H-5 (pyrazoline)], 6.54 (2H, s, SO2NH2), 6.80 (1H,
s, Ar-H), 6.84-7.06 (6H, m, Ar-H), 7.22 (1H, d, J = 7.4 Hz, Ar-H), 7.32 (1H, m, Ar-
H), 7.72 (2H, d, J = 8.7 Hz, Ar-H), 10.52 (1H, s, phenolic OH); 13C NMR (75 MHz,
CDCl3, d, ppm): 44.28 (CH2 of pyrazoline), 55.45 (2 x O-CH3), 61.42 (CH of
pyrazoline), 148.18 (Ar C-O-C), 149.11 (Ar C-O-C), 151.78 (C=N of pyrazoline),
156.28 (Ar C-OH); FAB-MS (m/z): 453 [M+]. 3r) m.p. 276 °C; yield 34%; IR
(t
max, cmÀ1, KBr): 3376 & 3266 (NH2), 1722 (C=O of coumarin), 1596 (C=N),
11. Winter, C. A.; Risely, E. A.; Nus, G. N. Proc. Soc. Exp. Biol. 1962, 111, 544.
12. Gierse, J. K.; Koboldt, C. M.; Walker, M. C.; Siebert, K.; Isakson, P. C. Biochem. J.
1999, 339, 607.
1326 & 1155 (SO2N<); 1H NMR (300 MHz, DMSO-d6, d ppm): 2.41 (3H, s, CH3),
3.78 (3H, s, OCH3), 3.81 [1H, dd, J = 6.5, 18.9 Hz, H-4 trans (pyrazoline)], 4.47