Synthesis and biological evaluation of some novel sulfamoylphenyl- pyridazinone as anti-inflammatory agents (Part-II)

Article abstract of DOI:10.3109/14756366.2011.577036

Seven novel 6-aryl-2-(p-sulfamoylphenyl)-4,5-dihydropyridazin-3(2H)-ones (2a-g) were synthesized by the condensation of appropriate aroylpropionic acid and 4-hydrazinobenzenesulfonamide hydrochloride in ethanol. Structure of all compounds have been elucidated by elemental analysis, IR, ¹H NMR, ¹³C NMR, DEPT and MS spectrscopy. These compounds were tested for their anti-inflammatory activity in carrageenan-induced rat paw edema model. Compound 2b exhibited anti-inflammatory activity comparable to that of celecoxib (at 5h). Two other compounds 2d and 2g showed promising anti-inflammatory activity (edema reduction more than 80% at 5h). These compounds (2b, 2d and 2g) did not produce any ulceration in gastric region.

Full text of DOI:10.3109/14756366.2011.577036

Journal of Enzyme Inhibition and Medicinal Chemistry, 2012; 27(1): 92–96
© 2012 Informa UK, Ltd.
ISSN 1475-6366 print/ISSN 1475-6374 online
DOI: 10.3109/14756366.2011.577036
ReseaRch aRtIcle
Synthesis and biological evaluation of some novel
sulfamoylphenyl-pyridazinone as anti-inflammatory agents
(Part-II*)
Rafia Bashir, Shafiya Yaseen, Syed Ovais, Shamim Ahmad, Hinna Hamid, M.S. Alam, Mohammad
Samim, and Kalim Javed
Department of Chemistry, Faculty of Science, Jamia Hamdard (Hamdard University), New Delhi, India
abstract
Seven novel 6-aryl-2-(p-sulfamoylphenyl)-4,5-dihydropyridazin-3(2H)-ones (2a-g) were synthesized by the
condensation of appropriate aroylpropionic acid and 4-hydrazinobenzenesulfonamide hydrochloride in ethanol.
Structure of all compounds have been elucidated by elemental analysis, IR, 1H NMR, 13C NMR, DEPT and MS spectrscopy.
These compounds were tested for their anti-inflammatory activity in carrageenan-induced rat paw edema model.
Compound 2b exhibited anti-inflammatory activity comparable to that of celecoxib (at 5h). Two other compounds
2d and 2g showed promising anti-inflammatory activity (edema reduction more than 80% at 5h). These compounds
(2b, 2d and 2g) did not produce any ulceration in gastric region.
Keywords: Pyridazinone, benzenesulfonamide, anti-inflammatory
Introduction
diuretic18,20, hypoglycemic21, antithyroid22, and antipro-
tons activities23–25. A large number of structurally novel
sulfonamide derivatives have recently been reported to
show substantial antitumor activity, both in vitro and/
or in vivo. Although they have a common chemical
motif of aromatic/heterocyclic sulfonamide, there are a
variety of mechanisms of their antitumor action, most of
them poorly understood at this moment. Some of these
derivatives are currently being evaluated in clinical trials,
and there is much optimism that they may lead to novel
alternative anticancer drugs, devoid of the side effects of
the presently available pharmacological agents26. Anti-
inflammatory activity of celecoxib (celebrex) which was
used clinically in the 1990s is attributed to the presence
of SO2NH2 substituted at the para position of one aryl
Pyridazin-3(2H)-one derivatives represent one of the
most active class of compounds possessing a wide
spectrum of pharmacological activities ranging from
cardiovascular properties, anti-inflammatory, antidi-
abetic, analgesic, anti-AIDs, anticancer and anticonvul-
sant activities1,2. Pyridazinone derivatives also possess
affinity for benzodiazepine receptors3 and the ability
to inhibit the human matrix metalloproteinase4 and
aldose reductase5 enzymes. Recently, these derivatives
have been reported as potent hepatoprotective agents6,
antibacterial and antifungal agents7, COX-2 inhibitors8,
platelet aggregation inhibitor9–12, phosphodiesterase13,14
.
ey also act as cytotoxic (cell-killing) agents and anti-
hormonal drugs, which reduce the proliferation of the
tumors15–16
.
groups27,28
.
e sulfonamides constitute an important class of
drugs, with several types of pharmacological agents
erefore, itwasthoughtworthwhiletosynthesizenovel
pyridazinone derivatives bearing sulphonamide moiety
and screen them for the anti-inflammatory activity.
possessing antibacterial17, anti-carbonic anhydrase18,19
,
Address for Correspondence: Kalim 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
*For part I see Journal of Enzyme Inhibition and Medicinal Chemistry, 25(2), 266–271, 2010
(Received 30 December 2010; revised 07 March 2011; accepted 29 March 2011)
92

Synthesis of anti-inflammatory pyridazinones 93
(comparable to that of celecoxib at 5 h). Compound 2d
and 2g showed promising activity.
Results and discussion
Synthesis of compounds
No specific structural activity relationship was estab-
e synthetic route used to synthesize title compounds
(2a-j) is outlined in Scheme 1. Various intermediates 1,4-
ketoacids (β-aroylpropionic acids) required for the syn-
thesis of pyridazinones were prepared by Friedel-Crafts
succinoylation of substituted aromatic compounds29. e
cyclization to pyridazinone derivatives bearing a benzene
sulfonamide moiety was afforded by the condensation of
appropriate aroylpropionic acid and 4-hydrazinoben-
zenesulfonamide hydrochloride in ethanol in 60–75%
yield. e structures of pyridazinone derivatives (2a-g)
lished from the data shown in Table 1.
Acute gastric ulcerogenic effect of the compound
2b, 2d and 2g at 60 mg/kg (three times) was evaluated
in Wistar rats31. No ulceration in gastric region was
observed.
Experimental
Melting points were determined by open capillary
tubes and are uncorrected. All the Fourier Transform
Infra Red spectra were recorded on a Brukers Vector 22
spectrophotometer in film; υmax values are given in cm−1.
1H NMR spectra were recorded on a Bruker Spectrospin
DPX 300-MHz spectrometer using deuterated DMSO as
a solvent and tetramethyl silane (TMS) as an internal
standard. Chemical shifts are given in δ (ppm) scale
and coupling constants (J values) are expressed in Hz.
Mass spectra were scanned by affecting FAB ionization
JEOL-JMS-DX 303 system, equipped with direct inlet
probe system and ESI Bruker Esquire 3000. e m/z val-
ues of the more intense peaks are mentioned. 13C NMR
and DEPT spectra were recorded on Bruker spectrospin
DPX 400 MHz and 500 MHz using deuterated DMSO as
a solvent and TMS as internal standard. Purity of the
compounds was checked on TLC plates (silica gel G)
which were visualized by exposing to iodine vapors.
Elemental analysis was carried out on CHNS Elementar
(Vario EL III).
1
were determined by elemental analysis, IR, H NMR, 13C
NMR, DEPT and MS.
e structure was supported by the evidence of
presence of prominent bands in IR spectra for NH2
(3284–3449, 3019–3298 and 2916–2954), cyclic car-
bonyl (1637–1657), C=N (1462–1595) and SO2N<
(1310–1377 and 1151–1189) groups. e structure was
further established by 1HNMR spectral data. e signal
for SO2NH2 was observed as two-proton singlet at δ
7.10–7.98. Two triplets each integrating for two protons
observed at δ 2.74–2.87 and δ 3.03–3.21 indicate the
presence of−CH2–CH2– system of dihydropyridazinone
ring. DEPT spectra indicate the presence of CH3, CH2
and CH carbons. Elemental analysis (C, H, N and S)
data were within 0.4 of the theoretical values.
Biological activity
All compounds (2a-g) where tested for anti-inflamma-
tory activity by using carrageenan-induced rat hind paw
edema method30. All the pyridazinone derivatives (2a-g)
exhibited varying degree of anti-inflammatory activ-
ity (23.3–78.9% at 3 h and 52.4–88.1% at 5 h) (Table 1).
Compound 2b has shown maximum activity at 5h
Procedure for the synthesis of Aroylpropionic acids (1a-g)
To liquid aromatic hydrocarbon (30 mL), anhydrous
aluminium chloride (16.6 g, 0.125 mole) was added.
It was stirred on magnetic stirrer at room temperature
Scheme 1. Reagents and conditions: EtOH, reflux 18–24h.
© 2012 Informa UK, Ltd.

94 R. Bashir et al.
Table 1. Effect of pyridazinone derivatives on carrageenan induced hind paw edema in rats.
Increase in paw volume (mL SEM) after carrageenan administration
Treatment
Dose per kg b.w.
10ml/kg
20 mg
3 h
5 h
Vehicle
0.38 0.0307
0.42 0.0401
Celecoxib
0.066 0.0210* (82.6%)
0.2 0.000* (47.4%)
0.15 0.02236* (60.5%)
0.28 0.01667* (23.3%)
0.08 0.01667* (78.9%)
0.23 0.0333* (39.4%)
0.2 0.02582* (47.3%)
0.1 0.02582* (73.6%)
0.06 0.02* (85.7%)
0.13 0.0210* (69%)
0.05 0.03416* (88.1%)
0.2 0.0258* (52.4%)
0.08 0.01667* (81%)
0.13 0.0333* (69%)
0.12 0.03073* (71.4%)
0.08 0.03073* (80.9%)
2a
2b
2c
2d
2e
2f
20 mg
20 mg
20 mg
20 mg
20 mg
20 mg
2g
20 mg
*P<0.05 compared to control (one-way analysis of variance followed by Dunnett’s test). Values are presented as mean S.E.M. (n=6)
.Values in parentheses represent percent inhibitions.
for 30 min. To it succinic anhydride (5 g, 0.05 mol) was
addedinfiveportionswithcontinuousstirring. Vigorous
reaction started with evolution of HCl gas. Stirring was
continued for another 6 h at room temperature. It was
left at room temperature for 48 h and then decomposed
by adding ice-cold hydrochloric acid (50%, 100 mL).
e excess solvent was removed by steam distillation.
e solid precipitated out was treated with aqueous
saturated sodium bicarbonate solution and filtered.
Filtrate was acidified with dilute HCl (4% v/v) to give a
precipitate. It was filtered and residue was washed with
cold water, dried and crystallized from the appropriate
solvent to give (1a-g)29.
C = 60.49, H = 5.36, N = 11.76, S = 8.97, Found: C = 60.87,
H = 4.98, N = 12.02, S = 9.13.
6-(4′-Phenylphenyl)-
2-(4-sulfamoylphenyl)-4,
5-dihydropyridazin-3(2H)-one (2b)
Yield = 55%, m.p. >260°C, Rf = 0.70 (toluene: ethyl ace-
tate: formic acid, 5: 4: 1). IR υmax (Solvent, in cm−1): 3317,
1
1657 (C=O), 1595 (C=N), 1326 and 1151cm−1 (SO2N). H
NMR (300 MHz, DMSO, δ): 2.80 (2H, t, CH2 of pyridazi-
none), 3.21 (2H, t, CH2 of pyridazinone), 7.40-7.98 (15H,
m, N-phenyl protons, biphenyl protons, SO2NH2). ESI+
(m/z): 405 (M+), 406 (M+ +1), 407 (M+ +2). 13C NMR
(DMSO, δ): 24.4 (-CH3), 32.4 (-CH2 of pyridazinone), δ
32.4 (-CH2 of pyridazinone), 152.50 (C=N), 165.70 (C=O).
DEPT (DMSO, δ): 22.20 (-CH2 of pyridazinone), 27.44
(-CH2 of pyridazinone). Anal. Calcd. For C22H19N3O3S,
Calculated: C = 65.17, H = 4.72, N = 10.36, S = 7.91, Found:
C = 65.12, H = 4.69, N = 10.36, S = 7.89.
General Procedure for the synthesis of pyridazinones (2a-g)
A mixture of appropriate aroylpropionic acid (1a-g)
(0.001 mol) and 4-hydrazinobenzenesulfonamide hydro-
chloride (0.001 mol) in absolute ethanol (20–30 mL)
was refluxed for 18–24 h. e reaction mixture was con-
centrated to one-third of its volume and left at room
temperature when a solid separated out. Crude product
was filtered off, washed with little volume of alcohol. e
residue thus obtained was stirred with 5% sodium bicar-
bonate solution (25 mL) for 1h. It was filtered, washed
with 2% acetic acid and then with water. It was dried and
crystallized from methanol to give (2a-g).
6-(4′-phenoxyphenyl)- 2-(4-sulfamoylphenyl)-4,5-
dihydropyridazin-3(2H)-one (2c)
Yield=65%, m.p. 235–2360C, Rf=0.57 (toluene: ethyl
acetate: formic acid, 5: 4: 1). IR υmax (Solvent, in cm−1): 3449
1
(NH2), 1637 (C=O), 1329 and 1153cm−1 (SO2N). H NMR
(300MHz,DMSO,d):2.80(2H,t,-CH2 ofpyridazinone),3.18
(2H, t, -CH2 of pyridazinone), 7.10- 7.94 (15H, m, SO2NH2,
phenyl phenoxy & N-phenyl). ESI+ (m/z): 421 (M+), 422
(M+ +1), 423 (M+ +2), 299. 13C NMR (DMSO, δ): 22.47 (-CH2
of pyridazinone), 27.59 (-CH2 of pyridazinone), 152.33
(C=N), 165.56 (C=O). DEPT (DMSO, δ): 22.23 (-CH2 of
pyridazinone), 27.46 (-CH2 of pyridazinone). Anal. Calcd.
for C22H19N3O4S, Calculated: C=62.69, H=4.54, N=9.97,
S=7.61, Found: C=62.63, H=4.51, N=9.96, S=7.60.
6-(2′,4′-Dimethylphenyl)-2-(4-sulfamoylphenyl)-4,5-
dihydropyridazin-3(2H)-one (2a)
Yield = 61%, m.p. 156–1580C, Rf = 0.61 (toluene: ethyl ace-
tate: formic acid, 5: 4: 1). IR υmax (Solvent, in cm−1): 3304,
3232 and 2920 (NH2), 1649 (C=O), 1310 and 1185 cm−1
1
(SO2N). H NMR (300 MHz, DMSO, δ): 2.30 (3H, s, CH3),
6-(β-napthyl)-2-(4-sulfamoylphenyl)-4,5-dihydropyridazin-
3(2H)-one(2d)
2.41 (3H, s, CH3), 2.78 & 3.03 (each t, 2x-CH2-), 7.11 (2H, s,
SO2NH2), 7.38 (3H, m, H-2′, H-5′, H-6′), 7.72 (2H, d, J = 8.59
Hz, H-3′′, H-5′′), 7.85 (2H, d, J = 8.59 Hz, H-2′′, H-6′′).
ESI+ (m/z): 356 (M+-1), 380 (M++Na). 13C NMR (DMSO,
δ): 20.92 (-CH3, C-3′), 22.19 (-CH3, C-4′), 27.42 (-CH2
of pyridazinone), 46.16 (-CH2 of pyridazinone), 165.73
(C=N), 177.95 (C=O). DEPT (DMSO, δ): 19.036 (2x-CH3,
C-3′, C-4′), 27.875 (-CH2 of pyridazinone), 46.680 (-CH2 of
pyridazinone). Anal. Calcd. For C18H19N3O3S, Calculated:
Yield = 65%, m.p. 252–2540C, Rf = 0.57 (toluene: ethyl
acetate: formic acid, 5: 4: 1). IR υmax (Solvent, in cm−1):
3298 (NH2), 1657 (C=O), 1590 (C=N), 1377 and 1189 cm−1
1
(SO2N). H NMR (300 MHz, DMSO, δ): 2.87 (2H, t, -CH2
of pyridazinone), 7.60-8.21 (10H, m, N-phenyl and
napthelene protons except H-α), 7.43 (2H, s, SO2NH2),
8.44 (1H, s, H-α). ESI+ (m/z): 379 (M+), 337, 300. 13C NMR
(DMSO, δ): 22.82 (-CH2 of pyridazinone), 28.07 (-CH2
Journal of Enzyme Inhibition and Medicinal Chemistry

Synthesis of anti-inflammatory pyridazinones 95
of pyridazinone), 153.19 (C=N), 166.20 (C=O). DEPT
(DMSO, δ): 20.76 (-CH2 of pyridazinone), 27.47 (-CH2 of
pyridazinone). Anal. Calcd. For C20H17N3O3S, Calculated:
C = 63.31, H = 4.52, N = 11.07, S = 8.45, Found: C = 63.25,
H = 4.48, N = 11.07, S = 8.43.
Central Animal House facility of Jamia Hamdard, New
Delhi (Registration no. 173/CPCSEA). e 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, Govternment of India,
January 2000. Overnight fasted rats (16h) were divided
into groups of six animals each. One group of rats, which
served as control was given vehicle (1% Carboxymethyl
cellulose (CMC) in water in a volume of 10mL/kg p.o.)
only. Test compounds (20mg/kg body weight.) and cele-
coxib (20mg/kg b.w.) suspended in vehicle (10mL/kg)
were administered orally to respective groups. After
30min, all animals were injected with 0.1mL of 1% car-
rageenan solution (prepared in normal saline) in the
subplantar aponeurosis of left hind paw to induce inflam-
mation and the volume of injected paw was measured
by using plethysmometer immediately (at 0h). e paw
volume was again measured after 3h and 5h. e 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:
6-(4′-bromophenyl)-2-(4-sulfamoylphenyl)-4,5-
dihydropyridazin-3(2H)-one (2e)
Yield=55%, m.p. 241–2420C, Rf=0.59 (toluene: ethyl ace-
tate: formic acid, 5: 4: 1). IR υmax (Solvent, in cm−1): 3312,
3019 and 2954 (NH2), 1651 (C=O), 1462 (C=N), 1338 and
1154cm−1 (SO2N). 1H NMR (300MHz, DMSO, δ): 2.76 (2H,
t, -CH2 of pyridazinone), 3.14 (2H, t, -CH2 of pyridazinone),
7.37 (2H, s, SO2NH2), 7.64− 7.87 (8H, m, N-phenyl protons
& bromophenyl protons). ESI+ (m/z): 409 (M++1), 431
(M++Na), 407 (M+-1), 405, 378, 338. 13C NMR (DMSO, δ):
22.11 (-CH2 of pyridazinone), 27.28 (-CH2 of pyridazinone),
151.79 (C=N), 165.57 (C=O). DEPT (DMSO, δ): 22.18 (-CH2
of pyridazinone), 27.35 (-CH2 ofpyridazinone). Anal. Calcd.
For C16H14BrN3O3S, Calculated:C=47.07, H=3.46, N=10.29,
S=7.85, Found: C=47.03, H=3.43, N=10.29, S=7.84.
6-(3′,4′-dimethoxyphenyl)-2-(4-sulfamoylphenyl)-4,5-
dihydropyridazin-3(2H)-one (2f)
Percent inhibition(1Vt/Vc)100
Yield = 65%, m.p. 203–2040C, Rf = 0.5 (toluene: ethyl for-
mate: formic acid, 7.5: 2: 0.5). 1H NMR (300 MHz, DMSO,
δ): 2.74 (2H, t, -CH2 of pyridazinone), 3.13 (2H, t, -CH2 of
pyridazinone), 3.79 (6H, s, 2 x OCH3), 7.02 (1H, d, J= 8.4
Hz, H-5′), 7.39 (4H, m, H-2′, H-6′, SO2NH2), 7.82 (4H, m,
N-phenyl protons). ESI+ (m/z): 389 (M+), 388 (M+-1), 412
(M++Na), 325, 311, 255. 13C NMR (DMSO, δ): 22.16 (-CH2
of pyridazinone), 27.6 (-CH2 of pyridazinone), 55.55
(OCH3,C-3’ and C-4’), 148.68 (C=N), 165.74 (C=O). DEPT
(DMSO, δ): 22.23 (-CH2 of pyridazinone), 27.63 (-CH2 of
pyridazinone), δ55.615 (2x OCH3, C-3′, C-4′). Anal. Calcd.
for C18H19N3O5S, Calculated: C = 55.52, H = 4.92, N = 10.79,
S = 8.23, Found: C = 55.47, H = 4.88, N = 10.78, S = 8.22.
Where Vt is the mean paw volume of the treated rats and
Vc is the mean paw volume of the control.
Ulcerogenic activity
Acute gastric ulcerogenic effect of the compound 2b,
2d and 2g was evaluated in Wistar rats31. Albino rats of
Wistar strain (150–200 g) fasted over 24 h were randomly
allotted into three groups of six animals each. e ani-
mals of one group were given vehicle 10mL/kg (CMC 1%
w/v in distilled water) orally. e compound 2b, 2d and
2g standard drug (60 mg/kg) suspended in vehicle was
administered orally in a volume of 10 mL/kg to the ani-
mals. ey were scarified under deep ether anesthesia
after 6 h of the oral treatment at a dose of 60 mg/kg. eir
stomach were removed and opened through greater cur-
vature for examining lesions or bleedings.
6-(3′,4′-dichlorophenyl)-2-(4-sulfamoylphenyl)-4,5-
dihydropyridazin-3(2H)-one (2g)
Yield=70%, m.p. 260–2610C, Rf=0.70 (toluene: ethyl ace-
tate: formic acid, 5: 4: 1). IR υmax (Solvent, in cm−1): 3284,
3218 and 2916 (NH2), 1643 (C=O), 1468 (C=N), 1336 and
1151cm−1 (SO2N). 1H NMR (300MHz, DMSO, δ): 2.74 (2H,
t, -CH2 of pyridazinone), 3.15 (2H, t, -CH2 of pyridazinone),
7.37 (2H, s, SO2NH2), 7.71-7.87 (6H, m, N-phenyl protons,
H-5′, H-6′), 8.05 (1H, s, H-2′). ES+-MS (m/z): 397 (M+),
399 (M+2), 365, 348. 13C NMR (DMSO, δ): 22.78 (-CH2 of
pyridazinone), 28.07 (-CH2 of pyridazinone), 153.19 (C=N),
166.20 (C=O). DEPT (DMSO, δ): 26.394 (-CH2 of pyridazi-
none), 28.225 (-CH2 of pyridazinone). Anal. Calcd. for
C16H13Cl2N3O3S, Calculated: C=48.25, H=3.29, N=10.55,
S=8.05, Found: C=48.21, H=3.26, N=10.55, S=8.04.
conclusions
e structures proposed to the synthesized compounds
(2a-g) are well supported by spectroscopic data and
elemental analysis. Among the synthesized compounds
2b exhibited potent anti-inflammatory activity which
is comparable to that of celecoxib (at 5 h). Other two
compounds (2d and 2g) were found to have promising
anti-inflammatory activity (edema reduction more than
80% at 5 h). ese compounds (2b, 2d and 2g) did not
produce any ulceration in gastric region.
Anti-inflammatory activity
acknowledgments
Carrageenan-induced hind paw edema method was
used for evaluating anti-inflammatory activity30. Wistar
rats (either sex) weighing 140–180g were procured from
is work was supported by Grant No. 32–228/2006 (SR)
from the University Grants Commission, New Delhi,
© 2012 Informa UK, Ltd.

96 R. Bashir et al.
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