Synthesis of N-benzenesulfonamide-1H-pyrazoles bearing arylsulfonyl moiety: Novel celecoxib analogs as potent anti-inflammatory agents

Article abstract of DOI:10.1016/j.ejmech.2014.04.065

The reaction of arylsulfones 11a-d with hydrazonoyl chloride derivative 13 furnished celecoxib analogs 4-(3-acetyl-5-aryl-4-(arylsulfonyl)-1H-pyrazol-1-yl) benzenesulfonamides 15a-d, respectively. Oximes 16a, b and hydrazones 17a, b were prepared by reacting sulfones 11a, b with hydroxyl amine and phenyl hydrazine, respectively. The anti-inflammatory activity of the synthesized compounds showed that, 5-(4-bromophenyl)-4-(phenylsulfonyl)pyrazole 15c and 5-(4-bromophenyl)-4-(4-tolylsulfonyl)pyrazole 15d exhibited excellent anti-inflammatory activity with ED₅₀ = 68 ± 2.2 and 51 ± 0.7 μM/kg, respectively, higher than that of celecoxib (ED ₅₀ = 86 ± 1.1 μM/kg) after 3 h with acceptable ulcer index. In addition, the LD₅₀ of 15c and 15d is 7.1 mM/kg for each, and 9.8 mM/kg for celecoxib. Compound 15d appeared selectivity index (COX-2/COX-1) almost the half of celecoxib while 15c is non-selective for COX-2. Compound 15c with ED₅₀ = 80 ± 2.8 μM/kg showed a significant analgesic activity when compared with celecoxib (ED₅₀ = 70 ± 3.9 μM/kg) after 2 h whereas 15b (ED₅₀ = 50 ± 1.2 μM/kg) and 15d (ED₅₀ = 69 ± 2.7 μM/kg) seemed to be more potent than celecoxib (ED₅₀ = 156 ± 4.8 μM/kg) but with a shorter duration (0.5 h).

Full text of DOI:10.1016/j.ejmech.2014.04.065

European Journal of Medicinal Chemistry 80 (2014) 416e422
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis of N-benzenesulfonamide-1H-pyrazoles bearing
arylsulfonyl moiety: Novel celecoxib analogs as potent anti-
inflammatory agents
,
b
,
a
c
Hatem A. Abdel-Aziz a , Khalid A. Al-Rashood , Kamal Eldin H. ElTahir ,
*
Ghada M. Suddek d
a Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia
b Department of Applied Organic Chemistry, National Research Center, Dokki, Cairo 12622, Egypt
c Department of Pharmacology, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia
d Department of Pharmacology, Faculty of Pharmacy, Mansoura University, P.O. Box 35516, Mansoura, Egypt
a r t i c l e i n f o
a b s t r a c t
Article history:
The reaction of arylsulfones 11aed with hydrazonoyl chloride derivative 13 furnished celecoxib analogs
4-(3-acetyl-5-aryl-4-(arylsulfonyl)-1H-pyrazol-1-yl)benzenesulfonamides 15aed, respectively. Oximes
16a, b and hydrazones 17a, b were prepared by reacting sulfones 11a, b with hydroxyl amine and phenyl
hydrazine, respectively. The anti-inflammatory activity of the synthesized compounds showed that, 5-(4-
bromophenyl)-4-(phenylsulfonyl)pyrazole 15c and 5-(4-bromophenyl)-4-(4-tolylsulfonyl)pyrazole 15d
Received 12 December 2013
Received in revised form
21 April 2014
Accepted 22 April 2014
Available online 24 April 2014
exhibited excellent anti-inflammatory activity with ED50 ¼ 68 ꢀ 2.2 and 51 ꢀ 0.7
mM/kg, respectively,
M/kg) after 3 h with acceptable ulcer index. In addition,
higher than that of celecoxib (ED50 ¼ 86 ꢀ 1.1
m
Keywords:
Sulfones
N-benzenesulfonamide-1H-pyrazoles
Anti-inflammatory activity
Cyclooxygenase inhibitors
Ulcerogenic activity
the LD50 of 15c and 15d is 7.1 mM/kg for each, and 9.8 mM/kg for celecoxib. Compound 15d appeared
selectivity index (COX-2/COX-1) almost the half of celecoxib while 15c is non-selective for COX-2.
Compound 15c with ED50 ¼ 80 ꢀ 2.8
with celecoxib (ED50 ¼ 70 ꢀ 3.9 M/kg) after 2 h whereas 15b (ED50 ¼ 50 ꢀ 1.2
(ED50 ¼ 69 ꢀ 2.7 M/kg) seemed to be more potent than celecoxib (ED50 ¼ 156 ꢀ 4.8
shorter duration (0.5 h).
m
M/kg showed a significant analgesic activity when compared
M/kg) and 15d
M/kg) but with a
m
m
m
m
InChIKeys:
Ó 2014 Elsevier Masson SAS. All rights reserved.
YUBACKPNNQKHMP-LNVKXUELSA-N
JGMRIHQYBXLTGM-UHFFFAOYSA-N
YYLNVVCNNQZCEK-XDOYNYLZSA-N
JWHMVCXCZLETGB-UHFFFAOYSA-N
DITVWQPTRBYVRP-UHFFFAOYSA-N
JJZAFNLTCGWRGB-UHFFFAOYSA-N
DREVPGKOIZVPQV-UHFFFAOYSA-N
KLKFNBIIVIGNCB-UHFFFAOYSA-N
KISJEJKQXLRPPO-UHFFFAOYSA-N
HBZUALMGOGLJFP-UHFFFAOYSA-N
IOWCJCHJZDLKMN-NXVVXOECSA-N
WVUQXZSJMSIFGV-PFONDFGASA-N
1. Introduction
pain, fever and inflammation as in case of rheumatoid arthritis.
Prostacyclin (PGI2) dilates blood vessels by inhibiting platelet ag-
gregation while thromboxane A2 (TXA2) having vasoconstrictive
and platelet aggregative effects [1e4]. Non-steroidal anti-inflam-
matory drugs (NSAIDs) such as aspirin and ibuprofen having
analgesic, antipyretic and anti-inflammatory effects usually indi-
cated for the treatment of pain, fever and inflammatory diseases.
NSAIDs inhibit the biosynthesis of the prostaglandins and throm-
boxanes by inhibiting COXs [5e7]. COXs isozymes are a membrane-
associated proteins which exists in two isoforms, a constitutive
The biotransformation of arachidonic acid via the enzyme
cyclooxygenase (COXs) resulting in the formation of prostaglandin
(PGs) which act as mediators and modulators in inflammation.
PGD2 is involved in allergic reactions while PGE2 is involved in
* Corresponding author. Department of Pharmaceutical Chemistry, College of
Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia.
E-mail address: hatem_741@yahoo.com (H.A. Abdel-Aziz).
http://dx.doi.org/10.1016/j.ejmech.2014.04.065
0223-5234/Ó 2014 Elsevier Masson SAS. All rights reserved.

H.A. Abdel-Aziz et al. / European Journal of Medicinal Chemistry 80 (2014) 416e422
417
form (COX-1) and an inducible form (COX-2). COX-1 enzyme is
responsible for maintenance of gastric mucosal integrity, kidney
function, and platelet aggregation whereas COX-2 induces inflam-
matory conditions. NSAIDs which act as inhibitors of both COX-1
and COX-2 have been found to cause gastric ulcers, GI bleeding
and suppression of the renal functions [8,9]. SC-558 1 (Fig. 1) a
marvelous inhibitor with 1900-fold selectivity for COX-2 over COX-
1 was found to be a potent anti-inflammatory agent [10]. COX-2
selective benzenesulfonamides rofecoxib 2, valdecoxib 3 and cel-
ecoxib 4 (Fig. 1), used for treating pain and inflammation and they
have been shown a much lower gastrointestinal side effects [11,12].
Market withdrawal of rofecoxib 2 and valdecoxib 3, and FDA mar-
keting alert for celecoxib 4 due to their adverse cardiovascular side
effects [13,14] shows the need to discover novel scaffolds with COX-
2 inhibitory activity and evaluate their anti-inflammatory effects
[15e19]. On the other hand, several sulfones such as methionine
10a, b (Scheme 1) according to the reported methods [31e33].
Sulfones 11aed reacted with 13 in ethanolic sodium ethoxide so-
lution at room temperature to furnish 4-(3-acetyl-5-aryl-4-(aryl-
sulfonyl)-1H-pyrazol-1-yl)benzenesulfonamides
15aed,
respectively (Scheme 1). The IR spectra of the latter pyrazoles
showed, in each case, the appearance of absorption band in the
region 1706e1702 cmꢁ1 corresponding to the carbonyl function.
Their 1H NMR spectra showed the disappearance of CH2 protons
signal and displayed the signals of NH2 protons around
addition to the singlet signal of acetyl protons in the region
d
7.5 in
2.58e
d
2.60. Mass spectra (ESI) of 15aed showed m/z ¼ Mþ ꢁ 1 in each
case.
In the light of reported anti-inflammatory activity of oximes and
hydrazones [34,35], we aimed to synthesize oximes 16a, b and
hydrazones 17a, b (Scheme 2) to evaluate their anti-inflammatory
activity. Thus, 1-(aryl)-2-(phenylsulfonyl)ethanone oximes 16a, b
were prepared by reacting sulfones 11a, b with hydroxyl amine in
the presence of sodium acetate (Scheme 2) [31,36]. The IR spectra of
oximes 16a, b showed the appearance of OH absorption band in
3246e2922 cmꢁ1 region, whereas their 1H NMR revealed the D2O
derivative, -methioninesulfone 5 [20] and austrasulfone derivative
L
dihydroaustrasulfone alcohol 6 (Fig. 1) [21] are effective as anti-
inflammatory agents. Moreover, arylsulfones PC-796 7 [22] and 2-
sulfonyl-O-aminoacetophenones 8 [23] (Fig. 1) exhibited a signifi-
cant anti-inflammatory activity.
exchangeable singlet signal of OH proton around
d
11.66e11.79 in
In this topic, keeping in mind the structure features of N-ben-
zenesulfonamides 1e4, the present study describes synthesis, anti-
inflammatory activity, selectivity index (COX-2/COX-1), ulcerogenic
activity and analgesic activity for N-benzenesulfonamide-1H-pyr-
azoles 15aed which bearing arylsulfonyl moiety in position 4 of
pyrazole ring as analogs of SC-588 1 and/or celecoxib 4 (Fig. 1). In
this study, sulfones 11aed with structure features similar to that of
sulfones 8 [23] used as starting materials in the synthesis of tar-
geted pyrazoles 15aed in addition to oximes 16a, b and hydrazones
17a, b (Schemes 1 and 2). In continuation of our interest in the
synthesis of novel bioactive compounds derived from hydrazonoyl
chlorides [24e30], included N-arylpyrazoles with anti-
inflammatory potency, herein we aimed to report the cyclization
reaction of sulfones 11aed with hydrazonoyl chloride 13 to pro-
duce celecoxib analogs 15aed.
addition to the methylene protons in the region
d 4.92e4.95.
Furthermore, the reaction of sulfones 11a, b with phenyl hy-
drazine in the presence of acetic acid afforded the corresponding 1-
(1-(aryl)-2-(phenylsulfonyl)ethylidene)-2-phenylhydrazines 17a, b
(Scheme 2). The IR spectra of hydrazones 17a, b showed the
appearance of NH absorption band in 3344e3349 cmꢁ1 region. The
1H NMR spectra of these compounds revealed the appearance of
D2O exchangeable singlet signal due to NH of hydrazone in the
region
protons in the region
d
9.64e9.75 in addition to the singlet signals of methylene
5.17e5.19 integral to two protons.
d
2.2. Biological evaluations
2.2.1. Anti-inflammatory activity
The anti-inflammatory activity was performed to get ED50 for
each tested compound after 1, 2 and 3 h, and to compare it with the
reference drug celecoxib, however, the significant decreasing in the
activity of all compounds was noticed after 6 h (Table 1). Regard to
the intermediates 11aed, they gave anti-inflammatory lower than
2. Results and discussion
2.1. Chemistry
that of celecoxib (ED50 ¼ 86 ꢀ 1.1
kg for 11b and 327 ꢀ 2.2 M/kg for 11c after 3 h. However, the
substitution in both X and Ar affect ED50 values of 11aed, for
m
M/kg) varied from 133 ꢀ 1.1
mM/
1-Aryl-2-(arylsulfonyl)ethanones 11aed were prepared by the
reaction of bromo-1-arylethanones 9aed with sodium arylsulfinate
m
Fig. 1. Structure of compounds 1e8 and 15.

418
H.A. Abdel-Aziz et al. / European Journal of Medicinal Chemistry 80 (2014) 416e422
Scheme 1. Synthesis of N-benzenesulfonamide-1H-pyrazoles 15aed as analogs of SC-588 1 and/or celecoxib 4.
Scheme 2. Synthesis of oximes 16a, b and hydrazones 17a, b as analogs of sulfones 8.
Table 1
The anti-inflammatory activity, ED50
(mM/kg), LD50 (mM/kg) for the test compounds, percentage of inhibition of COX-1 and COX-2, selectivity index (COX-2/COX-1) of most
active compounds at concentration of 5.0
m
M and ulcer index of most active compounds.
Compound
ED50
1 h
(
mM/kg)
LD50 (mM/kg)
% Inhibition
COX-1a
% Inhibition
COX-2a
Selectivity
Index
Ulcer index
2 h
3 h
11a
11b
11c
11d
15a
15b
15c
15d
16a
16b
238 ꢀ 1.9
145 ꢀ 2.7
550 ꢀ 9.7
213 ꢀ 0.9
363 ꢀ 12.3
112 ꢀ 3.1
87 ꢀ 3.1
232 ꢀ 0.9
137 ꢀ 3.1
350 ꢀ 0.9
213 ꢀ 2.7
376 ꢀ 11.3
102 ꢀ 1.1
64 ꢀ 1.9
242 ꢀ 1.7
133 ꢀ 1.1
327 ꢀ 2.2
200 ꢀ 2.7
372 ꢀ 3.6
95 ꢀ 0.9
19.7
14.3
12.4
12.7
10.1
10.1
7.1
7.1
17.4
9.0
e
e
e
e
e
18
34
3
e
e
e
e
2
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
33
27
39
e
1.83
0.79
13.0
e
2.25 ꢀ 0.5
68 ꢀ 2.2
2.86 ꢀ 0.6
75 ꢀ 1.3
54 ꢀ 1.3
51 ꢀ 0.7
0.98 ꢀ 0.3
285 ꢀ 1.1
271 ꢀ 6.9
270 ꢀ 12.1
280 ꢀ 7.5
89 ꢀ 1.3
245 ꢀ 1.9
238 ꢀ 2.3
248 ꢀ 3.1
181 ꢀ 1.5
89 ꢀ 0.8
256 ꢀ 1.0
237 ꢀ 2.1
256 ꢀ 1.4
169 ꢀ 1.5
86 ꢀ 1.1
e
e
e
e
17a
17b
Celecoxib
14.6
11.5
9.8
e
e
e
e
e
e
61
30.5
0.92 ꢀ 0.2
a
Values represents means of two determinations acquired using an ovine COX-2/COX-1 assay kits.

H.A. Abdel-Aziz et al. / European Journal of Medicinal Chemistry 80 (2014) 416e422
419
Table 2
The analgesic activity, ED50
example, X ¼ Me as in compound 11b get the best result among
M/kg after 3 h, but it still not good
(
m
M/kg) for the test compounds.
M/kg)
11aed with ED50 ¼ 133 ꢀ 1.1
m
related to the reference drug. Upon the deep view in the anti-
inflammatory activity of compounds 15aed, we discovered the
incorporation of substitution in position 5 of pyrazole moiety in
their activity, for example, the 5-phenyl pyrazole 15a showed the
lowest anti-inflammatory activity among 15aed with
Compound
ED50
0.5 h
(m
1 h
2 h
11a
11b
11c
11d
15a
15b
15c
15d
16a
16b
250 ꢀ 1.6
168 ꢀ 3.7
218 ꢀ 6.1
73 ꢀ 1.3
158 ꢀ 5.2
408 ꢀ 8.7
318 ꢀ 4.2
69 ꢀ 4.5
145 ꢀ 3.6
434 ꢀ 4.4
318 ꢀ 5.0
66 ꢀ 3.8
ED50 ¼ 372 ꢀ 3.6
exhibited a moderate activity with ED50 ¼ 95 ꢀ 0.9
5-(4-Bromophenyl)pyrazole 15c exhibited excellent anti-
inflammatory activity (ED50 ¼ 64 ꢀ 1.9 and 68 ꢀ 2.2 M/kg after
2 and 3 h, respectively) which is higher than that of celecoxib
M/kg after 2 and 3 h, respectively).
mM/kg after 3 h while 5-(4-tolyl)pyrazole 15b
311 ꢀ 6.9
50 ꢀ 1.2
261 ꢀ 9.8
147 ꢀ 4.8
81 ꢀ 3.1
261 ꢀ 3.4
147 ꢀ 4.9
80 ꢀ 2.8
mM/kg after 3 h.
57 ꢀ 1.6
m
69 ꢀ 2.7
195 ꢀ 6.3
265 ꢀ 6.5
203 ꢀ 7.9
319 ꢀ 8.5
260 ꢀ 4.6
72 ꢀ 1.2
204 ꢀ 5.2
244 ꢀ 6.1
200 ꢀ 4.0
345 ꢀ 5.8
288 ꢀ 4.7
70 ꢀ 3.9
320 ꢀ 11.3
212 ꢀ 8.4
285 ꢀ 9.1
220 ꢀ 1.2
156 ꢀ 4.8
(ED50 ¼ 89 ꢀ 0.8 and 86 ꢀ 1.1
m
17a
17b
Celecoxib
Interestingly, the activity of 15c increased when phenylsulfonyl
(X ¼ H) in position 4 replaced by 4-tolylsulfonyl group (X ¼ Me) to
give compound 15d with a marvelous anti-inflammatory activity
(ED50 ¼ 54 ꢀ 1.3 and 51 ꢀ 0.7
(Table 1). In addition, LD50 of 15c and 15d showed a low LD50
(LD50 ¼ 7.1 M/kg for each) related to celecoxib (LD50 ¼ 9.8 M/kg).
mM/kg after 2 and 3 h, respectively)
m
m
3. Conclusion
The anti-inflammatory activity showed a moderate activity for
sulfones 11aed and it showed high potency for 15aed. This find-
ings stimulated our interest to synthesize oximes 16a, b and
hydrazones 17a, b (Scheme 2) as analogs of sulfones 8 to evaluate
their anti-inflammatory activity in an attempt to improve the ac-
tivity of sulfones 11a, b in the light of reported anti-inflammatory
activity of oximes and hydrazones [34,35]. However, the oximes
16a, b and hydrazones 17a, b gave weak anti-inflammatory activity
when they compared with the reference drug which indicate that
oxime and hydrazone functions have not a positive change in their
activity.
In conclusion, N-benzenesulfonamide-1H-pyrazoles/arylsul-
fones hybrid 15c, d were found to have excellent anti-inflammatory
activity with ED50 ¼ 68 ꢀ 2.2 and 51 ꢀ 0.7
m
M/kg, respectively,
higher than that of celecoxib (ED50 ¼ 86 ꢀ 1.1
mM/kg) after 3 h with
acceptable ulcer index. Compound 15d appeared COX-2/COX-1
selectivity almost the half of celecoxib while 15c is non-selective
for COX-2. These results invite to further investigations for the
mechanism of action of this class of pyrazoles and/or to combine
their promising activity with high COX-2 selectivity through vari-
ation of substitutions in positions 4 and 5 of pyrazole moiety. On a
broad basis compounds 15c, d seemed to be a promising anti-
inflammatory agents and a new addition to the exciting group of
NSAIDs.
2.2.2. In vitro cyclooxygenase inhibitory activity
Percentage of inhibition of COX-1 and COX-2 and selectivity
(COX-2/COX-1) of test compounds at concentration of 5.0 mM were
illustrated in Table 1. Compounds 15b and 15c are non-selective for
COX-2 inhibitors whereas compound 15d showed good selectivity
towards COX-2. Its COX-2/COX-1 selectivity is 13.0, almost the half
of selectivity of celecoxib (COX-2/COX-1 ¼ 30.5) (Table 1). These
results indicate that, mechanism of action of test compounds need
further investigations.
4. Experimental
4.1. Chemistry
4.1.1. General
Melting points were determined on a Gallenkamp melting point
apparatus and are uncorrected. Infrared (IR) Spectra were recorded
as KBr disks using the Perkin Elmer FT-IR Spectrum BX apparatus.
NMR Spectra were scanned in DMSO-d6 on a Brucker NMR spec-
trophotometer operating at 500 MHz for 1H and 125 MHz for 13C.
2.2.3. Ulcerogenic activity
Compounds 15bed that showed the highest anti-inflammatory
activity were subjected to ulcerogenic activity against celecoxib as
reference drug (Table 1). Compound 15d revealed a good ulcer in-
dex (0.98 ꢀ 0.3) when compared with that of celecoxib (0.92 ꢀ 0.2)
while compounds 15b and 15c showed ulcer indexes ¼ 2.25 ꢀ 0.5
and 2.86 ꢀ 0.6, respectively (Table 1).
Chemical shifts are expressed in d-values (ppm) relative to TMS as
an internal standard. Coupling constants (J) are expressed in Hz.
D2O was added to confirm the exchangeable protons. Mass spectra
were measured on an Agilent Triple Quadrupole 6410 QQQ LC/MS
equipped with an ESI (electrospray ionization) source. Elemental
analyses were carried out at the Microanalytical Center of Cairo
University. 2-Bromo-1-arylethanones 9aed [37], sodium arylsulfi-
2.2.4. Analgesic activity
From the analgesic activity of synthesized compounds (Table 2),
the highest analgesic activity in 11aed was recorded for compound
nate 10a,
b
[38] and 2-oxo-N0-(4-sulfamoylphenyl)propane-
hydrazonoyl chloride (13) [39] were prepared according to the
reported method.
11d with ED50 ¼ 69 ꢀ 4.5 and 66 ꢀ 3.8
m
M/kg when compared with
celecoxib (ED50 ¼ 72 ꢀ 1.2 and 70 ꢀ 3.9
mM/kg) after 1 and 2 h,
respectively, this might be contributed to the presence of 4-
bromophenyl (X ¼ Br) and 4-tolyl (Ar ¼ MeeC6H4-) moieties.
With regard to the analgesic activity of 15aed, compound 15c with
4.1.2. Synthesis of 1-aryl-2-arylsulfonyl ethanones 11aed
These compounds were synthesized according to the reported
method [31e33]. To a solution of 2-bromo-1-arylethanone 9ae
d (10 mmol) in absolute ethanol (50 mL), the appropriate sodium
arylsulfinate dihydrate 10a, b (12 mmol) was added. The mixture
was refluxed for 3 h, then left to cool. The reaction mixture was
poured into cold water and the solid product filtered off, washed
with water, dried and finally recrystallized from EtOH to afford
compounds 11aed, respectively.
ED50 ¼ 80 ꢀ 2.8
compared with celecoxib (ED50 ¼ 70 ꢀ 3.9
15b (ED50 ¼ 50 ꢀ 1.2 M/kg) and 15d (ED50 ¼ 69 ꢀ 2.7
m
M/kg showed a significant analgesic activity when
mM/kg) after 2 h whereas
m
m
m
M/kg)
M/kg)
seemed to be more potent than celecoxib (ED50 ¼ 156 ꢀ 4.8
but with a shorter duration (after 0.5 h) (Table 2). However, 16a, b
and 17a, b appeared poor analgesic activity comparing with refer-
ence drug.

420
H.A. Abdel-Aziz et al. / European Journal of Medicinal Chemistry 80 (2014) 416e422
4.1.3. Synthesis of 4-(3-acetyl-5-aryl-4-(arylsulfonyl)-1H-pyrazol-
1-yl)benzenesulfonamides 15aed
4.1.4.1. 1-Phenyl-2-(phenylsulfonyl)ethanone
(73%); m.p. 120e2 ꢂC; IR 3230e2940 (OH) cmꢁ1; 1H NMR (DSMO-
d6) 4.95 (s, 2H, CH2), 7.35e7.37 (m, 3H, ArH), 7.56e7.59 (m, 2H,
oxime(16a). Yield
n
The appropriate 1-aryl-2-(arylsulfonyl) ethanones 11ae
d (10 mmol) was added to a stirred ethanolic sodium ethoxide
solution [prepared from sodium metal (0.23 g, 10 mmol) and 50 mL
of absolute ethanol]. After stirring for 20 min, 2-oxo-N0-(4-
sulfamoylphenyl)propanehydrazonoyl chloride (13) (2.76 g,
10 mmol) was added and the reaction mixture was left to stir at
room temperature for 12 h. Then added to cold water, the solid
product was collected by filtration, washed with water and dried.
Recrystallization from ethanol afforded 1H-pyrazoles 15aed.
d
ArH), 7.64e7.66 (m, 2H, ArH), 7.69e7.72 (m, 1H, ArH), 7.75e7.77 (m,
2H, ArH), 11.79 (s, D2O exchangeable, 1H, OH); 13C NMR (DSMO-d6)
d
51.37, 126.34, 127.77, 128.18, 128.96, 129.01, 133.83, 134.50, 139.71,
145.54; MS (ESI) m/z 275.1 (Mþ). Anal. Calcd for C14H13NO3S
(275.32): C, 61.07; H, 4.76; N, 5.09. Found: C, 61.30; H, 4.85; N, 5.11.
4.1.4.2. 1-(4-Methylphenyl)-2-(phenylsulfonyl)ethanone oxime(16b).
Yield (68%); m.p. 155e7 ꢂC; IR
n ;
3246e2922 (OH) cmꢁ1 1H NMR
(DSMO-d6)
d
2.32 (s, 3H, CH3), 4.92 (s, 2H, CH2), 7.16 (d, J ¼ 8 Hz, 2H,
4.1.3.1. 4-(3-Acetyl-5-phenyl-4-(phenylsulfonyl)-1H-pyrazol-1-yl)
ArH), 7.54 (d, J ¼ 8 Hz, 2H, ArH), 7.56e7.59 (m, 2H, ArH), 7.69e7.72
(m, 1H, ArH), 7.75e7.76 (m, 2H, ArH), 11.66 (s, D2O exchangeable,
benzenesulfonamide(15a). Yield (54%); m.p. 248e50 ꢂC; IR
n
3272
(NH2), 1705 (C]O) cmꢁ1
;
1H NMR (DSMO-d6)
d
2.60 (s, 3H, CH3),
1H, OH); 13C NMR (DSMO-d6)
d 20.76, 51.38, 126.27, 127.76, 127.88,
7.42e7.47 (m, 5H, ArH), 7.49 (s, 2H, D2O exchangeable, 2H, NH2),
7.58 (d, J ¼ 8.5 Hz, 2H, ArH), 7.61e7.62 (m, 2H, ArH), 7.67e7.73 (m,
1H, ArH), 7.80 (d, J ¼ 8.5 Hz, 2H, ArH), 7.91 (d, J ¼ 7.0 Hz, 2H, ArH);
128.15, 128.77, 131.75, 133.79, 138.53, 139.73, 145.42; MS (ESI) m/z
289.3 (Mþ). Anal. Calcd for C15H15NO3S (289.35): C, 62.26; H, 5.23;
N, 4.84. Found: C, 62.27; H, 5.17; N, 4.97.
13C NMR (DSMO-d6)
d 28.20, 121.04, 126.37, 126.87, 127.37, 127.99,
128.89, 129.97, 130.67, 133.35, 140.26, 141.75, 144.43, 147.93, 148.28,
192. MS (ESI) m/z 479.8 (Mþ ꢁ 1). Anal. Calcd for C23H19N3O5S2
(481.54): C, 57.37; H, 3.98; N, 8.73. Found: C, 57.56; H, 4.07; N, 8.79.
4.1.5. Synthesis of 1-(1-(aryl)-2-(phenylsulfonyl)ethylidene)-2-
phenylhydrazines 17a, b
To a solution of the appropriate 1-aryl-2-arylsulfonyl ethanones
11a, b (10 mmol) in ethanol (50 mL) and phenyl hydrazine (1.08 g,
10 mmol), catalytic amount of acetic acid were added. The reaction
mixture was refluxed for 1 h. After cooling, the precipitated product
was filtered off, washed with ethanol and dried. Recrystallization
from EtOH afforded compounds 17a, b, respectively.
4.1.3.2. 4-(3-Acetyl-4-(phenylsulfonyl)-5-p-tolyl-1H-pyrazol-1-yl)
benzenesulfonamide(15b). Yield (58%); m.p. 260e2 ꢂC; IR
n
3265
2.34 (s, 3H, CH3),
2.59 (s, 3H, CH3), 7.22e7.23 (m, 2H, ArH), 7.30e7.34 (m, 2H, ArH),
7.51 (s, 2H, D2O exchangeable, 2H, NH2), 7.55e7.92 (m, 9H, ArH); 13
NMR (DSMO-d6) 20.97, 28.23, 120.97, 126.40, 126.88, 127.37,
(NH2), 1702 (C]O) cmꢁ1 1H NMR (DSMO-d6)
; d
C
d
4.1.5.1. 1-Phenyl-2-(1-phenyl-2-(phenylsulfonyl)ethylidene)hydrazi-
127.97, 128.63, 128.88, 129.16, 129.20, 129.26, 129.65, 130.53, 133.31,
133.91, 139.56, 140.35, 141.83, 144.39, 144.87, 148.02, 148.37, 192.20;
MS (ESI) m/z 493.1 (Mþ ꢁ 1). Anal. Calcd for C24H21N3O5S2 (495.57):
C, 58.17; H, 4.27; N, 8.48. Found: C, 58.36; H, 4.18; N, 8.33.
ne(17a). Yield (66%); m.p. 160e2 ꢂC; IR 3349 (NH) cmꢁ1; 1H NMR
n
(DSMO-d6) d 5.17 (s, 2H, CH2), 6.82e6.84 (m, 1H, ArH), 7.13e7.14 (m,
2H, ArH), 7.23e7.30 (m, 5H, ArH), 7.51e7.54 (m, 2H, ArH), 7.59e7.60
(m, 1H, ArH), 7.70e7.72 (m, 2H, ArH), 7.88e7.90 (m, 2H, ArH), 9.75
(s, D2O exchangeable, 1H, NH); 13C NMR (DSMO-d6)
d 51.75, 112.95,
4.1.3.3. 4-(3-Acetyl-5-(4-bromophenyl)-4-(phenylsulfonyl)-1H-pyr-
119.85, 125.60, 127.34, 127.93, 128.10, 128.90, 128.96, 129.35, 133.89,
azol-1-yl)benzenesulfonamide(15c). Yield (52%); m.p. 265e7 ꢂC; IR
137.557, 139.38, 144.69; MS (ESI) m/z 349.5 (Mþ ꢁ 1). Anal. Calcd for
n
3270 (NH2), 1706 (C]O) cmꢁ1; 1H NMR (DSMO-d6)
d
2.58 (s, 3H,
C20H18N2O2S (350.43): C, 68.55; H, 5.18; N, 7.99. Found: C, 68.59; H,
CH3), 7.45 (d, J ¼ 8 Hz, 2H, ArH), 7.50 (s, 2H, D2O exchangeable, 2H,
5.04; N, 8.12.
NH2), 7.60e7.76 (m, 7H, ArH), 7.84 (d, J ¼ 8.5 Hz, 2H, ArH), 7.94 (d,
J ¼ 7.5 Hz, 2H, ArH); 13C NMR (DSMO-d6)
d
28.07, 121.25, 123.78,
4.1.5.2. 1-Phenyl-2-(2-(phenylsulfonyl)-1-p-tolylethylidene)hydrazi-
126.36, 126.49, 127.01, 127.43, 128.90, 131.07, 132.81, 133.40, 140.12,
141.65, 144.58, 146.94, 148.10, 191.88; MS (ESI) m/z 558.9 (Mþ ꢁ 1).
Anal. Calcd for C23H18BrN3O5S2 (560.44): C, 49.29; H, 3.24; N, 7.50.
Found: C, 49.24; H, 3.40; N, 7.37.
ne(17b). Yield (70%); m.p. 147e9 ꢂC; IR 3344 (NH) cmꢁ1; 1H NMR
n
(DSMO-d6)
d 2.29 (s, 3H, CH3), 5.19 (s, 2H, CH2), 6.80e6.83 (m, 1H,
ArH), 7.08e7.12 (m, 4H, ArH), 7.22e7.24 (m, 2H, ArH), 7.53e7.54 (m,
2H, ArH), 7.60e7.61 (m, 3H, ArH), 7.88e7.89 (m, 2H, ArH), 9.64 (s,
D2O exchangeable, 1H, NH); 13C NMR (DSMO-d6)
d 20.68, 51.79,
4.1.3.4. 4-(3-Acetyl-5-(4-bromophenyl)-4-tosyl-1H-pyrazol-1-yl)
112.85,119.68,125.59,128.08,128.56,128.90,129.56,133.85,134.88,
benzenesulfonamide(15d). Yield (57%); m.p. 271e3 ꢂC; IR
n
3259
136.74, 139.41, 144.78; MS (ESI) m/z 364.3 (Mþ). Anal. Calcd for
(NH2), 1706 (C]O) cmꢁ1
;
1H NMR (DSMO-d6)
d
2.39 (s, 3H, CH3),
C21H20N2O2S (364.46): C, 69.20; H, 5.53; N, 7.69. Found: C, 69.46; H,
2.58 (s, 3H, CH3), 7.42e7.43 (m, 3H, ArH), 7.50 (s, 2H, D2O
exchangeable, 2H, NH2), 7.59e7.65 (m, 4H, ArH), 7.74e7.85 (m, 5H,
5.55; N, 7.82.
ArH); 13C NMR (DSMO-d6)
d
21.05, 28.10, 121.70, 23.75, 126.40,
4.2. Anti-inflammatory activity
126.49, 126.98, 127.559, 128.05, 129.33, 129.64, 131.06, 131.78,
132.81, 138.80, 140.13, 143.96, 144.55, 146.63, 148.07, 191.92; MS
(ESI) m/z 573.4 (Mþ ꢁ 1). Anal. Calcd for C24H20BrN3O5S2 (574.47):
C, 50.18; H, 3.51; N, 7.31. Found: C, 49.96; H, 3.46; N, 7.42.
Male SpraugeeDawley rats weighing 250 g were purchased
from local source and kept at room temperature (22 ꢀ 2 ꢂC) in a
light-controlled room with an alternating 12 h light/dark cycle.
They were fasted with free access to water at least 16 h prior to
experiments. The tested compounds were prepared as suspension
in vehicle (0.5% methyl cellulose) and celebrex (Celecoxib) was
used as a standard drug. The positive control group animals
received the reference drug while the negative control received
only the vehicle. The anti-inflammatory activity was evaluated
using in vivo rat carrageenan-induced foot paw edema model re-
ported previously [40]. Edema was produced by injecting 0.2 mL of
4.1.4. Synthesis of 1-(aryl)-2-(phenylsulfonyl)ethanone oximes 16a,
b
A mixture of the appropriate 1-aryl-2-arylsulfonyl ethanones
11a, b (10 mmol), hydroxyl amine hydrochloride (1.1 g, 15 mmol)
and anhydrous sodium acetate (1.2 g, 15 mmol) in ethanol (50 mL)
was refluxed for 1 h, then left to cool. The reaction mixture was
poured into cold water and the solid product was filtered off,
washed with water, dried and finally recrystallized from EtOH to
afford compounds 16a, b, respectively [31,36].
a solution of 1%
l-carrageenan in the hind paw. The rats were
injected intraperitoneally with 1 mL suspension in 0.5% methyl

H.A. Abdel-Aziz et al. / European Journal of Medicinal Chemistry 80 (2014) 416e422
421
cellulose of the tested compounds and reference drug. Paw volume
Acknowledgment
was measured by water displacement with a plethysmometer (UGO
BASILE) before, 1 and 2 h after treatment. The percentage was
calculated by the following equation: anti-inflammatory activity
(%) ¼ (1 ꢁ D/C) ꢁ 100, where D represents the difference in paw
volume before and after drug was administered to the rats, and C
stands for the difference of volume in the control groups [40].
Values reported as mean ꢀ s.e.m., significant differences were
calculated using ANOVA.
The authors would like to extend their sincere appreciation to
the Deanship of Scientific Research at King Saud University for its
funding of this research through the Research Group Project no.
RGP-VPP-321.
Appendix A. Supplementary data
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.ejmech.2014.04.
065. These data include MOL files and InChiKeys of the most
important compounds described in this article.
4.2.1. Determination of LD50 for the active anti-inflammatory
compounds
Male mice were divided into various groups and test com-
pounds were administered in various doses, intraperitoneally.
Following treatments, the animals were observed for up to 6 h
continuously and were then kept under observation for 72 h. All
behavioral changes and death during the observation periods were
recorded. The percentage of death at each dose level was then
calculated, converted to probits and the LD50 (mM/kg) values were
calculated [41].
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