Synthesis and Biological Evaluation of New Diarylpyrazole and Triarylimidazoline Derivatives as Selective COX-2 Inhibitors

Article abstract of DOI:10.1002/ardp.201600386

New series of diarylpyrazoles 8a–f and triarylimidazoline-5-ones 11a–g were synthesized and evaluated for their in vitro cyclooxygenase-1 (COX-1) and COX-2 inhibitory activity and in vivo anti-inflammatory activity. The synthesized compounds showed good selectivity for COX-2; compounds 8a, 8d, 8f, 11a, and 11c exhibited the highest COX-2 selectivity indexes (SI = 4.77–5.43) compared to the reference drug celecoxib (SI = 7.8). All compounds showed good in vivo anti-inflammatory activity, especially compounds 8a, 8f, 11c, and 11d, which also showed some similarities to the time interval pattern of celecoxib at all different time intervals (1, 3, and 6 h).

Full text of DOI:10.1002/ardp.201600386

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Arch. Pharm. Chem. Life Sci. 2017, 350, e1600386
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Full Paper
Synthesis and Biological Evaluation of New Diarylpyrazole and
Triarylimidazoline Derivatives as Selective COX-2 Inhibitors
Khaled R.A. Abdellatif
1,2, Mohamed A. Abdelgawad1,3, Madlen B. Labib1, and Taha H. Zidan
1
Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Beni-Suef University,
Beni-Suef, Egypt
Department of Pharmaceutical Sciences, Ibn Sina National College for Medical Studies, Jeddah, Saudi
2
3
Arabia
Department of Pharmaceutical Chemistry, College of Pharmacy, Aljouf University, Sakaka, Aljouf, Saudi
Arabia
New series of diarylpyrazoles 8a–f and triarylimidazoline-5-ones 11a–g were synthesized and
evaluated for their in vitro cyclooxygenase-1 (COX-1) and COX-2 inhibitory activity and in vivo anti-
inflammatory activity. The synthesized compounds showed good selectivity for COX-2; compounds 8a,
8d, 8f, 11a, and 11c exhibited the highest COX-2 selectivity indexes (SI ¼ 4.77–5.43) compared to the
reference drug celecoxib (SI ¼ 7.8). All compounds showed good in vivo anti-inflammatory activity,
especially compounds 8a, 8f, 11c, and 11d, which also showed some similarities to the time interval
pattern of celecoxib at all different time intervals (1, 3, and 6 h).
Keywords: Anti-inflammatory / Imidazoline / Pyrazole / Selective COX-2 inhibitor
Received: December 19, 2016; Revised: May 10, 2017; Accepted: May 15, 2017
DOI 10.1002/ardp.201600386
Additional supporting information may be found in the online version of this article at the publisher’s web-site.
:
complications [11–15]. After the launch of several selective
COX-2 inhibitors as successful anti-inflammatory agents,
Introduction
Non-steroidalanti-inflammatory drugs(NSAIDs)suchasaspirin
(1) and indomethacin (2) are used to treat pain, inflammation,
andfever[1]. Alltheseagents producetheirtherapeuticeffects
through inhibition of cyclooxygenases enzyme (COX) which
exists in two isozymes (COX-1 and COX-2) [2–4]. Inhibition of
COX-1 isozyme leads to renal and gastrointestinal side effects,
while isozymeCOX-2inhibition leads to therapeutic effects [5].
TheclassicalNSAIDslikeaspirin(1)andindomethacin(2)inhibit
both COX-1 and COX-2 isozymes leading to undesirable side
effects [6–10]. Celecoxib (3) is a selective COX-2 inhibitor that
appeared on the world market as a safer replacement
for the classical NSAIDs due to its less gastrointestinal
rofecoxib (4) was withdrawn from the market with subsequent
evidence of atherothrombotic cardiovascular side effects
[16–18]. Fortunately, further studies revealed that cardiac
adverse effects are related to certain drug structures and their
metabolic products rather than COX-2 physiological role. For
example, rofecoxib (4) was said to produce highly reactive
oxidized metabolites leading to accumulation of oxidized
LDL [19, 20]. Most of the reported selective COX-2 inhibitors
possess two vicinal aryl groups attached to a heterocyclic core,
oneof thetwo arylringscontains the essentialpharmacophore
for COX-2 selectivity: SO2NH2 or SO2CH3 [21–27]. In a recent
study [28], we reported some triarylpyrazoline derivatives 5
with good anti-inflammatory activity and good safety profile
(Fig. 1).
Our aim in this work is to continue our recent study to
obtain other newly synthesized compounds with good anti-
inflammatory activity. Accordingly, we now describe the
synthesis, in vitro evaluation as COX-1/COX-2 inhibitors and in
vivo anti-inflammatory (AI) activity for two new series of
compounds: (i) diarylpyrazole compounds 8a–f with vicinal
Correspondence: Dr. Khaled R. A. Abdellatif, Department of
Pharmaceutical Organic Chemistry, Faculty of Pharmacy,
Beni-Suef University, Beni-Suef 62514, Egypt.
E-mail: khaled.ahmed@pharm.bsu.edu.eg
Fax: þ20-82-2317958
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O
Me
OH
O
COOH
O
N
SO2NH2
O
O
N
N
Cl
F3C
Aspirin (1)
(2)
Indomethacin
(3)
Celecoxib
H3CO2S
Ar
N
N
SO2Me
O
O
(5)
R
R = COOH, SO2NH2
Ar = C6H5, 4-FC6H4 , 4-ClC6H4 , 3-OCH3C6H4 , 4-
OCH3C6H4, 3,4 (OCH3)2C6H3 , 3,4,5 (OCH3)3C6H2 , 2-
thienyl
Rofecoxib (4)
-
-
Figure 1. Chemical structures of aspirin (1), indomethacin (2), celecoxib (3), rofecoxib (4), and reported triarylpyrazoline
derivatives (5).
diaryl rings containing SO2CH3 as an important pharmaco-
phore for COX-2 selectivity, and (ii) triarylimidazoline
derivatives 11a–g which also have two vicinal diaryl rings,
celecoxib CF3 was replaced by a bulky lipophilic arylidene
group and possess SO2NH2 moiety required for COX-2
selectivity (Fig. 2).
were obtained in good yields (60–85%) via heating oxazo-
lones 10a–g with sulfanilamide in glacial acetic acid
(Scheme 2).
Biological evaluation
In vitro COX inhibition assay
The in vitro COX-1/COX-2 isozyme inhibition studies measure the
ability of target compounds to inhibit ovine COX-1 and human
recombinant COX-2 using an enzyme immunoassay (EIA) [31].
The efficacy of the tested compounds is expressed as the
concentration causing 50% inhibition (IC50). In vitro COX-1 and
COX-2 isozyme inhibition studies (Table 1) showed that all the
tested compounds are weak inhibitors of COX-1 isozyme
(IC50 ¼ 3.9–13.2 mM range). In contrast, they have good COX-2
isozyme inhibitory activities (IC50 ¼ 0.74–4.74 mM) in comparison
with the reference drug celecoxib (IC50 ¼ 0.87 mM). Additionally,
the results showed COX-2 selectivity indexes (SI) ꢀ calculated as
Results and discussion
Chemistry
The (E)-3-dimethylamino-1-(4-methylsulfonylphenyl)-prop-2-
en-1-one(6)waspreparedfromp-methylsulfonylacetophenone
and dimethylformamide-dimethylacetal (DMF-DMA) according
topreviously reported procedures [29]. Heating 6 withdifferent
substituted phenylhydrazine hydrochlorides 7a–f in ethanol
under reflux condition afforded the target diarylpyrazole
compounds (8a–f) in good yields (55–77%) (Scheme 1).
Additionally, p-methoxybenzoylglycine 9 was synthesized
via heating mixture of glycine in sodium hydroxide (10%) with
4-methoxybenzoyl chloride as reported before [30]. Cyclo-
condensation of 9 with different aromatic aldehydes in acetic
anhydride containing catalytic amount of sodium acetate
afforded (E)-4-arylmethylene-2-(4-methoxyphenyl)-oxazol-
5(4H)-ones 10a–g [29]. The triarylimidazoline-5-ones 11a–g
IC50
(COX-1)/IC50
(COX-2)
ꢀ
in
the
range
of
2.58–5.43 in comparison with the selective COX-2 inhibitor,
celecoxib (SI ¼ 7.8). Within the diarylpyrazole compounds (8a–f),
when the phenyl group attached to position 1 of the central
pyrazole ring is unsubstituted (8a), para substituted with COOH
(8d) or para substituted with SO2NH2 (8f), the potency against
COX-2 isozyme was high (IC50 ¼ 1.52, 1.27 and 1.11 mM,
respectively) and consequently high COX-2 selectivity indexes
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Arch. Pharm. Chem. Life Sci. 2017, 350, e1600386
Diarylpyrazole and Triarylimidazoline Derivatives as COX-2 Inhibitors
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O
SO2CH3
R
H2NO2S
H2NO2S
N
N
N
N
N
N
O
CF3
H
Ar
Celecoxib
11a–g
8a–f
Ar = C6H5; 3-OCH3C6H4; 4-OCH3C6H4;
3,4-(OCH3)2C6H3; 3,4,5-(OCH3)3C6H2;
2-thienyl; 3-pyridiyl.
R = H, 2-COOH, 3-COOH, 4-
COOH, 4-SO2CH3, 4-
SO2NH2
Figure 2. Representive examples of celecoxib (3) as selective COX-2 inhibitors and designed compounds 8a–f and 11a–g.
(SI ¼ 4.80, 5.43 and 4.77, respectively) were obtained. Moreover,
within the triarylimidazoline-5-ones 11a–g, the unsubstituted
phenyl derivative (11a), the para methoxyphenyl derivative (11c)
and the dimethoxyphenyl derivative (11d) were the highest
potent derivatives against COX-2 isozyme (IC50 ¼ 0.87, 0.74 and
1.42 mM, respectively) and showed the highest COX-2 selectivity
indexes (SI ¼ 4.83, 5.27 and 3.59, respectively).
paw-volume changes at 1, 3 and 6 h after carrageenan injection as
presented in Table 1. A comparable study of the anti-inflamma-
tory activity of the test compounds relative to celecoxib as a
reference drug at the different time intervals revealed that, for
pyrazole compounds 8a–f, after 1 h they showed moderate anti-
inflammatory activity (AI ¼ 34–70%), and the most active com-
pounds were 8a (AI ¼ 70%) and 8b (AI ¼ 69%) in comparison with
celecoxib (AI ¼ 42%). While after 3 h, compounds 8a–f showed
anti-inflammatory activity (AI ¼ 29–63%), 8b and 8f showed the
highestanti-inflammatory activity (63% forboth). While after6 h,
8a–f showed anti-inflammatory activity (AI ¼ 29–56%).
In vivo anti-inflammatory activity
The in vivo anti-inflammatory activity (AI) of diarylpyrazoles 8a–f,
triarylimidazoline-5-ones 11a–g, and celecoxib was determined
using carrageenan-induced rat paw edema assay according to the
reported procedure [32] using a dose of 50 mg/kg body weight.
The anti-inflammatory activity was then calculated based on
The imidazoline derivatives11a–g showed anti-inflammatory
activityafter 1 hofcarrageenaninjection (AI ¼ 41–87%)andthe
mostpotentCOX-2derivatives(11cand11d)showedthehighest
SO2CH3
SO2CH3
R
+
a
NHNH2.HCl
N
R
O
N
N
7a–f
6
8a–f
b, R = 2-COOH;
a, R = H;
c, R = 3-COOH; d, R = 4-COOH;
e, R = 4-SO2CH3; f, R = 4-SO2NH2.
Scheme 1. Synthesis of compounds 8a–f. Reagents and conditions: (a) Ethanol 95%, reflux, 24 h.
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Ar
O
Ar
O
H
O
N
COOH
O
N
N
SO2NH2
a
N
b
O
O
a, Ar = C6H5;
O
b, Ar = 3-(OCH3)C6H4;
c, Ar = 4-(OCH3)C6H4;
9
11a–g
10a–g
d, Ar = 3,4-(OCH3)2C6H3;
e, Ar = 3,4,5-(OCH3)3C6H2;
f, Ar = 2-thienyl;
g, Ar = 3-pyridinyl.
Scheme 2. Synthesis of compounds 11a–g. Reagents and conditions: (a) Appropriate Ar-CHO, CH3COONa, acetic anhydride, water
bath, 100°C, 6 h. (b) H2NC6H4SO2NH2, CH3COONa, glacial acetic acid, reflux, 24 h.
AI activities (AI ¼ 87 and 75%, respectively). After 3 h, 11a–g
showed anti-inflammatory activity (AI ¼ 32–51%), compounds
11a and 11f showedthe highestactivity(AI ¼ 51.49%). After 6 h,
compounds 11a–gshowedmoderateanti-inflammatory activity
(AI ¼ 35–64%), the most active compounds were 11c and 11d
(AI ¼ 64 and 60%, respectively). Additionally, it was noted that
all compounds 8a–f and 11a–g significantly decreased inflam-
mation as compared with carragenan at alltime intervals and
were significantly different from each other. Compounds8a, 8f,
11c, and 11d along the different time intervals (1, 3, and 6 h)
Table 1. In vitro COX-1 (IC50%), COX-2 (IC50) inhibition, SI and in vivo anti-inflammatory activity (% inhibition) of
diarylpyrazoles 8a–f and triarylimidazoline-5-ones 11a–g in comparison with reference drug celecoxib.
% Inhibitionc)
Compound
no.
COX-1
COX-2
SIb)
(IC50% mM)a)
(IC50% mM)a)
1 h
3 h
6 h
8a
8b
8c
8d
8e
8f
11a
11b
11c
11d
11e
11f
11g
Celecoxib
7.3
4.9
10.9
6.9
11.4
5.3
4.2
9.8
3.9
5.1
13.2
8.6
10.1
7.7
1.52
1.42
4.23
1.27
3.22
1.11
0.87
3.51
0.74
1.42
4.74
2.33
2.87
0.87
4.80
3.45
2.58
5.43
3.54
4.77
4.83
2.79
5.27
3.59
2.78
3.69
3.52
7.8
70
69
38
34ꢁ
34ꢁ
66
41
71
87
75
71
45
50ꢁ
42
49
63
53
44ꢁ
29ꢁ
63
51
43
35
41
33
49
34ꢁ
51
54
56
38
29ꢁ
28ꢁ
55
35
36
64
60
35
38
26ꢁ
63
a)
The concentration of test compound that produces 50% inhibition of COX-1, COX-2 enzyme; the result is the mean of two
values obtained by assay of enzyme kits obtained from Cayman Chemicals Inc., Ann Arbor, MI, USA.
The in vitro COX-2 selectivity index (COX-1/COX-2).
Inhibitory activity of compounds determined at 1, 3, 6 h after carrageenan injection. The results were expressed using two-way
ANOVA followed by post-hoc Tukey’s test for multiple pairwise comparison between different compounds at P < 0.01.
`Significantly different from celecoxib.
b)
c)
ꢁ
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Arch. Pharm. Chem. Life Sci. 2017, 350, e1600386
Diarylpyrazole and Triarylimidazoline Derivatives as COX-2 Inhibitors
Archiv der Pharmazie
showed some similarities to the time interval pattern of
celecoxib (Fig. 3).
in vivo anti-inflammatory activity. Structure–activity rela-
tionship and biological studies revealed that (i) all
compounds were more selective COX-2 than COX-1 inhib-
itors, (ii) most of the evaluated compounds showed good
anti-inflammatory activity especially compounds 8a, 8f, 11c,
and 11d which along the different time intervals (1, 3, and
6 h) showed also some similarities to the time interval
pattern of celecoxib, and (iii) within each series, the most
potent COX-2 inhibitor derivatives had good anti-inflam-
matory activity (8a, 8d, and 8f for diarylpyrazoles 8a–f, 11a,
11c, and 11d for triarylimidazoline-5-ones 11a–g).
A common structural feature of the most active diary-
lpyrazoles 8a and 8f and triarylimidazolines 11c and 11d is the
occurrence of a central five—membered heterocyclic ring
attached to two vicinal aryl rings. Also, presence of lipophilic
group’s methanesulfonyl (SO2CH3) and/or sulfonamide
(SO2NH2) moieties attached to aryl groups at position-4
which is important for COX-2 selectivity. Additionally, the
presence of methoxy group at para position of arylidine
moiety in 11c and 11d is essential for anti-inflammatory
activity.
Experimental
Conclusion
Chemistry
General
Melting points were determined on
capillary apparatus and are uncorrected. Infrared (IR) spectra
were recorded as films on KBr plates using a Nicolet 550 Series
II Magna FT-IR spectrometer. 1H NMR and 13C NMR spectra
The present study describes the synthesis of two new series
of diarylpyrazoles 8a–f and triarylimidazoline-5-ones 11a–g
for evaluation as selective COX-2 inhibitors and anti-
inflammatory agents. The newly prepared compounds were
tested for their in vitro COX-1/COX-2 inhibitory activity and
a Thomas-Hoover
Figure 3. Line graph of two-way ANOVA analysis for diarylpyrazoles 8a–f and triarylimidazoline-5-ones 11a–g in comparison with
reference drug celecoxib.
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were measured on a Bruker Avence III 400 MHz spectropho-
tometer, Faculty of Pharmacy, Beni-Suef University, Egypt in
CDCl3 or DMSO-d6, where J (coupling constant) values are
estimated in Hertz (Hz). Microanalyses were performed for C,
H, and N and were carried out on a PerkinElmer 2400 analyzer
(PerkinElmer, Norwalk, CT, USA) at the Regional Center for
Mycology and Bio-Technology, Al-azhar University, Egypt. All
data were within þ0.4% of the theoretical values. The
C-4), 127.6 (methylsulfonylphenyl C-2, C-6), 128.9 (CH, benzoic
acid C-3), 129.2 (CH, methylsulfonylphenyl C-3, C-5), 129.6 (CH,
benzoic acid C-5), 130.8 (C, benzoic acid C-1), 130.9 (CH,
benzoic acid C-6), 132.7 (CH, benzoic acid C-4), 135.1
(C, methylsulfonylphenyl C-1), 138.8 (C, methylsulfonylphenyl
C-4), 140.4 (C, benzoic acid C-2), 140.6 (CH, pyrazole C-3), 142.1
(C, pyrazole C-5), 167.2 (C, COOH); MS m/z (ESþ) 342 (Mþ,
87.06%). Anal. calcd. for C17H14N2O4S; C, 59.64; H, 4.12; N,
8.18: Found; C, 59.83; H, 4.16; N, 8.34.
propene-1-one (6) [29], p-methoxybenzoylglycine
9 and
oxazolones 10a–c [30] were prepared according to the
previously reported procedures.
The InChI codes of the investigated compounds together
with some biological activity data are provided as Supporting
Information.
3-[5-(4-Methylsulfonylphenyl)-1H-pyrazol-1-yl]benzoic
acid (8c)
Yield 55%; pale yellow powder; mp 273–275°C; IR (KBr): 3433
(COOH), 3073 (C–H aromatic), 2927 (C–H aliphatic), 1684
(C O), 1604 (C N), 1310, 1154 (SO ) cmꢀ1; 1H NMR (DMSO-d6,
–
–
–
–
2
General procedure for synthesis of 5-(4-
methylsulfonylphenyl)-1-aryl-1H-pyrazoles (8a–f)
400 MHz, d ppm): 3.25 (s, 3H, SO2CH3), 6.86 (s, 1H, pyrazole H-
4), 7.42 (d, J ¼ 8.4 Hz, 2H, methylsulfonylphenyl H-3, H-5), 7.53
(d, J ¼ 7.2 Hz, 2H, benzoic acid H-4, H-5), 7.89 (s, pyrazole H-3),
7.92 (d, J ¼ 7.6 Hz, 2H, methylsulfonylphenyl H-2, H-6), 7.98
(d, J ¼ 8.0 Hz, 2H, benzoic acid H-2, H-6), 13.4 (s, 1H, COOH,
D2O exchangeable); 13C NMR (DMSO-d6, 100 MHz, d ppm):
43.7 (CH3, methylsulfonylcarbon), 110.4 (CH, pyrazole C-4),
125.3 (CH, benzoic acid C-2, C-4), 127.8 (CH, benzoic acid C-5,
C-6), 129.7 (CH, methylsulfonylphenyl C-2, C-6), 130.8
(C, benzoic acid C-1), 131.4 (CH, methylsulfonylphenyl C-3,
C-5), 135.0 (C, methylsulfonylphenyl C-1), 140.9 (C, benzoic
acid C-3), 141.6 (C, methylsulfonylphenyl C-4), 141.6 (CH,
pyrazole C-3), 143.1 (C, pyrazole C-5), 167.0 (C, COOH); MS m/z
(ESþ) 342 (Mþ, 100%). Anal. calcd. for C17H14N2O4S; C, 59.64;
H, 4.12; N, 8.18: Found; C, 59.87; H, 4.19; N, 8.30.
A
mixture of (E)-3-dimethylamino-1-(4-methylsulfonyl-
phenyl)-prop-2-en-1-one 6 (3 mmol) and the appropriate
substituted phenylhydrazine hydrochloride 7a–f (3 mmol) in
ethanol 95% was refluxed for 24 h. The reaction was
monitored by TLC. After the reaction was completed, reaction
mixture was poured onto crushed ice; the resulting precipi-
tate was filtered, crystallized from ethanol to give compounds
8a–f in good yield (60–70%).
5-(4-Methylsulfonylphenyl)-1-phenyl-1H-pyrazole (8a)
Yield 65%; dark yellow powder; mp 117–119°C; IR (KBr): 3103
–
–
(C–H aromatic), 2924 (C–H aliphatic), 1597 (C N), 1305, 1149
1
(SO2) cmꢀ1; H NMR (DMSO-d6, 400 MHz, d ppm): 3.24 (s, 3H,
SO2CH3), 6.83 (s, 1H, pyrazole H-4), 7.29 (d, J ¼ 6.8 Hz, 2H,
phenyl H-3, H-5), 7.38–7.51 (m, 5H, methylsulfonylphenyl H-3,
H-5, phenyl H-2, H-4, H-6), 7.83 (s, 1H, pyrazole H-3), 7.91
(d, J ¼ 7.2 Hz, 2H, methylsulfonylphenyl H-2, H6); 13C NMR
(DMSO-d6, 100 MHz, d ppm): 43.67 (CH3, methanesulphonyl-
carbon), 109.6 (CH, pyrazole C-4), 125.8 (CH, phenyl C-2, C-6),
127.6 (CH, phenyl C-4), 128.5 (CH, methylsulfonylphenyl C-2,
C-6), 129.6 (CH, methylsulfonylphenyl C-3, C-5), 129.7 (CH,
phenyl C-3, C-5), 135.3 (C, methylsulfonylphenyl C-1), 139.9 (C,
phenyl C-1), 140.6 (C, methylsulfonylphenyl C-4), 140.9 (CH,
pyrazole C-3), 141.3 (C, pyrazole C-5); MS m/z (ESþ) 298
(Mþ, 100%). Anal. calcd. for C16H14N2O2S: C, 64.41; H, 4.73; N,
9.39: Found; C, 64.58; H, 4.89; N, 9.48.
4-[5-(4-Methylsulfonylphenyl)-1H-pyrazol-1-yl]benzoic
acid (8d)
Yield 65%; pale yellow powder; mp 120–122°C; IR (KBr); 3428
(COOH), 3071 (C–H aromatic), 2923 (C–H aliphatic), 1686
(C O), 1604 (C N), 1294, 1148 (SO ) cmꢀ1; 1H NMR (DMSO-d6,
–
–
–
–
2
400 MHz, d ppm): 3.23 (s, 3H, SO2CH3), 6.84 (s, 1H, pyrazole H-
4), 7.26 (d, J ¼ 8.0 Hz, 2H, benzoic acid H-3, H-5), 7.48 (d,
J ¼ 8.0 Hz, 2H, methylsulfonylphenyl H-3, H-5), 7.85 (s, 1H,
pyrazole H-3), 7.90 (d, J ¼ 8.4 Hz, 2H, methylsulfonylphenyl
H-2, H-6), 7.98 (d, J ¼ 8.0 Hz, 2H, benzoic acid H-2, H-6), 13.04
(s, 1H, COOH, D2O exchangeable); 13C NMR (DMSO-d6,
100 MHz, d ppm): 43.3 (CH3, methanesulfonylcarbon), 109.8
(CH, pyrazole C-4), 124.8 (CH, benzoic acid C-3, C-5), 127.7
(CH, methylsulfonylphenyl C-2, C-6), 129.6 (CH, methylsulfo-
nylphenyl C-3, C-5), 130.6 (CH, benzoic acid C-2, C-6), 135.2
(C, benzoic acid C-1), 136.5 (C, methylsulfonylphenyl C-1),
140.7 (C, methylsulfonylphenyl C-4), 141.1 (CH, pyrazole C-3),
141.2 (C, benzoic acid C-4), 141.4 (C, pyrazole C-5), 170.5 (C,
COOH); MS m/z (ESþ) 342 (Mþ, 100%). Anal. calcd. for
2-[5-(4-Methylsulfonylphenyl)-1H-pyrazol-1-yl]benzoic
acid (8b)
Yield 60%; pale yellow powder; mp 227–229°C; IR (KBr): 3430
(COOH), 3072 (C–H aromatic), 2926 (C–H aliphatic), 1683
(C O), 1603 (C N), 1311, 1154 (SO ) cmꢀ1; 1H NMR (DMSO-d6,
–
–
–
–
2
400 MHz, d ppm): 3.20 (s, 3H, SO2CH3), 6.80 (s, 1H, pyrazole H-
4), 7.25 (m, 1H, benzoic acid H-5), 7.45 (d, J ¼ 7.2 Hz, 2H,
methylsulfonylphenyl H-3, H-5), 7.48–7.52 (m, 2H, benzoic
acid H-4, H-6), 7.75 (s, 1H, pyrazole H-3), 7.86 (d, J ¼ 7.2 Hz, 3H,
methylsulfonylphenyl H-2, H-6, benzoic acid H-3), 12.95 (s, 1H,
COOH, D2O exchangeable); 13C NMR (DMSO-d6, 100 MHz, d
ppm): 43.7 (CH3, methanesulfonylcarbon), 108.3 (CH, pyrazole
C
17H14N2O4S; C, 59.64; H, 4.12; N, 8.18: Found; C, 59.79;
H, 4.21; N, 8.32.
1,5-bis(4-Methylsulfonylphenyl)-1H-pyrazole (8e)
Yield 77%; light brown powder; mp 165–167°C; IR (KBr): 3099
–
(C–H aromatic), 2926 (C–H aliphatic), 1594 (C N), 1406, 1148;
–
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1304, 1191, (2 SO2CH3) cmꢀ1
;
1H NMR (DMSO-d6, 400 MHz, d
proton), 7.58 (d, J ¼ 8.0 Hz, dimethoxyphenyl H-6), 8.10 (d,
J ¼ 8.0 Hz, 2H, methoxyphenyl H-2, H-6), 8.19 (s, 1H,
dimethoxyphenyl H-2); 13C NMR (DMSO-d6, 100 MHz, d
ppm): 55.5 (OCH3, methoxyphenyl C-4), 55.9 (OCH3,
dimethoxyphenyl C-3), 56.0 (O-CH3, dimethoxyphenyl C-
4), 110.9 (CH, dimethoxyphenyl C-2), 113.3 (CH, dimethox-
yphenyl C-5), 114.5 (CH, olefinic carbon), 118.1 (C,
methoxyphenyl C-1), 127.0 (methoxyphenyl C-3, C-5),
127.3 (CH, dimethoxyphenyl C-6), 129.7 (oxazolone C-4),
130.5 (CH, methoxyphenyl C-2, C-6), 131.5 (C, dimethox-
yphenyl C-1), 149.1 (C, dimethoxyphenyl C-4), 151.7 (C,
dimethoxyphenyl C-3), 162.3 (C, oxazolone C-2), 163.6 (C,
methoxyphenyl C-4), 168.1 (C, oxazolone, C-5); MS m/z 339
(Mþ, 49.85 %). Anal. calcd. for C19H17NO5; C, 67.25; H, 5.05;
N, 4.13: Found; C; 67.43; H, 5.12; N, 4.18.
ppm): 3.27 (s, 6H, 2SO2CH3), 6.89 (s, 1H, pyrazole H-4),
7.55–7.58 (m, 4H, methylsulfonylphenyl H-2, H-3, H-5, H-6),
7.94 (s, 1H, pyrazole H-3), 7.98–8.02 (m, 4H, methylsulfonyl-
phenyl H-20, H-30, H-50 H-60). 13C NMR (DMSO-d6, 100 MHz, d
ppm): 43.7 (CH3, methanesulfonylcarbon), 110.8 (CH, pyrazole
C-4), 125.8 (CH, methylsulfonylphenyl C-2, C-6), 127.9 (CH,
methylsulfonylphenyl C-20, C-60), 128.7 (CH, methylsulfonyl-
phenyl C-30, C-50), 129.1 (CH, methylsulfonylphenyl C-3, C-5),
134.9 (C, methylsulphonylphenyl C-10), 140.0 (C, methylsulfo-
nylphenyl C-1), 141.1 (C, methylsulfonylphenyl C-40), 141.8 (C,
pyrazole C-5), 142.0 (CH, pyrazole C-3), 143.5 (C, methyl-
sulfonylphenyl C-1); MS m/z (ESþ) 376 (Mþ, 100%). Anal. calcd.
for C17H16N2O4S2; C, 54.24; H, 4.28; N, 7.44: Found; C, 54.4; H,
4.34; N, 7.53.
4-[5-(4-Methylsulfonylphenyl)-1H-pyrazol-1-yl]-
benzenesulfonamide (8f)
Yield 70%; pale yellow powder; mp 208–210°C; IR (KBr): 3361,
(E)-2-(4-Methoxyphenyl)-4-(3,4,5-
trimethoxybenzylidene)-oxazol-5(4H)-one (10e)
Yield 78%; yellow solid; mp 168–170°C; IR (KBr); 3073 (Cꢀ–H1
–
–
–
–
3284 (NH2), 3071 (C–H aromatic), 2929 (C–H aliphatic), 1595
aromatic), 2940 (C–H aliphatic), 1784 (C O), 1606 (C N) cm
;
(C N), 1342, 1152; 1302, 1095 (SO CH , SO NH ) cmꢀ1; 1H NMR
1H NMR (DMSO-d6, 400 MHz, d ppm): 3.93 (s, 3H, O-CH3,
methoxyphenyl C-4), 3.96 (s, 3H, O-CH3 trimethoxyphenyl
C-4), 3.99 (s, 6H, 2-OCH3, trimethoxyphenyl C-3, C-5), 7.04 (d,
J ¼ 8.0 Hz, 2H, methoxyphenyl H-3, H-5), 7.12 (s, 1H, olefinic
proton), 7.56 (s, 2H, trimethoxyphenyl H-2, H-6), 8.10 (d,
J ¼ 8.0 Hz, 2H, methoxyphenyl H-2, H-6); 13C NMR (DMSO-d6,
100 MHz, d ppm): 55.5 (O-CH3, methoxyphenyl C-4), 56.1 (2O-
CH3, trimethoxyphenyl C-3, C-5), 61.0 (O-CH3, trimethoxy-
phenyl C-4), 109.3 (CH, trimethoxyphenyl C-2, C-6), 114. (CH,
methoxyphenyl C-3, C-5), 117.9 (C, methoxyphenyl C-1), 129.1
(C, trimethoxyphenyl C-1), 129.7 (CH, olefinic CH), 130.7 (CH,
methoxyphenyl C-2, C-6), 132.7 (C, oxazolone, C-4), 140.9 (C,
trimethoxyphenyl C-4), 153.2 (C, trimethoxyphenyl C-3, C-5),
163.0 (C, oxazolone C-2), 163.8 (C, methoxyphenyl C-4), 167.8
(C, oxazolone C-5); MS m/z 369 (Mþ, 100%). Anal. calcd. for
–
–
2
3
2
2
(DMSO-d6, 400 MHz, d ppm): 3.26 (s, 3H, SO2CH3), 6.87 (s, 1H,
pyrazole H-4), 7.28–7.35 (m, 6H, benzenesulfonamide H-2, H-
3, H-5, H-6, D2O exchangeable SO2NH2), 7.77–7.88 (m, 3H,
pyrazole H-3, methylsulfonylphenyl H-3, H-5), 7.95 (d, J ¼ 8.0
Hz, 2H, methylsulfonylphenyl H-2, H-6); 13C NMR (DMSO-d6
100 MHz, d ppm): 43.7 (CH3, SO2CH3), 110.5 (CH, pyrazole C-4),
125.8 (CH, benzene sulfonamide C-3, C-5), 127.3 (CH, benzene
sulfonamide C-2, C-6), 127.8 (CH, methylsulfonylphenyl C-2, C-
6), 129.8 (CH, methylsulfonylphenyl C-3, C-5), 135.0 (C,
methylsulfonylphenyl C-1), 140.6 (C, methylsulfonylphenyl
C-4), 141.7 (C, benzene sulfonamide C-1), 141.8 (CH, pyrazole
C-3), 142.1 (C, benzene sulfonamide C-4), 143.2 (C, pyrazole C-
5); MS m/z (ESþ) 377 (Mþ, 100%). Anal. calcd. for
C
16H15N3O4S2; C, 50.91; H, 4.01; N, 11.13: Found; C, 51.17;
H, 4.06; N, 11.34.
C20H19NO6; C, 65.03; H, 5.18; N, 3.79: Found; C; 65.17; H, 5.24;
N, 3.85.
General procedure for the synthesis of (E)-4-arylidene-2-
(4-methoxyphenyl)oxazol-5(4H)-ones (10d–g)
(E)-2-(4-Methoxyphenyl)-4-(thiophen-2-ylmethylene)-
oxazol-5(4H)-one (10f)
Yield 76%; pale green solid; mp 198- 200°C; IR (KBr): 3100
A mixture of p-methoxy benzoyl glycine 9 (0.01 mol), the
appropriate aromatic aldehyde (0.01 mol) and anhydrous
sodium acetate (0.03 mol) in acetic anhydride (20 mL) was
refluxed at 100°C for 6 h. The precipitated product obtained
was filtered, washed with water, followed by aqueous
ethanol and crystallized from ethanol to give oxazolone
10a–g in excellent yield 70–90%.
–
–
–
(C–H aromatic), 2925 (C–H aliphatic), 1779 (C O), 1602 (C N)
–
cmꢀ1 1H NMR (DMSO-d6, 400 MHz, d ppm): 3.89 (s, 3H,
;
O-CH3), 7.18 (d, J ¼ 8.0 Hz, 2H, methoxyphenyl H-3, H-5), 7.26
(t, 1H, thienyl H-4), 7.65 (s, 1H, olefinic proton), 7.82 (d,
J ¼ 3.2 Hz, 1H, thienyl H-3), 8.02 (d, J ¼ 8.0 Hz, 2H, methox-
yphenyl H-2, H-6), 8.05 (d, J ¼ 4.8 Hz, 1H, thienyl H-5).
13C NMR (DMSO-d6 100 MHz, d ppm): 56.1 (O-CH3, methox-
yphenyl C-4), 115.4 (CH, methoxyphenyl C-3, C-5), 117.6 (C,
methoxyphenyl C-1), 123.4 (CH, olefinic CH), 128.6 (CH,
thienyl C-4), 130.4 (CH, methoxyphenyl C-2, C-6), 130.9
(C, oxazolone C-4), 136.1 (CH, thienyl C-3), 136.5 (CH, thienyl
C-5), 137.7 (C, thienyl C-2), 162.0 (oxazolone C-2), 163.9 (C,
methoxyphenyl C-4), 166.6 (C, oxazolone C-5); MS m/z 285
(Mþ, 54.85%). Anal. calcd. for C15H11NO3S; C, 63.14; H, 3.89;
N, 4.9: Found; C, 63.32; H, 3.96; N, 5.02.
(E)-4-(3,4-Dimethoxybenzylidene)-2-(4-methoxyphenyl)-
oxazol-5(4H)-one (10d)
Yield 75%; yellow powder; mp 175–177°C; IR (KBr): 3092
–
(C–H aromatic), 2933 (C–H aliphatic), 1782 (C O), 1602
–
ꢀ1
1H NMR (DMSO-d6, 400 MHz, d ppm): 3.93 (s,
–
(C N) cm
;
–
3H, OCH3, methoxyphenyl C-4), 3.99 (s, 3H, OCH3, dime-
thoxyphenyl C-3), 4.05 (s, 3H, OCH3, dimethoxyphenyl C-4),
6.95 (d, J ¼ 8.0 Hz, 1H, dimethoxyphenyl H-5), 7.03 (d,
J ¼ 8.0 Hz, 2H, methoxyphenyl H-3, H-5), 7.08 (s, 1H, olefinic
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(E)-2-(4-Methoxyphenyl)-4-(pyridin-3-ylmethylene)-
oxazol-5(4H)-one (10g)
Yield 78%; light brown solid; mp 216–218°C; IR (KBr): 3077
(E)-4-[4-(3-Methoxybenzylidene)-2-(4-methoxyphenyl)-5-
oxo-4,5-dihydro-1H-imidazol-1-yl)benzenesulfonamide
(11b)
–
(C–H aromatic), 2928 (C–H aliphatic), 1783 (C O), 1603
Yield 72%; pale yellow powder; mp 238–240°C; IR (KBr): 3415,
–
ꢀ1
1H NMR (DMSO-d6, 400 MHz, d ppm): 3.93 (s,
3262 (NH2), 3073 (C–H aromatic), 2935 (C–H aliphatic), 1781
–
(C N) cm
;
–
(C O), 1601 (C N), 1307, 1162 (SO ) cmꢀ1; 1H NMR (DMSO-d6,
–
2
–
–
–
3H, O-CH3), 7.1 (d, J ¼ 8.0 Hz, 2H, methoxyphenyl H-3, H-5),
7.3 (s, 1H, olefinic proton), 7.5 (dd, J ¼ 4.8, 7.2 Hz, 1H,
pyridine H-5), 8.1 (d, J ¼ 8.0 Hz, methoxyphenyl H-2, H-6),
8.63 (d, J ¼ 4.4 Hz, 1H, pyridine H-6), 8.76 (d, J ¼ 7.2 Hz, 1H,
pyridine H-4), 9.26 (s, 1H, pyridine, H-2); 13C NMR (DMSO-d6
100 MHz, d ppm): 56.2 (O-CH3, methoxyphenyl), 115.4
(CH, olefinic proton), 117.6 (C, methoxyphenyl C-1), 124.5
(CH, methoxyphenyl C-3, C-5), 125.9 (CH, pyridine C-5),
130.2 (C, oxazolone C-4), 130.9 (CH, methoxyphenyl C-2, C-
6), 133.2 (C, pyridine C-1), 138.6 (CH, pyridine C-6), 151.2
(CH, pyridine C-2), 153.0 (CH, pyridine C-4), 162.0 (oxazo-
lone C-2), 163,9 (C, methoxyphenyl C-4), 166.6 (C, oxazo-
lone C-5); MS m/z 280 (Mþ, 100 %). Anal. calcd. for
400 MHz, d ppm): 3.79 (s, 3H, O-CH3, methoxyphenyl C-4), 3.83
(s, 3H, O-CH3, methoxyphenyl C-3), 7.0 (d, J ¼ 8.0 Hz, 2H,
methoxyphenyl H-3, H-5), 7.06 (d, J ¼ 7.6 Hz, 2H, methox-
yphenyl H-4, H-5), 7.22 (s, 1H, olefinic proton), 7.41–7.50 (m,
7H, SO2NH2, D2O exchangeable, methoxyphenyl H-2, H-6,
benzenesulfonamide H-2, H-6, methoxyphenyl H-2), 7.84 (d,
J ¼ 7.6 Hz, 1H, methoxyphenyl H-6), 7.92 (d, J ¼ 8.2 Hz,
benzenesulfonamide H-3, H-5), 8.06 (s, 1H, methoxyphenyl
H-2); 13C NMR (DMSO-d6, 100 MHz, d ppm): 55.6 (O-CH3,
methoxyphenyl C-4), 55.9 (O-CH3, methoxyphenyl C-3), 114.6
(CH, methoxyphenyl C-3, C-5), 116.1 (CH, methoxyphenyl C-2),
117.3 (CH, methoxyphenyl C-4), 120.7 (C, 4-methoxyphenyl
C-1), 120.8 (CH, olefinic carbon), 125.4 (CH, methoxyphenyl
C-6), 127.2 (CH, benzene sulfonamide C-3, C-5), 128.7 (CH,
benzene sulfonamide C-2, C-6), 130.3 (CH, methoxyphenyl
C-5), 131.3 (CH, methoxyphenyl C-2, C-6), 135.8 (C, oxazolone
C-4), 138.0 (C, benzene sulfonamide C-1), 138.9 (C,
3-methoxyphenyl C-1), 144.1 (C, benzene sulfonamide C-4),
159.7 (C, oxazolone C-2), 160.3 (C, 3-methoxyphenyl C-3),
162.4 (C, methoxyphenyl C-4), 170.0 (C, oxazolone C-5); MS
m/z 463 (Mþ, 19.74%). Anal. calcd. for C24H21N3O5S; C, 62.19;
H, 4.57; N, 9.07: Found; C, 62.38; H, 4.65; N, 9.19.
C
16H12N2O3; C, 68.56; H, 4.32; N, 9.99: Found; C, 68.74; H,
4.39; N, 10.18.
General procedure for the synthesis of (E)-4-[4-
benzylidene-2-(4-methoxyphenyl)-5-oxo-4,5-dihydro-1H-
imidazol-1-yl]benzenesulfonamide (11a–g)
A mixture of the appropriate (E)-4-arylidene-2-(4-methox-
yphenyl)oxazol-5(4H)-ones 10a–g (0.01 mol) and sulfanil-
amide (0.01 mol) in glacial acetic acid (15 mL) containing
anhydrous sodium acetate (0.03 mol) was heated on a boiling
water bath with continuous stirring for the 24 h. The
precipitated product was filtered off, washed with aqueous
ethanol and crystallized from ethanol to give compounds
11a–g in good yield (60–70%).
(E)-4-[4-(4-Methoxybenzylidene)-2-(4-methoxyphenyl)-5-
oxo-4,5-dihydro-1H-imidazol-1-yl]benzenesulfonamide
(11c)
Yield 70%; yellow powder; mp 247–249°C; IR (KBr); 3430, 3260
–
(E)-4-[4-Benzylidene-2-(4-methoxyphenyl)-5-oxo-4,5-
dihydro-1H-imidazol-1-yl]benzenesulfonamide (11a)
Yield 60%; yellow powder; mp 277–279°C; IR (KBr): 3370;
(NH ), 3098 (C–H aromatic), 2932 (C–H aliphatic), 1687 (C O),
–
2
1
–
1600 (C N), 1313, 1164 (SO ); H NMR (DMSO-d , 400 MHz, d
–
2
6
ppm): 3.79 (s, 3H, O-CH3, methoxybenzylidene), 3.85 (s, 3H,
O-CH3, methoxyphenyl), 6.98 (d, J ¼ 8.0 Hz, 2H, methoxyben-
zylidene H-3, H-5), 7.11 (d, J ¼ 8.0 Hz, 2H, methoxyphenyl H-3,
H-5), 7.22 (s, 1H, olefinic proton), 7.47–7.49 (m, 6H,
methoxyphenyl H-2, H-6, methoxybenzylidene H-2, H-6,
SO2NH2, D2O exchangeable), 7.90 (d, J ¼ 8.2 Hz, 2H, benze-
nesulfonamide H-2, H-6), 8.35 (d, J ¼ 8.2 Hz, 2H, benzenesul-
fonamide H-3, H-5); 13C NMR (DMSO-d6, 100 MHz, d ppm): 55.8
(O-CH3, methoxyphenyl C-4), 55.9 (O-CH3, methoxyphenyl
C-4), 114.5 (CH, methoxybenzylidene C-3, C-5), 115.0 (CH,
methoxyphenyl C-3, C-5), 121.0 (C, methoxyphenyl C-1), 127.1
(CH, benzene sulfonamide C-3, C-5), 127.4 (C, methoxybenzy-
lidene), 127.7 (CH, olefinic carbon), 128.7 (CH, benzene
sulfonamide C-2, C-6), 131.1 (CH, methoxybenzylidene C-2,
C-6), 134.8 (CH, methoxyphenyl C-2, C-6), 136.7 (C, oxazolone
C-4), 138.1 (C, benzene sulfonamide C-1), 144.02 (C, benzene
sulfonamide C-4), 158.9 (C, oxazolone C-2), 161.7 (C,
methoxybenzylidene C-4), 162.1 (C, methoxyphenyl C-4),
169.9 (C, oxazolone C-5); MS m/z 463 (Mþ, 31.47%). Anal.
calcd. for C24H21N3O5S; C, 62.19; H, 4.57; N, 9.07: Found; C,
62.43; H, 4.62; N, 9.23.
3261 (NH2), 3093 (C–H aromatic), 2928 (C–H aliphatic), 1695
ꢀ1
(C O), 1603 (C N), 1342, 1166 (SO ) cm
;
1H NMR (DMSO-
–
–
–
–
2
d6, 400 MHz, d ppm): 3.79 (s, 3H, O-CH3), 6.98 (d, J ¼ 8.0 Hz,
2H, methoxyphenyl H-3, H-5), 7.41 (s, 1H, olefinic proton),
7.49–7.60 (m, 7H, methoxyphenyl H-2, H-6, phenyl H-2, H-3,
H-4, H-5, H-6, SO2NH2, D2O exchangeable), 7.80 (d, J ¼ 8.2 Hz,
2H, benzenesulfonamide H-2, H-6), 7.92 (d, J ¼ 8.2 Hz, 2H,
benzenesulfonamide H-3, H-5); 13C NMR (DMSO-d6,
100 MHz, d ppm): 56.0 (O-CH3, methoxyphenyl C-4), 114.6
(CH, methoxyphenyl C-3, C-5), 120.4 (C, methoxyphenyl C-1),
123.3 (CH, olefinic CH), 126.6 (C, oxazolone C-4), 127.2 (CH,
benzene sulfonamide C-3, C-5), 128.7 (CH, phenyl C-4), 128.8
(CH, phenyl C-2, C-6), 131.5 (CH, phenyl C-3, C-5), 132.3 (CH,
benzene sulfonamide C-2, C-6), 133.5 (C, phenyl C-1), 133.7
(CH, methoxyphenyl C-2, C-6), 137.8 (C, benzene sulfon-
amide C-1), 140.2 (C, benzene sulfonamide C-4), 161.9 (C,
oxazolone C-2), 162.8 (C, methoxyphenyl C-4), 170.0 (C,
oxazolone C-5); MS m/z 433 (Mþ, 0.77%). Anal. calcd. for
C
23H19N3O4S; C, 63.73; H, 4.42; N, 9.69: Found; C, 63.94; H,
4.46; N, 9.82.
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(E)-4-[4-(3,4-Dimethoxybenzylidene)-2-(4-
methoxyphenyl)-5-oxo-4,5-dihydro-1H-imidazol-1-yl]-
benzenesulfonamide (11d)
(E)-4-[2-(4-Methoxyphenyl)-5-oxo-4-(thiophen-2-
ylmethylene)-4,5-dihydro-1H-imidazol-1-yl]-
benzenesulfonamide (11f)
Yield 65%; yellow powder; mp 280–282°C; IR (KBr): 3430, 3315
Yield 85%; brown powder; mp 254–256°C; IR (KBr): 3422, 3250
–
–
(NH ), 3091 (C–H aromatic), 2941 (C–H aliphatic), 1684 (C O),
(NH ), 3100 (C–H aromatic), 2926 (C–H aliphatic), 1724 (C O),
–
–
2
2
ꢀ1
ꢀ1
1594 (C N), 1348, 1163 (SO ) cm
;
1H NMR (DMSO-d6,
1603 (C N), 1324, 1163 (SO ) cm
;
1H NMR (DMSO-d6,
–
–
–
–
2
2
400 MHz, d ppm): 3.79 (s, 3H, O-CH3, dimethoxyphenyl C-3),
3.86 (s, 6H, 2O-CH3, methoxyphenyl C-4, dimethoxyphenyl
C-4), 6.98 (d, J ¼ 8.0 Hz, 2H, methoxyphenyl H-3, H-5), 7.12 (d,
J ¼ 8.0 Hz, 1H, dimethoxyphenyl H-5), 7.21 (s, 1H, olefinic
proton), 7.49–7.51 (m, 6H, methoxyphenyl H-2, H-6, benze-
nesulfonamide H-2, H-6, SO2NH2, D2O exchangeable), 7.86 (d,
J ¼ 8.0 Hz, 1H, dimethoxyphenyl H-6), 7.92 (d, J ¼ 8.2 Hz, 2H,
benzene sulfonamide H-3, H-5), 8.24 (s, 1H, dimethoxyphenyl
H-2); 13C NMR (DMSO-d6, 100 MHz, d ppm): 55.8 (O-CH3,
methoxyphenyl C-4), 56.1 (O-CH3, dimethoxyphenyl C-3, C-4),
112.1 (CH, dimethoxyphenyl C-2), 114.6 (CH, methoxyphenyl
C-3, C-5), 115.0 (CH, dimethoxyphenyl C-5), 121.0 (C,
methoxyphenyl C-1), 127.2 (CH, benzene sulfonamide C-3,
C-5), 127.5 (CH, olefinic carbon), 127.7 (C, oxazolone C-4),
128.0 (CH, dimethoxyphenyl C-6), 128.6 (CH, benzene sulfon-
amide C-2, C-6), 131.0 (CH, methoxyphenyl C-2, C-6), 136.7 (C,
dimethoxyphenyl C-1), 138.2 (C, benzene sulfonamide C-1),
144.0 (C, benzene sulfonamide C-4), 149.1 (C, dimethoxy-
phenyl C-4), 151.6 (C, dimethoxyphenyl C-3), 158.7 (C,
oxazolone C-2), 162.2 (C, methoxyphenyl C-4), 169.8 (C,
oxazolone C-5); MS m/z 493 (Mþ2, 1.19%). Anal. calcd. for
400 MHz, d ppm): 3.80 (s, 3H, O-CH3), 6.99 (d, J ¼ 8.0 Hz,
2H, methoxyphenyl H-3, H-5), 7.23 (s, 1H, olefinic proton),
7.49–7.52 (m, 6H, methoxyphenyl H-2, H-6, benzene sulfon-
amide H-2, H-6, SO2NH2, D2O exchangeable), 7.61 (t, 1H,
thienyl H-4), 7.8 (d, J ¼ 3.2 Hz, 1H, thienyl H-3), 7.91 (d,
J ¼ 8.2 Hz, 2H, benzene sulfonamide H-3, H-5), 7.97 (d,
J ¼ 4.8 Hz, 1H, thienyl H-5); 13C NMR (DMSO-d6, 100 MHz, d
ppm): 55.9 (CH3, OCH3), 114.6 (CH, methoxyphenyl C-3, C-5),
120.8 (C, methoxyphenyl C-1), 121.7 (CH, olefinic carbon),
127.2 (CH, benzene sulfonamide C-3, C-5), 128.3 (CH, thienyl
C-4), 128.7 (CH, benzene sulfonamide C-2, C-6), 131.1 (CH,
methoxyphenyl C-2, C-6), 135.8 (CH, thienyl C-3), 136.0 (CH,
thienyl C-5), 136.1 (C, oxazolone C-4), 138.2 (C, benzene
sulfonamide C-1), 138.7 (C, thienyl C-2), 144.2 (C, benzene
sulfonamide C-4), 158.2 (C, oxazolone C-2), 162 (C, methox-
yphenyl C-4), 169.2 (C, oxazolone C-5); MS m/z 439 (Mþ,
77.83%). Anal. calcd. for C21H17N3O4S2; C, 57.39; H, 3.90; N,
9.56: Found; C, 57.52; H, 3.93; N, 9.67.
(E)-4-[2-(4-Methoxyphenyl)-5-oxo-4-(pyridin-3-
ylmethylene)-4,5-dihydro-1H-imidazol-1-yl]-
benzenesulfonamide (11g)
C
25H23N3O6S; C, 60.84; H, 4.70; N, 8.51: Found; C, 61.02; H,
4.79; N, 8.59.
Yield 80%; pale brown powder; mp 241–243°C; IR (KBr): 3430,
3313 (NH2), 3044 (C–H aromatic), 2925 (C–H aliphatic), 1725
–
–
–
(E)-4-[2-(4-Methoxyphenyl)-5-oxo-4-(3,4,5-
trimethoxybenzylidene)-4,5-dihydro-1H-imidazol-1-yl]-
benzenesulfonamide (11e)
(C O), 1601 (C N), 1344, 1164 (SO ) cmꢀ1; 1H NMR (DMSO-d6,
–
2
400 MHz, d ppm): 3.8 (s, 3H, O-CH3), 6.99 (d, J ¼ 8.0 Hz, 2H,
methoxyphenyl H-3, H-5), 7.29 (s, 1H, olefinic proton), 7.51–
7.57 (m, 7H, methoxyphenyl H-2, H-6, pyridine H-5, benze-
nesulfonamide H-2, H-6, SO2NH2, D2O exchangeable), 7.94 (d,
J ¼ 8.2 Hz, 2H, benzenesulfonamide H-3, H-5), 8.62 (d, J ¼ 4.0
Hz, 1H, pyridine H-6), 8.85 (d, J ¼ 7.6 Hz, 1H, pyridine H-4),
9.33 (s, 1H, pyridine H-2); 13C NMR (DMSO-d6, 100 MHz, d
ppm): 55.9 (O-CH3, methoxyphenyl C-4), 114.6 (CH, methox-
yphenyl C-3, C-5), 120.5 (C, methoxyphenyl C-1), 123.5 (CH,
olefinic carbon), 124.4 (CH, pyridine C-5), 127.2 (CH, benzene
sulfonamide C-3, C-5), 128.8 (CH, benzene sulfonamide C-2,
C-6), 130.8 (C, pyridine C-1), 131.4 (CH, methoxyphenyl C-2, C-
6), 137.8 (C, oxazolone C-4), 138.7 (CH, pyridine C-6), 140.3 (C,
benzene sulfonamide C-1), 144.2 (C, benzene sulfonamide
C-4), 150.8 (CH, pyridine C-2), 153.2 (CH, pyridine C-4), 161.2
(C, oxazolone C-2), 162.6 (C, methoxyphenyl C-4), 169.6 (C,
oxazolone C-5); MS m/z 434 (Mþ, 100%). Anal. calcd. for
Yield 77%; yellow powder; mp 217–219°C; IR (KBr): 3424, 3305
–
(NH ), 3103 (C–H aromatic), 2938 (C–H aliphatic), 1786 (C O),
–
2
1604(C N),1332,1127(SO )cmꢀ1;1HNMR(DMSO-d6,400 MHz,
–
–
2
d ppm): 3.77 (s, 3H, O-CH3, trimethoxyphenyl C-4), 3.79 (s, 3H,
O-CH3, methoxyphenyl), 3.86 (s, 6H, 2O-CH3, trimethoxyphenyl
C-3, C-5), 6.98 (d, J ¼ 8.0 Hz, 2H, methoxyphenyl H-3, H-5), 7.16
(s,1H,olefinicproton),7.49–7.51(m,6H,methoxyphenylH-2,H-
6, benzene sulfonamide H-2, H-6, SO2NH2, D2O exchangeable),
7.8 (s, 2H, trimethoxyphenyl H-2, H-6), 7.93 (d, J ¼ 8.2 Hz,
benzenesulfonamide, H-3, H-5);13CNMR(DMSO-d6, 100 MHz,d
ppm): 55.9 (O-CH3, methoxyphenyl), 56.3 (O-CH3, trimethox-
yphenyl C-3, C-5), 60.7 (O-CH3, trimethoxyphenyl C-4), 110.3
(CH, trimethoxyphenyl C-2, C-6), 114.6 (CH, methoxyphenyl C-3,
C-5), 120.8 (C, methoxyphenyl C-1), 127.2 (CH, benzene
sulfonamide C-3, C-5), 127.5 (CH, olefinic carbon), 128.7 (CH,
benzenesulfonamideC-2,C-6),130.1(C,trimethoxyphenylC-1),
131.1 (CH, methoxyphenyl C-2, C-6), 137.8 (C, oxazolone C-4),
138.1(C, benzenesulfonamideC-1), 140.2(C, trimethoxyphenyl
C-4), 144.1 (C, benzene sulfonamide C-4), 153.2 (C, trimethox-
yphenyl C-3, C-5), 159.5 (C, oxazolone C-2), 162.3 (C, methox-
yphenyl C-4), 169.3 (C, oxazolone C-5); MS m/z 523 (Mþ, 5.4%).
Anal. calcd. for C26H25N3O7S; C, 59.65; H, 4.81; N, 8.03: Found; C,
59.87; H, 4.86; N, 8.16.
C
22H18N4O4S; C, 60.82; H, 4.18; N, 12.90: Found; C, 61.04; H,
4.24; N, 13.08.
Biological evaluation
COX-1/COX-2 inhibition colorimetric assay
The ability of the target compounds listed in Table 1 to inhibit
ovine COX-1 and human recombinant COX-2 (IC50 value, mM)
was determined using an enzyme immunoassay (EIA) kit
ß 2017 Deutsche Pharmazeutische Gesellschaft
www.archpharm.com
(9 of 10) e1600386

RCHH HARM
A P
Arch. Pharm. Chem. Life Sci. 2017, 350, e1600386
K. R. A. Abdellatif et al.
Archiv der Pharmazie
(catalog no. 560131, Cayman Chemical, Ann Arbor, MI, USA)
according to the previously reported method [31].
[12] M. A. Chowdhury, K. R. A. Abdellatif, Y. Dong, G. Yu,
ꢀ
Z. Huang, M. Rahman, D. Das, C. A. Velazquez,
M. R. Suresh, E. E. Knaus, Bioorg. Med. Chem. Lett.
2010, 20, 1324–1329.
In vivo anti-inflammatory activity
Adult male Wistar albino rats (100–150 g) were used in the
pharmacological studies. The animals (five per cage) were
maintained under standard laboratory conditions (light
period of 12 h/day and temperature 27 ꢂ 2°C), with access
to food and water. The experimental procedures were carried
out in strict compliance with the Institutional Animal Ethics
Committee regulations. All experiments were performed in
the morning according to the guidelines for the care of
laboratory animals.
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(10 of 10) e1600386