Synthesis, Molecular Docking, Analgesic, and Anti-Inflammatory Activities of New 1,2,4-Oxadiazolo-Sulfonamides

Article abstract of DOI:10.1134/S1070363218040278

In the present study novel 1,2,4-oxadiazolo sulfonamides 3a–3o are synthesized by an efficient method based on the reaction of 1,2,4-oxadiazole amines with aryl sulfonyl chlorides. Structures of the synthesized compounds are confirmed by IR, NMR and Mass

Full text of DOI:10.1134/S1070363218040278

ISSN 1070-3632, Russian Journal of General Chemistry, 2018, Vol. 88, No. 4, pp. 804–811. © Pleiades Publishing, Ltd., 2018.
Synthesis, Molecular Docking, Analgesic,
and Anti-Inflammatory Activities
of New 1,2,4-Oxadiazolo-Sulfonamides1
M. Vijaya Bhargavia,b*, P. Shashikalaa, M. Sumakanthb, and C. Krishnac
a Department of Pharmacy, Faculty of Technology, Osmania University, Hyderabad, 500007 India
*e-mail: mvijayabhargavi@gmail.com
b RBVRR Women's College of Pharmacy, Osmania University, Hyderabad, 500007 India
c
Department of Chemistry, Osmania University, Hyderabad, 500007 India
Received February 27, 2018
Abstract—In the present study novel 1,2,4-oxadiazolo sulfonamides 3a–3o are synthesized by an efficient
method based on the reaction of 1,2,4-oxadiazole amines with aryl sulfonyl chlorides. Structures of the
synthesized compounds are confirmed by IR, NMR and Mass spectra. Molecular interactions of the obtained
compounds are studied by Discovery Studio v3.5, molecular docking with COX-2 enzyme. The compounds
with high LibDock score are screened for their in vivo analgesic and anti inflammatory activities. The
compound 3l demonstrates the highest activity.
Keywords: 1,2,4-oxadiazole sulfonamide, molecular docking, analgesic, anti inflammatory activity
DOI: 10.1134/S1070363218040278
INTRODUCTION
In view of the above, we have synthesized 1,2,4-
oxadiazole-sulfonamide hybrids 3a–3o in the coupling
reaction of substituted 1,2,4 oxadiazole amines 1a–1d
with aryl sulfonylchlorides 2a–2d (Scheme1). The
novel 1,2,4-oxadiazolo-sulfonamides were screened for
their in vivo analgesic and antiinflammatory activities.
Various side effects such as gastrointestinal
bleeding, ulceration and heart failure are associated
with long term use of ibuprofen, aspirin, indomethacin,
diclofenac, nimesulide, celecoxib, and other drugs.
Search of potent safe anti-inflammatory drugs is one of
top objectives of contemporary studies in organic
synthesis. The 1,2,4-oxadiazole scaffold is a core
structure found in a broad class of natural and
synthetic compounds. This cycle was the basis for
design of therapeutically important molecules. Several
1,2,4-oxadiazole derivatives possess anti-inflammatory
activity [1].
RESULTS AND DISCUSSION
In the present study, we have synthesized 1,2,4-
oxadiazole sulfonamides via coupling reaction of 1,2,4-
oxadiazole amines with aryl sulfonylchlorides at room
temperature. Initial (3-aryl-1,2,4-oxadiazol-5-yl)-methan-
amines were synthesized by alkylation of potassium
phthalimide with 5-(chloromethyl)-3-aryl-1,2,4-oxa-
diazoles in DMF followed by the reaction with NH2· NH2·
H2O in ethanol. Structures of the title compounds 3a–
3o were elucidated from IR, 1H NMR and MS data.
Heterocycles containing sulfonamido moieties have
attracted very close attention due to their significant
biological properties and their role as pharmacophores
[2–7]. Sulfonamides are well known as antibacterial
[8–10], anticancer [11–13], anti-inflammatory, analgesic
[14–16], antifungal [17], and antiviral [18] agents.
1,2,4-Oxadiazoles with long hydrocarbon chains at C5
possess not only anti-inflammatory but also antitumor
activities [19].
Molecular docking studies. All synthesized com-
pounds have been docked with Structure of celecoxib
bound at the COX-2 active site (PDB ID: 3LN1) for
determining binding affinities and molecular interac-
tions (Table 1 anf figure). The Lib dock scores of the
compounds were measured. All 1,2,4-oxadiazole sulfon-
amide analogues displayed better Lib dock scores than
aspirin and indomethacin but lower than celecoxib.
1 The text was submitted by the authors in English.
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SYNTHESIS, MOLECULAR DOCKING, ANALGESIC, AND ANTI-INFLAMMATORY ACTIVITIES
805
Scheme 1. Synthesis of 1,2,4-oxadiazolo-sulfonamides.
Cl
N
O
O
S O
H
N
O
O
Ar
N
N
Et3N/CH2Cl2
Ar
S
NH2
+
N
room temperature
O
R
R
3a−3o
1a−1d
2a−2d
R = H (2a, 3a, 3e, 3i, 3m), 4-CH3 (2b, 3b, 3f, 3j, 3n), R = 4-Cl (2c), 4-OCH3 (2d, 3d, 3h, 3l); Ar = 4-fluoro phenyl (1a, 3a,
3b–3d), 4-methyl phenyl (1b, 3e, 3f–3h), R = 4-Cl (3c, 3g, 3k, 3o), 4-methoxy phenyl (1c, 3i–3l), 2-chloro phenyl (1d, 3m–3o).
In vivo analgesic and anti-inflammatory activities.
Analgesic activity of the newly synthesized oxadiazole
fused sulfonamides 3d, 3f, 3l, 3n were evaluated by
the hot plate and tail immersion methods using male
albino wistar rats Tables 2, 3). Aspirin was used as a
standard. Anti-inflammatory activity of the compounds
was tested by the carrageenan induced rat paw edema
method using indomethacin as a standard (Tables 4, 5).
All target compounds were tested at the doses of 20
and 40 mg/kg p.o., and demonstrated high analgesic
Table 1. LibDforock scores of the compounds
Compound
Libdock score
101.188
100.800
100.297
104.068
81.071
Compound
Libdock score
87.979
Compound
3m
Libdock score
102.781
107.362
98.904
3a
3b
3c
3d
3e
3f
3g
3h
3i
106.181
96.712
3n
3o
3j
107.095
104.448
110.482
Celecoxib
Aspirin
Indomehacin
145.691
71.885
3k
3l
108.545
103.714
Table 2. Analgesic activity as tested by the hot plate method
Time, min
60
Compound
dose
0
30
90
120
6.50±0.22
15.83±1.74c 13.33±1.68c
180
Control
Standard
3d
1% CMCa
5.50±0.22
6.67±0.21b 10.00±0.81c
6.00±0.26
6.16±0.17
13.50±1.69c
6.70±0.57
6.66±0.21
23.17±2.32d
8.70±0.30b
6.33±0.21
10
20
5.50±0.32
5.50±0.34
5.60±0.25
5.60±0.47
5.70±0.26
5.70±0.35
5.60±0.22
5.60±0.41
5.80±0.29b
5.80±0.32
6.30±0.35b
6.98±0.34b
6.60±0.41b
7.22±0.49b
6.00±0.28b
6.79±0.30b
6.00±0.31
7.90±0.42b
6.90±0.36
8.50± .47b
7.00±0.45
9.30±0.58b
6.40±0.38
8.00±0.79b
5.80±0.46
6.20±0.22
6.00±0.35
7.20±0.37
6.30±0.58
7.60±0.74
5.90±0.49
6.50±0.69
40
20
40
20
40
20
40
7.03±0.36b
7.50±0.04b
8.07±0.39b
8.10±0.36c
8.34±0.28c
7.00±0.45b
11.80±0.88
9.50±0.32b
13.7±0.60b
10.00±0.25c
14.30±0.28c
9.00±0.33b
3f
3l
3n
7.98±0.32b 12.90±0.49b
a
(CMC) Carboxy methyl cellulose, values are expressed as mean ± SEM, (n = 6) and analyzed by ANOVA using Graph pad prism 7.
p < 0.05; c p < 0.01; d p < 0.001.
b
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VIJAYA BHARGAVI et al.
(a)
(b)
(c)
(d)
Hydrogen bond interactions of selected compounds [(a) 3d, (b) 3f, (c) 3l, and (d) 3n] with the structure of celecoxib bound at the
COX-2 active site (PDB ID: 3LN1). H-bonds are presented as green-dotted lines and blue or grey letters indicate the amino acids
involved in the bonding.
and anti-inflammatory activity at the higher dose
(Table 4). Various potencies of the compounds suggested
their structure dependent activity. The compound 3l
exhibited the highest analgesic and anti- inflammatory
activity. Compound 3f demonstrated the lowest
activity.
Synthesis of N-{[3-(4-fluorophenyl)-1,2,4-oxadi-
azol-5-yl]methyl}benzenesulfonamide (3a). To a mix-
ture of (3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)methyl-
amine 1a (0.3g, 1.55 mmol) with DCM (20 mL) was
added TEA (0.5 mL). The mixture was stirred for
15 min. Benzene sulfonylchloride 2a (0.41g, 2.32 mmol)
was added and stirring continued at room temperature
for 2 h. Upon completion of the process, according to
TLC, the reaction mixture was quenched with 30 mL
of H2O, extracted by DCM (2×30 mL), dried over
Na2SO4, and concentrated under vacuum. The crude
product was purified by column chromatography using
petether : ethylacetate (6 : 4) as an eluent to
accumulate the pure compound as white solid. Off
white solid, yield 81%, mp 213–215°C. IR spectrum,
EXPERIMENTAL
All materials and solvents were industrially
available and used as purchased. Melting points were
recorded on a Polmon instrument, India (model
MP96). IR spectra (KBr discs) were recorded on a
Perkin-Elmer 337 Spectrophotometer. 1H and 13C NMR
spectra were measured on a Bruker 400 MHz
spectrometer in CDCl3 using TMS as an internal
standard. Mass spectra were measured on an Agilent
6310 ion trap mass spectrometer, USA. All
synthesized compounds were purified by recrystalliza-
tion or column chromatography on silica gel (60–
120 mesh, Spectrochem, Mumbai, India).
1
ν, cm–1: 1225 (C–N), 1584 (C=N), 3262 (NH). H
NMR spectrum, δ, ppm: 4.54 d (5-CH2), 5.38 t (NH),
7.12–7.16 m (H3', H5'), 7.42–7.52 m (H2', H6'), 7.86–
7.94 m (H2'' to H6''). 13C NMR spectrum, δ, ppm: 38.8
(5-CH2), 127.2 (C3', C5'), 127.2 (C1'), 129.5 (C2', C6'),
129.6 (C3'', C5''), 129.7 (C2', C6'), 136.1 (C4''), 141.8
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SYNTHESIS, MOLECULAR DOCKING, ANALGESIC, AND ANTI-INFLAMMATORY ACTIVITIES
807
Table 3. Analgesic activity as tested by the tail immersion method
Time, min
Compound
dose
0
30
60
90
120
180
Control
Standard
3d
1% CMCa
4.00±0.26
4.50±0.22
4.00±0.52
4.17±0.65
4.17±0.31
6.17±0.48b
4.50±0.72b
5.00±0.68
4.00±0.37
9.17±1.14c
5.00±0.65b
6.83±0.24b
4.00±0.37
11.33±0.21c
6.00±0.65b
7.00±0.24b
3.67±0.33
7.83±0.79b
4.50±0.26b
5.00±0.59b
4.33±0.33
6.67±0.21
4.00±0.25
4.50±0.38
10
20
40
3f
3l
20
40
20
40
20
40
4.17±0.53
4.33±0.23
4.17±0.31
4.50±0.22
4.00±0.42
4.33±0.42
5.00±0.53b
5.33±0.48
5.33±0.41b
5.67±0.48b
4.95±0.62b
5.17±0.58
5.50±0.65b
7.17±0.91b
5.67±0.28b
7.33±0.55b
5.33±0.58b
7.00±0.64b
6.33±0.62b
7.50±1.05b
6.50±1.08b
8.00±1.13b
6.17±0.86b
7.33±0.94b
5.33±0.81b
5.83±0.28b
5.50±0.44b
6.00±0.73b
5.00±0.36b
5.33±0.29b
4.50±0.47
5.00±0.56
4.50±0.62
5.17±0.30
4.33±0.61
5.00±0.37
3n
a
(CMC) Carboxy methyl cellulose, values are expressed as mean ± SEM, (n = 6) and analyzed by ANOVA using Graph pad prism 7.
p < 0.05; c p < 0.01.
b
Table 4. Anti-inflammatory activity as tested by the carrageenan induced rat paw edema method
Mean paw edema volume ± SEM, mL
Dose,
mg/kg
Group
Treatment
1 h
3 h
5 h
7 h
I
Control
Standard
3d
1% CMCa 0.45±0.024
0.65±0.029
0.19±0.031d
0.39±0.034c
0.33 ±0.049b
0.35±0.026c
0.30±0.074c
0.34±0.029c
0.29±0.085c
0.37±0.037c
0.32±0.091b
0.68±0.027
0.32±0.038d
0.45±0.028b
0.44±0.069b
0.43±0.022c
0.40±0.045c
0.42±0.043c
0.38±0.046c
0.44±0.054b
0.41±0.660b
0.59±0.029
0.36±0.03d
0.50±0.018b
0.48±0.038b
0.47±0.043b
0.45±0.044b
0.46±0.022b
0.43±0.067b
0.49±0.017b
0.47±0.039b
II
10
20
40
20
40
20
40
20
40
0.26±0.032c
0.41±0.014b
0.36±0.024b
0.38±0.011b
0.32±0.034b
0.37 ±0.025b
0.31±0.067c
0.40±0.092b
0.34±0.075b
III
IV
V
3f
3l
VI
VII
VIII
IX
X
3n
a
(CMC) Carboxy methyl cellulose, values are expressed as mean ± SEM, (n = 6) and analyzed by ANOVA using Graph pad prism 7.
p < 0.05; c p < 0.01; d p < 0.001.
b
(C1''), 144.0 (C4'), 168.1 (C5), 174.4 (C3). DIPMS: m/z:
332 [M – 1].
1235 (C–N), 1580 (C=N), 3246 (NH). 1H NMR
spectrum, δ, ppm: 2.25 s (4''-CH3), 4.51 d (5-CH2),
5.42 t (NH), 7.13–7.22 m (H3', H3'', H5', H5''), 7.71–7.73
m (H2'', H6''), 7.90–7.94 m (H2' to H6'). 13C NMR
spectrum, δ, ppm: 21.5 (4''-CH3), 38.9 (5-CH2), 127.2
(C3', C5'), 127.2 (C1'), 129.5 (C2', C6'), 129.6 (C3'', C5''),
129.7 (C2', C6'), 136.1 (C4''), 141.8 (C1''), 144.0 (C4'),
168.1 (C5), 174.4 (C3). DIPMS: m/z: 348 [M + 1].
The compounds 3b–3o were synthesized according
to the method presented above for 3a.
N-{[3-(4-Fluorophenyl)-1,2,4-oxadiazol-5-yl]-
methyl}-4-methylbenzenesulfonamide (3b). White
solid, yield 77%, mp 221–223°C. IR spectrum, ν, cm–1:
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VIJAYA BHARGAVI et al.
Table 5. Inhibition of acute inflammation (carrageenan-induced paw edema)
Inhibition of acute inflammation, %
Compound
Dose
1 h
0
3 h
0
5 h
0
7 h
0
Control
Standard
3d
1% CMCa
10
20
40
20
40
20
40
20
40
44
70.7
40.0
49.2
46.2
53.8
47.7
55.4
43.1
50.8
52.9
33.8
35.3
36.8
41.1
38.2
44.1
35.3
39.7
38.9
15.3
18.6
20.3
23.7
22.0
27.1
16.9
20.3
8.9
20.0
15.6
28.9
17.8
31.1
11.1
24.4
3f
3l
3n
a
(CMC) Carboxy methyl cellulose, values are expressed as mean ± SEM, (n = 6) and analyzed by ANOVA using Graph pad prism 7.
4-Chloro-N-{[3-(4-fluorophenyl)-1,2,4-oxadiazol-
(4'-CH3), 4.53 d (J = 5.6 Hz, 5-CH2), 5.36 t (NH), 7.25–
7.27 m (H3', H5'), 7.44–7.47 m (H3'', H4'', H5''), 7.79–
7.81 m (H2'', H6''), 7.85–7.88 m (H2', H6'). 13C NMR
spectrum, δ, ppm: 24.9 (4'-CH3), 38.9 (5-CH2), 115.9
(C2', C6'), 116.1 (C1'), 122.3 (C3'', C5''), 127.1 (C3', C5'),
129.1 (C2'', C6''), 129.6 (C4''), 133.0 (C4'), 139.2 (C1''),
167.4 (C5), 174.8 (C3). DIPMS: m/z: 330 [M + 1].
5-yl]methyl}benzenesulfonamide (3c). Light yellow
solid, yield 79%, mp 195–196°C. IR spectrum, ν, cm–1:
1225 (C–N), 1581 (C=N), 3268 (NH) 1H NMR
spectrum, δ, ppm: 4.56 d (5-CH2), 5.71 t (NH), 7.13–
7.18 m (H3', H5'), 7.39–7.41 m (H3'', H5''), 7.78–7.80 m
(H2' to H6'), 7.89–7.92 m (H2'', H6''). 13C NMR
spectrum, δ, ppm: 38.8 (5-CH2), 116.0 (C3', C5'), 116.2
(C1'), 128.6 (C2'', C6''), 129.4 (C3'', C5''), 129.6 (C2', C6'),
137.8 (C4''), 139.7 (C1''), 165.9 (C4'), 167.4 (C5), 174.6
(C3). DIPMS: m/z: 368 [M + 1].
4-Methyl-N-[(3-p-tolyl-1,2,4-oxadiazol-5-yl)-
methyl]benzenesulfonamide (3f). Off white solid, yield
78%, mp 209–210°C. IR spectrum, ν, cm–1: 1239 (C–N),
1
1572 (C=N), 3240 (NH). H NMR spectrum, δ, ppm:
N-{[3-(4-Fluorophenyl)-1,2,4-oxadiazol-5-yl]-
methyl}-4-methoxybenzenesulfonamide (3d). Light
orange solid, yield 83%, mp 232–233°C. IR spectrum,
2.24 s (4'-CH3), 2.41 s (4''-CH3), 4.50 d (J = 4.4 Hz,
5-CH2), 5.48 t (NH), 7.19 d.d ( H3', H5'), 7.25 d.d (H3'',
H5''), 7.71 d.d (H2'', H6'' ), 7.78 d.d (H2', H6'). 13C NMR spec-
trum, δ, ppm: 24.9 (4'-CH3), 25.5 (4''-CH3), 38.8 (5-CH2),
125.3 (C2', C6'), 127.2 (C1'), 129.8 (C2'', C6''), 130.9 (C3',
C5'), 131.9 (C3'', C5''), 133.3 (C4'), 136.1 (C4''), 144.0
(C1''), 166.9 (C5), 174.3 (C3). DIPMS: m/z: 344 [M + 1].
1
ν, cm–1: 1222 (C–N), 1577 (C=N), 3273 (NH). H
NMR spectrum, δ, ppm: 3.71 s (4''-OCH3), 4.50 d (J =
5.2 Hz, 5-CH2), 5.41 t (NH), 6.86 d.d (J = 2.4 Hz, J =
2 Hz, H3'', H5''), 7.13 d.d (J = 8.8 Hz, J = 8.8 Hz, H3',
H5'), 7.76 d.d (J = 2 Hz, J = 2.4 Hz, H2'', H6''), 7.91 d.d
(J = 5.2 Hz, J = 5.2 Hz, H2', H6'). 13C NMR spectrum
(CDCl3, 100.6 MHz), δ, ppm: 38.9 (5-CH2), 55.3
(4''-OCH3), 114.3 (C3', C5'), 115.9 (C1'), 116.1 (C2', C6'),
122.3 (C3'', C5''), 129.5 (C2', C6'), 129.7 (C4''), 130.5
(C1''), 131.1 (C4'), 165.9 (C5), 174.8 (C3). DIPMS: m/z:
364 [M + 1].
4-Chloro-N-[(3-p-tolyl-1,2,4-oxadiazol-5-yl)-
methyl]benzenesulfonamide (3g). Light yellow solid,
yield 79%, mp 193–195°C. IR spectrum, ν, cm–1: 1217
(C–N), 1571 (C=N), 3261 (NH). 1H NMR spectrum, δ,
ppm: 2.41 s (4'-CH3), 4.55 d (J = 4.4 Hz, 5-CH2), 5.51
t (NH), 7.28–7.31 m (H3', H5'), 7.39–7.41 m (H3'', H5''),
7.77–7.80 m (H2'', H6'', H2', H6'). 13C NMR spectrum, δ,
ppm: 24.8 (4'-CH3), 38.8 (5-CH2), 125.1 (C2', C6'),
127.6 (C1'), 129.5 (C2'', C6''), 131.9 (C3', C5'), 132.9 (C3'',
C5''), 134.3 (C4'), 137.1 (C4''), 144.2 (C1''), 166.7 (C5),
174.1 (C3). DIPMS: m/z: 364 [M + 1], 366 (M+H+2).
N-{(3-p-Tolyl-1,2,4-oxadiazol-5-yl]methyl}-
benzenesulfonamide (3e). White solid, yield 82%, mp
179–181°C. IR spectrum, ν, cm–1: 1224 (C–N), 1573
1
(C=N), 3249 (NH). H NMR spectrum, δ, ppm: 2.41 s
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4-Methoxy-N-[(3-p-tolyl-1,2,4-oxadiazol-5-yl)-
methyl]-benzenesulfonamide (3h). Light orange
solid, yield 75%, mp 222–223°C. IR spectrum, ν, cm–1:
1225 (C–N), 1576 (C=N), 3237 (NH). 1H NMR
spectrum, δ, ppm: 2.41 s (4'-CH3), 3.68 s (4''-OCH3),
4.50 d (J = 5.2 Hz, 5-CH2), 5.49 t (NH), 6.84 d.d (J =
2.4 Hz, J = 2 Hz, H3'', H5''), 7.25 d.d (J = 8.8 Hz, J =
8.8 Hz, H3', H5'), 7.76–7.81 m (H2'', H6'', H2', H6'). 13C
NMR spectrum, δ, ppm: 21.5 (4'-CH3), 38.9 (5-CH2),
55.6 (4''-OCH3), 114.3 (C3'', C5''), 123.2 (C1'), 127.4
(C2', C6'), 129.5 (C2'', C6''), 130.5 (C3', C5'), 131.1 (C4'),
141.8 (C1''), 163.2 (C5), 168.2 (C4'), 174.5 (C3).
DIPMS: m/z: 360 [M + 1].
solid, yield 75%, mp 225–226°C. IR spectrum, ν, cm–1:
1259 (C–N), 1573 (C=N), 3251 (NH). H NMR spec-
1
trum, δ, ppm: 3.69 s (4'-OCH3), 3.87 s (4''-OCH3), 4.49
d (J = 5.2 Hz, 5-CH2), 5.48 t (NH), 6.84 d.d (J =
2.4 Hz, J = 2 Hz, H3', H5'), 7.25 d.d (J = 8.8 Hz, J =
8.8 Hz, H3'', H5''), 7.76 d.d (J = 2.4 Hz, J = 2 Hz, H2'',
H6'') 7.92 d.d (J = 8.8 Hz, J = 8.8 Hz, H2', H6'). 13C
NMR spectrum, δ, ppm: 38.9 (5-CH2), 55.5 (4'-OCH3),
55.6 (4''-OCH3), 114.2 (C3', C5'), 114.3 (C3'', C5''), 118.4
(C1'), 129.4 (C2', C6'), 130.5 (C2'', C6''), 131.1 (C1''),
162.1 (C4'), 163.1 (C5), 167.8 (C4''), 174.4 (C3).
DIPMS: m/z: 376 [M + 1].
N-{[3-(2-Chlorophenyl)-1,2,4-oxadiazol-5-yl]-
methyl}benzenesulfonamide (3m). Light yellow
solid, yield 80%, mp 173–175°C. IR spectrum, ν, cm–1:
N-{[3-(4-Methoxyphenyl)-1,2,4-oxadiazol-5-yl]-
methyl}benzenesulfonamide (3i). Off white solid,
yield 81%, mp 198–199°C. IR spectrum, ν, cm–1: 1255
(C–N), 1597 (C=N), 3253 (NH). 1H NMR spectrum, δ,
ppm: 3.86 s (4'-OCH3), 4.52 d (J = 5.6 Hz, 5-CH2),
5.68 t (NH), 6.94–6.96 m (H3', H5'), 7.42–7.49 m (H3'',
H4'', H5''), 7.84–7.88 m (H2'', H6'', H2', H6'). 13C NMR
spectrum, δ, ppm: 38.9 (5-CH2), 58.9 (4'-OCH3), 115.9
(C2', C6'), 116.1 (C1'), 122.3 (C3'', C5''), 127.1 (C3', C5'),
129.1(C2'', C6''), 129.6 (C4''), 133.0 (C4'), 139.2 (C1''),
167.4 (C5), 174.8 (C3). DIPMS: m/z: 346 [M + 1].
1
1247 (C–N), 1570 (C=N), 3254 (NH). H NMR spec-
trum, δ, ppm: 4.58 d (5-CH2), 5.61 t (NH), 7.11–7.15
m (H3', H5'), 7.32–7.48 m (H2', H6'), 7.82–7.92 m (H2''
to H6''). 13C NMR spectrum, δ, ppm: 38.8 (5-CH2),
127.2 (C5'), 127.2 (C3'), 129.5 (C3'', C5''), 129.6 (C4'),
129.7 (C2'', C6''), 130.1 (C4'), 136.1 (C2'), 141.8 (C1'),
144.0 (C1''), 168.1 (C5), 174.4 (C3). DIPMS: m/z: 350
[M + 1].
N-{[3-(2-Chlorophenyl)-1,2,4-oxadiazol-5-yl]-
methyl}-4-methylbenzenesulfonamide (3n). Off white
solid, yield 72%, mp 184–185°C. IR spectrum, ν, cm–1:
N-{[3-(4-Methoxyphenyl)-1,2,4-oxadiazol-5-yl]-
methyl}-4-methylbenzene sulfonamide (3j). White
solid, yield 78%, mp 213–215°C. IR spectrum, ν, cm–1:
1
1332 (C–N), 1592 (C=N), 3293 (NH). H NMR spec-
1
1254 (C–N), 1574 (C=N), 3249 (NH). H NMR spec-
trum, δ, ppm: 2.31 s (4''-CH3), 4.56 d (5-CH2), 5.51 t
(NH), 7.22–7.24 m (H3'', H5''), 7.34–7.38 m (H4'), 7.41–
7.46 m (H5'), 7.51 d.d (J = 1.2 Hz, J = 1.2 Hz, H2'),
7.71–7.74 m (H6', H2'', H6''). 13C NMR spectrum, δ,
ppm: 21.5 (4''-CH3), 38.9 (5-CH2), 127.2 (C3', C5'),
127.2 (C1'), 129.5 (C2', C6'), 129.6 (C3'', C5''), 129.7 (C2',
C6'), 136.1 (C4''), 141.8 (C1''), 144.0 (C4'), 168.1 (C5),
174.4 (C3). DIPMS: m/z: 364 [M + 1].
trum, δ, ppm: 2.25 s (4''-CH3), 3.86 s (4'-OCH3), 4.50 d
(J = 4.4 Hz, 5-CH2), 5.46 t (NH), 6.95 d.d (J = 2 Hz,
J = 2.4 Hz, H3', H5'), 7.25 d.d (J = 8 Hz, J = 8 Hz, H3'',
H5''), 7.71 d.d (J = 8.4 Hz, J = 8.4 Hz, H2'', H6'' ), 7.78
d.d (J = 2 Hz, J = 2 Hz, H2', H6'). 13C NMR spectrum,
δ, ppm: 24.9 (4''-CH3), 38.8 (5-CH2), 55.4 (4'-OCH3),
114.2 (C3', C5'), 118.4 (C1'), 127.1 (C2', C6'), 129.0 (C2'',
C6''), 129.1 (C3'', C5''), 133.0 (C4''), 139.2 (C1''), 162.1
(C4'), 167.9 (C5), 174.3 (C3). DIPMS: m/z: 360 [M + 1].
4-Chloro-N-{[3-(2-chlorophenyl)-1,2,4-oxadiazol-
5-yl]methyl}benzenesulfonamide (3o). Off white solid,
yeield 86%, mp 195–196°C. IR spectrum, ν, cm–1:
4-Chloro-N-{[3-(4-methoxyphenyl)-1,2,4-oxadi-
azol-5-yl]methyl}benzenesulfonamide (3k). Off white
solid, yield 83%, mp 182–184°C. IR spectrum, ν, cm–1:
1
1277 (C–N), 1586 (C=N), 3254 (NH). H NMR spec-
trum, δ, ppm: 4.60 d (5-CH2), 5.84 t (NH), 7.13–7.18
m (H4', H5'), 7.39–7.41 m (H3', H6'), 7.51 d.d (J =
1.2 Hz, J = 1.2 Hz, H5''), 7.67 d.d (J = 2 Hz, J = 2 Hz,
H3''), 7.78–7.80 m (H2'', H6''). 13C NMR spectrum, δ,
ppm: 38.8 (5-CH2), 116.0 (C3', C5'), 116.2 (C1'), 128.6
(C2'', C6''), 129.4 (C3'', C5''), 129.6 (C2', C6'), 137.8 (C4''),
139.7 (C1''), 165.9 (C4'), 167.4 (C5), 174.6 (C3).
DIPMS: m/z: 385 [M + 1], 387 (M+H+2).
1
1258 (C–N), 1575 (C=N), 3289 (NH). H NMR spec-
trum, δ, ppm: 3.86 s (4'-OCH3), 4.53 d (J = 4.4 Hz, 5-
CH2), 5.75 t (NH), 6.95–6.97 m (H3', H5'), 7.38–7.41 m
(H3'', H5''), 7.78–7.84 m (H2'', H6'', H2', H6'). 13C NMR
spectrum, δ, ppm: 38.8 (5-CH2), 54.8 (4'-OCH3), 125.1
(C2', C6'), 127.6 (C1'), 129.5 (C2'', C6''), 131.9 (C3', C5'),
132.9 (C3'', C5''), 134.3 (C4'), 137.1 (C4''), 144.2 (C1''),
166.7 (C5), 174.1 (C3). DIPMS: m/z: 380 [M + 1].
Molecular docking. Molecular docking method
was used for studying the binding modes and affinities
of the synthesized compounds with Musmusculus
4-Methoxy-N-{[(4-methoxyphenyl)-1,2,4-oxadi-
azol-5-yl]methyl}benzenesulfonamide (3l). Off white
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 88 No. 4 2018

810
VIJAYA BHARGAVI et al.
COX 2 (PDB ID: 3LN1). All the ligands were targeted
to celecoxib bound at the COX-2 site. The three
dimensional structure of celecoxib bound at the COX-
2 active site (PDB ID: 3LN1) was retrieved from the
Brookhaven Protein Data Bank (PDB), USA (http://
www.rcsb.org/pdb). Protein and ligand preparation
wizard were used, respectively. Initially, ions, water
molecules, and all the internal ligands were removed
and missing atoms were inserted before minimization
of the target protein. Alternative conformations
(disorder) were removed. The best ligand conforma-
tion was chosen on the base of Lib Dock score and
highly interacting amino acid residues. Of ten
conformations generated for each compound, the
compound with the highest Lib Dock score was chosen
for interaction analysis of the hydrogen bonding.
carrageenan-induced rat paw edema method [21]. The
animals were housed under standard environmental
conditions, one week before the start and also during
the experiment as per the rules and regulations of the
institutional ethics committee (registered no. RBVRR1328/
01/2017/CPCSEA).
CONCLUSIONS
Herein, we report simple and efficient method of
synthesis of fused 1,2,4-oxadiazolo-sulfonamides via
the coupling reaction. Molecular docking studies
indicated high binding affinity of the compounds with
3LN1. In vivo analgesic and anti-inflammatory tests
demonstrated that 4-methoxy-N-{[(4-methoxyphenyl)-
1,2,4-oxadiazol-5-yl]methyl}benzenesulfonamide had
the highest activity. If the phenyl ring contained the
electron releasing substituents, like methoxy and
methyl groups, the compounds demonstrated high Lib
Dock scores, as well as significant analgesic and anti
inflammatory activities.
In vivo analgesic activity. a. Hot plate method:
The hot-plate test was performed to measure response
latencies according to the method described by Eddy
and Leimbach (1953) [20]. Swiss albino male wistar
rats (170–210 g body weight) were divided into groups
of six animals each. Group I served as control; group II
served as standard, received aspirin (10 mg/kg);
Groups III and IV served as test samples, received 20
and 40 mg/kg of 3d, 3f, 3l, 3n test samples respec-
tively. The animals were placed on the hot plate,
maintained at 55±2°C. The pain threshold was
considered to be reached when the animals lifted and
licked their paws or attempted to jump out of the hot
plate. Time needed for the rats to react in this fashion
was considered as basal reaction time. A latency
period of 30 s (cut-off) was defined as complete
analgesia, and the measurement was terminated if it
exceeded the latency period in order to avoid injury.
The reaction time was reinvestigated at 30, 60, 120,
and 180 min after the treatment and changes in the
reaction time were noted.
ACKNOWLEDGMENTS
Authors express their thanks to Head-Department
of University College of Technology, Osmania
University and management of RBVRR Women’s
College of Pharmacy for their constant support and
providing necessary facilities.
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