Synthesis, characterization and anti-inflammatory activity of 5-{[((5-substituted-aryl)-1,3,4-thiadiazol-2-yl)thio]-n-alkyl}-1,3, 4-oxadiazole-2-thiol

Article abstract of DOI:10.1002/cjoc.201090244

A series of potent and less toxic, 5-{[((5-substituted aryl)-1,3,4- thiadiazol-2-yl) thio]-n-alkyl}-1,3,4-oxadiazole-2-thiol was synthesized. Each compound was evaluated for anti-inflammatory activity by carrageenan-induced rat paw oedema method. Compounds PS1, PS4, PS9, and PS12 showed comparatively potent anti-inflammatory activity as compared to control as well as other test compounds. These potent compounds were also tested for acute ulcerogenic activity. Results of both studies were found statistically significant.

Full text of DOI:10.1002/cjoc.201090244

FULL PAPER
Synthesis, Characterization and Anti-inflammatory Activity of
5-{[((5-Substituted-aryl)-1,3,4-thiadiazol-2-yl)thio]-n-alkyl}-
1,3,4-oxadiazole-2-thiol
Shirote, Pramodkumar Jaykumar*
Bhatia, Manish Sudesh
Department of Pharmaceutical Chemistry, Bharati Vidyapeeth College of Pharmacy, Near Chitranagari, Morewadi,
Kolhapur, 416013, India
A series of potent and less toxic, 5-{[((5-substituted aryl)-1,3,4-thiadiazol-2-yl) thio]-n-alkyl}-1,3,4-oxadiazole-
2-thiol was synthesized. Each compound was evaluated for anti-inflammatory activity by carrageenan-induced rat
paw oedema method. Compounds PS1, PS4, PS9, and PS12 showed comparatively potent anti-inflammatory activ-
ity as compared to control as well as other test compounds. These potent compounds were also tested for acute ul-
cerogenic activity. Results of both studies were found statistically significant.
Keywords nonsteroidal antiinflammatory drug, oxadiazole, thiadiazoles, anti-inflammatory activity, ulcerogenic
activity
Introduction
Scheme 1
Synthesis of new potent and less toxic drug candi-
date for treatments of various inflammatory conditions
has been a research area of concern for medicinal
chemists. In present era most of the nonsteroidal antin-
flammatory drugs, e.g., Diclofenac sodium (1a), Ibu-
profen (1b), Ketoprofen (1c) and Naproxen (1d)
(Scheme 1), possess free carboxylic acid functional
group that renders the drug candidate therapeutically
less effective because of gastrointestinal disturbances.
Recently, synthetic chemists have accepted that chemi-
cal modification of this functional group could possibly
improve the safety profile of these drugs.1 Synthesis of
various derivatives of 1,3,4-oxadiazoles and 1,3,4-thia-
diazoles has been attracting wide attention due to their
wide spectrum of biological activities,1-16 such as an-
timicrobial, antimycobacterial, antifungal, antidepres-
sive, antiviral, analgesic, anti-inflammatory, antitumor,
vascular smooth muscle relaxant and cardiovascular
activity. It was therefore considered worthwhile to re-
place free carboxylic acid group of nonsteroidal antin-
flammatory drugs by these basic nuclei along with a
S(CH2)n bridge to study the effect on biological activity.
The targeted heteronuclei was incorporated in the com-
pounds employing the feasibility of converting SH
group to S-substituted derivatives.17,18 As a continuation
of our research on synthesis of heterocyles containing
these basic nuclei, it was thought worthwhile to convert
free carboxylic acid functional group to 1,3,4-thia-
diazole and connecting with 1,3,4-oxadiazole nucleus
through S(CH2)n bridge with the aim of enhancing
anti-inflammatory activity and minimizing ulcerogenic
activity. The synthesis of title compound is outlined in
Scheme 2.
Experimental
General
Melting points were determined by open capillary
method and were uncorrected. IR spectra (KBr wafer
technique) were recorded on Nicolet Impact-410FT
(Nicolet Instrumentation Corporation, Madison WI,
USA), and 1H NMR spectra were recorded in CDCl3 on
a Brucker 300 MHz (Brucker Magnetics AG, Faellan-
den, Switzerland) using TMS as the internal standard.
Mass spectra were obtained with a HPLC/MS
LCQDECA spectrometer. Elemental analysis was per-
formed on a Perkin Elmer model 240C analyzer and the
data were within ±0.4% of the theoretical values. The
purity of the compounds was confirmed by TLC on sil-
*
E-mail: padmpramod@rediffmail.com
Received October 9, 2009; revised February 5, 2010; accepted March 20, 2010.
Chin. J. Chem. 2010, 28, 1429— 1436
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1429

Shirote & Bhatia
FULL PAPER
Scheme 2
Reagents and conditions: (a) H2NNHCSNH2/POCl3, (b) NaNO2, Cu/HCl, (c) H2NCSNH2, (d) Ethyl bromo esters, (e) Hydrazine hydrate (100%), (f) CS2,
KOH
ica gel ‘G’ (60—120 mesh size) coated glass plates.
was cooled to room temperature and extracted with
CHCl3. The extracts were washed with NaHCO3 solu-
tion and dried over anhydrous Na2SO4. After evaporat-
ing the solution under reduced pressure, an oily product
was obtained. This was recrystallized from ethanol to
afford compounds.
Synthesis of 5-{aryl}-1,3,4-thiadiazol-2-amine (2a—
2d)
A mixture of corresponding aryl acetic/propionic
acid (10 mmol) and an equivalent amount of thiosemi-
carbazide in phosphorus oxychloride (20 mL) was re-
fluxed in a water bath for 2 h. After evaporating the re-
action content under reduced pressure, an oily product
was obtained. This was recrystallized from ethanol to
obtain the desired product.
2-Chloro-5-{[(2,6-dichlorophenyl)amino]benzyl}-1,
3,4-thiadiazole (3a): m.p. 56—58 ℃; 1H NMR (CDCl3,
300 MHz) δ: 10.1 (s, 1H), 2.7 (s, 2H), 6.90—7.86 (m,
7H); IR (KBr) ν: 3373－, 2965, 2848, 1675, 1612, 1455,
1
1378, 797,774, 722 cm .
5-{2-[(2,6-Dichlorophenyl)amino]benzyl}-1,3,4-thia-
diazol-2-amine (2a): m.p. 102—104 ℃; 1H NMR
(CDCl3, 300 MHz) δ: 10.1 (s, 1H,), 4.74 (s, 2H), 2.7 (s,
2-Chloro-5-[1-(4-isobutylphenyl)ethyl]-1,3,4-thia-
1
diazole (3b): m.p. 54—56 ℃; H NMR (CDCl3, 300
MHz) δ: 1.54 (q, 1H), 1.81—1.84 (m, 1H), 1.29 (d, 9H),
2H), 6.90—7.86 (m, 7H); IR (KBr) ν: 3370, 2925, 2844,
2.1 (d, 2H), 7.10—7.60 (m, 4H); IR (KBr) ν:－2980,
－1
1
1665, 1610, 1453, 1374, 795, 720 cm

2845, 1645, 1588, 1485, 1415, 1395, 865, 778 cm .
5-[1-(4-Isobutylphenyl)ethyl]-1,3,4-thiadiazol-2-
2-Chloro-5-[1-(3-benzoylphenyl)ethyl]-1,3,4-thia-
1
1
amine (2b): m.p. 105—107 ℃; H NMR (CDCl3, 300
diazole (3c): m.p. 52—55 ℃; H NMR (CDCl3, 300
MHz) δ: 1.54 (q, 1H), 4.65 (s, 2H), 1.81—1.82 (m, 1H),
1.32 (d, 9H), 2.1 (d, 2H), 7.10—7.60 (m, 4H); IR (KBr)
MHz) δ: 1.62 (q, 1H), 1.45 (d, 3H), 7.40—8.10 (m, 9H) ;
IR －(KBr) ν: 2984, 2865, 1683, 1625, 1545, 815, 768
－1
1
ν: 2980, 2845, 1645, 1588, 1485, 1415, 1395, 865 cm .
cm .
5-[1-(3-Benzoylphenyl)ethyl]-1,3,4-thiadiazol-2-
amine (2c): m.p. 103—106 ℃; 1H NMR (CDCl3, 300
MHz) δ: 1.62 (q, 1H), 4.67 (s, 2H), 1.45 (d, 3H), 7.40—
8.10 (m－, 9H); IR (KBr) ν: 2984, 2865, 1683, 1625, 1545,
2-Chloro-5-[(6-methoxy-2-naphthyl)methyl]-1,3,4-
1
thiadiazole (3d): m.p. 59—62 ℃; H NMR (CDCl3,
300 MHz) δ: 3.6 (s, 3H), 2.9 (s, 2H), 6.70—7.45 (m,
6H); IR (KBr) ν: 2978, 2885, 1674, 1610, 1588, 1465,
1
－1
815 cm .
810, 768, 782 cm .
5-[(6-Methoxy-2-naphthyl)methyl]-1,3,4-thiadiazol-
2-amine (2d): m.p. 110—112 ℃; 1H NMR (CDCl3, 300
MHz) δ: 3.6 (s, 3H), 2.9 (s, 2H), 4.72 (s, 2H), 6.70—
7.45 (m, 6H); IR (KBr) ν: 2978, 2885, 1674, 1610, 1588,
Synthesis of 5-{aryl}-1,3,4-thiadiazole-2-thiol (4a—
4d)
The solution of corresponding compound 3 (10
mmol) in ethanol was refluxed with an excess amount
of thiourea (30 mmol) for 5 h. After cooling the reaction
mixture to room temperature, a mixture consisting of
conc. HCl (3 mL) and water was added. The solid thus
obtained was filtered, washed with water and recrystal-
lized from ethanol.
－1
1465, 810, 768 cm .
Synthesis of 2-chloro-5-{aryl}-1,3,4-thiadiazole (3a—
3d)
A mixture of corresponding compound 2 (10 mmol)
and an excess amount of NaNO2 (30 mmol) was added
in the form of small amounts into a solution of conc.
HCl (30 mL) and ice-water containing Cu powder (0.5 g)
while stirring. After stirring the reaction content at 0 ℃
for 1 h, the mixture was allowed to reach room tem-
perature and was stirred for an additional 2 h. Then it
was heated in a water bath for 2 h. The reaction mixture
5-{2-[(2,6-Dichlorophenyl)amino]benzyl}-1,3,4-thia-
diazole-2-thiol (4a): m.p. 67—69 ℃; 1H NMR (CDCl3,
300 MHz) δ: 10.1 (s, 1H), 2.7 (s, 2H), 6.90—7.86 (m,
7H), 12.35 (s, 1H); IR (KBr) ν: 3373,－2929, 2844, 2565,
1
1666, 1614, 1455, 1375, 794, 722 cm .
5-[1-(4-Isobutylphenyl)ethyl]-1,3,4-thiadiazole-2-
1430
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Chin. J. Chem. 2010, 28, 1429— 1436

Synthesis of 5-{[((5-Substituted-Aryl)-1,3,4-thiadiazol-2-yl)thio]-n-alkyl}-1,3,4-oxadiazole-2-thiol
thiol (4b): m.p. 69—71 ℃; 1H NMR (CDCl3, 300 MHz)
δ: 1.54 (q, 1H), 1.8 (m, 1H), 1.26—1.35 (d, 9H), 2.1 (d,
2H), 7.10—7.60 (m, 4H), 12.45 (s, 1H); IR (KBr) ν:
2980, 2845, 2568, 1645, 1588, 1485, 1415, 1395, 865
2H), 2.3 (t, J＝7.30 Hz, 2H), 4.23 (q, J＝6.14 Hz, 2H),
1.17 (t, J＝5.80 Hz, 3H), 7.33—7.96 (m, 4H) ; IR (KBr)
ν: 2982－, 2845, 1687, 1646, 1582, 1486, 1415, 1398, 863,
1
674 cm .
－1
cm .
Ethyl 4-({5-[1-(4-isobutylphenyl)ethyl]-1,3,4-thia-
1
5-[1-(3-Benzoylphenyl)ethyl]-1,3,4-thiadiazole-2-
thiol (4c): m.p. 61—63 ℃; 1H NMR (CDCl3, 300 MHz)
δ: 1.62 (q, 1H, CH), 1.45 (d, 3H, CH3), 7.40—8.10 (m,
9H, aromatic), 12.42 (s, 1H, SH); IR (KBr) ν: 2984,
diazol-2-yl}thio)butanoate (5f): m.p. 92—94 ℃; H
NMR (CDCl3, 300 MHz) δ: 1.53 (q, 1H), 1.4 (m, 1H),
1.27—1.36 (d, 9H), 2.1 (d, 2H), 3.92 (t, J＝7.80 Hz,
2H), 2.24 (q, J＝7.30 Hz, 2H), 2.27 (t, J＝7.60 Hz, 2H),
4.20 (q, J＝6.13 Hz, 2H), 1.16 (t, J＝5.84 Hz, 3H), 7.25
—7.66 (m, 4H); IR (KBr) ν: 2980, －2846, 1688, 1640,
－1
2865, 2573, 1683, 1625, 1545, 845 cm .
5-[(6-Methoxy-2-naphthyl)methyl]-1,3,4-thiadiazole-
1
1
2-thiol (4d): m.p. 72—74 ℃; H NMR (CDCl3, 300
1578, 1485, 1414, 1393, 860, 672 cm .
MHz) δ: 3.6 (s, 3H), 2.9 (s, 2H), 6.70—7.45 (m, 6H),
12.52 (s, 1H) ; IR (KBr) ν: 2978, 2885, 2567, 1674,
Ethyl ({5-[1-(3-benzoylphenyl)ethyl]-1,3,4-thiadiazol-
1
2-yl}thio)acetate (5g): m.p. 83 — 85 ℃ ; H NMR
－1
1610, 1588, 1465, 810, 768 cm .
(CDCl3, 300 MHz) δ: 1.62 (q, 1H), 1.45 (d, 3H), 3.90 (s,
2H), 4.18 (q, J＝6.13 Hz, 2H), 1.13 (t, J＝5.85 Hz, 3H),
7.40—8.10 (m, 9H); IR (KB－r) ν: 2984, 2865, 1692,
Synthesis of ethyl [(aryl-1,3,4-thiadiazol-2-yl)thio]
esters (5a— 5l)
1
1683, 1625, 1545, 815, 672 cm .
The corresponding compound 4 (10 mmol) was re-
fluxed with an equivalent amount of sodium in absolute
ethanol for 1 h. Then ethyl bromo acetate/propanoate/
butanoate (10 mmol) was added and refluxed for addi-
tional 5 h. After evaporation at 35—40 ℃ under re-
duced pressure, a solid appeared. This was recrystal-
lized from ethanol-water (1∶1, V∶V) to obtain the
desired compound.
Ethyl 3-({5-[1-(3-benzoylphenyl)ethyl]-1,3,4-thia-
1
diazol-2-yl}thio)propanoate (5h): m.p. 86—88 ℃; H
NMR (CDCl3, 300 MHz) δ: 1.67 (q, 1H), 1.43 (d, 3H),
3.85 (t, J＝7.80 Hz, 2H), 2.08 (t, J＝7.28 Hz, 2H), 4.20
(q, J＝6.14 Hz, 2H), 1.16 (t, J＝5.78 Hz, 3H), 7.38—
8.23 (m, 9H); IR (KBr) ν: 2985, 2866, 1695, 1687, 1622,
－1
1546, 824, 673 cm .
Ethyl 4-({5-[1-(3-benzoylphenyl)ethyl]-1,3,4-thia-
1
Ethyl [(5-{2-[(2,6-dichlorophenyl)amino]benzyl}-
1,3,4-thiadiazol-2-yl)thio]acetate (5a): m.p. 74—76 ℃;
1H NMR (CDCl3, 300 MHz) δ: 10.2 (s, 1H), 2.7 (s, 2H),
3.95 (s, 2H), 4.14 (q, J＝6.12 Hz, 2H), 1.12 (t, J＝5.85
Hz, 3H), 6.90—7.86 (m, 7H); IR (KBr) ν: 3374, 2926,
2844, 1687, 1669, 1616, 1453, 1374, 795, 778, 720, 665
diazol-2-yl}thio)butanaote (5i): m.p. 95—97 ℃; H
NMR (CDCl3, 300 MHz) δ: 1.61 (q, 1H), 1.44 (d, 3H),
3.86 (t, J＝7.80 Hz, 2H), 2.15 (q, J＝7.30 Hz, 2H), 2.26
(t, J＝7.60 Hz, 2H), 4.21 (q, J＝6.15 Hz, 2H), 1.18 (t,
J＝5.83 Hz, 3H), 7.42—8.22 (m, 9H); IR (KBr) ν: 2986,
－1
2863, 1693, 1686, 1623, 1544, 816, 677 cm .
－1
cm .
Ethyl ({5-[(6-methoxy-2-naphthyl)methyl]-1,3,4-thia-
diazol-2-yl}thio)acetate (5j): m.p. 98 — 100 ℃ ; 1H
NMR (CDCl3, 300 MHz) δ: 3.6 (s, 3H), 2.9 (s, 2H),
3.83 (s, 2H), 4.19 (q, J＝6.13 Hz, 2H), 1.10 (t, J＝5.85
Hz, 3H), 6.93—7.57 (m, 6H); IR (KBr) ν: 2978, 2875,
Ethyl 3-[(5-{2-[(2,6-dichlorophenyl)amino]benzyl}-
1,3,4-thiadiazol-2-yl)thio]propanoate (5b): m.p. 83—85
℃; 1H NMR (CDCl3, 300 MHz) δ: 10.3 (s, 1H), 2.63 (s,
2H), 3.87 (t, J＝7.80 Hz, 2H), 2.10 (t, J＝7.28 Hz, 2H),
4.23 (q, J＝6.12 Hz, 2H), 1.18 (t, J＝5.80 Hz, 3H), 6.89
—7.75 (m, 7H); IR (KBr) ν: 3373, 2929, 2842, 1687,
－1
1687, 1674, 1610, 1585, 1467, 817, 769, 675 cm .
Ethyl 3-({5-[(6-methoxy-2-naphthyl)methyl]-1,3,4-
thiadiazol-2-yl}thio)propanoate (5k): m.p. 96—99 ℃;
1H NMR (CDCl3, 300 MHz) δ: 3.8 (s, 3H), 2.12 (s, 2H),
3.94 (t, J＝7.80 Hz, 2H), 2.03 (t, J＝7.30 Hz, 2H), 4.22
(q, J＝6.15 Hz, 2H), 1.17 (t, J＝5.78 Hz, 3H), 6.57—
7.46 (m, 6H); IR (KBr) ν: 298－8, 2865, 1689, 1678, 1618,
－1
1667, 1614, 1453, 1373, 795, 775, 722, 663 cm .
Ethyl 4-[(5-{2-[(2,6-dichlorophenyl)amino]benzyl}-
1,3,4-thiadiazol-2-yl)thio]butanoate (5c): m.p. resinous;
1H NMR (CDCl3, 300 MHz) δ: 10.15 (s, 1H), 2.72 (s,
2H), 3.84 (t, J＝7.82 Hz, 2H), 2.14 (q, J＝7.30 Hz, 2H),
2.26 (t, J＝7.60 Hz, 2H), 4.19 (q, J＝6.13, 2H), 1.16 (t,
J＝5.85 Hz, 3H), 6.50—7.84 (m, 7H); IR (KBr) ν: 3370,
2925, 2－844, 1689, 1665, 1615,1452,1374, 791,774, 725,
1
1587, 1465, 816, 769, 674 cm .
Ethyl 4-({5-[(6-methoxy-2-naphthyl)methyl]-1,3,4-
thiadiazol-2-yl}thio)butanoate (5l): m.p. 102—104 ℃;
1H NMR (CDCl3, 300 MHz) δ: 3.5 (s, 3H), 2.8 (s, 2H),
3.90 (t, J＝7.80 Hz, 2H), 2.11 (q, J＝7.30 Hz, 2H), 2.23
(t, J＝7.60 Hz, 2H), 4.26 (q, J＝6.15 Hz, 2H), 1.19 (t,
J＝5.82 Hz, 3H), 6.74—7.48 (m, 6H); IR (KBr) ν: 2994,
2885, 1686, 1676, 1615, 1583, 1464, 818, 768, 673
1
668 cm .
Ethyl ({5-[1-(4-isobutylphenyl)ethyl]-1,3,4-thiadiazol-
1
2-yl}thio)acetate (5d): m.p. 76 — 79 ℃ ; H NMR
(CDCl3, 300 MHz) δ: 1.54 (q, 1H), 1.8 (m, 1H), 1.26—
1.35 (d, 9H), 2.2 (d, 2H), 3.86 (s, 2H), 4.21 (q, J＝6.12
Hz, 2H), 1.14 (t, J＝5.85 Hz,3H),7.18-7.96 (m, 4H); IR
(KBr) ν: 2980, 2844, 1685, 1645, 1585, 1485, 1416,
－1
cm .
－1
Synthesis of [5-{aryl}-1,3,4-thiadiazole-2-thiol] n-al-
kanehydrazide (6a— 6l)
1395, 865, 669 cm .
Ethyl 3-({5-[1-(4-isobutylphenyl)ethyl]-1,3,4-thia-
1
diazol-2-yl}thio)propanoate (5e): m.p. 79—81 ℃; H
A solution of the corresponding compound 5 (10
mmol) was refluxed with hydrazine hydrate (100%) (25
mmol) for 4 h. After cooling it to room temperature, a
NMR (CDCl3, 300 MHz) δ: 1.58 (q, 1H), 1.7 (m, 1H),
1.29—1.34 (d, 9H), 1.96 (d, 2H), 3.89 (t, J＝7.80 Hz,
Chin. J. Chem. 2010, 28, 1429— 1436
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Shirote & Bhatia
FULL PAPER
white solid appeared. This was recrystallized from
ethanol to obtain the desired product.
NMR (CDCl3, 300 MHz) δ: 1.58 (q, 1H), 1.46 (d, 3H),
3.86 (t, J＝7.80 Hz, 2H), 2.15 (q, J＝7.30 Hz, 2H), 2.26
(t, J＝7.60 Hz, 2H), 4.61 (d, 2H), 9.39 (t, 1H), 7.38—
8.58 (m, 9H); IR (－KBr) ν: 2996, 2869, 1690, 1689, 1627,
2-[(5-{2-[(2,6-Dichlorophenyl)amino]benzyl}-1,3,4-
thiadiazol-2-yl)thio]acetohydrazide (6a): m.p. 78—80
℃; 1H NMR (CDCl3, 300 MHz) δ: 10.6 (s, 1H) 2.75 (s,
2H), 3.95 (s, 2H), 4.69 (d, 2H), 9.25 (t, 1H), 6.90—7.86
(m, 7H); IR (KBr) ν: 3373, 2925, 2847, 1695, 1665,
1
1546, 818,677 cm .
2-({5-[(6-Methoxy-2-naphthyl)methyl]-1,3,4-thiadi-
azol-2-yl}thio)acetohydrazide (6j): m.p. 102—105 ℃;
1H NMR (CDCl3, 300 MHz) δ: 3.5 (s, 3H), 2.9 (s, 2H),
3.83 (s, 2H), 4.59 (d, 2H), 9.34 (t, 1H), 6.82—7.47 (m,
6H); IR (KBr) ν: 2978,－2885, 1694, 1674, 1610, 1588,
－1
1610, 1453, 1374, 795,779, 720, 665 cm .
3-[(5-{2-[(2,6-Dichlorophenyl)amino]benzyl}-1,3,4-
thiadiazol-2-yl)thio]propanehydrazide (6b): m.p. 86—
1
1
89 ℃; H NMR (CDCl3, 300 MHz) δ: 10.2 (s, 1H),
1465, 816, 768, 675 cm .
2.74 (s, 2H), 3.87 (t, J＝7.80 Hz, 2H), 2.10 (t, J＝7.28
Hz, 2H), 4.72 (d, 2H), 9.30 (t, 1H), 7.13—7.66 (m, 7H);
IR (KBr) ν: 3370, 2927, 2846, 1694, 1669, 1613, 1453,
3-({5-[(6-Methoxy-2-naphthyl)methyl]-1,3,4-thiadi-
azol-2-yl}thio)propanehydrazide (6k): m.p. 99—102 ℃;
1H NMR (CDCl3, 300 MHz) δ: 3.6 (s, 3H), 2.74 (s, 2H),
3.94 (t, J＝7.80 Hz, 2H), 2.03 (t, J＝7.30 Hz, 2H), 4.65
(d, 2H), 9.32 (t, 1H), 6.75—7.68 (m, 6H); IR (KBr) ν:
2995, 2875, 1693, 1678, 1616, 1589, 1466, 815, 767,
－1
1375, 785, 775, 724, 663 cm .
4-[(5-{2-[(2,6-Dichlorophenyl)amino]benzyl}-1,3,4-
thiadiazol-2-yl)thio]butanehydrazide (6c): m.p. 82—85
℃; 1H NMR (CDCl3, 300 MHz) δ: 10.4 (s, 1H), 2.68 (s,
2H), 3.84 (t, J＝7.82 Hz, 2H), 2.14 (q, J＝7.30 Hz, 2H),
2.26 (t, J＝7.60 Hz, 2H), 4.73 (d, 2H), 9.32 (t, 1H), 6.99
—7.46 (m, 7H, aromatic); IR (KBr) ν: 3372, 2926, 2844,
－1
674 cm .
4-({5-[(6-Methoxy-2-naphthyl)methyl]-1,3,4-thia-
diazol-2-yl}thio)butanehydrazide (6l): m.p. 106—108
1
℃; H NMR (CDCl3, 300 MHz) δ: 3.4 (s, 3H), 2.83 (s,
－1
1689, 1667, 1612,14 53,1376, 789, 778, 723, 668 cm .
2H), 3.90 (t, J＝7.80 Hz, 2H), 2.11 (q, J＝7.30 Hz, 2H),
2.23 (t, J＝7.60 Hz, 2H), 4.63 (d, 2H), 9.32 (t, 1H), 6.79
—7.88 (m, 6H); IR (KBr) ν: 2985, 2865, 1692, 1670,
2-({5-[1-(4-Isobutylphenyl)ethyl]-1,3,4-thiadiazol-
1
2-yl}thio)acetohydrazide (6d): m.p. 78—80 ℃; H
－1
NMR (CDCl3, 300 MHz) δ: 1.54 (q, 1H), 1.8 (m, 1H),
1.26—1.35 (d, 9H), 2.2 (d, 2H), 3.86 (s, 2H), 4.66 (d,
2H), 9.34 (t, 1H), 7.10—7.60 (m, 4H); IR (KBr) ν: 2989,
2845, 1690, 1655, 1589, 1485, 1415, 1394, 867, 669
1615, 1587, 1468, 819, 766, 673 cm .
Synthesis of 5-{[((5-substituted aryl)-1,3,4-thiadiazol-
2-yl)thio]-n-alkyl}-1,3,4-oxadiazole-2-thiol (PS1 —
PS12)
－1
cm .
The reaction mixture containing corresponding
compound 6 (10 mol) and equimolar quantities of CS2
and KOH in the mixture of water and ethanol was re-
fluxed for 3 h. After evaporating it under reduced pres-
sure, a solid was obtained. This was dissolved in excess
of H2O and acidified with conc. HCl. The precipitate
was filtered, washed with H2O and recrystallized from
an appropriate solvent to obtain the desired compound.
5-{[(5-{2-[(2,6-Dichlorophenyl)amino]benzyl}-1,3,
4-thiadiazol-2-yl)thio]methyl}-1,3,4-oxadiazole-2-thiol
(PS1): m.p. 92—95 ℃; 1H NMR (CDCl3, 300 MHz) δ:
10.4 (s, 1H), 2.64 (s, 2H), 3.98 (s, 2H), 13.76 (s, 1H)
6.90—7.86 (m, 7H); IR (KBr) ν: 3370, 2975, 2846,
2567, 1662, 1635, 1616, 1453, 1375, 795, 720, 665
3-({5-[1-(4-Isobutylphenyl)ethyl]-1,3,4-thiadiazol-
1
2-yl}thio)propanehydrazide (6e): m.p. 83—85 ℃; H
NMR (CDCl3, 300 MHz) δ: 1.54 (q, 1H), 1.8 (m, 1H),
1.26—1.35 (d, 9H), 1.96 (d, 2H), 3.89 (t, J＝7.80 Hz,
2H), 2.3 (t, J＝7.30 Hz, 2H), 4.67 (d, 2H), 9.35 (t, 1H),
7.10—7.60 (m, 4H); IR (KBr) ν: 2998, 2847, 1692,
－1
1645, 1587, 1483, 1418, 1396, 866, 674 cm .
4-({5-[1-(4-Isobutylphenyl)ethyl]-1,3,4-thiadiazol-2-
yl}thio)butanehydrazide (6f): m.p. 96—98 ℃; 1H NMR
(CDCl3, 300 MHz) δ: 1.54 (q, 1H), 1.8 (m, 1H), 1.26—
1.35 (d, 9H), 2.1 (d, 2H), 3.92 (t, J＝7.80 Hz, 2H), 2.24
(q, J＝7.30 Hz, 2H), 2.27 (t, J＝7.60 Hz, 2H), 4.68 (d,
2H), 9.32 (t, 1H), 7.10—7.60 (m, 4H); IR (KBr) ν: 3012,
2843, 1693, 1649, 1588, 1484, 1417, 1395, 865, 672
＋
－1
－1
cm ; MS (70 eV) m/z: 482 (M ). Anal. calcd for
C18H13Cl2N5OS3: C 44.81, H 2.72, N 14.52; found C
44.78, H 2.69, N 14.50. HRMS calcd for C18H13-
Cl2N5OS3 482.4352, found 482.4346.
cm .
2-({5-[1-(3-Benzoylphenyl)ethyl]-1,3,4-thiadiazol-2-
yl}thio)acetohydrazide (6g): m.p. 85—87 ℃; 1H NMR
(CDCl3, 300 MHz) δ: 1.68 (q, 1H), 1.45 (d, 3H), 3.90 (s,
2H), 4.69 (d, 2H), 9.29 (t, 1H),7.40—8.10 (m, 9H); IR
(KBr) ν: 2979, 2875, 1696, 1688, 1625, 1548, 818, 672
5-{2-[(5-{2-[(2,6-Dichlorophenyl)amino]benzyl}-1,
3,4-thiadiazol-2-yl)thio]ethyl}-1,3,4-oxadiazole-2-thiol
(PS2): m.p. 100—103 ℃; 1H NMR (CDCl3, 300 MHz)
δ: 10.2 (s, 1H), 2.7 (s, 2H), 3.87 (t, J＝8.12 Hz, 2H),
2.10 (t, J＝8.14 Hz, 2H), 13.85 (s, 1H) 6.85—7.57 (m,
7H); IR (KBr) ν: 3356, 2932, 2844－, 2565, 1694, 1665,
－1
cm .
3-({5-[1-(3-Benzoylphenyl)ethyl]-1,3,4-thiadiazol-2-
1
yl}thio) propanehydrazide (6h): m.p. 88—90 ℃; H
NMR (CDCl3, 300 MHz) δ: 1.55 (q, 1H), 1.47 (d, 3H),
3.85 (t, J＝7.80 Hz, 2H), 2.08 (t, J＝7.28 Hz, 2H), 4.62
(d, 2H), 9.33 (t, 1H), 7.48—8.57 (m, 9H); IR (KBr) ν:
1
1610, 1458, 1374, 799, 723, 663 cm ; MS (70 eV) m/z:
497 (M＋). Anal. calcd for C19H15Cl2N5OS3: C 45.97, H
3.05, N 14.11; found C 45.24, H 3.16, N 13.95. HRMS
calcd for C19H15Cl2N5OS3 496.4623, found 496.4617.
5-{3-[(5-{2-[(2,6-Dichlorophenyl)amino]benzyl}-1,
－1
2984, 2865, 1698, 1683, 1620, 1545, 816, 673 cm .
4-({5-[1-(3-Benzoylphenyl)ethyl]-1,3,4-thiadiazol-2-
1
yl}thio)butanehydrazide (6i): m.p. 99 — 104 ℃ ; H
1432
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© 2010 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2010, 28, 1429— 1436

Synthesis of 5-{[((5-Substituted-Aryl)-1,3,4-thiadiazol-2-yl)thio]-n-alkyl}-1,3,4-oxadiazole-2-thiol
3,4-thiadiazol-2-yl)thio]propyl}-1,3,4-oxadiazole-2-thiol
(PS3): m.p. 86—88 ℃; 1H NMR (CDCl3, 300 MHz) δ:
10.5 (s, 1H), 2.67 (s, 2H), 3.84 (t, J＝8.13 Hz, 2H), 2.14
(q, J＝8.14 Hz, 2H), 2.26 (t, J＝8.12 Hz, 2H), 13.96 (s,
1H,) 6.76—7.48 (m, 7H); IR (KBr) ν: 3370, 2928, 2845,
2568, 1689, 1668, 1615, 1455, 1377, 796, 726, 668
IR (KBr) ν: 2988, 2858, 2563, 1697, 168＋6, 1628, 1544,
for C21H18N4O2S3: C 55.49 H 3.99 N 12.32; found C
55.44, H 3.96, N 12.35. HRMS calcd for C21H18N4O2S3
454.5952, found 454.5946.
－1
813, 674 cm ; MS (70 eV) m/z: 455 (M ). Anal. calcd
5-[3-({5-[1-(3-Benzoylphenyl)ethyl]-1,3,4-thiadiazol-
2-yl}thio)propyl]-1,3,4-oxadiazole-2-thiol (PS9): m.p.
93—96 ℃; 1H NMR (CDCl3, 300 MHz) δ: 1.68 (q, 1H),
1.46 (d, J＝5.67 Hz, 3H), 3.86 (t, J＝8.13 Hz, 2H), 2.15
(q, J＝8.22 Hz, 2H), 2.26 (t, J＝8.14 Hz, 2H), 13.97 (s,
H),7.42—7.89 (m, 9H); IR (KBr) ν: 2985, 2864, 2564,
＋
－1
cm . MS (70 eV) m/z: 510 (M ). Anal. calcd for
C20H17Cl2N5OS3: C 47.06, H 3.36, N 13.72; found C
47.10, H 3.34, N 13.49. HRMS calcd for C20H17-
Cl2N5OS3 510.4894, found 510.4886.
5-[({5-[1-(4-Isobutylphenyl)ethyl]-1,3,4-thiadiazol-2-
yl}thio)methyl]-1,3,4-oxadiazole-2-thiol (PS4): m.p. 84
—87 ℃; 1H NMR (CDCl3, 300 MHz) δ: 1.56 (q, 1H),
1.67 (m, 1H), 1.26—1.35 (d, J＝7.88 Hz, 9H), 2.2 (d,
J＝5.67 Hz, 2H), 3.86 (s, 2H), 14.23 (s, H), 7.23—7.89
(m, 4H); IR (KBr) ν: 2985, 2844, 2565, 1－690, 1665,
－1
1695, 1647, 1624, 1545, 1469, 816, 677 cm ; MS (70
eV) m/z: 469 (M＋). Anal. calcd for C22H20N4O2S3: C
56.39, H 4.30, N 1.96; found C 56.34, H 4.32, N 1.94.
HRMS calcd for C22H20N4O2S3 468.6223, found
468.6217.
1
1645, 1588, 1482,＋1422, 1394, 863, 669 cm ; MS (70
5-[({5-[(6-Methoxy-2-naphthyl)methyl]-1,3,4-thiadi-
azol-2-yl}thio)methyl]-1,3,4-oxadiazole-2-thiol (PS10):
m.p. 98—101 ℃; 1H NMR (CDCl3, 300 MHz) δ: 3.63
(s, 3H), 2.84 (s, 2H), 3.83 (s, 2H), 13.88 (s, 1H), 6.67—
7.46 (m, 6H); IR (KBr) ν: 2978, 2875, 2568, 1676, 1615,
eV) m/z: 393 (M ). Anal. calcd for C17H20N4OS3: C
52.01, H 5.14, N 14.27; found C 52.04, H 5.16, N 14.23.
HRMS calcd for C17H20N4OS3 392.5671, found
392.5665.
－1
5-[2-({5-[1-(4-Isobutylphenyl)ethyl]-1,3,4-thiadiazol-
2-yl}thio)ethyl]-1,3,4-oxadiazole-2-thiol (PS5): m.p. 94
—97 ℃; 1H NMR (CDCl3, 300 MHz) δ: 1.53 (q, 1H),
1.75 (m, 1H), 1.23—1.38 (d, J＝7.88 Hz, 9H), 1.96 (d,
J＝5.69 Hz, 2H), 3.89 (t, J＝8.12 Hz, 2H), 2.3 (t, J＝
8.14 Hz, 2H), 13.46 (s, H) 7.18—7.64 (m, 4H); IR (KBr)
ν: 2982, 2845, 25－70, 1692, 1645, 1584, 148＋7, 1418,
1585, 1468, 813, 768, 669 cm ; MS (70 eV) m/z: 403
(M＋). Anal. calcd for C17H14N4O2S3: C 50.73, H 3.51, N
13.92; found C 50.74, H 3.56, N 13.89. HRMS calcd for
C17H14N4O2S3 402.5187, found 402.5181.
5-[2-({5-[(6-Methoxy-2-naphthyl)methyl]-1,3,4-thia-
diazol-2-yl}thio)ethyl]-1,3,4-oxadiazole-2-thiol (PS11):
m.p. 100—103 ℃; 1H NMR (CDCl3, 300 MHz) δ:
3.64 (s, 3H), 2.85 (s, 2H), 3.94 (t, J＝8.14Hz, 2H), 2.03
(t, J＝8.16 Hz, 2H), 13.57 (s, H) 6.90—8.05 (m, 6H);
IR (KBr) ν: 2998,－2885, 2572, 1673, 1610, 1588, 1465,
1
1395, 865, 674 cm ; MS (70 eV) m/z: 407 (M ). Anal.
calcd for C18H22N4OS3: C 53.17, H 5.45, N 13.78; found
C 53.18, H 5.46, N 13.76. HRMS calcd for
C18H22N4OS3 406.5942, found 406.5937.
＋
1
810, 766, 674 cm ; MS (70 eV) m/z: 417 (M ). Anal.
calcd for C18H16N4O2S3: C 51.90, H 3.87, N 13.45;
found C 51.92, H 3.86, N 13.44. HRMS calcd for
C18H16N4O2S3 416.5458, found 416.5451.
5-[3-({5-[1-(4-Isobutylphenyl)ethyl]-1,3,4-thiadiazol-
2-yl}thio)propyl]-1,3,4-oxadiazole-2-thiol (PS6): m.p.
103—106 ℃; 1H NMR (CDCl3, 300 MHz) δ: 1.54 (q,
1H), 1.8 (m, 1H), 1.27—1.34 (d, J＝7.88 Hz, 9H), 2.1
(d, J＝5.67 Hz , 2H), 3.92 (t, J＝8.13 Hz, 2H), 2.24 (q,
J＝8.22 Hz ,2H), 2.27 (t, J＝8.14 Hz, 2H),13.57 (s, 1H)
7.15—7.72 (m, 4H); IR (KBr) ν: 2980, 2844, 2572,
5-[3-({5-[(6-Methoxy-2-naphthyl)methyl]-1,3,4-thia-
diazol-2-yl}thio)propyl]-1,3,4-oxadiazole-2-thiol (PS12):
m.p. 111—113 ℃; 1H NMR (CDCl3, 300 MHz) δ: 3.7
(s, 3H), 2.9 (s, 2H), 3.90 (d, J＝7.88 Hz, 2H), 2.09 (q,
J＝8.18 Hz, 2H), 2.31 (t, J＝7.98 Hz, 2H), 14.21 (s, H),
6.70—7.45 (m, 6H); IR (KBr) ν: 3012, 2915, 2567,
－1
1693, 1647, 1587, 1483, ＋1419, 1397, 867, 672 cm ;
MS (70 eV) m/z: 421 (M ). Anal. calcd for C19H24N4-
OS3: C 54.26, H 5.75, N 13.32; found C 54.24, H 5.73,
N 13.35. HRMS calcd for C19H24N4OS3 420.6213,
found 420.6207.
－1
1674, 1622, 1567＋, 1465, 812, 764, 675 cm ; MS (70
eV) m/z: 431 (M ). Anal. calcd for C19H18N4O2S3: C
53.00, H 4.21, N 13.01; found C 53.02, H 4.26, N 13.05.
HRMS calcd for C19H18N4O2S3 430.5729, found
430.5721.
5-[({5-[1-(3-Benzoylphenyl)ethyl]-1,3,4-thiadiazol-2-
yl}thio)methyl]-1,3,4-oxadiazole-2-thiol (PS7): m.p. 96
1
—99 ℃; H NMR (CDCl3, 300 MHz) δ: 1.62 (q, 1H),
Biological activity
1.45 (d, J＝5.64 Hz, 3H), 3.90 (s, 2H), 14.32 (s, H),
7.40—8.10 (m, 9H); IR (KBr) ν: 2984, 2865, 2564,
Anti-inflammatory activity Suspension of test
compounds was prepared in distilled water using 2%
gum acacia and in all cases; control received the same
quantity of gum acacia. Anti-inflammatory activity was
evaluated by carrageenin-induced rat paw oedema
method.19,20 Six-albino rat of either sex weighing about
100—150 g, were randomly divided in control as well
as in test group. At 0 h, the test compounds were ad-
ministered orally and after half an hour, carrageenin
(0.05 mL, 1%) was injected into the planter tissue of
paw using 26 guage needle. The paw oedema was
－1
1696, 1683,＋1625, 1545, 815, 672 cm ; MS (70 eV)
m/z: 441 (M ). Anal. calcd for C20H16N4O2S3: C 54.53,
H 3.66, N 12.72; found C 54.62, H 3.64, N 12.75.
HRMS calcd for C20H16N4O2S3 440.5681, found
440.5675.
5-[2-({5-[1-(3-Benzoylphenyl)ethyl]-1,3,4-thiadiazol-
2-yl}thio)ethyl]-1,3,4-oxadiazole-2-thiol (PS8): m.p. 96
—98 ℃; 1H NMR (CDCl3, 300 MHz) δ: 1.65 (q, 1H),
1.43 (d, J＝5.65 Hz, 3H), 3.85 (t, J＝8.12 Hz, 2H), 2.08
(t, J＝8.14 Hz, 2H), 13.42 (s, H), 7.35—7.98 (m, 9H);
Chin. J. Chem. 2010, 28, 1429— 1436
© 2010 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
1433

Shirote & Bhatia
Yield/%
FULL PAPER
Table 1 Physical characteristics of compound
Compound
Molecular formula
Molecular weight
Colour
PS1
PS2
PS3
PS4
PS5
PS6
PS7
PS8
PS9
PS10
PS11
PS12
C18H13Cl2N5OS3
C19H15Cl2N5OS3
C20H17Cl2N5OS3
C17H20N4OS3
C18H22N4OS3
C19H24N4OS3
C20H16N4O2S3
C21H18N4O2S3
C22H20N4O2S3
C17H14N4O2S3
C18H16N4O2S3
C19H18N4O2S3
482.44
496.46
510.49
392.57
406.59
420.62
440.57
454.60
468.62
402.52
416.55
430.57
Light brown
Off white
75
68
62
73
65
67
78
68
65
72
64
59
Pale yellow
Light brown
Yellow
Pale yellow
Brown
Yellowish brown
Cream
White
Pale yellow
Light brown
Table 2 Anti-inflammatory activity of compounda
Percentage of inhibition ±S.E.M.
No.
Sample code
0.5 h
1 h
2 h
3 h
1
2
Ibuprofen
62.12±1.54
52.0±2.67
40.23±1.52
43.24±1.15
45.67±2.12
49.78±3.16
51.21±1.45
37.34±2.23
48.23±1.54
45.67±2.45
56.23±1.23
62.42±2.56
64.26±1.46
65.15±1.26
69.58±2.46
63.49±1.24
48.35±1.34
51.34±1.34
54.56±1.3
55.12±1.5
56.12±2.53
48.23±1.25
53.0±1.35
49.11±1.53
58.15±1.24
64.46±2.34
69±1.23
78.86±3.11
71.33±1.44
62.45±1.58
64.34±1.29
59.2±1.39
63.65±2.37
63.23±1.81
52.27±1.37
62.23±2.16
56.61±1.24
69.3±2.51
68.5±1.24
70.10±2.41
75±1.23
89.25±1.84b
82.63±2.55b
76.64±1.65b
67.82±1.78
63.19±1.96
74.72±1.45b
68.45±1.79
58.74±2.15
67.45±2.87
63.43±2.45
74.23±1.98b
70.81±2.32
72.72±1.87
81.29±2.35b
Diclofenac sodium
3
PS1
PS2
PS3
PS4
PS5
PS6
PS7
PS8
PS9
PS10
PS11
PS12
4
5
6
7
8
9
10
11
12
13
14
70.45±2.1
a n＝6, b p＜0.01 compared to control, Dose: 100 mg/kg b.w.
measured, before and at regular interval of 1 h, for 3 h
after the injection of carrageenin. The percent inhibition
values were calculated by the formula given below,
after oral administration of the test compound, rats were
anaesthetized with chloral hydrate and the stomach was
removed and fixed in 1% formaldehyde solution for
about 15 min. Each stomach was then clamped with
hemostats at the oesophagal and pyloric end and about
10 mL of air is introduced using 10cc syringe. After 5
min, the stomachs were cut out along its great curvature.
The number and the length of ulcers were examined by
means of magnifier. The lesions were considered posi-
tive response for ulcerogenic response. The overall total
length of ulcer was designated as the ‘ulcer index.’23,24
Ulcerogenic index was found out by:
anti-inflammatory activity (% Inhibition)＝
[1－Dt/Dc]×100
Dt and Dc are paw volumes of oedema in test and con-
trol groups, respectively.
Acute ulcerogenesis21,22 Six albino rats of either
sex weighing about 100—150 g were randomly divided
into test as well as standard group. Acute ulcerogensis
was evaluated after oral administration of the test com-
pound or the reference drug (Ibuprofen) at the dose of
100 mg/kg. Control rats were fed with the suspension of
0.5% methylcellulose. Food but not water was removed
24 h before administration of the test compound. 8 h
Ulcerogenic index＝number of ulcer＋Ulcer score＋
(% Incidence/number of animals).
1434
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© 2010 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2010, 28, 1429— 1436

Synthesis of 5-{[((5-Substituted-Aryl)-1,3,4-thiadiazol-2-yl)thio]-n-alkyl}-1,3,4-oxadiazole-2-thiol
Table 3 Acute ulcerogenicity of compound
No.
1
Sample code
No. of ulcer
0.0
Ulcer score
0.0
Incidence/%
0.0
Ulcer index
0.0
Control (0.5% methyl cellulose)
2
Aspirin
Ibuprofen
Diclofenac sodium
PS1
15.32
8.35
4.94
100
36.92
29.39
30.74
7.5
3
4.65
98.33
100
4
9.25
4.82
5
0.57
1.04
35.33
38.67
57.33
38.97
6
PS4
1.25
1.55
9.24
7
PS9
2.62
2.12
14.3
8
PS12
0.64
1.45
8.58
contributing significantly to biological activity. The
compounds with significant anti-inflammatory activity
were tested for acute ulcerogenecity. The gastric ulcer
index was used to ascertain the toxicity of drugs. Con-
ventional NSAIDs act by inhibition of COX-1 and
COX-2 enzymes. Prostaglandins derived from COX-1
enzyme pathways are responsible for maintaining ho-
meostasis, while those derived from COX-2 enzymes
pathways are pro-inflammatory. Inhibition of both en-
zymes and local irritation produced by free carboxylic
group results into gastrointestinal disturbances. Selec-
tive inhibitions of the inducible isoform COX-2 by
compounds PS1, PS4, PS9, and PS12 may be contrib-
uting to the significant reduction in ulcer index. The
results of both studies were found statistically signifi-
cant. From the results of acute ulcerogenic study, it is
quite evident that one of the major drawbacks of ul-
cerogenecity associated with all NSAID has been suc-
cessfully overcome by this synthetic approach. The
findings thus deserve systematic and more comprehen-
sive studies involving QSAR in search of safe and novel
anti-inflammatory drugs.
Results and discussion
Compounds 2a—2d were obtained by reacting vari-
ous aryl carboxylic acid with thiosemicarbazide in
equimolar concentration in presence of phosphorous
oxychloride. These compounds were confirmed by
1
presence of NH2 signal in H NMR spectra. As per re-
ported reviews, diazotization of amino thiadiazoles in
presence of Cu/HCl resulted in the substitution of the
amino group with chlorine. Synthesis of compounds 3a
—3d were confirmed by disappearance of NH2 singlet
1
in H NMR spectra. Further, reaction of 3a—3d with
thiourea and ethanol produced 5-substituted 1,3,4-thia-
diazole-2-thiol 4a—4d in good yield. The signals ob-
served at δ 12.35—12.52 confirmed the presence of SH
group in these compounds.
Subsequently, with a view of enhancing lipophilicity
and biological activity, various bromo ethyl esters were
reacted with the thiol of the thiadiazoles to synthesize
5a—5l. The IR spectrum of these esters displayed
C＝Ostr.(exocyclic) at around 1695 cm－ and thus sup-
1
ports formation of esters. These ester derivatives with
hydrazine hydrate afforded corresponding hydrazides 6a
—6l, which were confirmed by 1H NMR and IR spectra.
The reaction of compounds 6a—6l, with carbon di-
sulfide in the presence of KOH leads to the conversion
of the hydrazide group to the 1,3,4-oxadiazole ring. This
was confirmed by disappearance of hydrazide peak
from 1H NMR spectrum. Thus, compounds PS1—PS12
were obtained in fair yield.
Acknowledgement
The authors are thankful to Cipla Ltd, Pharma R&D,
Vikhroli (W), Mumbai, for providing free sample of
Ibuprofen, Ketoprofen, and Diclofenac sodium for this
research work. Authors wish to expresses thanks to IIT,
Mumbai and CDRI, Luknow for spectral analysis. Au-
thors are also thankful to Dr. F. V. Manvi Principal,
KLE’s College of Pharmacy, Belgaum and Dr. H. N.
More, Principal, Bharati Vidyapeeth College of Phar-
macy, Morewadi, Kolhapur (India) for providing the
necessary facilities to carry out this research work.
Further, these compounds were subjected for
anti-inflammatory activity using carrrageenan induced
rat paw oedema method. Unexpectedly, interesting re-
sults were obtained from the biological data. Com-
pounds PS1, PS4, PS9, and PS12 showed significant
activity exhibiting comparable reduction in edema. Re-
sults indicate that compounds possessing S(CH2)2 link-
ages were less potent than the other homologous com-
pounds and this indicates that the improvement in lipo-
philicity by increase in the carbon chain linkage of the
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