Pharm. Pharmacol. Commun. 2000, 6: 31±33
Received November 11, 1999
Accepted November 30, 1999
# 2000 Pharm. Pharmacol. Commun.
Synthesis and Anticonvulsant Activity of
5-Aryl-1,3,4-thiadiazole Derivatives
A. FOROUMADI, S. A. TABATABAI*, G. GITINEZHAD{, M. R. ZARRINDAST{ AND A. SHAFIEE{
Department of Medicinal Chemistry, Faculty of Pharmacy, Kerman University of Medical Sciences,
Kerman, *Department of Medicinal Chemistry, Faculty of Pharmacy, Shaheed Beheshti University of
Medical Sciences and Health Services, Tehran, {Department of Medicinal Chemistry,
Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran and {Department of Pharmacology,
Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
Abstract
5-Aryl-1,3,4-thiadiazole derivatives were synthesized and tested for anticonvulsant activity
using the pentylenetetrazole-induced lethal convulsion test. The results showed that 2-
1
amino derivatives have anticonvulsant activity (LD50 > 500 mg kg ) and this effect was
not mediated through benzodiazepine receptors. The ¯uoro electron-withdrawing substi-
tuent on the phenyl ring did not potentiate the activity of the compounds.
It has been shown that some 2-aryl-5-hydrazino-
1,3,4-thiadiazole, 5-aryl-3-(alkylthio)-4 H-thiadi-
azole and 2,4-dihydro-3 H-1,2,4-triazole-3-thione
derivatives have anticonvulsant activity (Chapleo
et al 1986; Kane et al 1994). We found that some
2-aryl-1,3,4-oxadiazole derivatives had the same
effect. It would appear that amino, thione, alkylthio
or alkylsulphone may exert an anticonvulsant effect
on these heterocyclic compounds. We therefore
synthesized 5-aryl-1,3,4-thiadiazoles 4±8 and
evaluated their anticonvulsant activity in the pen-
tylenetetrazole-induced lethal convulsion test.
nerbeck 1966) afforded 5-aryl-2-mercapto-1,3,4-
thiadiazoles 6. Alkylation of compound 6 with
methyl iodide (Foroumadi et al 1998) gave 5-aryl-
2-methylmercapto-1,3,4-thiadiazoles 7 in good
yield. Subsequent oxidation of sulphides 7 with
hydrogen peroxide in acetic acid (Baldwin et al
1977; Firoozi et al 1995) gave sulphones 8. The
compounds were characterized by H-NMR, IR
and mass spectrometry. Microanalyses were within
Æ 0Á4% of theoretical values for C, H, and N.
1
Pharmacology
Male NMRI mice (Pasteur Institute, Iran), 20±25 g,
were kept in cages in groups of ten under constant
temperature (24Æ 1ꢀC) and a 12 h light±dark
schedule. They had free access to a standard mouse
diet before the experiment. On the day of experi-
ment, animals were randomly transferred to indi-
vidual cages and allowed to acclimatize for 30 min
before injection of drugs or vehicle.
Materials and Methods
Chemical procedures
1,3,4-Thiadiazoles 4±8 were synthesized according
to Figure 1. The 2-amino-5-aryl-1,3,4-thiadiazoles
4a±d were obtained in quantitative yield from
either arylthiosemicarbazone (Rao & Srinivasan
1970) or by a direct cyclization of the corre-
sponding carboxylic acids and thiosemicarbazide
in phosphorous oxychloride (Lalezari & Sha®ee
1971). Diazotation of amines 4 by a sandmeyer
reaction (Alemagna et al 1968) gave 2-aryl-5-
chloro-1,3,4-thiadiazoles 5. Treatment of 5 with
thiourea in re¯uxing ethanol (Sandstrom & Wen-
Anticonvulsant activity was measured by the
pentylenetetrazole-induced lethal convulsion test
(Morpugo 1971). Test compounds and vehicle were
given to groups of ten mice 1 h before injection of
1
pentylenetetrazole (100 mg kg , i.p.). The protec-
tion against pentylenetetrazole-induced lethal con-
vulsion was evaluated over a 30 min period. Test
compounds and ¯umazenil (Hoffman La Roche)
were suspended in a solution of 0Á5% carboxy-
methylcellulose and 0Á25% Tween 80. Diazepam
ampoules (Daru Pakhsh Co.) were diluted with
Correspondence: A. Sha®ee, Department of Medicinal
Chemistry, Faculty of Pharmacy, Tehran University of Med-
ical Sciences, Tehran, Iran.
E-Mail: sha®ee@nrcgeb.ac.ir