SYNTHESIS AND ANTICONVULSANT ACTIVITY OF SOME ,3,3A-TETRAHYDROPYRROLO[2,1-B]-BENZOTHIAZOL-1-ONE, 1,2,3,3A-TETRAHYDROPYRROLO[2,1-B]-THIAZOL-1-ONE OR 1,2,3,3A-TETRAHYDROPYRROLO[2,1-B]-OXAZOL-1-ONE IN RODENTS

To identify more potent anticonvulsant agents and to gain insights int o the structural properties determining the potency of a new class of anticonvulsants, some 3a-substituted tetrahydropyrrolo[2,1-b]benzothia zol-1-ones (1a-d) and the thiazole and oxazole analogues (2a-c and 3a- c, respectively) have been synthesized and tested for anticonvulsant a ctivity against isoniazid-induced seizures in rodents. The most active compound, 2a, with a median effective dose (ED50, i.p.) of 24.3 mg kg (-1) and 15.9 mg kg(-1) in mice and in rats, respectively, was more ex tensively investigated and found to strengthen the effects of diazepam . No clear correlation was observed between the anticonvulsant activit y and molecular lipophilicity descriptors of compounds 1-3. Structural similarity between the antiepileptic drug phenobarbital and compounds 1-3 was evidenced by molecular modelling studies and used to derive p reliminary structure-activity relationships. The results demonstrate t hat 2a is an attractive candidate as an anticonvulsant agent worthy of further study and may help the design of other anticonvulsant drugs.