Synthesis and anticonvulsant activity of some 1,2,3,3a-tetrahydropyrrolo[2,1-b]-benzothiazol-, -thiazol- or -oxazol-1-ones in rodents.
To identify more potent anticonvulsant agents and to gain insights into the structural properties determining the potency of a new class of anticonvulsants, some 3a-substituted tetrahydropyrrolo[2,1-b]benzothiazol-1-ones (1a-d) and the thiazole and oxazole analogues (2a-c and 3a-c, respectively) have been synthesized and tested for anticonvulsant activity 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 extensively investigated and found to strengthen the effects of diazepam. No clear correlation was observed between the anticonvulsant activity 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 preliminary structure-activity relationships. The results demonstrate that 2a is an attractive candidate as an anticonvulsant agent worthy of further study and may help the design of other anticonvulsant drugs.
Dipartimento Farmaco-Chimico, Facoltà di Farmacia, Università degli Studi di Bari, Italy.
G
G
Trapani
M
M
Franco
A
A
Latrofa
A
A
Carotti
S
S
Cellamare
M
M
Serra
C A
CA
Ghiani
G
G
Tuligi
G
G
Biggio
G
G
Liso
D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis* / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D007538:Isoniazid; D008297:Male; D051379:Mice; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000139:chemically induced / Q000517:prevention & control*; D013844:Thiazoles / Q000138:chemical synthesis* / Q000494:pharmacology*
D000927:Anticonvulsants; D011759:Pyrrolidines; D013844:Thiazoles; D007538:Isoniazid