Biheterocyclic Benzothiazoles with Anticonvulsant, Antidepressant and Antinociceptive Activity: Design, Synthesis & Pharmacological Evaluation

Abstract

A novel series of N-thiazol-2-yl-benzamide derivatives 3a-u was synthesized and evaluated in vivo for anticonvulsant,
antidepressant, and antinociceptive activity. Anticonvulsant activity was assessed using the maximal electroshock and
pentylenetetrazole-induced seizure tests in mice, with sodium valproate and phenytoin sodium as reference drugs. The majority
of compounds demonstrated robust activity against MES, and all exhibited promising activity against PTZ-induced seizures;
compounds 3d and 3g provided complete protection. Acute neurotoxicity was evaluated using the rotarod test. Compounds
3d and 3g exhibited the greatest potency without neurotoxicity compared to traditional pharmacotherapies. Compound 3d
exhibited a median hypnotic dose of 867 mg/kg, approximately twice its TD50 value, while compound 3g displayed an
HD50 of 632 mg/kg and an LD50 of 834 mg/kg. Compound 3d demonstrated significant antinociceptive activity (p <
0.01) with an increased reaction time. The physicochemical properties and pharmacokinetic profiles of the target compounds
were also evaluated.