Design, synthesis, and molecular docking study of benzothiazolotriazine derivatives for anticonvulsant potential

Scheme A series of newer benzothiazolotriazine derivatives (4a-k) was designed, synthesized, and characterized as anticonvulsant agents against the two classically used MES and scPTZ animal models. The synthesized derivatives were tested in vivo in both the animal models, followed by a neurotoxicity study by the rotarod method. Compound 4e, 8-chloro-4-(2-chlorocyclohexa-1,5-dien-1-yl)-2-((4-methoxybenzyl)thio)-10aH-benzo[4,5]thiazolo[3,2a][1,3,5]triazine was found most promising among the series in both the animal models, with no neurotoxicity. From this it may be confirmed that the presence of a methoxy (OCH3) group at the lipophilic aryl ring was showing high anticonvulsant potency. In the molecular modeling study, compound 4e (docking score = -8.70) showed important hydrogen bond interaction with the amino acids LYS 329, SER 137, GLY 136 and pi-pi interactions with PHE 189 at the active site of GABA-AT. These derivatives can be further explored for the development of newer/novel anticonvulsant agents.