DESIGN, IN SILICO STUDY, SYNTHESIS AND BIOLOGICAL EVALUATION OF BENZOTHIAZOLE-BASED NITROGEN HETEROCYCLE DERIVATIVES AS NOVEL ANTIEPILEPTIC AGENTS

Abstract

Background: This study explores how novel benzothiazole-based nitrogen heterocycles would address drug resistance in epilepsy that occurs in approximately 30 percent of patients. We prepared four new 2-aminobenzothiazole analogs (DD1-DD4) by molecular hybridization and performed comprehensive in silico and in vivo experiments. Methodology: Pharmacokinetic profiling and toxicity predictions indicated that these compounds were highly drug-like, could cross the blood-brain barrier, and appeared to be quite safe. Docking to the human GABA-A homopentamer (PDB ID: 4COF) identified DD3 and DD4 as the best hits in the in silico evaluation, with a binding energy of -7.7 kcal/mol, matching the clinical reference, Riluzole. Results and Discussions: After synthesizing the molecules, we tested their anticonvulsant activity in vivo in a PTZ (Pentylenetetrazole)- induced seizure model in Swiss albino mice. Among the set, DD2 was the most promising, as it had the highest safety margin among all compounds, as shown by an acute toxicity study. Based on the acute toxicity results and highest safety margin, only DD2 was selected for in vivo activity, and it significantly reduced seizure latency and episode duration at higher doses than controls. Conclusion: Overall, these findings indicate that adding nitrogen heterocycles at C-2 of the benzothiazole core fine-tunes interactions with neurological targets. Ultimately, the evidence suggests that DD2, DD3, and DD4 are viable leads to develop next-generation antiepileptic drugs that would be more effective in controlling drug-resistant seizures.