Development of isatin-functionalized benzenesulfonamides as novel carbonic anhydrase II and VII inhibitors with antiepileptic potential

Abstract

Epilepsy continues to be a challenging neurological disorder with a partially understood etiology that necessitates novel therapeutic strategies. This study introduces isatin-functionalized benzenesulfonamides (5a-f and 7a-e) targeting carbonic anhydrase (CA) isoforms II and VII implicated in seizure mechanisms. The design exploits a one-tail approach, integrating a sulfonamide warhead for zinc coordination in the CA active site, a triazole linker (inspired by FDA-approved antiepileptic rufinamide), and an isatin-based tail. In vitro evaluation revealed potent inhibition of hCA II and VII, with sulfonamides 5c, 5e, 5f, 7a, and 7d showing notable activity. The anticonvulsant activity of five carbonic anhydrase inhibitors (5c, 5e, 5f, 7a, and 7d) was assessed using PTZ and pilocarpine-induced convulsions in mice. These compounds were selected based on their superior in vitro inhibitory potency against hCA II and VII isoforms, as reflected by their low nanomolar K_I values. Among them, 5e and 7a exhibited the highest efficacy, achieving 100 % protection in the PTZ model and significantly delaying seizure onset in the pilocarpine model. These compounds also reduced seizure severity and improved survival rates, surpassing valproic acid's effectiveness. Additionally, biochemical evaluation revealed that both compounds restored hippocampal KCC2 and mTOR levels, suggesting their role in modulating neuronal excitability and ionic balance. Safety assessments, including Rotarod and biochemical toxicity tests, confirmed their favorable safety profile, supporting their potential as promising anticonvulsant candidates.