Identification of Benzenesulfonamide-Containing Thiazolidine-2,4-Dione Derivatives as Novel Carbonic Anhydrase II and VII Inhibitors with Anti-Epileptic Activity

Abstract

We report new anticonvulsant thiazolidine-2,4-diones with pendant benzenesulfonamide group that target epilepsy-associated carbonic anhydrase isoforms II and VII. Among these, <b>6b</b>, <b>6c</b>, <b>6e</b>, and <b>6g</b> exhibited remarkable inhibitory efficacy toward hCA II (<i>K</i>_I values of 4.1, 47.8, 9.6, and 6.9 nM, respectively) and hCA VII (<i>K</i>_I values of 9.4, 3.6, 41.6, and 98.3 nM, respectively), and selectivity over hCA I. <b>6c</b> was found to significantly reduce seizure severity and susceptibility, delay seizure onset, and lower seizure intensity in in vivo study of pilocarpine (PIL)-induced seizure model. Its superior in vivo stability and quick absorption were validated by pharmacokinetic studies. According to toxicological evaluations, there was no indication of neurotoxicity and a large safety margin (LD₅₀ > 2000 mg/kg). According to mechanistic research, <b>6c</b> increased expression of KCC2 in the hippocampus, maintained neuronal integrity, and reduced mTOR activity. Molecular docking clarified <b>6c</b> interactions with hCA II and hCA VII.