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

We report new anticonvulsant thiazolidine-2,4-diones with pendant benzenesulfonamide group that target epilepsy-associated carbonic anhydrase isoforms II and VII. Among these, 6b, 6c, 6e, and 6g exhibited remarkable inhibitory efficacy toward hCA II (KI values of 4.1, 47.8, 9.6, and 6.9 nM, respectively) and hCA VII (KI values of 9.4, 3.6, 41.6, and 98.3 nM, respectively), and selectivity over hCA I. 6c 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, 6c increased expression of KCC2 in the hippocampus, maintained neuronal integrity, and reduced mTOR activity. Molecular docking clarified 6c interactions with hCA II and hCA VII.