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.