Shooting an Arrow against Convulsion: Novel Triazole-Grafted Benzenesulfonamide Derivatives as Carbonic Anhydrase II and VII Inhibitors

Abstract

This study investigates new anticonvulsant substances that target the epilepsy-associated carbonic anhydrase isoforms II and VII. The 1,2,3-triazole with a benzenesulfonamide motif is present in the produced molecules. Of these, 5b and 5c exhibited remarkable selectivity and inhibitory efficacy toward hCA VII and hCA II over hCA I. The K_I values of 5b and 5c were 6.3 and 10.1 nM, respectively, and 21.6 and 18.9 nM, respectively. In a pilocarpine-induced paradigm, in vivo assessments showed decreased seizure severity and susceptibility with delayed seizure onset and diminished intensity. The quick absorption and in vivo stability of 5b were demonstrated by pharmacokinetic investigations. Evaluations of toxicity showed no neurotoxic effects and a high safety margin (LD₅₀ > 2000 mg/kg). Mechanistic research has shown effectiveness in maintaining neuronal integrity, reducing mTOR activation, and raising hippocampus KCC2 levels. Compound 5b’s binding interactions with hCA II and hCA VII were clarified by docking and dynamics experiments.