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

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 KI 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.