Design, synthesis, and biological evaluation of isatin-based benzenesulfonamides as carbonic anhydrase II/VII inhibitors with anticonvulsant activity.

Epilepsy remains a challenging neurological disorder, with a significant proportion of patients exhibiting resistance to current antiseizure medications. Herein, we report the rational design, synthesis, and biological evaluation of a new series of isatin-thiazolidine-2,4-dione hybrids bearing a pendant benzenesulfonamide moiety as potential antiepileptic agents targeting epilepsy-associated carbonic anhydrase isoforms II and VII. The molecular design integrates key pharmacophoric features shared by established anticonvulsants, including dual aromatic systems, hydrogen-bond donor/acceptor functionalities, and electron-donating groups, and combines them with a sulfonamide zinc-binding motif to enable carbonic anhydrase inhibition. Several compounds exhibited promising nanomolar inhibitory activity against hCA II and hCA VII, with compounds 4c, 6a, 6d, and 6e prioritized for in vivo screening based on their combined hCA II/VII inhibition and selectivity over hCA I. Among them, compound 6a showed the strongest phenotypic anticonvulsant activity, providing complete protection in the PTZ model and, in the pilocarpine model, delaying seizure onset, reducing severity, and improving survival. Molecular docking and molecular dynamics simulations provided structural insights into the binding mode and dynamic behavior of compound 6a within the active sites of hCA II and hCA VII, complementing the experimentally determined enzyme inhibition data. Collectively, these results highlight isatin-thiazolidine-2,4-dione-benzenesulfonamide hybrids as a promising scaffold for the development of new antiepileptic agents.