Discovery of Potent Carbonic Anhydrase Inhibitors as Effective Anticonvulsant Agents: Drug Design, Synthesis, and In Vitro and In Vivo Investigations

Two sets of benzenesulfonamide-based
effective human carbonic anhydrase
(hCA) inhibitors have been developed using the tail approach. The
inhibitory action of these novel molecules was examined against four
isoforms: hCA I, hCA II, hCA VII, and hCA XII. Most of the molecules
disclosed low to medium nanomolar range inhibition against all tested
isoforms. Some of the synthesized derivatives selectively inhibited
the epilepsy-involved isoforms hCA II and hCA VII, showing low nanomolar
affinity. The anticonvulsant activity of selected sulfonamides was
assessed using the maximal electroshock seizure (MES) and subcutaneous
pentylenetetrazole (sc-PTZ) in vivo models of epilepsy. These potent
CA inhibitors effectively inhibited seizures in both epilepsy models.
The most effective compounds showed long duration of action and abolished
MES-induced seizures up to 6 h after drug administration. These sulfonamides
were found to be orally active anticonvulsants, being nontoxic in
neuronal cell lines and in animal models.