Discovery of Benzenesulfonamide Derivatives as Carbonic Anhydrase Inhibitors with Effective Anticonvulsant Action: Design, Synthesis, and Pharmacological Evaluation

Two series of novel benzenesulfonamide
derivatives were synthesized and evaluated for their human carbonic
anhydrase (CA, EC 4.2.1.1) inhibitory activity against four isoforms,
hCA I, hCA II, hCA VII, and hCA IX. It was found that compounds of
both series showed low to medium nanomolar inhibitory potential against
all isoforms. Some of these derivatives displayed selective inhibition
against the epileptogenesis related isoforms hCA II and VII, within
the nanomolar range. These potent hCA II and VII inhibitors were evaluated
as anticonvulsant agents against MES and sc-PTZ induced convulsions.
These sulfonamides effectively abolished induced seizures in both
models. Furthermore, time dependent seizure protection capability
of the most potent compound was also evaluated. A long duration of
action was displayed, with efficacy up to 6 h after drug administration.
The compound appeared as an orally active anticonvulsant agent without
showing neurotoxicity in a rotarod test, a nontoxic chemical profile
being observed in subacute toxicity study.