Discovery of potent anti-convulsant carbonic anhydrase inhibitors: Design, synthesis, in vitro and in vivo appraisal

We report the design, synthesis and pharmacological assessment of novel benzenesulfonamide derivatives acting as effective carbonic anhydrase (CA, EC 4.2.1.1) inhibitors. All the synthesized compounds were screened for their CA inhibitory action against four isoforms of human origin (h), i.e. hCA I, hCA II, hCA VII and hCA IX. In-vitro carbonic anhydrase inhibition studies have shown that first series, 4-(2-(4-(4-substitutedpiperazin-1-yl)benzylidene)hydrazinyl)benzenesulfonamides (4a- 4i) bestowed low nanomolar range to medium nanomolar range inhibitors against hCA II and hCA VII, effectively involved in epileptogenesis. Furthermore, compounds belonging to the second series, 4-(2-(4-(4-substitutedpiperazin-yl)benzylidene)hydrazinecarbonyl)benzenesulfonamides (8a-8k) showed effective inhibition against hCA VII, being less effective against other hCA isoforms. Inspiring with obtained CA inhibition results, we have chosen some of the potent hCA II and hCA VII inhibitors (4g, 4i and 8d) to test their anti-convulsant efficacy in MES and sc-PTZ seizure tests in Swiss Albino male mice. In result, these compounds significantly attenuated both electrical (MES) as well as chemical (sc-PTZ) induced seizures. Next, in advance anticonvulsant tests, compound 8d displayed long duration of action in time course study and successfully attenuated MES induced seizure in mice up to 6 h after drug administration without showing neurotoxicity in rotarod test. Moreover, this compound was also found to be orally active and effectively abolished generalized tonic-clonic seizures in male Wistar rats upon oral administration, being non-toxic in sub acute toxicity studies. (C) 2018 Elsevier Masson SAS. All rights reserved.