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

Abstract

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.

Bioenergetic Mechanisms of Seizure Control

“…Nevertheless, intracellular acidosis could directly influence GABAergic transmission as the GABA receptor channel is permeable to HCO 3 - ( Pavlov et al, 2013 ; Ruusuvuori and Kaila, 2014 ). Indeed, inhibitors of brain carbonic anhydrases, which actively control pH balance by catalyzing the interconversion of carbon dioxide to bicarbonate (HCO3 - ) and a proton (H + ), possess anticonvulsant effects ( Reiss and Oles, 1996 ; Mishra et al, 2018 ).…”

Progress in the development of human carbonic anhydrase inhibitors and their pharmacological applications: Where are we today?

“…Further, this lead has been modified by providing more flexible linker between benzenesulfonamide and piperazine tail that bestowed some selective hCA VII inhibitors like compound 176 (Figure 14) which has shown a K i Value of 27.1 nM for hCA VII. This derivative also inhibited hCA I, hCA II, and hCA IX with a K i value of 93.3, 80.4, and 1627.9 nM, respectively 248 . Furthermore, optimization is extended and recently reported benzenesulfonamides containing substituted piperazine tail as effective as well as selective hCA VII inhibitors.…”

“…237 To the search of potent anticonvulsant agents by targeting hCA isoforms several novel chemical entities have been developed and these compounds were shown effective anticonvulsant action in various in vivo models of epilepsy. 234,237,248 Our research group has designed and synthesized benzenesulfonamide-based potent and selective hCA II/hCA VII inhibitors and their anticonvulsant activity were assessed by using Maximal electroshock (MES-test) and pentylenetetrazol (sc-PTZ test). The result of this investigation exposed that compounds 383, 384, and 385 (Potent hCA II/hCA VII in inhibitors) showed excellent anticonvulsant activity in MES as well as sc-PTZ test (Figure 28).…”

“…Compounds 126 and 127 have inhibited hCA II with nanomolar range inhibitory action by exhibiting a K i value of 75.5 and 33.2 nM, respectively. Compound 126 has shown 5‐, 7‐, and 21‐fold selectivity for hCA II over hCA I, hCA VII, and hCA IX, respectively, while derivative 127 was 24‐, 10‐, and 3‐fold selective for hCA II over hCA I, hCA VII, and hCA IX, respectively 248 . Novel hybrid compounds consisting of nonsteroidal‐anti‐inflammatory drugs (NSAIDs) and CAI fragment benzenesulfonamide type have been also tested against five hCA isoforms, hCA I, hCA II, hCA IV, hCA IX, and hCA XII.…”

“…Several potent CAIs such as AAZ and TPM have shown effective anticonvulsant effect and successfully being used clinically 237 . To the search of potent anticonvulsant agents by targeting hCA isoforms several novel chemical entities have been developed and these compounds were shown effective anticonvulsant action in various in vivo models of epilepsy 234,237,248 …”