Discovery of Benzenesulfonamides with Potent Human Carbonic Anhydrase Inhibitory and Effective Anticonvulsant Action: Design, Synthesis, and Pharmacological Assessment

Abstract

We report two series of novel benzenesulfonamide derivatives acting as effective carbonic anhydrase (CA, EC 4.2.1.1) inhibitors. The synthesized compounds were tested against human (h) isoforms hCA I, hCA II, hCA VII, and hCA XII. The first series of compounds, 4-(3-(2-(4-substitued piperazin-1-yl)ethyl)ureido)benzenesulfonamides, showed low nanomolar inhibitory action against hCA II, being less effective against the other isoforms. The second series, 2-(4-substitued piperazin-1-yl)-N-(4-sulfamoylphenyl)acetamide derivatives, showed low nanomolar inhibitory activity against hCA II and hCA VII, isoforms involved in epileptogenesis. Some of these derivatives were evaluated for their anticonvulsant activity and displayed effective seizure protection against MES and scPTZ induced seizures in Swiss Albino mice. These sulfonamides were also found effective upon oral administration to Wistar rats and inhibited MES induced seizure episodes in this animal model of the disease. Some of the new compounds showed a long duration of action in the performed time course anticonvulsant studies, being nontoxic in subacute toxicity studies.

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

“…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).…”

“…Remarkably, these three potent anticonvulsant agents did not exert any significant toxicity to the experimental animals in sub-acute toxicity study. 237…”

“…But other mechanisms have been also hypothesized that are blockade of sodium channels, kainate/AMPA receptors, and intensification of GABA-ergic transmission. 234,237,350,351 AAZ alone or in combination with dexamethasone was shown to be effective in the preclusion and management of mountain sickness and high altitude associated cerebral edema, due to the enhanced arterial oxygen concentrations after red blood cell/brain enzyme inhibition by AAZ. 352 Use of AAZ has been also noticed in the treatment of hydrocephalus by inhibition of CAs present in choroid plexus.…”

“…Yet, another derivative 110 displayed a K i value of 8.7 nM toward hCA II along with 379-fold selectivity over hCA I and >5747-fold selectivity over hCA VII as well as hCA IX. Hence, both derivatives, specially, 109 emerged as highly selective and potent hCA II inhibitors which may prove as a suitable lead molecule to generate more potent and selective hCA II inhibitors 237. Carta et al reported design and synthesis of pritelivir (antiviral agent) related compounds and evaluated for their CA Inhibitory action against six -pyridinyl)phenyl]acetamide, is a helicase-primase inhibitor used for the treatment of herpes simplex virus infections.…”

Sulphonamide inhibition studies of the β-carbonic anhydrase from the bacterial pathogenClostridium perfringens

“… 1–12 . The α-class CAs present in vertebrates, including humans 1–6 , are drug targets for obtaining antiglaucoma agents 13 , 14 , anticonvulsants 15 , drugs for the treatment of idiopathic intracranial hypertension and other neurologic disorders 15 , 16 , antiobesity agents 17 and diuretics 18–20 . Most of these clinically used CA inhibitors (CAIs) belong to the sulphonamide class, as they possess the primary sulphonamide (or its isosteres, sulphamate and sulphamide moieties) as the zinc-binding function 1–6 , 21 .…”