Carbonic anhydrase inhibitors. Inhibition of isoforms I, II, IV, VA, VII, IX, and XIV with sulfonamides incorporating fructopyranose–thioureido tails

Abstract

A series of aromatic/heterocyclic sulfonamides incorporating 2,3:4,5-bis- O-(isopropylidene)-β- d-fructopyranosyl-thioureido moieties has been synthesized and assayed for the inhibition of seven human isoforms of the zinc enzyme carbonic anhydrase (hCA, EC 4.2.1.1). The new derivatives behaved as weak hCA I inhibitors ( K Is of 9.4 −13.3 μM), were efficient hCA II inhibitors ( K Is of 6–750 nM), and slightly inhibited isoforms hCA IV and hCA VA. Only the sulfanilamide derivative showed efficient and selective inhibition of hCA IV ( K I of 10 nM). These derivatives also showed excellent hCA VII inhibitory activity ( K Is of 10–79 nM), being less efficient as inhibitors of the transmembrane isoforms hCA IX ( K Is of 10–4500 nM) and hCA XIV ( K Is of 21–3500 nM). Two of the new compounds showed anticonvulsant action in a maximal electroshock seizure test in mice, with the fluorosulfanilamide derivative being a more efficient anticonvulsant than the antiepileptic drug topiramate.