Carbonic anhydrase inhibitors. Inhibition of isoforms I, II, IV, VA, VII, IX, and XIV with sulfonamides incorporating fructopyranose-thioureido tails |
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Authors: | Winum Jean-Yves Thiry Anne Cheikh Khaled El Dogné Jean-Michel Montero Jean-Louis Vullo Daniela Scozzafava Andrea Masereel Bernard Supuran Claudiu T |
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Affiliation: | Institut des Biomolécules Max Mousseron (IBMM) UMR 5247 CNRS-UM1-UM2 Batiment de Recherche Max Mousseron, Ecole Nationale Supérieure de Chimie de Montpellier, 8 rue de l'Ecole Normale, 34296 Montpellier Cedex, France. |
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Abstract: | A series of aromatic/heterocyclic sulfonamides incorporating 2,3:4,5-bis-O-(isopropylidene)-beta-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(I)s of 9.4 -13.3microM), were efficient hCA II inhibitors (K(I)s of 6-750nM), and slightly inhibited isoforms hCA IV and hCA VA. Only the sulfanilamide derivative showed efficient and selective inhibition of hCA IV (K(I) of 10nM). These derivatives also showed excellent hCA VII inhibitory activity (K(I)s of 10-79nM), being less efficient as inhibitors of the transmembrane isoforms hCA IX (K(I)s of 10-4500nM) and hCA XIV (K(I)s of 21-3500nM). 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. |
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