title: Carbonic anhydrase inhibitors: 2-substituted-1,3,4-thiadiazole-5-sulfamides act as powerful and selective inhibitors of the mitochondrial isozymes VA and VB over the cytosolic and membrane-associated carbonic anhydrases I, II and IV.
abstract: A series of 2-substituted-1,3,4-thiadiazole-5-sulfamides was prepared and assayed as inhibitors of several carbonic anhydrase (CA, EC 4.2.1.1) isoforms, the cytosolic CA I and II, the membrane-associated CA IV and the mitochondrial CA VA and VB. The new compounds showed weak inhibitory activity against hCA I (K(I)s of 102 nM-7.42 microM), hCA II (K(I)s of 0.54-7.42 microM) and hCA IV (K(I)s of 4.32-10.05 microM) but were low nanomolar inhibitors of hCA VA and hCA VB, with inhibition constants in the range of 4.2-32 nM and 1.3-74 nM, respectively. Furthermore, the selectivity ratios for inhibiting the mitochondrial enzymes over CA II were in the range of 67.5-415, making these sulfamides the first selective CA VA/VB inhibitors.
authors.affiliation: Institut des Biomolécules Max Mousseron UMR 5247 CNRS-UM1-UM2 Bâtiment de Recherche Max Mousseron, Ecole Nationale Supérieure de Chimie de Montpellier, 8 rue de l'Ecole Normale, 34296 Montpellier Cedex, France.
authors.forename: Fatma-Zohra
authors.initials: FZ
authors.lastname: Smaine
authors.forename: Fabio
authors.initials: F
authors.lastname: Pacchiano
authors.forename: Marouan
authors.initials: M
authors.lastname: Rami
authors.forename: Véronique
authors.initials: V
authors.lastname: Barragan-Montero
authors.forename: Daniela
authors.initials: D
authors.lastname: Vullo
authors.forename: Andrea
authors.initials: A
authors.lastname: Scozzafava
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Winum
authors.forename: Claudiu T
authors.initials: CT
authors.lastname: Supuran
mesh_terms: D024401:Carbonic Anhydrase I / Q000737:chemistry*; D024402:Carbonic Anhydrase II / Q000737:chemistry*; D030741:Carbonic Anhydrase IV / Q000737:chemistry*; D002257:Carbonic Anhydrase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D024404:Carbonic Anhydrase V / Q000737:chemistry*; D002626:Chemistry, Pharmaceutical / Q000379:methods; D003600:Cytosol / Q000201:enzymology / Q000378:metabolism; D015195:Drug Design; D006801:Humans; D007527:Isoenzymes; D007700:Kinetics; D008928:Mitochondria / Q000201:enzymology; D008954:Models, Biological; D008956:Models, Chemical; D013830:Thiadiazoles / Q000138:chemical synthesis* / Q000494:pharmacology*
chemical_list: D002257:Carbonic Anhydrase Inhibitors; D007527:Isoenzymes; D013830:Thiadiazoles; D024401:Carbonic Anhydrase I; D024402:Carbonic Anhydrase II; D030741:Carbonic Anhydrase IV; D024404:Carbonic Anhydrase V