title: Recent advances in the discovery of zinc-binding motifs for the development of carbonic anhydrase inhibitors.
abstract: In addition to the sulfonamides and their isosteres, recently novel carbonic anhydrase (CA, EC 4.2.1.1) inhibitors (CAIs) which act by binding to the metal ion from the active site were discovered. Based on the X-ray crystal structure of the CA II-trithiocarbonate adduct, dithiocarbamates, xanthates and thioxanthates were shown to potently inhibit α- and β-CAs. The hydroxamates constitute another class of recently studied CAIs both against mammalian and protozoan enzymes. Another chemotype for which CA inhibitory properties were recently reported is the salicylaldoxime scaffold. X-ray crystal structures were reported for CA II complexed with dithiocarbamates and hydroxamates, whereas the xanthates and salicylaldoximes were investigated by kinetic measurements and docking studies. The dithiocarbamates and the xanthates showed potent antiglaucoma activity in animal models of the disease whereas some hydroxamates inhibited the growth of Trypanosoma cruzii probably by inhibiting the protozoan CA.
authors.affiliation: Institut des Biomolécules Max Mousseron (IBMM), UMR 5247, CNRS-UM1-UM2, Bâtiment de Recherche Max Mousseron, Ecole Nationale Supérieure de Chimie de Montpellier , Montpellier Cedex , France and.
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Winum
authors.forename: Claudiu T
authors.initials: CT
authors.lastname: Supuran
mesh_terms: D001665:Binding Sites; D002257:Carbonic Anhydrase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002256:Carbonic Anhydrases / Q000737:chemistry*; D018360:Crystallography, X-Ray; D055808:Drug Discovery / Q000379:methods*; D006877:Hydroxamic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D010091:Oximes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013859:Thiocarbamates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D015032:Zinc / Q000737:chemistry*
chemical_list: D002257:Carbonic Anhydrase Inhibitors; D006877:Hydroxamic Acids; D010091:Oximes; D013859:Thiocarbamates; C005704:salicylaldoxime; D002256:Carbonic Anhydrases; D015032:Zinc
keywords: Carbonic anhydrase; inhibitors; zinc-binding motif