title: Inhibition of β-carbonic anhydrases with ureido-substituted benzenesulfonamides.
abstract: A series of sulfonamides was prepared by reaction of sulfanilamide with aryl/alkyl isocyanates. The ureido-substituted benzenesulfonamides showed a very interesting profile for the inhibition of several carbonic anhydrases (CAs, EC 4.2.1.1) such as the human hCA II and three β-CAs from pathogenic fungal or bacterial species. The Candida albicans enzyme was inhibited with potencies in the range of 3.4-3970 nM, whereas the Mycobacterium tuberculosis enzymes Rv1284 and Rv3273 were inhibited with K(i)s in the range of 4.8-6500 nM and of 6.4-6850 nM, respectively. The structure-activity relationship for this class of inhibitors is rather complex, but the main features associated with effective inhibition of both α- and β-CAs investigated here have been delineated. The nature of the moiety substituting the second ureido nitrogen is the determining factor in controlling the inhibitory power, probably due to the flexibility of the ureido linker and the possibility of this moiety to orientate in different subpockets of the active site cavities of these enzymes.
authors.affiliation: Laboratorio di Chimica Bioinorganica, Università degli Studi di Firenze, Polo Scientifico, Rm 188, Via della Lastruccia 3, 50019 Sesto Fiorentino, Florence, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Pacchiano
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Carta
authors.forename: Daniela
authors.initials: D
authors.lastname: Vullo
authors.forename: Andrea
authors.initials: A
authors.lastname: Scozzafava
authors.forename: Claudiu T
authors.initials: CT
authors.lastname: Supuran
mesh_terms: D002176:Candida albicans / Q000201:enzymology; D024402:Carbonic Anhydrase II / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D009169:Mycobacterium tuberculosis / Q000201:enzymology; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000096926:Benzenesulfonamides
chemical_list: D024402:Carbonic Anhydrase II; D004791:Enzyme Inhibitors; D013449:Sulfonamides; D000096926:Benzenesulfonamides