title: Carbonic anhydrase inhibitors. Sulfonamide diuretics revisited--old leads for new applications?
abstract: Sulfonamide diuretics such as hydrochlorothiazide, hydroflumethiazide, quinethazone, metolazone, chlorthalidone, indapamide, furosemide and bumetanide were tested as inhibitors of the zinc enzyme carbonic anhydrases (CAs, EC 4.2.1.1). These drugs were discovered in a period when only isoform CA II was known and considered physiologically/pharmacologically relevant. We prove here that although acting as moderate to weak inhibitors of CA II, all these drugs considerably inhibit other isozymes known nowadays to be involved in critical physiologic processes, among the 16 CAs present in vertebrates. Some low nanomolar/subnanomolar inhibitors against such isoforms were detected, such as among others metolazone against CA VII, XII and XIII, chlorthalidone against CA VB, VII, IX, XII and XIII, indapamide against CA VII, IX, XII and XIII, furosemide against CA I, II and XIV, and bumethanide against CA IX and XII. The X-ray crystal structure of the CA II-indapamide adduct was also resolved at high resolution, and the binding of this sulfonamide to the enzyme was compared to that of dichlorophenamide, sulpiride and a pyridinium containing sulfonamide. Indapamide binds to CA II in a manner not seen earlier for any other CA inhibitor, which might be important for the design of compounds with a different inhibition profile.
authors.affiliation: Università degli Studi di Firenze, Laboratorio di Chimica Bioinorganica, Rm. 188, Via della Lastruccia 3, I-50019 Sesto Fiorentino (Firenze), Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Temperini
authors.forename: Alessandro
authors.initials: A
authors.lastname: Cecchi
authors.forename: Andrea
authors.initials: A
authors.lastname: Scozzafava
authors.forename: Claudiu T
authors.initials: CT
authors.lastname: Supuran
mesh_terms: D024402:Carbonic Anhydrase II / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D002257:Carbonic Anhydrase Inhibitors / Q000378:metabolism* / Q000494:pharmacology*; D002256:Carbonic Anhydrases / Q000737:chemistry / Q000378:metabolism*; D002384:Catalysis; D018360:Crystallography, X-Ray; D004232:Diuretics / Q000378:metabolism* / Q000494:pharmacology*; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D006801:Humans; D007190:Indapamide / Q000737:chemistry; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D011487:Protein Conformation; D013449:Sulfonamides / Q000378:metabolism* / Q000494:pharmacology*
chemical_list: D002257:Carbonic Anhydrase Inhibitors; D004232:Diuretics; D007527:Isoenzymes; D013449:Sulfonamides; D024402:Carbonic Anhydrase II; D002256:Carbonic Anhydrases; D007190:Indapamide