title: Carbonic anhydrase inhibitors. Inhibition of the cytosolic and tumor-associated carbonic anhydrase isozymes I, II, and IX with a series of 1,3,4-thiadiazole- and 1,2,4-triazole-thiols.
abstract: A series of heterocyclic mercaptans incorporating 1,3,4-thiadiazole- and 1,2,4-triazole rings have been prepared and assayed for the inhibition of three physiologically relevant carbonic anhydrase (CA, EC 4.2.1.1) isozymes, the cytosolic human isozymes I and II, and the transmembrane, tumor-associated hCA IX. Against hCA I the investigated thiols showed inhibition constants in the range of 97 nM to 548 microM, against hCA II in the range of 7.9-618 microM, and against hCA IX in the range of 9.3-772 microM. Thiadiazoles were generally more active than triazoles against all investigated isozymes. Generally, the best inhibitors were the simple derivative 5-amino-1,3,4-thiadiazole-2-thiol and its N-acetylated derivative, which were anyhow at least two orders of magnitude less effective inhibitors when compared to the corresponding sulfonamides, acetazolamide, and its deacetylated derivative. An exception was constituted by 5-(2-pyridylcarboxamido)-1,3,4-thiadiazole-2-thiol, which is the first hCA I-selective inhibitor ever reported, possessing an inhibition constant of 97 nM against isozyme I, and being a 105 times less effective hCA II inhibitor, and 3154 times less effective hCA IX inhibitor. Thus, the thiol moiety may lead to effective CA inhibitors targeting isozyme I, whereas it is a less effective zinc-binding function for the design of CA II and CA IX inhibitors over the sulfonamide group.
authors.affiliation: Organic Chemistry Department, Faculty of Pharmacy, Traian Vuia Street 6, 77210 Bucharest, Romania.
authors.forename: Gabriela Laura
authors.initials: GL
authors.lastname: Almajan
authors.forename: Alessio
authors.initials: A
authors.lastname: Innocenti
authors.forename: Luca
authors.initials: L
authors.lastname: Puccetti
authors.forename: Gheorghe
authors.initials: G
authors.lastname: Manole
authors.forename: Stefania
authors.initials: S
authors.lastname: Barbuceanu
authors.forename: Ioana
authors.initials: I
authors.lastname: Saramet
authors.forename: Andrea
authors.initials: A
authors.lastname: Scozzafava
authors.forename: Claudiu T
authors.initials: CT
authors.lastname: Supuran
mesh_terms: D000951:Antigens, Neoplasm / Q000378:metabolism*; D024401:Carbonic Anhydrase I / Q000378:metabolism*; D024402:Carbonic Anhydrase II / Q000378:metabolism*; D000071231:Carbonic Anhydrase IX; D002257:Carbonic Anhydrase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D002256:Carbonic Anhydrases / Q000378:metabolism*; D003600:Cytosol / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D015394:Molecular Structure; D009369:Neoplasms / Q000201:enzymology; D013329:Structure-Activity Relationship; D013438:Sulfhydryl Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D013830:Thiadiazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D014230:Triazoles / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D000951:Antigens, Neoplasm; D002257:Carbonic Anhydrase Inhibitors; D004791:Enzyme Inhibitors; D013438:Sulfhydryl Compounds; D013830:Thiadiazoles; D014230:Triazoles; D024401:Carbonic Anhydrase I; D024402:Carbonic Anhydrase II; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases