title: A thiabendazole sulfonamide shows potent inhibitory activity against mammalian and nematode alpha-carbonic anhydrases.
abstract: A sulfonamide derivative of the antihelmintic drug thiabendazole was prepared and investigated for inhibition of the zinc enzyme carbonic anhydrase CA (EC 4.2.1.1). Mammalian isoforms CA I-XIV and the nematode enzyme of Caenorhabditis elegans CAH-4b were included in this study. Thiabendazole-5-sulfonamide was a very effective inhibitor of CAH-4b and CA IX (K(I)s of 6.4-9.5nm) and also inhibited effectively isozymes CA I, II, IV-VII, and XII, with K(I)s in the range of 17.8-73.2nM. The high resolution X-ray crystal structure of its adduct with isozyme II evidenced the structural elements responsible for this potent inhibitory activity.
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: Letizia
authors.initials: L
authors.lastname: Crocetti
authors.forename: Alfonso
authors.initials: A
authors.lastname: Maresca
authors.forename: Claudia
authors.initials: C
authors.lastname: Temperini
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Hall
authors.forename: Andrea
authors.initials: A
authors.lastname: Scozzafava
authors.forename: Fritz A
authors.initials: FA
authors.lastname: Mühlschlegel
authors.forename: Claudiu T
authors.initials: CT
authors.lastname: Supuran
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000201:enzymology*; D029742:Caenorhabditis elegans Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002257:Carbonic Anhydrase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D002256:Carbonic Anhydrases / Q000378:metabolism*; D018360:Crystallography, X-Ray; D008322:Mammals; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000494:pharmacology; D013827:Thiabendazole / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D029742:Caenorhabditis elegans Proteins; D002257:Carbonic Anhydrase Inhibitors; D013449:Sulfonamides; D002256:Carbonic Anhydrases; D013827:Thiabendazole