title: Carbonic anhydrase inhibitors: inhibition of isozymes I, II and IV with heterocyclic mercaptans, sulfenamides, sulfonamides and their metal complexes.
abstract: A series of sulfenamides, sulfonamides and sulfonamide metal complexes have been prepared starting from 4,5-disubstituted-3-mercapto-1,2,4-triazole derivatives. The heterocyclic mercaptans were oxidized to the corresponding sulfenamides by hypochlorite in the presence of ammonia. The sulfonamides were obtained by oxidation of sulfenamides with potassium permanganate. The Zn(II) and Cu(II) complexes of the new heterocyclic sulfonamides have been prepared via the sodium salt of the ligand. Inhibition of three carbonic anhydrase (CA) isozymes, hCA I, hCA II and bCA IV (h = human, b = bovine) with the prepared compounds has been investigated. Mercaptans were generally less inhibitory than sulfenamides, which in turn behaved as weaker inhibitors than the sulfonamides. The strongest inhibitors were the Zn(II) and Cu(II) complexes of the heterocyclic sulfonamides. Susceptibility to inhibition was generally: hCA II > bCA IV > hCA I. Although none of the obtained simple inhibitors (mercaptans, sulfenamides, sulfonamides) possessed antiglaucoma action when administered directly into the eye in experimental animals, the Zn(II) and Cu(II) complexes of some sulfonamides acted as more efficient intraocular pressure lowering agents as compared to the clinical drug dorzolamide. This constitutes an encouraging result for obtaining novel antiglaucoma drugs from this class of CA inhibitors.
authors.affiliation: Università degli Studi, Laboratorio di Chimica Inorganica e Bioinorganica, Firenze, Italia. scoz@riscl.lrm.fi.cnr.it
authors.forename: C T
authors.initials: CT
authors.lastname: Supuran
authors.forename: A
authors.initials: A
authors.lastname: Scozzafava
authors.forename: I
authors.initials: I
authors.lastname: Saramet
authors.forename: M D
authors.initials: MD
authors.lastname: Banciu
mesh_terms: D000818:Animals; D002257:Carbonic Anhydrase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D002417:Cattle; D015195:Drug Design; D005901:Glaucoma / Q000517:prevention & control; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D007700:Kinetics; D008670:Metals; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D013438:Sulfhydryl Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D002257:Carbonic Anhydrase Inhibitors; D007527:Isoenzymes; D008670:Metals; D013438:Sulfhydryl Compounds; D013449:Sulfonamides; D013844:Thiazoles