title: A class of 4-sulfamoylphenyl-ω-aminoalkyl ethers with effective carbonic anhydrase inhibitory action and antiglaucoma effects.
abstract: We report a series of 4-sulfamoylphenyl-ω-aminoalkyl ethers as carbonic anhydrase (CA, EC 4.2.1.1) inhibitors. The structure-activity relationship was drawn for the inhibition of four physiologically relevant isoforms: hCA I, II, IX, and XII. Many of these compounds were highly effective, low nanomolar inhibitors of all CA isoforms, whereas several isoform-selective were also identified. X-ray crystal structures of two new sulfonamides bound to the physiologically dominant CA II isoform showed the tails of these derivatives bound within the hydrophobic half of the enzyme active site through van der Waals contacts with Val135, Leu198, Leu204, Trp209, Pro201, and Pro202 amino acids. One of the highly water-soluble compound (as trifluoroacetate salt) showed effective IOP lowering properties in an animal model of glaucoma. Several fluorescent sulfonamides incorporating either the fluorescein-thiourea (7a-c) or tetramethylrhodamine-thiourea (9a,b) moieties were also obtained and showed interesting CA inhibitory properties for the tumor-associated isoforms CA IX and XII.
authors.affiliation: Polo Scientifico, Neurofarba Department and Laboratorio di Chimica Bioinorganica, Rm 188, Università degli Studi di Firenze , Via della Lastruccia 3, Sesto Fiorentino, Florence 50019, Italy.
authors.forename: Murat
authors.initials: M
authors.lastname: Bozdag
authors.forename: Melissa
authors.initials: M
authors.lastname: Pinard
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Carta
authors.forename: Emanuela
authors.initials: E
authors.lastname: Masini
authors.forename: Andrea
authors.initials: A
authors.lastname: Scozzafava
authors.forename: Robert
authors.initials: R
authors.lastname: McKenna
authors.forename: Claudiu T
authors.initials: CT
authors.lastname: Supuran
mesh_terms: D000818:Animals; D002245:Carbon Dioxide; D002257:Carbonic Anhydrase Inhibitors / Q000737:chemistry*; D002256:Carbonic Anhydrases / Q000737:chemistry*; D018360:Crystallography, X-Ray / Q000379:methods; D004195:Disease Models, Animal; D015195:Drug Design; D004987:Ethers / Q000737:chemistry*; D005456:Fluorescent Dyes / Q000737:chemistry; D005901:Glaucoma / Q000188:drug therapy*; D006801:Humans; D007700:Kinetics; D008297:Male; D008956:Models, Chemical; D015394:Molecular Structure; D009369:Neoplasms / Q000378:metabolism; D011817:Rabbits; D013329:Structure-Activity Relationship; D014867:Water / Q000737:chemistry
chemical_list: D002257:Carbonic Anhydrase Inhibitors; D004987:Ethers; D005456:Fluorescent Dyes; D014867:Water; D002245:Carbon Dioxide; D002256:Carbonic Anhydrases