title: Benzenesulfonamides Incorporating Flexible Triazole Moieties Are Highly Effective Carbonic Anhydrase Inhibitors: Synthesis and Kinetic, Crystallographic, Computational, and Intraocular Pressure Lowering Investigations.
abstract: Herein we report the synthesis of two series of benzenesulfonamide containing compounds that incorporate the phenyl-1,2,3-triazole moieties. We explored the insertion of appropriate linkers, such as ether, thioether, and amino type, into the inner section of the molecules with the intent to confer additional flexibility. All obtained compounds were screened in vitro as inhibitors of the physiologically relevant human (h) isoforms of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1). Many of them were low nanomolar or subnanomolar hCA II, IX, and XII inhibitors, whereas they did not potently inhibit hCA I. Computational and X-ray crystallographic studies of the enzyme-inhibitor adducts helped us to rationalize the obtained results. Some of the sulfonamides reported here showed significant intraocular pressure lowering activity in an animal model of glaucoma.
authors.affiliation: Università degli Studi di Firenze , Neurofarba Department., Sezione di Scienze Farmaceutiche, Via Ugo Schiff 6, 50019 Sesto Fiorentino (Florence), Italy.|Università degli Studi di Firenze , Neurofarba Department., Sezione di Scienze Farmaceutiche, Laboratory of Molecular Modeling Cheminformatics & QSAR, via U. Schiff 6, 50019 Sesto Fiorentino (Florence), Italy.
authors.forename: Alessio
authors.initials: A
authors.lastname: Nocentini
authors.affiliation: Università degli Studi di Firenze , Polo Scientifico, Via della Lastruccia 3, 50019 Sesto Fiorentino (Florence), Italy.
authors.forename: Marta
authors.initials: M
authors.lastname: Ferraroni
authors.affiliation: Università degli Studi di Firenze , Neurofarba Department., Sezione di Scienze Farmaceutiche, Via Ugo Schiff 6, 50019 Sesto Fiorentino (Florence), Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Carta
authors.affiliation: Università degli Studi di Firenze , Polo Scientifico, Via della Lastruccia 3, 50019 Sesto Fiorentino (Florence), Italy.
authors.forename: Mariangela
authors.initials: M
authors.lastname: Ceruso
authors.affiliation: Università degli Studi di Firenze , Neurofarba Department., Sezione di Scienze Farmaceutiche, Laboratory of Molecular Modeling Cheminformatics & QSAR, via U. Schiff 6, 50019 Sesto Fiorentino (Florence), Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Gratteri
authors.affiliation: Università degli Studi di Firenze , Neurofarba Department., Sezione di Farmacologia, Viale Pieraccini 6, 50139 Florence, Italy.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Lanzi
authors.affiliation: Università degli Studi di Firenze , Neurofarba Department., Sezione di Farmacologia, Viale Pieraccini 6, 50139 Florence, Italy.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Masini
authors.affiliation: Università degli Studi di Firenze , Neurofarba Department., Sezione di Scienze Farmaceutiche, Via Ugo Schiff 6, 50019 Sesto Fiorentino (Florence), Italy.
authors.forename: Claudiu T
authors.initials: CT
authors.lastname: Supuran
mesh_terms: D000818:Animals; D002257:Carbonic Anhydrase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002256:Carbonic Anhydrases / Q000378:metabolism*; D018360:Crystallography, X-Ray; D006801:Humans; D007429:Intraocular Pressure / Q000187:drug effects*; D007700:Kinetics; D008297:Male; D008958:Models, Molecular; D015394:Molecular Structure; D011817:Rabbits; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology*; D014230:Triazoles / Q000737:chemistry / Q000494:pharmacology*; D000096926:Benzenesulfonamides
chemical_list: D002257:Carbonic Anhydrase Inhibitors; D002256:Carbonic Anhydrases; D013449:Sulfonamides; D014230:Triazoles; D000096926:Benzenesulfonamides