title: Synthesis and crystallographic analysis of new sulfonamides incorporating NO-donating moieties with potent antiglaucoma action.
abstract: Several aromatic/heterocyclic sulfonamide scaffolds have been used to synthesize compounds incorporating NO-donating moieties of the nitrate ester type, which have been investigated for the inhibition of five physiologically relevant human carbonic anhydrase (hCA, EC 4.2.1.1) isoforms: hCA I (offtarget), II, IV and XII (antiglaucoma targets) and IX (antitumor target). Some of the new compounds showed effective in vitro inhibition of the target isoforms involved in glaucoma, and the X-ray crystal structure of one of them revealed factors associated with the marked inhibitory activity. In an animal model of ocular hypertension, one of the new compounds was twice more effective than dorzolamide in reducing elevated intraocular pressure characteristic of this disease, anticipating their potential for the treatment of glaucoma.
authors.affiliation: U.O. Oculistica Az. USL 3, Val di Nievole, Ospedale di Pescia, Pescia, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Mincione
authors.forename: Francesca
authors.initials: F
authors.lastname: Benedini
authors.forename: Stefano
authors.initials: S
authors.lastname: Biondi
authors.forename: Alessandro
authors.initials: A
authors.lastname: Cecchi
authors.forename: Claudia
authors.initials: C
authors.lastname: Temperini
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Formicola
authors.forename: Ilaria
authors.initials: I
authors.lastname: Pacileo
authors.forename: Andrea
authors.initials: A
authors.lastname: Scozzafava
authors.forename: Emanuela
authors.initials: E
authors.lastname: Masini
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; D018360:Crystallography, X-Ray; D004195:Disease Models, Animal; D005901:Glaucoma / Q000188:drug therapy; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D009569:Nitric Oxide / Q000737:chemistry; D009798:Ocular Hypertension / Q000188:drug therapy; D020033:Protein Isoforms / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011817:Rabbits; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D013876:Thiophenes / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D002257:Carbonic Anhydrase Inhibitors; D020033:Protein Isoforms; D013449:Sulfonamides; D013876:Thiophenes; D009569:Nitric Oxide; C062765:dorzolamide