title: Synthesis, structure-activity relationship studies, and X-ray crystallographic analysis of arylsulfonamides as potent carbonic anhydrase inhibitors.
abstract: A series of arylsulfonamides has been synthesized and investigated for the inhibition of some selected human carbonic anhydrase isoforms. The studied compounds showed significant inhibitory effects in the nanomolar range toward druggable isoforms (hCA VII, hCA IX, and hCA XIV) (K(i) values from 4.8 to 61.7 nM), whereas they generally exhibited significant selectivity over hCA I and hCA II, that are ubiquitous and considered off-target isoforms. On the basis of biochemical data, we herein discussed structure-affinity relationships for this series of arylsulfonamides, suggesting a key role for alkoxy substituents in CA inhibition. Furthermore, X-ray crystal structures of complexes of two active inhibitors (I and 2a) with hCA II allowed us to elucidate the main interactions between the inhibitor and specific amino acid residues within the catalytic site.
authors.affiliation: Dipartimento Farmaco-Chimico, Università di Messina, Viale Annunziata, I-98168 Messina, Italy. rgitto@unime.it
authors.forename: Rosaria
authors.initials: R
authors.lastname: Gitto
authors.forename: Francesca M
authors.initials: FM
authors.lastname: Damiano
authors.forename: Pavel
authors.initials: P
authors.lastname: Mader
authors.forename: Laura
authors.initials: L
authors.lastname: De Luca
authors.forename: Stefania
authors.initials: S
authors.lastname: Ferro
authors.forename: Claudiu T
authors.initials: CT
authors.lastname: Supuran
authors.forename: Daniela
authors.initials: D
authors.lastname: Vullo
authors.forename: Jiří
authors.initials: J
authors.lastname: Brynda
authors.forename: Pavlína
authors.initials: P
authors.lastname: Rezáčová
authors.forename: Alba
authors.initials: A
authors.lastname: Chimirri
mesh_terms: D002257:Carbonic Anhydrase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D008958:Models, Molecular; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D002257:Carbonic Anhydrase Inhibitors; D007527:Isoenzymes; D013449:Sulfonamides