title: Inhibition studies of the β-carbonic anhydrases from the bacterial pathogen Salmonella enterica serovar Typhimurium with sulfonamides and sulfamates.
abstract: The two β-carbonic anhydrases (CAs, EC 4.2.1.1) from the bacterial pathogen Salmonella enterica serovar Typhimurium, stCA 1 and stCA 2, were investigated for their inhibition with a large panel of sulfonamides and sulfamates. Unlike inorganic anions, which are weak, millimolar inhibitors of the two enzymes [Vullo et al., Bioorg. Med. Chem. Lett.2011, 21, 3591], sulfonamides and sulfamates are effective micro-to nanomolar inhibitors of the two enzymes. Various types of inhibitors have been detected among the 38 investigated sulfonamides/sulfamates, with K(I)s in the range of 31 nM-5.87 μM. The best stCA 1 inhibitors were acetazolamide and benzolamide-based compounds, whereas the best stCA 2 inhibitors were sulfonylated benzenesulfonamides and amino-benzolamide derivatives (K(I)s in the range of 31-90 nM). 3-Fluoro-5-chloro-4-aminobenzolamide showed an inhibition constant of 51 nM against stCA 1 and of 38 nM against stCA 2, being the best inhibitor detected so far for these enzymes. As many strains of S. enterica show extensive resistance to classical antibiotics, inhibition of the β-CAs investigated here may be useful for developing novel antibacterials, targeting β-CAs which may be involved in pathogenicity and invasion of some bacteria.
authors.affiliation: Department of Gastroenterology, Kochi Medical School, Nankoku, Kochi 783-8505, Japan.
authors.forename: Isao
authors.initials: I
authors.lastname: Nishimori
authors.forename: Tomoko
authors.initials: T
authors.lastname: Minakuchi
authors.forename: Daniela
authors.initials: D
authors.lastname: Vullo
authors.forename: Andrea
authors.initials: A
authors.lastname: Scozzafava
authors.forename: Claudiu T
authors.initials: CT
authors.lastname: Supuran
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D002257:Carbonic Anhydrase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D002256:Carbonic Anhydrases / Q000737:chemistry / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D012480:Salmonella Infections / Q000188:drug therapy* / Q000201:enzymology; D012486:Salmonella typhimurium / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013451:Sulfonic Acids / Q000737:chemistry
chemical_list: D000900:Anti-Bacterial Agents; D002257:Carbonic Anhydrase Inhibitors; D013449:Sulfonamides; D013451:Sulfonic Acids; C005741:sulfamic acid; D002256:Carbonic Anhydrases