title: Discovery of pyrazolthiazoles as novel and potent inhibitors of bacterial gyrase.
abstract: Bacterial DNA gyrase is an attractive target for the investigation of new antibacterial agents. Inhibitors of the GyrB subunit, which contains the ATP-binding site, are described in this communication. Novel, substituted 5-(1H-pyrazol-3-yl)thiazole compounds were identified as inhibitors of bacterial gyrase. Structure-guided optimization led to greater enzymatic potency and moderate antibacterial potency. Data are presented for the demonstration of selective enzyme inhibition of Escherichia coli GyrB over Staphylococcus aureus GyrB.
authors.affiliation: Vertex Pharmaceuticals Inc., 130 Waverly Street, Cambridge, MA 02139, USA. steven_Ronkin@vrtx.com
authors.forename: Steven M
authors.initials: SM
authors.lastname: Ronkin
authors.forename: Michael
authors.initials: M
authors.lastname: Badia
authors.forename: Steve
authors.initials: S
authors.lastname: Bellon
authors.forename: Anne-Laure
authors.initials: AL
authors.lastname: Grillot
authors.forename: Christian H
authors.initials: CH
authors.lastname: Gross
authors.forename: Trudy H
authors.initials: TH
authors.lastname: Grossman
authors.forename: Nagraj
authors.initials: N
authors.lastname: Mani
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Parsons
authors.forename: Dean
authors.initials: D
authors.lastname: Stamos
authors.forename: Martin
authors.initials: M
authors.lastname: Trudeau
authors.forename: Yunyi
authors.initials: Y
authors.lastname: Wei
authors.forename: Paul S
authors.initials: PS
authors.lastname: Charifson
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D018360:Crystallography, X-Ray; D027081:DNA Gyrase / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D059005:Topoisomerase II Inhibitors
chemical_list: D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D013844:Thiazoles; D059005:Topoisomerase II Inhibitors; D027081:DNA Gyrase