Discovery of pyrazolthiazoles as novel and potent inhibitors of bacterial gyrase.
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.
Ronkin
Steven M
SM
Vertex Pharmaceuticals Inc., 130 Waverly Street, Cambridge, MA 02139, USA. steven_Ronkin@vrtx.com
Badia
Michael
M
Bellon
Steve
S
Grillot
Anne-Laure
AL
Gross
Christian H
CH
Grossman
Trudy H
TH
Mani
Nagraj
N
Parsons
Jonathan D
JD
Stamos
Dean
D
Trudeau
Martin
M
Wei
Yunyi
Y
Charifson
Paul S
PS
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
D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D013844:Thiazoles; D059005:Topoisomerase II Inhibitors; D027081:DNA Gyrase