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Discovery of pyrazolthiazoles as novel and potent inhibitors of bacterial gyrase |
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| Authors: | Steven M. Ronkin Michael Badia Steve Bellon Anne-Laure Grillot Christian H. Gross Trudy H. Grossman Nagraj Mani Jonathan D. Parsons Dean Stamos Martin Trudeau Yunyi Wei Paul S. Charifson |
| Affiliation: | 1. Vertex Pharmaceuticals Inc., 130 Waverly Street, Cambridge, MA 02139, USA;2. Constellation Pharmaceuticals, 148 Sydney St., Cambridge, MA 02139, USA;3. Tetraphase Parmaceuticals, Inc, 480 Arsenal St., Suite 110, Watertown, MA 02472, USA |
| 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 Staphlococcus aureus GyrB. |
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