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Novel hydroxyl tricyclics (e.g., GSK966587) as potent inhibitors of bacterial type IIA topoisomerases |
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| Authors: | Timothy J. Miles Alan J. Hennessy Ben Bax Gerald Brooks Barry S. Brown Pamela Brown Nathalie Cailleau Dongzhao Chen Steven Dabbs David T. Davies Joel M. Esken Ilaria Giordano Jennifer L. Hoover Jianzhong Huang Graham E. Jones Senthill K. Kusalakumari Sukmar Claus Spitzfaden Roger E. Markwell Neil D. Pearson |
| Affiliation: | 1. Diseases of the Developing World CEDD, GlaxoSmithKline, Calle Severo Ochoa, 2, 28760 Tres Cantos, Madrid, Spain;2. Infectious Diseases CEDD, GlaxoSmithKline, Gunnels Wood Road, Stevenage SG1 2NY, UK;3. Computational and Structural Chemistry, GlaxoSmithKline, Gunnels Wood Road, Stevenage SG1 2NY, UK;4. Infectious Diseases CEDD, GlaxoSmithKline, Third Avenue, Harlow CM19 5AW, UK;5. Infectious Diseases CEDD, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA 19426, USA;6. Protein Dynamics DPU, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA 19426, USA |
| Abstract: | During the course of our research to find novel mode of action antibacterials, we discovered a series of hydroxyl tricyclic compounds that showed good potency against Gram-positive and Gram-negative pathogens. These compounds inhibit bacterial type IIA topoisomerases. Herein we will discuss structure–activity relationships in this series and report advanced studies on compound 1 (GSK966587) which demonstrates good PK and in vivo efficacy properties. X-ray crystallographic studies were used to provide insight into the structural basis for the difference in antibacterial potency between enantiomers. |
| Keywords: | Antibacterials Bacterial type IIA topoisomerase Hydroxyl tricyclics Pharmacokinetic In vivo efficacy |
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