Novel hydroxyl tricyclics (e.g., GSK966587) as potent inhibitors of bacterial type IIA topoisomerases
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- 作者：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 ; Elisabeth A. Minthorn ; Steve Rittenhouse ; et al.
- 关键词：Antibacterials ; Bacterial type IIA topoisomerase ; Hydroxyl tricyclics ; Pharmacokinetic ; In vivo efficacy
- 刊名：Bioorganic and Medicinal Chemistry Letters
- 出版年：2013
- 出版时间：1 October, 2013
- 年：2013
- 卷：23
- 期：19
- 页码：5437-5441
- 全文大小：1180 K
文摘
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.