Antibacterial Optimization of 4-Aminothiazolyl Analogues of the Natural Product GE2270 A: Identification of the Cycloalkylcarboxylic Acids

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• 作者：Matthew J. LaMarche ; Jennifer A. Leeds ; Kerri Amaral ; Jason T. Brewer ; Simon M. Bushell ; Janetta M. Dewhurst ; JoAnne Dzink-Fox ; Eric Gangl ; Julie Goldovitz ; Akash Jain ; Steve Mullin ; Georg Neckermann ; Colin Osborne ; Deborah Palestrant ; Michael A. Patane ; Elin M. Rann ; Meena Sachdeva ; Jian Shao ; Stacey Tiamfook ; Lewis Whitehead ; Donghui Yu
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：December 8, 2011
• 年：2011
• 卷：54
• 期：23
• 页码：8099-8109
• 全文大小：587K
• 年卷期：v.54,no.23(December 8, 2011)
• ISSN：1520-4804

文摘

4-Aminothiazolyl analogues of the antibiotic natural product GE2270 A (1) were designed, synthesized, and optimized for their activity against Gram positive bacterial infections. Optimization efforts focused on improving the physicochemical properties (e.g., aqueous solubility and chemical stability) of the 4-aminothiazolyl natural product template while improving the in vitro and in vivo antibacterial activity. Structure鈥揳ctivity relationships were defined, and the solubility and efficacy profiles were improved over those of previous analogues and 1. These studies identified novel, potent, soluble, and efficacious elongation factor-Tu inhibitors, which bear cycloalkylcarboxylic acid side chains, and culminated in the selection of development candidates amide 48 and urethane 58.