5-Fluoroimidazo[4,5-b]pyridine Is a Privileged Fragment That Conveys Bioavailability to Potent Trypanosomal Methionyl-tRNA Synthetase Inhibitors

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• 作者：Zhongsheng Zhang ; Cho Yeow Koh ; Ranae M. Ranade ; Sayaka Shibata ; J. Robert Gillespie ; Matthew A. Hulverson ; Wenlin Huang ; Jasmine Nguyen ; Nagendar Pendem ; Michael H. Gelb ; Christophe L. M. J. Verlinde ; Wim G. J. Hol ; Frederick S. Buckner ; Erkang Fan
• 刊名：ACS Infectious Diseases
• 出版年：2016
• 出版时间：June 10, 2016
• 年：2016
• 卷：2
• 期：6
• 页码：399-404
• 全文大小：386K
• ISSN：2373-8227

文摘

Fluorination is a well-known strategy for improving the bioavailability of drug molecules. However, its impact on efficacy is not easily predicted. On the basis of inhibitor-bound protein crystal structures, we found a beneficial fluorination spot for inhibitors targeting methionyl-tRNA synthetase of Trypanosoma brucei. In particular, incorporating 5-fluoroimidazo[4,5-b]pyridine into inhibitors leads to central nervous system bioavailability and maintained or even improved efficacy.