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


ABSTRACT: 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.

SUBMITTER: Zhang Z 

PROVIDER: S-EPMC5108244 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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

Zhang Zhongsheng Z   Koh Cho Yeow CY   Ranade Ranae M RM   Shibata Sayaka S   Gillespie J Robert JR   Hulverson Matthew A MA   Huang Wenlin W   Nguyen Jasmine J   Pendem Nagendar N   Gelb Michael H MH   Verlinde Christophe L M J CL   Hol Wim G J WG   Buckner Frederick S FS   Fan Erkang E  

ACS infectious diseases 20160411 6


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. ...[more]

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