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Structure-guided design of novel Trypanosoma brucei Methionyl-tRNA synthetase inhibitors.

ABSTRACT: A screening hit 1 against Trypanosoma brucei methionyl-tRNA synthetase was optimized using a structure-guided approach. The optimization led to the identification of two novel series of potent inhibitors, the cyclic linker and linear linker series. Compounds of both series were potent in a T. brucei growth inhibition assay while showing low toxicity to mammalian cells. The best compound of each series, 16 and 31, exhibited EC50s of 39 and 22 nM, respectively. Compounds 16 and 31 also exhibited promising PK properties after oral dosing in mice. Moreover, compound 31 had moderately good brain permeability, with a brain/plasma ratio of 0.27 at 60 min after IP injection. This study provides new lead compounds for arriving at new treatments of human African trypanosomiasis (HAT).

SUBMITTER: Huang W

PROVIDER: S-EPMC5120670 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Structure-guided design of novel Trypanosoma brucei Methionyl-tRNA synthetase inhibitors.

Huang Wenlin W Zhang Zhongsheng Z Barros-Álvarez Ximena X Koh Cho Yeow CY Ranade Ranae M RM Gillespie J Robert JR Creason Sharon A SA Shibata Sayaka S Verlinde Christophe L M J CLMJ Hol Wim G J WGJ Buckner Frederick S FS Fan Erkang E

European journal of medicinal chemistry 20161014

A screening hit 1 against Trypanosoma brucei methionyl-tRNA synthetase was optimized using a structure-guided approach. The optimization led to the identification of two novel series of potent inhibitors, the cyclic linker and linear linker series. Compounds of both series were potent in a T. brucei growth inhibition assay while showing low toxicity to mammalian cells. The best compound of each series, 16 and 31, exhibited EC<sub>50</sub>s of 39 and 22 nM, respectively. Compounds 16 and 31 also ...[more]

PMID: 27788467

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Structure-guided discovery of selective methionyl-tRNA synthetase inhibitors with potent activity against <i>Trypanosoma brucei</i>.

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