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

Eur J Med Chem. 2016 Nov 29:124:1081-1092. doi: 10.1016/j.ejmech.2016.10.024.

Wenlin Huang ¹, Zhongsheng Zhang ¹, Ximena Barros-Álvarez ², Cho Yeow Koh ¹, Ranae M Ranade ³, J Robert Gillespie ³, Sharon A Creason ³, Sayaka Shibata ¹, Christophe L M J Verlinde ¹, Wim G J Hol ¹, Frederick S Buckner ⁴, Erkang Fan ⁵

Affiliations

1 Department of Biochemistry, University of Washington, Seattle, WA 98195, United States.
2 Department of Biochemistry, University of Washington, Seattle, WA 98195, United States; Laboratorio de Enzimología de Parásitos, Facultad de Ciencias, Universidad de los Andes, Mérida, Venezuela.
3 Department of Medicine, Division of Allergy and Infectious Diseases, and the Center for Emerging and Re-emerging Infectious Diseases (CERID), University of Washington, Seattle, WA 98109, United States.
4 Department of Medicine, Division of Allergy and Infectious Diseases, and the Center for Emerging and Re-emerging Infectious Diseases (CERID), University of Washington, Seattle, WA 98109, United States. Electronic address: fbuckner@uw.edu.
5 Department of Biochemistry, University of Washington, Seattle, WA 98195, United States. Electronic address: erkang@uw.edu.

PMID: 27788467 DOI: 10.1016/j.ejmech.2016.10.024

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).

Keywords

Human African trypanosomiasis; Methionyl-tRNA synthetase; Structure-guided design.

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