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Bioorg Med Chem Lett. 2017 Jun 15;27(12):2702-2707. doi: 10.1016/j.bmcl.2017.04.048. Epub 2017 Apr 17.

Optimization of a binding fragment targeting the "enlarged methionine pocket" leads to potent Trypanosoma brucei methionyl-tRNA synthetase inhibitors.

Author information

1
Department of Biochemistry, University of Washington, Seattle, WA 98195, United States.
2
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.
3
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.
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.

Abstract

Potent inhibitors of Trypanosoma brucei methionyl-tRNA synthetase were previously designed using a structure-guided approach. Compounds 1 and 2 were the most active compounds in the cyclic and linear linker series, respectively. To further improve cellular potency, SAR investigation of a binding fragment targeting the "enlarged methionine pocket" (EMP) was performed. The optimization led to the identification of a 6,8-dichloro-tetrahydroquinoline ring as a favorable fragment to bind the EMP. Replacement of 3,5-dichloro-benzyl group (the EMP binding fragment) of inhibitor 2 using this tetrahydroquinoline fragment resulted in compound 13, that exhibited an EC50 of 4nM.

KEYWORDS:

Human African trypanosomiasis; Methionyl-tRNA synthetase; Structure-based design; Trypanosoma brucei

PMID:
28465105
PMCID:
PMC5542777
DOI:
10.1016/j.bmcl.2017.04.048
[Indexed for MEDLINE]
Free PMC Article

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