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

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Binding Sites / drug effects
  • Brain / metabolism
  • Cell Line
  • Cell Survival / drug effects
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / administration & dosage
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Hep G2 Cells
  • Humans
  • Methionine / administration & dosage
  • Methionine / chemistry
  • Methionine / pharmacology*
  • Methionine-tRNA Ligase / antagonists & inhibitors*
  • Methionine-tRNA Ligase / metabolism
  • Mice
  • Molecular Structure
  • Structure-Activity Relationship
  • Trypanosoma brucei brucei / enzymology*


  • Enzyme Inhibitors
  • Methionine
  • Methionine-tRNA Ligase