Structure-guided discovery of selective methionyl-tRNA synthetase inhibitors with potent activity against Trypanosoma brucei?

RSC Medicinal Chemistry Pub Date: 2020-05-18 DOI: 10.1039/D0MD00057D

Abstract

Based on crystal structures of Trypanosoma brucei methionyl-tRNA synthetase (TbMetRS) bound to inhibitors, we designed, synthesized, and evaluated two series of novel TbMetRS inhibitors targeting this parasite enzyme. One series has a 1,3-dihydro-imidazol-2-one containing linker, the other has a rigid fused aromatic ring in the linker. For both series of compounds, potent inhibition of parasite growth was achieved with EC50 < 10 nM and most compounds exhibited low general toxicity to mammalian cells with CC50s > 20?000 nM. Selectivity over human mitochondrial methionyl tRNA synthetase was also evaluated, using a cell-based mitochondrial protein synthesis assay, and selectivity in a range of 20–200-fold was achieved. The inhibitors exhibited poor permeability across the blood brain barrier, necessitating future efforts to optimize the compounds for use in late stage human African trypanosomiasis.

Graphical abstract: Structure-guided discovery of selective methionyl-tRNA synthetase inhibitors with potent activity against Trypanosoma brucei
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