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

Abstract

Based on crystal structures of <i>Trypanosoma brucei</i> methionyl-tRNA synthetase (<i>Tb</i>MetRS) bound to inhibitors, we designed, synthesized, and evaluated two series of novel <i>Tb</i>MetRS 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.