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

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.