Figure 6.

Cellular efficacy of LdMetRS inhibition. (A) A panel of LdMetRS inhibitors show a range of potencies (IC₅₀ 94 nM to 100 μM) in the LdMetRS enzymatic assay. Plotting the −log IC₅₀ (pIC₅₀) of this enzymatic data against −log EC₅₀ (pEC₅₀) data from the L. donovani promastigote assay reveals these potencies correlate well. Solid line represents linear regression with a correlation coefficient of 0.76. (B) When the same compounds are tested in the L. donovani axenic amastigote assay, most are inactive. In both (A) and (B), dashed lines represent equipotency in the LdMetRS enzyme assay and the Leishmania phenotypic assay. (C) Confirmation of on-target activity of DDD806905 in L. donovani promastigotes was carried out by testing this compound in the absence (closed circles) and presence (open circles) of excess methionine (2 mM). The EC₅₀ shifts from 0.46 to 1.9 μM in the absence and presence of excess methionine, respectively. Data presented as mean ± SD (n = 3 biological replicates).