Structure guided optimization of novel inhibitors of Plasmodium lysyl-tRNA synthetase with multistage activity against malaria parasites

A fused dihydropyrrolidino-pyrimidine hit with low lipophilicity and excellent ligand efficiency (LE=0.4, LLE 4.9) was identified in a biochemical screen of the Global Health Chemical Diversity Library (GHCDL) against Plasmodium lysyl-tRNA synthetase (KRS). A structurally enabled lead optimization campaign led to the identification of analogues with potent parasite growth inhibition, excellent biochemical and cellular selectivity (>1000 fold) and efficacy in the malaria NOD-scid IL2Rγnull (SCID) mouse model after oral dosing. Structural information and computational methods were deployed to identify a potent and selective basic KRS inhibitor (30) with an extended half-life to reduce the dose regimen to a single-dose cure. This basic lead displayed long half-life across preclinical species, a favourable safety profile, and activity across Plasmodium species as well as against drug-resistant and sensitive P. falciparum strains and field isolates. Unfortunately, 30 lacked oral bioavailability that could not be mitigated with a prodrug approach. Nevertheless, learnings from this series will assist future programmes on new KRS inhibitors to deliver a clinical candidate with this novel mode of action.