Discovery of Potent Orally Active Plasmodium N -Myristoyltransferase Inhibitors Using Fragment-Linking Approaches

N-Myristoyltransferase (NMT) is an essential eukaryotic enzyme and an attractive potential drug target for parasitic infections such as malaria and leishmaniasis. Co-crystallisation of a high-throughput screening hit with P. vivax NMT identified a novel binding mode, and cooperative binding experiments with fragments identified synergistic improvements in potency and opportunities for fragment-linking. Optimisation of the torsional angle of fragment linkage through phenolic ether enabled the desired activity spectrum and selectivity profile, and examples were progressed to a mouse malaria model, resulting in the selection of IMP-1002 for further evaluation. This early lead compound was efficacious after oral administration in a SCID mouse model and is highly active against both blood- and liver-stage forms of the parasite. Finally, we discovered that highly potent human NMT inhibitors, including IMP-1088, could be generated by introducing an additional fluorine atom to further tune the torsion angle.