N-Myristoyltransferase (NMT) is an essential eukaryotic enzyme and an attractive drug target in parasitic
infections such as malaria. We have previously reported that 2-(3-(piperidin-4-yloxy)benzo[b]thiophen-2-yl)-5-((1,3,5-trimethyl-
1H-pyrazol-4-yl)methyl)-1,3,4-oxadiazole (34c) is a high affinity inhibitor of both Plasmodium falciparum and P. vivax NMT and
displays activity in vivo against a rodent malaria model. Here we describe the discovery of 34c through optimization of a
previously described series. Development, guided by targeting a ligand efficiency dependent lipophilicity (LELP) score of less
than 10, yielded a 100-fold increase in enzyme affinity and a 100-fold drop in lipophilicity with the addition of only two heavy
atoms. 34c was found to be equipotent on chloroquine-sensitive and -resistant cell lines and on both blood and liver stage forms
of the parasite. These data further validate NMT as an exciting drug target in malaria and support 34c as an attractive tool for
further optimization.