Abstract:
: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.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Rackham MD,Brannigan JA,Rangachari K,Meister S,Wilkinson AJ,Holder AA,Leatherbarrow RJ,Tate EWdoi
10.1021/jm500066bsubject
Has Abstractpub_date
2014-03-27 00:00:00pages
2773-88issue
6eissn
0022-2623issn
1520-4804journal_volume
57pub_type
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