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Design and Synthesis of High Affinity Inhibitors of Plasmodium falciparum and Plasmodium vivax N-Myristoyltransferases Directed by Ligand Efficiency Dependent Lipophilicity (LELP)

DOI: 10.1021/jm500066b DOI Help
PMID: 24641010 PMID Help

Authors: Mark D. Rackham (Department of Chemistry, Imperial College London, U.K.) , James A. Brannigan (Structural Biology Laboratory, University of York) , Kaveri Rangachari (MRC National Institute for Medical Research, London, U.K.) , Stephan Meister (Department of Pediatrics, School of Medicine, University of California San Diego, USA.) , Anthony Wilkinson (Structural Biology Laboratory, University of York, U.K.) , Anthony A. Holder (MRC National Institute for Medical Research, London, U.K.) , Robin J. Leatherbarrow (Department of Chemistry, Imperial College London, U.K.) , Edward W. Tate (Department of Chemistry, Imperial College London, U.K.)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Medicinal Chemistry , VOL 57 (6) , PAGES 2773 - 2788

State: Published (Approved)
Published: March 2014
Diamond Proposal Number(s): 7864

Open Access Open Access

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 Keywords: Animals ; Antimalarials ; Blood ; Chloroquine ; Crystallography ; X-Ray ; Drug; Drug; Humans ; Hydrogen; Indicators; Ligands ; Lipids ; Liver ; Mice ; Models ; Molecular ; Plasmodium; Plasmodium; Structure-Activity; Thiophenes

Subject Areas: Biology and Bio-materials, Medicine, Chemistry


Instruments: I04-Macromolecular Crystallography , I24-Microfocus Macromolecular Crystallography