title: Design and synthesis of high affinity inhibitors of Plasmodium falciparum and Plasmodium vivax N-myristoyltransferases directed by ligand efficiency dependent lipophilicity (LELP).
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.
authors.affiliation: Department of Chemistry, Imperial College London , London SW7 2AZ, U.K.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Rackham
authors.forename: James A
authors.initials: JA
authors.lastname: Brannigan
authors.forename: Kaveri
authors.initials: K
authors.lastname: Rangachari
authors.forename: Stephan
authors.initials: S
authors.lastname: Meister
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Wilkinson
authors.forename: Anthony A
authors.initials: AA
authors.lastname: Holder
authors.forename: Robin J
authors.initials: RJ
authors.lastname: Leatherbarrow
authors.forename: Edward W
authors.initials: EW
authors.lastname: Tate
mesh_terms: D000217:Acyltransferases / Q000037:antagonists & inhibitors*; D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000494:pharmacology*; D001769:Blood / Q000469:parasitology; D002738:Chloroquine / Q000494:pharmacology; D018360:Crystallography, X-Ray; D015195:Drug Design; D004351:Drug Resistance; D006801:Humans; D006860:Hydrogen Bonding; D007202:Indicators and Reagents; D008024:Ligands; D008055:Lipids / Q000737:chemistry; D008099:Liver / Q000469:parasitology; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000201:enzymology*; D010966:Plasmodium vivax / Q000187:drug effects* / Q000201:enzymology*; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis* / Q000494:pharmacology*
chemical_list: D000962:Antimalarials; D007202:Indicators and Reagents; D008024:Ligands; D008055:Lipids; D013876:Thiophenes; C088015:benzothiophene; D002738:Chloroquine; D000217:Acyltransferases; C050480:glycylpeptide N-tetradecanoyltransferase