title: Discovery of novel and ligand-efficient inhibitors of Plasmodium falciparum and Plasmodium vivax N-myristoyltransferase.
abstract: N-Myristoyltransferase (NMT) is an attractive antiprotozoan drug target. A lead-hopping approach was utilized in the design and synthesis of novel benzo[b]thiophene-containing inhibitors of Plasmodium falciparum (Pf) and Plasmodium vivax (Pv) NMT. These inhibitors are selective against Homo sapiens NMT1 (HsNMT), have excellent ligand efficiency (LE), and display antiparasitic activity in vitro. The binding mode of this series was determined by crystallography and shows a novel binding mode for the benzothiophene ring.
authors.affiliation: Department of Chemistry, Imperial College London, South Kensington Campus, 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: David K
authors.initials: DK
authors.lastname: Moss
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Yu
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Wilkinson
authors.forename: Anthony A
authors.initials: AA
authors.lastname: Holder
authors.forename: Edward W
authors.initials: EW
authors.lastname: Tate
authors.forename: Robin J
authors.initials: RJ
authors.lastname: Leatherbarrow
mesh_terms: D000217:Acyltransferases / Q000037:antagonists & inhibitors*; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018360:Crystallography, X-Ray; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects / Q000201:enzymology*; D010966:Plasmodium vivax / Q000187:drug effects / Q000201:enzymology*; D011485:Protein Binding; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000962:Antimalarials; D008024:Ligands; D013876:Thiophenes; D000217:Acyltransferases; C050480:glycylpeptide N-tetradecanoyltransferase