title: Discovery of pyridyl-based inhibitors ofPlasmodium falciparum N-myristoyltransferase.
abstract: N-Myristoyltransferase (NMT) represents an attractive drug target in parasitic infections such as malaria due to its genetic essentiality and amenability to inhibition by drug-like small molecules. Scaffold simplification from previously reported inhibitors containing bicyclic cores identified phenyl derivative3, providing a versatile platform to study the effects of substitution on the scaffold, which yielded pyridyl19. This molecule exhibited improved enzyme and cellular potency, and reduced lipophilicity compared to inhibitor3. Further structure-based inhibitor design led to the discovery of30, the most potent inhibitor in this series, which showed single-digit nM enzyme affinity and sub-μM anti-plasmodial activity.
authors.affiliation: Department of Chemistry , Imperial College London , London , SW7 2AZ , UK . Email: e.tate@imperial.ac.uk ; Tel: +44 (0)2075 943 752.
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Yu
authors.affiliation: York Structural Biology Laboratory , Department of Chemistry , University of York , York , YO10 5DD , UK.
authors.forename: James A
authors.initials: JA
authors.lastname: Brannigan
authors.affiliation: The Francis Crick Institute , Mill Hill Laboratory , The Ridgeway , London , NW7 1AA , UK.
authors.forename: Kaveri
authors.initials: K
authors.lastname: Rangachari
authors.affiliation: Department of Chemistry , Imperial College London , London , SW7 2AZ , UK . Email: e.tate@imperial.ac.uk ; Tel: +44 (0)2075 943 752.
authors.forename: William P
authors.initials: WP
authors.lastname: Heal
authors.affiliation: York Structural Biology Laboratory , Department of Chemistry , University of York , York , YO10 5DD , UK.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Wilkinson
authors.affiliation: The Francis Crick Institute , Mill Hill Laboratory , The Ridgeway , London , NW7 1AA , UK.
authors.forename: Anthony A
authors.initials: AA
authors.lastname: Holder
authors.affiliation: Department of Chemistry , Imperial College London , London , SW7 2AZ , UK . Email: e.tate@imperial.ac.uk ; Tel: +44 (0)2075 943 752.
authors.forename: Robin J
authors.initials: RJ
authors.lastname: Leatherbarrow
authors.affiliation: Department of Chemistry , Imperial College London , London , SW7 2AZ , UK . Email: e.tate@imperial.ac.uk ; Tel: +44 (0)2075 943 752.
authors.forename: Edward W
authors.initials: EW
authors.lastname: Tate