Discovery of novel and ligand-efficient inhibitors of Plasmodium falciparum and Plasmodium vivax N-myristoyltransferase

J Med Chem. 2013 Jan 10;56(1):371-5. doi: 10.1021/jm301474t. Epub 2012 Dec 17.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acyltransferases / antagonists & inhibitors*
  • Antimalarials / chemical synthesis*
  • Antimalarials / chemistry
  • Antimalarials / pharmacology
  • Crystallography, X-Ray
  • Ligands
  • Models, Molecular
  • Molecular Structure
  • Parasitic Sensitivity Tests
  • Plasmodium falciparum / drug effects
  • Plasmodium falciparum / enzymology*
  • Plasmodium vivax / drug effects
  • Plasmodium vivax / enzymology*
  • Protein Binding
  • Structure-Activity Relationship
  • Thiophenes / chemical synthesis*
  • Thiophenes / chemistry
  • Thiophenes / pharmacology

Substances

  • Antimalarials
  • Ligands
  • Thiophenes
  • Acyltransferases
  • glycylpeptide N-tetradecanoyltransferase