Diversity-oriented Synthesis Yields Novel Multistage Antimalarial Inhibitors

Nature. 2016 Oct 20;538(7625):344-349. doi: 10.1038/nature19804. Epub 2016 Sep 7.

Abstract

Antimalarial drugs have thus far been chiefly derived from two sources-natural products and synthetic drug-like compounds. Here we investigate whether antimalarial agents with novel mechanisms of action could be discovered using a diverse collection of synthetic compounds that have three-dimensional features reminiscent of natural products and are underrepresented in typical screening collections. We report the identification of such compounds with both previously reported and undescribed mechanisms of action, including a series of bicyclic azetidines that inhibit a new antimalarial target, phenylalanyl-tRNA synthetase. These molecules are curative in mice at a single, low dose and show activity against all parasite life stages in multiple in vivo efficacy models. Our findings identify bicyclic azetidines with the potential to both cure and prevent transmission of the disease as well as protect at-risk populations with a single oral dose, highlighting the strength of diversity-oriented synthesis in revealing promising therapeutic targets.

MeSH terms

  • Animals
  • Antimalarials / administration & dosage
  • Antimalarials / chemical synthesis*
  • Antimalarials / pharmacology*
  • Antimalarials / therapeutic use
  • Azabicyclo Compounds / administration & dosage
  • Azabicyclo Compounds / chemical synthesis
  • Azabicyclo Compounds / pharmacology
  • Azabicyclo Compounds / therapeutic use
  • Azetidines / administration & dosage
  • Azetidines / adverse effects
  • Azetidines / pharmacology
  • Azetidines / therapeutic use*
  • Cytosol / enzymology
  • Disease Models, Animal
  • Drug Discovery*
  • Female
  • Life Cycle Stages / drug effects*
  • Liver / drug effects
  • Liver / parasitology
  • Macaca mulatta / parasitology
  • Malaria, Falciparum / drug therapy*
  • Malaria, Falciparum / prevention & control
  • Malaria, Falciparum / transmission
  • Male
  • Mice
  • Phenylalanine-tRNA Ligase / antagonists & inhibitors
  • Phenylurea Compounds / administration & dosage
  • Phenylurea Compounds / chemical synthesis
  • Phenylurea Compounds / pharmacology
  • Phenylurea Compounds / therapeutic use
  • Plasmodium falciparum / cytology
  • Plasmodium falciparum / drug effects*
  • Plasmodium falciparum / enzymology
  • Plasmodium falciparum / growth & development*
  • Safety

Substances

  • Antimalarials
  • Azabicyclo Compounds
  • Azetidines
  • BRD7929
  • Phenylurea Compounds
  • Phenylalanine-tRNA Ligase