Synthesis, Design, and Structure⁻Activity Relationship of the Pyrimidone Derivatives as Novel Selective Inhibitors of Plasmodium falciparum Dihydroorotate Dehydrogenase

Molecules. 2018 May 24;23(6):1254. doi: 10.3390/molecules23061254.

Abstract

The inhibition of Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) potentially represents a new treatment option for malaria, as P. falciparum relies entirely on a de novo pyrimidine biosynthetic pathway for survival. Herein, we report a series of pyrimidone derivatives as novel inhibitors of PfDHODH. The most potent compound, 26, showed high inhibition activity against PfDHODH (IC50 = 23 nM), with >400-fold species selectivity over human dihydroorotate dehydrogenase (hDHODH). The brand-new inhibitor scaffold targeting PfDHODH reported in this work may lead to the discovery of new antimalarial agents.

Keywords: P. falciparum; PfDHODH; antimalarial agents; pyrimidone.

MeSH terms

  • Dihydroorotate Dehydrogenase
  • Drug Design
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Oxidoreductases Acting on CH-CH Group Donors / antagonists & inhibitors*
  • Oxidoreductases Acting on CH-CH Group Donors / chemistry
  • Plasmodium falciparum / drug effects
  • Plasmodium falciparum / enzymology*
  • Protozoan Proteins / antagonists & inhibitors
  • Protozoan Proteins / chemistry
  • Pyrimidinones / chemical synthesis*
  • Pyrimidinones / chemistry
  • Pyrimidinones / pharmacology
  • Species Specificity
  • Structure-Activity Relationship

Substances

  • Dihydroorotate Dehydrogenase
  • Enzyme Inhibitors
  • Protozoan Proteins
  • Pyrimidinones
  • Oxidoreductases Acting on CH-CH Group Donors