Chroman-4-One Derivatives Targeting Pteridine Reductase 1 and Showing Anti-Parasitic Activity

Molecules. 2017 Mar 8;22(3):426. doi: 10.3390/molecules22030426.


Flavonoids have previously been identified as antiparasitic agents and pteridine reductase 1 (PTR1) inhibitors. Herein, we focus our attention on the chroman-4-one scaffold. Three chroman-4-one analogues (1-3) of previously published chromen-4-one derivatives were synthesized and biologically evaluated against parasitic enzymes (Trypanosoma brucei PTR1-TbPTR1 and Leishmania major-LmPTR1) and parasites (Trypanosoma brucei and Leishmania infantum). A crystal structure of TbPTR1 in complex with compound 1 and the first crystal structures of LmPTR1-flavanone complexes (compounds 1 and 3) were solved. The inhibitory activity of the chroman-4-one and chromen-4-one derivatives was explained by comparison of observed and predicted binding modes of the compounds. Compound 1 showed activity both against the targeted enzymes and the parasites with a selectivity index greater than 7 and a low toxicity. Our results provide a basis for further scaffold optimization and structure-based drug design aimed at the identification of potent anti-trypanosomatidic compounds targeting multiple PTR1 variants.

Keywords: Leishmania spp.; Trypanosoma brucei; chroman-4-one; chromen-4-one; crystallographic studies; pteridine reductase 1.

MeSH terms

  • Antiparasitic Agents / chemical synthesis
  • Antiparasitic Agents / chemistry*
  • Antiparasitic Agents / pharmacology*
  • Binding Sites
  • Chromans / chemical synthesis
  • Chromans / chemistry*
  • Chromans / pharmacology*
  • Enzyme Activation / drug effects
  • Inhibitory Concentration 50
  • Leishmania major / drug effects
  • Leishmania major / enzymology
  • Molecular Conformation
  • Molecular Docking Simulation
  • Molecular Dynamics Simulation
  • Molecular Structure
  • Oxidoreductases / antagonists & inhibitors*
  • Oxidoreductases / chemistry
  • Protein Binding
  • Trypanosoma brucei brucei / drug effects
  • Trypanosoma brucei brucei / enzymology


  • Antiparasitic Agents
  • Chromans
  • Oxidoreductases
  • pteridine reductase