Exploiting the Chromone Scaffold for the Development of Inhibitors of Corticosteroid Biosynthesis

J Med Chem. 2016 Mar 24;59(6):2468-77. doi: 10.1021/acs.jmedchem.5b01609. Epub 2016 Mar 11.


The inhibition of corticosteroid biosynthesis could be considered as an emerging strategy to reduce their abnormally high levels, and in this framework CYP11B1 and CYP11B2 represent the most promising targets. In continuing our studies on flavonoid-like scaffolds as privileged structures in medicinal chemistry, in this paper we describe a small library of pyridyl- and imidazolylmethylchromones as potential inhibitors of these enzymes. Testing results proved that position 3 of the chromone scaffold is the most favorable for the introduction of the heme-coordinating heterocycles and, among them, the 4-imidazolyl moiety is the most convenient for the interaction with the heme iron of the selected cytochromes. A low nanomolar inhibitor of CYP11B1 (5c) was obtained, endowed with reasonable selectivity toward CYP11B2 and able to better discriminate with respect to CYP17 and CYP19.

MeSH terms

  • Adrenal Cortex Hormones / antagonists & inhibitors*
  • Adrenal Cortex Hormones / biosynthesis*
  • Animals
  • Aromatase Inhibitors / chemical synthesis
  • Aromatase Inhibitors / pharmacology
  • Cell Survival / drug effects
  • Chromones / chemical synthesis*
  • Chromones / chemistry*
  • Chromones / pharmacology
  • Cytochrome P-450 CYP11B2 / antagonists & inhibitors
  • Cytochrome P-450 Enzyme Inhibitors / chemical synthesis*
  • Cytochrome P-450 Enzyme Inhibitors / pharmacology*
  • Drug Design
  • Heterocyclic Compounds / chemical synthesis
  • Heterocyclic Compounds / pharmacology
  • Humans
  • Models, Molecular
  • Molecular Docking Simulation
  • Pyridines / chemical synthesis
  • Pyridines / pharmacology
  • Rats
  • Small Molecule Libraries
  • Steroid 11-beta-Hydroxylase / antagonists & inhibitors
  • Steroid 17-alpha-Hydroxylase / antagonists & inhibitors
  • Structure-Activity Relationship
  • Substrate Specificity


  • Adrenal Cortex Hormones
  • Aromatase Inhibitors
  • Chromones
  • Cytochrome P-450 Enzyme Inhibitors
  • Heterocyclic Compounds
  • Pyridines
  • Small Molecule Libraries
  • Steroid 17-alpha-Hydroxylase
  • Cytochrome P-450 CYP11B2
  • Steroid 11-beta-Hydroxylase