Novel styryl-indoles as small molecule inhibitors of 25-hydroxyvitamin D-24-hydroxylase (CYP24A1): Synthesis and biological evaluation

Eur J Med Chem. 2014 Nov 24:87:39-51. doi: 10.1016/j.ejmech.2014.09.035. Epub 2014 Sep 16.

Abstract

The synthesis of a series of imidazole styrylindoles and sulfonyl styrylindoles derivatives is described. Evaluation of binding affinity and inhibitory activity against CYP24A1 identified the imidazole styrylindoles as potent inhibitors with activity greater or comparable with the standard ketoconazole. Flexible alignment and docking studies of the inhibitors in the CYP24A1 enzyme active site confirmed that complete occupation of the vitamin D access tunnel is essential to inhibitory activity, allowing exposure to multiple hydrophobic binding interactions and optimal conformation for the interaction of the imidazole nitrogen lone pair and the active site haem.

Keywords: CYP24A1; Imidazole styrylindoles; Molecular modelling; Sulfonyl styrylindoles; Vitamin D.

Publication types

  • Evaluation Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Catalytic Domain
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Indoles / chemistry*
  • Models, Molecular
  • Molecular Structure
  • Protein Conformation
  • Small Molecule Libraries / chemical synthesis*
  • Small Molecule Libraries / pharmacology*
  • Structure-Activity Relationship
  • Styrene / chemistry*
  • Vitamin D3 24-Hydroxylase / antagonists & inhibitors*

Substances

  • Enzyme Inhibitors
  • Indoles
  • Small Molecule Libraries
  • Styrene
  • CYP24A1 protein, human
  • Vitamin D3 24-Hydroxylase