Synthesis, molecular modelling and CYP24A1 inhibitory activity of novel of (E)-N-(2-(1H-imidazol-1-yl)-2-(phenylethyl)-3/4-styrylbenzamides

Bioorg Med Chem. 2017 Aug 1;25(15):4076-4087. doi: 10.1016/j.bmc.2017.05.055. Epub 2017 May 29.

Abstract

CYP24A1 (25-hydroxyvitamin D-24-hydroxylase) is a useful enzyme target for a range of medical conditions including cancer, cardiovascular and autoimmune disease, which show elevated CYP24A1 levels and corresponding reduction of calcitriol (the biologically active form of vitamin D). A series of (E)-N-(2-(1H-imidazol-1-yl)-2-(phenylethyl)-3/4-styrylbenzamides have been synthesised using an efficient synthetic route and shown to be potent inhibitors of CYP24A1 (IC50 0.11-0.35μM) compared with the standard ketoconazole. Molecular modelling using our CYP24A1 homology model showed the inhibitors to fill the hydrophobic binding site, forming key transition metal interaction between the imidazole nitrogen and the haem Fe3+ and multiple interactions with the active site amino acid residues.

Keywords: (E)-N-(2-(1H-imidazol-1-yl)-2-(phenylethyl)-3/4-styrylbenzamides; CYP24A1; Enzyme inhibition; Molecular modelling; Vitamin D.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Benzamides / chemical synthesis
  • Benzamides / chemistry*
  • Benzamides / pharmacology*
  • Carbon-13 Magnetic Resonance Spectroscopy
  • Catalytic Domain
  • Chromatography, High Pressure Liquid
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology*
  • Hydrophobic and Hydrophilic Interactions
  • Models, Molecular
  • Proton Magnetic Resonance Spectroscopy
  • Structure-Activity Relationship
  • Vitamin D3 24-Hydroxylase / antagonists & inhibitors*

Substances

  • Benzamides
  • Enzyme Inhibitors
  • CYP24A1 protein, human
  • Vitamin D3 24-Hydroxylase