Design and synthesis of substituted imidazole and triazole N-phenylbenzo[d]oxazolamine inhibitors of retinoic acid metabolizing enzyme CYP26

Abstract

The design of N-phenylbenzo[d]oxazolamines as CYP26A1 inhibitors involved ligand docking experiments using molecular modeling (FlexX) and analysis of ligand interactions at the binding domain. The synthesis of the benzooxazol-2-yl-[phenyl-imidazol-1-yl-methyl)phenyl]amines was achieved by cyclisation of the corresponding isothiocyanates with subsequent introduction of the haem-binding heterocycle. Triazole and tetrazole derivatives were also prepared for comparison with the lead imidazole derivative. The benzooxazol-2-yl-[phenyl-imidazol-1-yl-methyl)phenyl]amines with small substituents in the phenyl ring were moderately potent CYP26A1 inhibitors (IC₅₀ 8 and 12 μM) and comparable with liarozole (IC₅₀ 7 μM).

Keywords::

• N-phenylbenzo[d]oxazolamines
• molecular modeling
• retinoic acid
• CYP26A1
• enzyme inhibition
• IC₅₀

Acknowledgements

For ASA we acknowledge the Embassy of the Arab Republic of Egypt for the award of a PhD scholarship. We thank the technical staff of the Tenovus Cancer Centre, Welsh School of Pharmacy, Cardiff University, UK for the preparation of cells and media, and the EPSRC Mass Spectrometry Centre, Swansea, UK for mass spectroscopy data.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.