Design and synthesis of substituted imidazole and triazole N-phenylbenzo[d]oxazolamine inhibitors of retinoic acid metabolizing enzyme CYP26 |
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Authors: | Stephane Pautus Ahmed S. Aboraia Claire E. Bassett Andrea Brancale Michael P. Coogan |
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Affiliation: | 1. Medicinal Chemistry, Welsh School of Pharmacy, Cardiff University, Cardiff, UK;2. School of Chemistry, Cardiff University, Cardiff, UK |
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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). |
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Keywords: | N-phenylbenzo[d]oxazolamines molecular modeling retinoic acid CYP26A1 enzyme inhibition IC50 |
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