Synthesis and CYP26A1 inhibitory activity of 1-[benzofuran-2-yl-(4-alkyl/aryl-phenyl)-methyl]-1H-triazoles

Methodology previously described by our group was applied to the preparation of a series of 4-alkyl/aryl-substituted 1-[benzofuran-2-yl-phenylmethyl]-1H-triazoles. The [1,2,4]-triazole derivatives were prepared for a range of alkyl and aryl substituents, and for the 4-methyl, 4-ethyl, 4-ipropyl, 4-tbutyl, 4-phenyl and 4-chlorophenyl derivatives, the minor [1,3,4]-triazole isomer also isolated. All the triazole derivatives were evaluated for CYP26A1 inhibitory activity using a MCF-7 cell-based assay. The 4-ethyl and 4-phenyl-1,2,4-triazole derivatives displayed inhibitory activity (IC50 4.5 and 7 μM, respectively) comparable with that of the CYP26 inhibitor liarozole (IC50 7 μM). Using a CYP26A1 homology model (based on CYP3A4) template, docking experiments were performed with MOE with multiple hydrophobic interactions observed in addition to coordination between the triazole nitrogen and the haem transition metal.

A series of 4-alkyl/aryl-substituted 1-[benzofuran-2-yl-phenylmethyl]-1H-[1,2,4] and [1,3,4]triazoles derivatives were prepared and evaluated for CYP26A1 inhibitory activity using a MCF-7 cell based assay. The 4-ethyl and 4-phenyl-1,2,4-triazole derivatives displayed inhibitory activity (IC50 4.5 and 7 μM, respectively) comparable with the CYP26 inhibitor liarozole (IC50 7 μM). Using a CYP26A1 homology model, docking experiments were performed with the inhibitor compounds.Figure optionsDownload as PowerPoint slide