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-(i)propyl, 4-(t)butyl, 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 (IC(50) 4.5 and 7 microM, respectively) comparable with that of the CYP26 inhibitor liarozole (IC(50) 7 microM). 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.
Pautus
Stephane
S
Welsh School of Pharmacy, Cardiff University, King Edward VII Avenue, Cardiff CF10 3XF, UK.
Yee
Sook Wah
SW
Jayne
Martyn
M
Coogan
Michael P
MP
Simons
Claire
C
D001572:Benzofurans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D045744:Cell Line, Tumor; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D011487:Protein Conformation; D000072516:Retinoic Acid 4-Hydroxylase; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014212:Tretinoin / Q000378:metabolism; D014230:Triazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D001572:Benzofurans; D065607:Cytochrome P-450 Enzyme Inhibitors; D007093:Imidazoles; D008024:Ligands; D014230:Triazoles; D014212:Tretinoin; D003577:Cytochrome P-450 Enzyme System; D000072516:Retinoic Acid 4-Hydroxylase; C061121:liarozole