The synthesis of a series of novel 1-[(benzofuran-2-yl)phenylmethyl]-pyridine, -imidazole, and -triazole derivatives is described. All the compounds were evaluated in vitro for inhibitory activity against aromatase (P450(AROM), CYP19), using human placental microsomes. The 6-methoxy- and 6-hydroxy-substituted benzofuran derivatives were shown to be potent CYP19 inhibitors (IC(50) = 0.01-1.46 microM) with activity greater than that observed for the unsubstituted parent compounds and inhibitory activity comparable with or greater than the reference compound arimidex (IC(50) = 0.6 microM). Six of the benzofuran derivatives were subjected to in vitro cytotoxicity assays, using rat liver hepatocytes with cytotoxicity determined from alteration in cell morphology and lactate dehydrogenase enzyme retention over a period of 24 h, and selectivity (CYP17, 17beta-HSD types 1 and 3, CYP24, and CYP26) determination; negligible inhibitory activity was observed, suggesting a good selectivity for CYP19. The pyridine benzofuran 4a containing the 4-fluorophenyl group was the most promising (IC(50) = 44 nM; LC(50) >100 microM) compared with arimidex (IC(50) = 600 nM; LC(50) > 200 microM).

A series of benzofuran-2-yl-(phenyl)-3-pyridylmethanol derivatives were prepared using an efficient 1-step procedure in good yields. In addition furan-2-yl-(phenyl)-3-pyridylmethanol derivatives were also prepared to determine the effect of the benzene ring in benzofuran with respect to inhibitory activity. The pyridylmethanol derivatives were all evaluated in vitro for inhibitory activity against aromatase (P450 AROM , CYP19), using human placental microsomes. The benzofuran-2-yl-(phenyl)-3-pyridylmethanol derivatives showed good to moderate activity ðIC 50 ¼ 1:3 -25:1 mMÞ; which was either better than or comparable with aminoglutethimide ðIC 50 ¼ 18:5 mMÞ but lower than arimidex ðIC 50 ¼ 0:6 mMÞ; with the 4-methoxyphenyl substituted derivative displaying optimum activity. Molecular modelling of the benzofuran-2-yl-(4-fluorophenyl)-3-pyridylmethanol derivative suggested activity to reside with the (S)-enantiomer. The furan-2-yl-(phenyl)-3-pyridylmethanol derivatives were devoid of activity indicating the essential role of the benzene ring of the benzofuran component for enzyme binding.