SYNTHESIS AND IN-VITRO EVALUATION OF 3-(1-AZOLYLMETHYL)-1H-INDOLES AND 3-(1-AZOLYL-1-PHENYLMETHYL)-1H-INDOLES AS INHIBITORS OF P450 AROM

In the challenge to develop potent inhibitors of aromatase for reducin g the levels of estrogens, we found that azolyl-substituted indoles in hibit aromatase activity. 3-(1-Azolylmethyl)-1H-indoles 9-15 and 3-(1- azolyl-1-phenylmethyl)-1H-indoles 22-25 were prepared, and tested on t heir ability to inhibit P450 atom. Analysis of the inhibitory effect e xerted by several derivatives (11, 12, 22, and 23) on microsomal aroma tase in vitro activity indicates that azolyl-substituted indoles conta ining an imidazole moiety are more potent inhibitors than triazole der ivatives. In the first series, the introduction of the N-benzyl moiety has been found to enhance the inhibitory profile of these 3-(1-azolyl methyl)-1H-indole derivatives. The corresponding 4-fluoro derivative 1 2 displays the highest inhibitory activity (IC50 = 0.0718 mu M) of all investigated compounds; thus, 12 is 258 times as potent as aminoglute thimide (AG). The presence of a chloro grouping in pain position of th e phenyl ring in compounds 22 and 24 exerts a positive effect only in the triazol-1-yl sub series: compound 25 is 4-fold more potent than 24 .