Synthesis and <i>In Vitro</i> Evaluation of 3‐(1‐Azolylmethyl)‐1<i>H</i>‐indoles and 3‐(1‐Azolyl‐1‐phenylmethyl)‐1<i>H</i>‐indoles as Inhibitors of P450 arom

Abstract

In the challenge to develop potent inhibitors of aromatase for reducing the levels of estrogens, we found that azolyl-substituted indoles inhibit aromatase activity, 3-(1-Azolylmethyl)-1H-indoles 9-15 and 3-(1-azolyl-1-phenylmethyl)-1H-indoles 22-25 were prepared, and tested on their ability to inhibit P450 arom. Analysis of the inhibitory effect exerted by several derivatives (11, 12, 22, and 23) on microsomal aromatase in vitro activity indicates that azolyl-substituted indoles containing an imidazole moiety are more potent inhibitors than triazole derivatives. In the first series, the introduction of the N-benzyl moiety has been found to enhance the inhibitory profile of these 3-(1-azolylmethyl)-1H-indole derivatives. The corresponding 4-fluoro derivative 12 displays the highest inhibitory activity (IC50 = 0.0718 microM) of all investigated compounds; thus, 12 is 258 times as potent as aminoglutethimide (AG). The presence of a chloro grouping in para position of the phenyl ring in compounds 22 and 24 exerts a positive effect only in the triazol-l-yl sub-series: compound 25 is 4-fold more potent than 24.