Comparison of the In-vitro Aromatase Inhibitory Activity of 3-(Azolylmethyl)-1H-indoles

Abstract

Abstract The synthesis of 3-(imidazol- 1-ylmethy1)-N-R-alkyl- 1H-indoles [R = H (l), ethyl (2), benzyl (3)], N-benzyl-3-(triazol-l-ylmethyl)-lH-indole (4) and N-benzyl-3-(triazol-4-yl-methyl)- lH-indole (5) is described. The compounds were tested for human placental aromatase inhibition in-vitro, using [ lj-3H]androstenedione and lj,2fi-3H]testosterone as substrates for the aromatase enzyme. Inhibition of androgen aromatization by compounds 1-5 was effective in both enzyme systems. The most interesting compounds were 3 (imidazole derivative) and 4 (triazole derivative) showing comparable percent inhibition values with both androgen substrates. The absence of a substituent (1) or the presence of an ethyl group (2) gave weak inhibitors in imidazole-substituted indoles. Triazole derivatives 4 and 5, with an N-benzyl group, were less potent aromatase inhibitors than compound 3, the imidazole analogue. The 4- triazole derivative 5 was the least active inhibitor in the series. The simultaneous introduction of benzyl and imidazole (rather than triazole) moieties was found to enhance the inhibitory profile of these 3-azolylmethylindole derivatives. Sex steroids are known to be extensively biode- graded by various cytochrome P450 families due to their endobiotic nature. Thus, the biosynthesis