Purpose: Some aromatase inhibitors are FDA-approved agents as first-line therapy in the treatment of
endocrine-responsive breast cancer. In this study, we aimed to develop new azole derivatives with higher specificity
Methods: New aromatase inhibitors were designed by Molecular Operating Environment (MOE) software and
synthesized in a one-step SN2 reaction. These compounds were characterized by melting point, 1H- and 13CNMR,
elemental analysis and mass spectra. The in vitro and in vivo aromatase inhibition of these compounds
was evaluated using the Estrone ELISA assay, and by measuring the inhibition of androstenedione-induced
uterine hypertrophy. The selectivity of aromatase inhibition was investigated by the inhibition of ACTH stimulation
on the plasma concentrations of aldosterone and cortisol.
Results: Docking simulations showed that four new azole derivatives could efficiently interact with enzyme
active sites. The in vitro aromatase-inhibition assay showed that the compounds 1,3,5-tris(imidazol-1-
ylmethyl)benzene (3b) and 1,3-Bis(imidazole-1- ylmethyl) benzene (3d) effectively inhibited aromatase, with
IC50 values of 0.2 nM and 6.8 nM, respectively; these values were similar to known aromatase inhibitor letrozole
(IC50 0.3 nM). The in vivo aromatase-inhibitory potency of compound 3b was similar to letrozole, although
compound 3b acted more selectively.
Conclusion: This report introduced a new compound that can be considered as a new lead for further investigation
to explore more-potent and more-selective aromatase inhibitors.