Design, Synthesis and Molecular Modeling Studies of Triazole Derivatives as Aromatase İnhibitors

Based on the structural characteristics of non-steroidal aromatase inhibitors used in the treatment of estrogen receptor-positive (ER+) breast cancer, a novel series of 1,3,4-triazole derivatives was designed and synthesized in this study. The cytotoxicity of the synthesized compounds was evaluated against the MCF-7 human breast cancer cell line using the MTT assay. In contrast, the L929 mouse fibroblast cell line was employed as a normal cell model to assess selectivity. Among the tested derivatives, compounds 6e and 6g exhibited significant cytotoxic activity against MCF-7 cells, with IC₅₀ values of 19.96 μM and 15.75 μM, respectively, demonstrating stronger activity than the reference drug cisplatin (21.42 μM). In contrast, compounds 6k and 6l showed lower cytotoxicity toward L929 cells and displayed favorable selectivity profiles. Based on their cytotoxic potency and selectivity indices, compounds 6g, 6e, 6l, and 6k were selected for further biological and in silico investigations. Aromatase inhibition assays revealed that these compounds inhibited the enzyme with IC₅₀ values of 8.59, 11.98, 11.41, and 7.69 μM, respectively. Molecular docking analysis demonstrated that the selected compounds exhibited binding interactions similar to letrozole within the aromatase active site. Based on combined cytotoxicity, enzyme inhibition, molecular docking, and ADME predictions, compound 6l emerged as the most promising candidate as a potential non-steroidal aromatase inhibitor.