Amporn Saekee, Pichjira Sooknual, Sakdiphong Punpai, Veda Prachayasittikul*, Sakchai Hongthong, Wanlaya Tanechpongtamb, Supaluk Prachayasittikul, Somsak Ruchirawat, Virapong Prachayasittikul, Ratchanok Pingaew*

Breast cancer is one of the most common cancers in women worldwide. High levels of estrogen have been noted to increase the risk of developing breast malignancy. Aromatase is well-known as a rate-limiting enzyme for estrogen production, and its inhibition has been noted as one of treatment strategies for management of estrogen-dependent breast cancer. Besides the availability of clinical drugs, their significant adverse effects (such as reduced bone density and an elevated risk of cardiovascular illnesses) and possible drug resistance after extended usage are still challenging issues to be addressed. In this study, twenty-seven coumarin-triazole and isatin-triazole derivatives were designed, synthesized, and investigated for their biological activities. Coumarin-triazoles 5h and 6i were shown to be the two most effective antiproliferative agents in an anti-proliferative study against the hormone-dependent breast cancer (T47D) cell line. In particular, compound 5h outperformed the reference drug, doxorubicin, in terms of selectivity index and potency. Additionally, the coumarin-triazole 5h induced cellular apoptosis of the estrogen-dependent breast cancer (MCF-7) cells. Furthermore, four compounds 5i, 6f, 6g and 6i were identified as possible aromatase inhibitors (IC₅₀ =1.4–2.4 µM) based on results from the aromatase inhibitory assay. QSAR models were constructed to identify important characteristics determining antiproliferative and aromatase inhibitory actions. To clarify the potential binding modalities against the target aromatase enzyme, molecular docking was performed. Important structural features that are necessary for the binding were highlighted. Moreover, the drug-like properties of top-ranking compounds were evaluated to guarantee their potential for successful development.

Keywords:  Coumarin, Triazole, Breast cancer, Apoptosis, Aromatase inhibitor, Molecular docking, QSAR

Reference: Archives of Biochemistry and Biophysics 2025, 765, 110308.

          DOI: https://doi.org/10.1016/j.abb.2025.110308