Punpai S.Mahalapbutr P.Leechaisit R.Win K.S.Prachayasittikul V.Tanechpongtamb W.Prachayasittikul S.Ruchirawat S.Prachayasittikul V.Pingaew R.Mahidol University2026-04-102026-04-102026-06-04Biochemical and Biophysical Research Communications Vol.816 (2026)0006291Xhttps://repository.li.mahidol.ac.th/handle/123456789/116073Aromatase enzyme is a rate-limiting enzyme playing a key role in estrogen biosynthesis, and its inhibition has been noted as a strategy for the management of hormone-dependent breast cancers. Naphthoquinone and triazole are attractive pharmacophores due to their wide-ranging bioactivities and unique chemical properties. Molecular hybridization is a strategy widely applied in drug design to create several novel compounds with promising therapeutic advantages. In this study, a series of hybridized naphthoquinone-triazoles (1–17) were investigated for their aromatase inhibitory effects. Twelve compounds were found to be active aromatase inhibitors (IC<inf>50</inf> = 1.3–14.9 μM). Molecular docking was conducted to reveal that the three most potent inhibitors (2, 5, and 7, IC<inf>50</inf> = 1.3–1.8 μM) could occupy the allosteric binding site of human aromatase. These three most potent inhibitors (2, 5, and 7) were further explored for their antiproliferative and apoptosis-inducing activities against the estrogen-positive MCF-7 breast cancer cell line. Interestingly, these three aromatase inhibitors exhibited antiproliferative activity (IC<inf>50</inf> = 17.51–36.54 μM) and apoptosis-inducing effects, as observed by increased levels of the cell accumulated in the sub-G1 phase. Notably, methyl derivative 2 outperformed the other derivatives with its comparable potency (IC<inf>50</inf> = 17.51, SI = 4.60) and higher selectivity index than the standard drug, tamoxifen (IC<inf>50</inf> = 18.11, SI = 1.56). Collectively, this study suggested that these naphthoquinone-triazole derivatives were aromatase inhibitors possessing the apoptosis-inducing effect, which could be further developed as multi-acting anticancer agents for combating estrogen-dependent breast cancer.Biochemistry, Genetics and Molecular BiologyArticleSCOPUS10.1016/j.bbrc.2026.1536832-s2.0-10503464277210902104