Aromatase inhibitory, anti-proliferative, and apoptosis-inducing effects of naphthoquinone-triazole derivatives for potential anti-breast cancer agents: In vitro and molecular docking studies.

Aromatase 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 (IC50= 1.3-14.9 μM). Molecular docking was conducted to reveal that the three most potent inhibitors (2, 5, and 7, IC50= 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 (IC50= 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 (IC50 = 17.51, SI = 4.60) and higher selectivity index than the standard drug, tamoxifen (IC50 = 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.