Nuclear factor kappa B (NF–κB) is a potential therapeutic target in breast cancer. In the current study, a new class of oxazine– and piperazine–linked pyrimidines was developed as inhibitors of NF–κB, overcoming the complexity of the oxazine structure found in nature and enabling synthesis under laboratory conditions. Among the series of synthesized and tested oxazine–pyrimidine and piperazine–pyrimidine derivatives, compounds 3a and 5b inhibited breast cancer cell (MCF–7) viability with an IC₅₀ value of 9.17 and 6.29 µM, respectively. In silico docking studies showed that the pyrimidine ring of 3a and the 4–methoxybenzyl thiol group of 5b could strongly bind the p65 subunit of NF–κB, with the binding energies −9.32 and −7.32 kcal mol⁻¹. Furthermore, compounds 3a and 5b inhibited NF–κB in MCF–7 breast cancer cells. In conclusion, we herein report newer structures that target NF–κB in BC cells.

Breast cancer (BC) is the second-largest cause of cancer-related deaths among women worldwide. The development of BC is a complex and multi-step process involving multiple cell types, creating a real challenge for the development of potential therapeutics against it. Several researchers have demonstrated that JNK family members have been associated with BC regulation and progression. In general, JNK is phosphorylated and activated by a number of upstream kinases, and phospho-JNK regulates a variety of cellular functions by phosphorylating c-Jun and other downstream targets. Thus, JNK has become a vital target for the development of potential therapeutics for BC treatment. In past years, electrosynthesis has emerged as a fascinating area superior to traditional chemical processes, as the evolved electrochemical technologies function at higher reaction rates for the synthesis of desired compounds. In this study, we have synthesized a series of triazole compounds using both conventional and electrochemical methods for targeting JNK in human BC cells. All the synthesized molecules were preliminarily evaluated for a cytotoxicity study against MCF-7 cells and the compound 1-(3,4-dichlorophenyl)-4-(((4-isopropyl-5-(4-methoxybenzyl)-4H-1,2,4-triazol-3-yl)thio)methyl)-1H-1,2,3-triazole (5b) is the most potent candidate among the series based on its lower inhibition concentration (IC₅₀) of 4.78 μM. Further studies were performed to evaluate the anticancer potential of novel 5b in human BC cells and the results showed that 5b significantly inhibited colony formation, migration and induced apoptosis by increasing the expression of pro-apoptotic protein BAX, and inhibiting the anti-apoptotic protein BCL2. Furthermore, the novel 5b also induced the phosphorylation of JNK in BC cells in a dose-dependent manner. Additionally, an in silico docking study revealed that compound 5b has a strong binding affinity (−8.88 kcal mol⁻¹) towards JNK3S. In conclusion, the novel synthesized compound 5b triggers apoptosis and JNK phosphorylation in BC cells, and may provide a new and potent therapeutic strategy against BC.