Design, Synthesis, and Evaluation of Halo‐Substituted Flavonols Against Melanoma A375 Cells

Malignant melanoma is one of the most aggressive forms of skin cancer. Despite advances in targeted therapy and immunotherapy, the emergence of drug resistance and limited therapeutic efficacy in advanced stages remain major clinical challenges. In this study, a series of novel flavonols were synthesized and evaluated for their cytotoxic activity against human malignant melanoma A375 cells. Among the tested compounds, compound 4j exhibited the most potent inhibitory effect, with an IC 50 value of 25.07 ± 2.24 μM, outperforming 5‐fluorouracil (5‐FU) used as a positive control. Furthermore, Western blot analysis revealed that compound 4j modulated the expression of key apoptotic regulators: it downregulated the anti‐apoptotic protein Bcl‐2, upregulated the pro‐apoptotic protein Bax, and activated caspase‐3, indicating induction of apoptosis via a caspase‐dependent mitochondrial pathway. Molecular docking analysis further showed that the halogenated derivatives exhibited distinct interaction patterns within the Bcl‐2 binding groove, supporting the observed positional structure–activity relationship. These findings demonstrate that compound 4j possesses promising anticancer activity against malignant melanoma cells. They support flavonols as valuable scaffolds for the development of new anti‐melanoma agents, with compound 4j emerging as a particularly compelling lead candidate.