Design, synthesis, and molecular docking of triazole-coumarin hybrids as potent breast cancer inhibitors targeting cell cycle and apoptosis

Abstract

Breast cancer continues to pose a significant global health burden, highlighting the urgent need for novel chemotherapeutic agents with improved selectivity and reduced toxicity. In this study, we rationally designed and synthesized six novel amide-bridged triazole-coumarin hybrids (5a–f) based on the known anticancer potential of both pharmacophores. The synthesized compounds were evaluated for their cytotoxicity in MCF-7 and MDA─MB─231 breast cancer cell lines and non-tumorigenic MCF-10A cells. Among them, derivative 5f showed the most potent anticancer activity with minimal toxicity toward normal cells. Mechanistic studies revealed that 5f induced apoptosis by modulating Bax and Bcl─2 expression and arrested the cell cycle at the S phase via downregulation of CDK2 and Cyclin E. Molecular docking analyses confirmed its high binding affinity to CDK2 and Bcl─2, supporting its potential as a dual-target inhibitor. These findings suggest that compound 5f is a promising lead structure for the development of selective anticancer agents targeting breast cancer.