Design, Synthesis, and Anticancer Activity of Novel Coumarin-1,2,3-triazole Hybrids: ROS-Mediated Cytotoxicity and Structure-Activity Relationships Studies

Abstract

Coumarin-triazole hybrid systems are among the molecules that attract attention in anticancer drug development studies due to their biological activities and facile derivatization. However, the developments in the potential of these compounds by adding different substituents and testing their biological activities are still a necessity. In this study, coumarin-based compounds were hybridized with 1,2,3-triazole groups with different substituents using click chemistry, and the synthesized compounds were tested for their anti-cancer activities in the human neuroblastoma SH-SY5Y cells. As a result of the experiments, it was observed that Compound 5a showed a significant cytotoxic effect on SH-SY5Y cells. In mechanism studies, it was determined that the selected compounds significantly increased intracellular reactive oxygen species (ROS) levels; consequently, cell death occurred predominantly via necrotic pathways. Furthermore, clonogenic analyses showed that Compound 5a strongly suppressed the long-term proliferation and colony-forming abilities of the cells. Structure-activity analyses demonstrated that molecular hybridization made significant contributions to biological activity. Compounds 5a–e were evaluated for their interactions with EGFR and human DNA topoisomerase I. The results demonstrated that while Compounds 5c and 5e are promising candidates for EGFR inhibition, Compound 5a emerged as the most prominent compound, showing both the strongest interaction with human DNA topoisomerase I and the highest in vitro cytotoxicity.