Akademik Veri Yönetim Sistemi
Journal of Molecular Structure, cilt.1374, 2026 (SCI-Expanded, Scopus)
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, novel coumarin-1,2,3-triazole hybrids (5a-e) were synthesized via Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) between alkyne-substituted coumarin derivatives and aryl azides with acceptable yields of 40% to 70%, and their cytotoxicities were evaluated against SH-SY5Y neuroblastoma and HK-2 healthy cells by MTT assays. Compound 5a showed the greatest cytotoxicity against SH-SY5Y cells with an IC50 value of 337.9 µM. In mechanism studies, it was determined that the selected Compound 5a significantly increased intracellular reactive oxygen species (ROS) levels; consequently, cell death occurred predominantly via necrotic pathways. Furthermore, Compounds 5a–e were evaluated for their interactions with EGFR and human DNA topoisomerase I. Among these, Compounds 5c and 5e exhibited favorable binding interactions with EGFR, while Compound 5a showed the strongest interaction with human DNA topoisomerase I and the highest in vitro cytotoxicity. Due to the more promising docking scores and binding energies obtained for EGFR, subsequent molecular dynamics (MD) simulations were focused on this target to prioritize the most relevant interactions. Structure-activity analyses demonstrated that molecular hybridization made significant contributions to biological activity. Collectively, these findings suggest that EGFR inhibition may represent a key mechanistic trigger underlying the oxidative stress and necrotic cell death induced by coumarin-1,2,3-triazole hybrids (5a–e) in SH-SY5Y cells, a conclusion consistent with the refined molecular docking and simulation analyses.