Novel 1,2,3-Triazole-Coumarin Hybrid Glycosides and Their Tetrazolyl Analogues: Design, Anticancer Evaluation and Molecular Docking Targeting EGFR, VEGFR-2 and CDK-2

This study represents the design and synthesis of a new set of triazole-coumarin-glycosyl hybrids and their tetrazole hybrid analogues possessing various sugar moieties and modified analogues. All the newly synthesized derivatives were screened for their cytotoxic activities against a panel of human cancer cell lines. The coumarin derivatives 10, 13 and 15 derivatives revealed potent cytotoxic activities against Paca-2, Mel-501, PC-3 and A-375 cancer cell lines. These promising analogues were further examined for their inhibitory assessment against EGFR, VEGFR-2 and CDK-2/cyclin A2 kinases. The coumarin-tetrazole 10 displayed broad superior inhibitory activity against all screened enzymes compared with the reference drugs, erlotinib, sorafenib and roscovitine, respectively. The impact of coumarin-tetrazole 10 upon cell cycle and apoptosis induction was determined to detect its mechanism of action. Additionally, it upregulated the levels of casp-3, casp-7 and cytochrome-c proteins and downregulated the PD-1 level. Finally, molecular docking study was simulated to afford better rationalization and gain insight into the binding affinity between the promising derivatives and their targeted enzymes, which could be used as an optimum lead for further modification in the anticancer field.

Automated summary

This study focuses on the design and synthesis of new triazole-coumarin-glycosyl hybrids and their tetrazole analogues for cancer treatment. The synthesized derivatives showed promising cytotoxic activity against various cancer cell lines and strong inhibitory activity against certain kinases. Furthermore, the mechanism of action was investigated, revealing an upregulation of certain proteins and downregulation of another protein. Molecular docking study provided insights into the binding affinity between the derivatives and the targeted enzymes, suggesting potential for further modification as anticancer lead compounds.