Synthesis, anticancer activity and computational studies of new benzimidazole-triazole-pyridine glycoside conjugates

The discovery of novel compounds as potential cancer drug candidates has garnered significant interest and widespread attention.
A novel series of benzimidazole-1,2,3-triazole-pyridine-glycosyl hybrids was rationally designed and synthesized to explore their potential anticancer activity.
The targeted compounds were achieved via click chemistry. The acetylated N1-glycosyl-1,2,3-triazoles were deprotected, producing the free hydroxy glycosides. Their cytotoxicity was evaluated against human colorectal (HCT-116), hepatic (HepG-2), and breast (MCF-7) cancers. Molecular docking and dynamics, in addition to Density functional theory (DFT) calculations, were studied.
Glycosyl-1,2,3-triazoles 15 and 17 exhibited the highest cytotoxic activity among the tested compounds, while others demonstrated selective efficacy against specific cancer cell lines. Notably, compound 17 showed a 1.808-fold increase in cytotoxicity compared to doxorubicin when tested on MCF-7 breast cancer cells (IC50 = 33.32 µM). Molecular docking studies with the epidermal growth factor receptor (EGFR) indicated favorable-binding interactions and potential inhibitory effects. Molecular dynamics further confirmed the stable integration of 17 within the EGFR active site, preserving the structural integrity of its catalytic domain. DFT calculations provided insights into the electronic structure, molecular orbitals, and electrostatic potential of compound 17.