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 <b>15</b> and <b>17</b> exhibited the highest cytotoxic activity among the tested compounds, while others demonstrated selective efficacy against specific cancer cell lines. Notably, compound <b>17</b> 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 <b>17</b> 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 <b>17</b>.