Abstract

Liver cancer remains a major global health challenge, necessitating the development of new therapeutic agents. In this study, a series of 1,2,4,5-tetrasubstituted imidazole derivatives were synthesized via a green, one-pot four-component reaction using the recyclable deep eutectic solvent [Bet]₂[PTSA] under solvent-free conditions, affording high yields. Among them, compounds 16d, 16j, and 16n exhibited notable cytotoxicity against HepG2 cells, with 16n showing the strongest activity (IC₅₀ = 32.54 µM), outperforming camptothecin. Molecular docking and dynamics simulations revealed strong and stable binding of 16n to GLUT1, involving key residues such as Trp388, Asn288, and Trp412. Structure-activity relationship (SAR) analysis indicated that phenolic hydroxyl and para-methoxy substituents enhance anticancer activity. These results identify compound 16n as a promising lead for targeted liver cancer therapy.