New benzimidazole-triazole glycoconjugates as anti-cancer agents and EGFR inhibitors

A new series of glycosyl heterocyclic scaffolds, 5a-10b with N-glycosidic linkage, were synthesized, starting with 2-acetyl-1H-benzimidazole as a precursor of the propargyl-derived substrates (2) and (3), which were then converted to the target 1,2,3-triazole glycosides (8a-10b) bearing unprotected hydroxyl groups. The new chemical entities have been assessed for their cytotoxic properties on diverse human Cancer cell lines, namely HepG-2 (human liver Cancer), HCT-116 (human colorectal), and MCF-7 (human breast Cancer), in addition to a human normal cell line (BJ-1), following the LDH assay and with erlotinib and doxorubicin as the standard references. Most of the tested compounds demonstrated potent activity, particularly the triazole glycosides 6b, 7b, 8b, 9a, 9b, 10a, and 10b. Compound 9a was the best against all targeted cell lines, particularly HepG-2 and HCT-116, by IC₅₀ values of 1.64 ± 0.11 and 5.00 ± 0.51 µM, superior to that of erlotinib, IC₅₀ = 2.07 ± 0.07 and 5.14 ± 0.33 µM, respectively. Furthermore, it showed a safe profile against the tested normal cell line BJ-1. The triazole glycosides 8a-10b were investigated to assess their capability to inhibit EGFR. Remarkably, 9a and 9b exhibited noteworthy inhibitory activity against EGFR (IC₅₀ = 0.069 ± 0.003 and 0.075 ± 0.003 µM, respectively) in comparison with erlotinib, the reference drug (0.048 ± 0.002 µM). Molecular docking confirmed these findings, suggesting that the incorporation of the α,β-unsaturated ketone function enhances compounds' stability within the EGFR active site. Thus, these results indicate that compounds 9a and 9b disclosed potential anti-cancer agents targeting EGFR kinase.

1,2,3-Triazole; Anti-cancer; Benzimidazole; Cytotoxicity; EGFR; LDF assay.