Design, synthesis, and preliminary antitumor mechanism of benzimidazole derivatives

Fourteen novel benzimidazole derivatives were designed, synthesized, and evaluated for their antitumor activities against four human cancer cell lines, A549 (lung carcinoma), 5637 (bladder cancer), PC-3 (prostate cancer), and K562 (chronic myelogenous leukemia- CML), using the MTT assay. Among these, compound
E12
demonstrated the most potent activity against the K562 cells, exhibiting significant growth inhibition with an IC
50
value of 11.07 μM, while demonstrating low toxicity towards the normal HEK-293 (embryonic kidney) cell line, with an IC
50
greater than 40 μM. Flow cytometry analysis revealed that
E12
induced apoptosis, increased reactive oxygen species levels, decreased mitochondrial membrane potential, and caused cell cycle arrest at the G2/M phase. Additionally, western blot analysis showed that
E12
effectively inhibited BCR-ABL expression, upregulated Bax expression, and downregulated Cyclin B1 and CDK-1 expression to induce apoptosis. Molecular docking results also showed that compound
E12
had a strong binding ability with the BCR-ABL protein, and the binding energy was -9.3 kcal/mol. These findings suggest that
E12
is a promising candidate for further development as an anti-chronic myeloid leukemia drug.