Synthesis, Biological Evaluation, and Molecular Docking of Benzimidazole‐hydrazone Derivatives as Potential Anticancer Agents Targeting Tyrosine Kinases: Induces G ₀ –G ₁ Phase Arrest in HepG2 Cells

Cancer continues to be a leading cause of morbidity and mortality worldwide, with significant variability in incidence and treatment outcomes. This study investigates novel benzimidazole-hydrazone derivatives aimed at inhibiting receptor tyrosine kinases essential for cancer progression. We synthesized a series of compounds, verifying their structures using IR, NMR, and mass spectral analyses. Biological evaluations assessed cytotoxicity against cancer cell lines (HCT-116, MCF-7, HepG2) alongside a normal cell line (WI-38). Several compounds, particularly 6f and 6h-j, demonstrated potent cytotoxicity, with IC₅₀ values as low as 4.82-10.23 µM against MCF-7 cells, surpassing reference drugs like sorafenib and doxorubicin. Compound 6i exhibited the highest activity against kinases such as EGFR, Her2, and VEGFR2, while cell cycle analysis showed G₀-G₁ phase arrest in HepG2 cells. Apoptotic mechanisms were activated, with significant increases in caspase-3 and BAX levels and decrease in Bcl2. In silico studies indicated strong binding interactions of the compounds with kinases, and pharmacokinetic assessments revealed favorable properties. These findings underscore the potential of benzimidazole-hydrazone derivatives as effective cancer therapeutics, meriting further investigation into their mechanisms and clinical implications.