Design, Synthesis, and Biological Evaluation of Novel Benzimidazole/Schiff Base Hybrid Derivatives With Potential Biological Activities

A novel series of benzimidazole-based derivatives (5a-g), (6a-b), and (7a-b) were designed, synthesized, and evaluated for their potential as dual inhibitors of EGFR and HER-2. The synthesized compounds were subjected to in vitro screening against a panel of selected human cancer cell lines. Additionally, their cytotoxicity was assessed using normal human mammary epithelial cells (MCF-10A) to evaluate their safety profile. Among the tested derivatives, compounds 5b, 5f, and 6a demonstrated the most pronounced antiproliferative activity, exhibiting IC₅₀ values of 6, 8, and 5 µM, respectively. These values reflect a potency at least fourfold greater than that of the reference drug Doxorubicin (IC₅₀ = 33 µM). EGFR and HER-2 enzyme inhibition assays were conducted to explore the potential molecular targets responsible for the observed anticancer effects. Notably, compound 6a (R₁ = phenyl, thiosemicarbazide) exhibited superior efficacy against the MCF-7 breast cancer cell line, with an IC₅₀ of 5 µM, approximately six times more potent than Doxorubicin. Conversely, compound 7b, with an IC₅₀ value of 85 µM against MCF-7 cells, was the least active, underscoring the critical role of the phenyl moiety in antiproliferative activity. Furthermore, a molecular docking study was conducted to investigate the binding interactions of 6a within the active sites of EGFR and HER-2, providing insight into its potential mechanism of action.