Design, synthesis, and antitumor activity of benzimidazole derivatives as CDK4/6 inhibitors

A series of benzimidazole derivatives were synthesized and characterized using 1H NMR, 13C NMR, HR-MS, FTIR and UV Vis. The cytotoxicity of these compounds was evaluated against various cell lines, including 293T (kidney cell), HeLa (cervical cancer), A498 (kidney cancer), and MDA-MB-321 (breast cancer), using the MTT assay. It was observed that the majority of the benzimidazole derivatives exhibited superior anti-tumor activity compared to Abemaciclib. Among them, compound 9f demonstrated the most potent anti-proliferative activity on the MDA-MB-321 cell line, with an IC50 value of 0.028±0.0016 μM, significantly lower than that of Abemaciclib (IC50=10.36 ± 5.08 μM). Further investigation into the anti-tumor activity of compound 9f revealed its effectiveness in inhibiting not only tumor cell proliferation, migration, and adhesion of tumor cells but also in demonstrating significant inhibitory effects in experiments involving a cell xenograft tumor growth model using MDA-MB-231 cells. Additionally, molecular docking studies provided insights into the mechanism of interaction between compound 9f and the CDK4/6 protein. These findings suggest that compound 9f holds considerable potential for breast cancer treatment and serves as a promising CDK4/6 inhibitors for further research.