Benzimidazole Derivatives as Potential CDK2 Inhibitors: Synthesis, Molecular Docking, and Antiproliferative Investigations

Abstract

From numerous threats, malignancies are outstanding as one of the most hazardous diseases facing human life in the current time. Thus, novel medicines that selectively target tumor cells will inevitably add to the therapeutic arsenal already possessed for curing these malignancies. In light of this, the current study strives to create a novel class of small compounds with the advantageous benzimidazole scaffold that may be used as CDK2 inhibitors versus cancer. The synthesized candidates 2a–2c and 4 markedly impeded the development of the four cell lines under investigation with IC₅₀ values of 4.36 ± 0.27 to 11.54 ± 0.29 μM against MCF-7, 9.48 ± 0.28 to 25.94 ± 0.33 μM against HCT-15, 41.76 ± 0.76 to 70.61 ± 1.45 against K-562, and 15.04 ± 0.70 to 32.38 ± 1.13 against HepG2. Moreover, compounds 2a–2c and 4 showed robust CDK2 inhibitory effect (IC₅₀ = 0.76 ± 0.28, 1.26 ± 0.049, 0.84 ± 0.075, and 1.37 ± 0.062 μM, respectively). In order to assess the selectivity towards cancer cells, their cytotoxicity against normal kidney epithelial cells Vero was evaluated. The examined compounds were found to be more selective toward cancer cells when compared to the reference standard (SI = 2.13), and compound 2a demonstrated higher selectivity for the breast cancer MCF-7 cell line with the highest selectivity index (SI = 14.98), followed by compound 2c (SI = 8.42). Ultimately, a molecular docking study was performed to examine the potential binding pattern and interactions of benzimidazole derivatives with CDK2 kinase, suggesting it as an enzymatic target. In the final result, benzimidazole derivatives 2a–2c and 4, especially compound 2a, showed significant anticancer efficacy in addition to their ability to inhibit CDK2.