Design, synthesis, biological evaluation and in silico studies of 2-anilino- 4-(benzimidazol- 1-yl)pyrimidine scaffold as antitumor agents

In an attempt to rationalize the search for new potential Chemotherapeutic agents, a new series of 2-anilinobenzimidazol derivatives with CDK activity have been synthesized. The newly synthesized compounds have been assessed for their cytotoxic effects and CDK activity. These presented compounds showed strong inhibition of cell proliferation in various solid cancer cell lines, suggesting a promising approach for treating malignant tumors. Compounds 4 g, 4j, 4 m, and 4q displayed remarkably strong anticancer potencies against HepG2 cells, with IC₅₀ of 7.59, 8.54, 3.56 and 5.88 µM, respectively, compared to the positive control, DOX (IC₅₀ = 4.50 µM). while compound 4 m, and 4q had the highest anticancer activity against HeLa cells, with an IC₅₀ of 6.39 and 9.71 µM, respectively, compared to the positive control DOX (IC₅₀ = 5.57 µM). On the other hand, comparison of IC₅₀ values against MCF-7 cells revealed that compounds 4 g, 4 m, and 4q showed significant anticancer potency with IC₅₀ of 5.08, 2.18 and 8.19 µM, respectively compared to that of the positive control DOX (IC₅₀ = 4.17 µM). Moreover, compound 4 m and 4q were the most potent CDK9 and CDK12 inhibitors. Furthermore, a molecular docking simulation were performed to explore the ability of compounds 4 m to adopt the common binding pattern of CDK9 and CDK12/T1 inhibitors. In silico ADMET results showed that all compounds have favourable drug-like properties since they met Lipinski's rule of five criteria. Overall, the synthesized anilinopyrimidine derivatives exhibit significant potential as chemotherapeutic agents.