Aim: A fragment-based design and synthesis of three novel series of aminopyridone-linked benzimidazoles as potential anticancer candidates with significant CDK9 inhibition was implemented. Materials & methods: All synthesized compounds were submitted to National Cancer Institute, 60 cell lines and seven-dose cytotoxicity toward three cancer cells. Results: Compounds 2, 4a, 4c, 4d, 6a and 8a exhibited significant cytotoxicity and selectivity with IC50 range of 7.61-57.75 μM. Regarding the mechanism either in vitro or in silico, 4a, 6a and 8a displayed potent CDK9 inhibition with IC50 value of 0.424-8.461 μM. Compound 6a arrested the cell cycle at S phase and induced apoptosis in MCF-7 cells. Conclusion: Compound 6a is a promising CDK9 inhibitor that warrants additional research for cancer treatment.
Keywords: CDK9; aminopyridone; apoptosis; benzimidazole; cancer; cell cycle; docking; drug discovery; fragment-based design; synthesis.