Aminopyridone-linked benzimidazoles: a fragment-based drug design for the development of CDK9 inhibitors.

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 IC 50 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 IC 50 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.