DOI: 10.4155/fmc-2023-0139 ISSN:

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

Ebtehal M Husseiny, Hamada S Abulkhair, Sanadelaslam SA El-Hddad, Nada Osama, Mona S El-Zoghbi
  • Drug Discovery
  • Pharmacology
  • Molecular Medicine

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.

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