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

  • Future Med Chem. 2023 Aug 16. doi: 10.4155/fmc-2023-0139.
Ebtehal M Husseiny  1 ,  Hamada S Abulkhair  2  3 ,  Sanadelaslam Sa El-Hddad  4 ,  Nada Osama  5 ,  Mona S El-Zoghbi  6
Affiliations
  • 1. Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy (Girls), Al-Azhar University, Nasr City, Cairo, 11754, Egypt.
  • 2. Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Al-Azhar University, Nasr City, Cairo, 11884, Egypt.
  • 3. Pharmaceutical Chemistry Department, Faculty of Pharmacy, Horus University - Egypt, New Damietta, 34518, Egypt.
  • 4. Pharmaceutical Chemistry Department, Faculty of Pharmacy, Omar Almukhtar University, Al Bayda, 102345, Libya.
  • 5. Biochemistry Department, Faculty of Pharmacy, Menoufia University, Shibin Elkom, Menoufia, 32511, Egypt.
  • 6. Pharmaceutical Chemistry Department, Faculty of Pharmacy, Menoufia University, Shebin El-Koum, 32511, Egypt.
PMID: 37584185 DOI: 10.4155/fmc-2023-0139
Abstract

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.
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