Aminopyridone-Linked Benzimidazoles: A Fragment-Based Drug Design for the Development of CDK9 Inhibitors

Abstract

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