Synthesis, Cytotoxic Evaluation, and Structure-Activity Relationship of Substituted Quinazolinones as Cyclin-Dependent Kinase 9 Inhibitors

Cyclin-dependent kinase 9 (CDK9) plays a critical role in transcriptional elongation, through which short-lived antiapoptotic proteins are overexpressed and make cancer cells resistant to apoptosis. Therefore, CDK9 inhibition depletes antiapoptotic proteins, which in turn leads to the reinstatement of apoptosis in cancer cells. Twenty-seven compounds were synthesized, and their CDK9 inhibitory and cytotoxic activities were evaluated. Compounds 7, 9, and 25 were the most potent CDK9 inhibitors, with IC50 values of 0.115, 0.131, and 0.142 mu M, respectively. The binding modes of these molecules were studied via molecular docking, which shows that they occupy the adenosine triphosphate binding site of CDK9. Of these three molecules, compound 25 shows good drug-like properties, as it does not violate Lipinski's rule of five. In addition, this molecule shows promising ligand and lipophilic efficiency values and is an ideal candidate for further optimization.

Automated summary

Twenty-seven compounds were synthesized and evaluated for their CDK9 inhibitory and cytotoxic activities. Compounds 7, 9, and 25 were identified as the most potent CDK9 inhibitors, with IC50 values of 0.115, 0.131, and 0.142 μM, respectively. Molecular docking studies revealed that these compounds occupy the adenosine triphosphate binding site of CDK9. Compound 25 showed favorable drug-like properties, satisfying Lipinski's rule of five, and exhibited promising ligand and lipophilic efficiency values, making it an ideal candidate for further optimization.