Design, synthesis, anticancer estimation, and computational studies of novel benzochromenoimidazopyrimidines as CDK-2 inhibitors and apoptosis stimulators.

Adopting both molecular hybridization and substituent variation strategies, a novel set of benzochromenoimidazopyrimidines with expected cyclin-dependent kinase 2 (CDK-2) inhibition potential was designed and synthesized. The NCI evaluated all novel hybrids in the 60 cell line panel, where five derivatives 6b, 6d, 6e, 6f, and 6 g showed superior activity. The most active hybrids were assessed for the five-dose cytotoxicity toward the most sensitive NCI cancer cells EKVX, UACC-62, and HS 578 T in addition to healthy cells (WI-38). Among the tested analogs, 6e, 6f, and 6 g exerted promising cytotoxicity toward HS 578 T cells where compound 6f exhibited significant antiproliferative activity with an IC50 of 3.06 µM, exceeding that of Lapatinib by 7.6 fold. It also displayed a superior selectivity index (8.49) toward HS 578 T cells that is greater than that of Lapatinib by 7.08 fold. Additional tests have been done on these hybrids to ascertain their precise mechanism of action. Hence, CDK-2 inhibition, apoptosis assay, and cell cycle analysis for the superior analogs were estimated. The findings illustrated that analog 6f exerted the most potent CDK-2 inhibition with an IC50 equal to 0.277 µM, which is approximately threefold the activity of Roscovitine (0.833 µM). As well, compound 6f arrested HS 578 T cell cycle at both S and G2/M phases and stimulated apoptosis by increasing Bax and Caspase-3 expression with a concurrent decline in the expression of Bcl-2. Additionally, ADMET prediction and the binding interaction of the most active derivatives with CDK-2 have been studied in silico to evaluate their potential as important antitumor agents.