Pharmacophore-based virtual screening, synthesis, biological evaluation, and molecular docking study of novel pyrrolizines bearing urea/thiourea moieties with potential cytotoxicity and CDK inhibitory activities.

In the current study, virtual screening of a small library of 1302 pyrrolizines bearing urea/thiourea moieties was performed. The top-scoring hits were synthesised and evaluated for their cytotoxicity against three cancer (MCF-7, A2780, and HT29) and one normal (MRC-5) cell lines. The results of the MTT assay revealed potent cytotoxic activities for most of the new compounds (IC = 0.16-34.13 μM). The drug-likeness study revealed that all the new compounds conform to Lipinski's rule. Mechanistic studies of compounds , , and revealed the induction of apoptosis and cell cycle arrest at the G phase in MCF-7 cells. The three compounds also displayed potent inhibitory activity against CDK-2 (IC = 25.53-115.30 nM). Moreover, the docking study revealed a nice fitting of compound into the active sites of CDK-2/6/9. These preliminary results suggested that compound could serve as a promising scaffold in the discovery of new potent anticancer agents.