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

摘要

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 50 = 0.16–34.13?μM). The drug-likeness study revealed that all the new compounds conform to Lipinski’s rule. Mechanistic studies of compounds 18?b , 19a , and 20a revealed the induction of apoptosis and cell cycle arrest at the G 1 phase in MCF-7 cells. The three compounds also displayed potent inhibitory activity against CDK-2 (IC 50 = 25.53–115.30?nM). Moreover, the docking study revealed a nice fitting of compound 19a into the active sites of CDK-2/6/9. These preliminary results suggested that compound 19a could serve as a promising scaffold in the discovery of new potent anticancer agents. Graphical Highlights Virtual screening of 1302 pyrrolizines was done using the pharmacophore model of the multi-CDKI 3 . The top-scoring hits were synthesised and evaluated for their cytotoxic activities. Compound 19a showed potent in?vitro cytotoxic activity against CDK-2. Compound 19a induced apoptosis and cell cycle arrest at the G 1 phase in MCF-7 cells. The docking study revealed nice fitting of compound 19a into CDK-2/6/9 with high binding affinities.