Novel pyrrolizines bearing 3,4,5-trimethoxyphenyl moiety: design, synthesis, molecular docking, and biological evaluation as potential multi-target cytotoxic agents

In the present study, two new series of pyrrolizines bearing 3,4,5-trimethoxyphenyl moiety were designed, synthesised, and evaluated for their cytotoxic activity. The benzamide derivatives 16a–e showed higher cytotoxicity than corresponding Schiff bases 15a–e. Compounds 16a,b,d also inhibited growth MCF-7/ADR cells with IC50 in range 0.52–6.26 ?M. Interestingly, compounds less against normal MRC-5 (IC50=0.155–17.08 ?M). Mechanistic studies revealed ability to inhibit tubulin polymerisation multiple oncogenic kinases. Moreover, induced preG1 G2/M cell cycle arrest early apoptosis MCF-7 cells. molecular docking analyses into active site tubulin, CDK-2, EGFR proteins binding affinities compared co-crystallised ligands. These preliminary results suggested that could serve as promising lead future development potent anticancer agents.HighlightsTwo moieties synthesized.Compounds displayed highest three cancer lines.Kinase profiling test inhibition kinases by 16a,b,d.Compounds exhibited weak moderate tubulin-polymerization.Compounds cells.Docking high 16a,b towards CDK-2.