Scaffold hopping and redesign approaches for quinazoline based urea derivatives as potent VEGFR-2 inhibitors.

Scaffold hopping was applied to design quinazoline-based derivatives featuring ester (4a-j) , (6a-e), (7a,b) and amide (5a-j) moieties linked to biarylurea motif (DFG anchoring motif) as potent VEGFR-2 inhibitors. Compounds (5d, 5e, 5h, 5i, 7a and 7b) exhibited nanomolar VEGFR-2 inhibition. • Twenty seven novel quinazoline derivatives were designed, synthesized and biologically evaluated. • Inhibitory activities of all derivatives were evaluated toward VEGFR-2 kinase at 10 μM concentration. • Calculate the IC 50 values for the promising candidates, which exhibited VEGFR-2 inhibition percent above 90%. • In-vitro antiproliferative activity assay against NCI 60-cell line panel. • Docking study and Field alignment technique were performed to interpret and understand the biological evaluation results. In our attempt to discover effective anticancer agents, three series of novel quinazoline-based compounds have been designed, synthesized and tested as VEGFR-2 inhibitors. Five quinazoline −2-carboxamide derivatives (5d, 5e, 5 h, 5i, 5j) revealed potent nanomolar VEGFR-2 inhibition with IC 50 values of 12.1, 40.3, 15.5, 13.1 and 57.4 nM, respectively, superior to that of the reference drug sorafenib (IC 50 78.9 nM). Additionally, the quinazoline 2-carboxylate derivative bearing a fluorine substituent in middle ring (7a) showed IC 50 values of 14.8 nM. Most of the new synthesized compounds are examined on NCI sixty cell lines of human cancer cells. Furthermore, molecular modeling study was administered to realize any clarification of the binding mode in the inactive VEGFR-2 conformation that demonstrates compatible binding modes similar to those of sorafenib and regorafenib. Finally, several ADME descriptors were calculated through a predictive kinetic study. [ABSTRACT FROM AUTHOR]