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

Abstract

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 IC50 values of 12.1, 40.3, 15.5, 13.1 and 57.4 nM, respectively, superior to that of the reference drug sorafenib (IC50 78.9 nM). Additionally, the quinazoline 2-carboxylate derivative bearing a fluorine substituent in middle ring (7a) showed IC50 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.