Discovery of novel VEGFR-2 inhibitors. Part II: Biphenyl urea incorporated with salicylaldoxime

•Discovery of biphenyls incorporating with urea as novel VEGFR-2 inhibitors.•The salicylaldoxime group was introduced and identified as hinge binding fragment.•A pseudo six-membered ring was formed through intramolecular hydrogen bond.

A series of novel VEGFR-2 inhibitors containing oxime as hinge binding fragment were described. A strategy of pseudo six-membered ring formed through intramolecular hydrogen bond was employed to mimic the planar quinazoline. The oxime group was firstly introduced to interact with hinge region of VEGFR-2. Most of compounds tested showed moderate to high VEGFR-2 inhibitory activity. In particular, 12l, 12p and 12y exhibited significant enzymatic inhibitory activity as well as potent antiproliferative activity against cancer cells. Molecular docking suggested that the salicylaldoxime formed two hydrogen bonds with hinge region. These biphenylureas could serve as promising lead compounds for developing novel anticancer agents.

Graphical abstractNovel biphenyl ureas incorporation with salicylaldoxime were synthesized and evaluated for their antitumor activity. Most of them exhibited potent VEGFR-2 inhibitory activity comparable to that of positive control.Figure optionsDownload full-size imageDownload as PowerPoint slide