Synthesis and evaluation of 2-anilinopyrimidines bearing 3-aminopropamides as potential epidermal growth factor receptor inhibitors

•Compounds 12a–i were synthesized and biologically evaluated as EGFR inhibitors.•Compounds 12a–h could be converted to WZ4002 (1) in the presence of arginine.•NO donating compound 12i displayed stronger antiproliferative activity than 12a–h.•12i produced high levels of NO in H1975 cells but not in normal human cells.•12i inhibited the EGFR activation and downstream signaling in H1975 cells.

Novel compounds 12a–i were synthesized and biologically evaluated. Several ones exhibited stronger inhibitory activity than gefitinib against EGFR L858R/T790M and antiproliferative effects on H1975 and HCC827 cells. The 3-aminopropamide in compounds like 12h could be converted to the active acrylamide in the presence of arginine. Importantly, 12h showed improved stability relative to compound 1 whose structure is same to 12h excepting an acrylamide moiety. Interestingly, 12i, a NO donating compound of 12h, showed more potent and selective inhibition than 12h on H1975 cells. Significantly, 12i produced high levels of NO in H1975 cells but not in non-tumorous 16HBE cells, and its inhibition was diminished by NO scavenger. Furthermore, 12i dose-dependently produced inhibitory effects on EGFR downstream signaling in H1975 cells.

Graphical abstractCompound 12h could be converted to the active compound 1 in the presence of arginine and NO donating compound 12i showed more potent and selective antiproliferative effects than 12h.Figure optionsDownload full-size imageDownload as PowerPoint slide