Design, synthesis and biological evaluation of novel benzo-α-pyrone containing piperazine derivatives as potential BRAFV600E inhibitors

Virtual screening and scaffold growth were combined together to achieve a series of novel compounds (3a-3n) bearing the benzo-α-pyrone scaffold. Among them, compound 3l showed most powerful antiproliferative activity (IC50 = 2.24 μM for A375 and IC50 = 1.35 μM for WM266-4) and enzyme inhibition activity (IC50 = 0.37 μM). 3l could effectively cause melanoma cells apoptosis in a dose-dependent manner, significantly induce DNA fragmentation and arrest cell cycle at the G0/G1 phase. Docking simulation was performed to explore the binding model of compound 3l with BRAFV600E.74