Design, synthesis and biological evaluation of novel benzo-α-pyrone containing piperazine derivatives as potential BRAF(V600E) inhibitors.

Abstract The increasingly acquired resistance to vemurafenib and side effects of known inhibitors motivate the search for new and more effective anti-melanoma drugs. In this Letter, virtual screening and scaffold growth were combined together to achieve new molecules as BRAF V600E inhibitors. Along with docking simulation, a primary screen in vitro was performed to filter the modifications for the lead compound, which was then substituted, synthesized and evaluated for their inhibitory activity against BRAF V600E and several melanoma cell lines. Out of the obtained compounds, derivative 3l was identified as a potent BRAF V600E inhibitor and exerted an anticancer effect through BRAF V600E inhibition. The following biological evaluation assays confirmed that 3l could induce cell apoptosis and marked DNA fragmentation. Furthermore, 3l could arrest the cell cycle at the G0/G1 phase in melanoma cells. The docking simulation displayed that 3l could tightly bind with the crystal structure of BRAF V600E at the active site. Overall, the biological profile of 3l suggests that this compound may be developed as a potential anticancer agent.