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

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.