SIRT2,which is a NAD+(nicotinamide adenine dinucleotide)dependent deacetylase,has been demonstrated to play an important role in the occurrence and development of a variety of diseases such as cancer,ischemia-reperfusion,and neurodegenerative diseases.Small molecule inhibitors of SIRT2 are thought to be potential interfering agents for relevant diseases.Discovery of SIRT2 inhibitors has attracted much attention recently.In this investigation,we adopted a consensus docking/scoring strategy to screen for novel SIRT2 inhibitors.Structural optimization and structure-activity relationship(SAR)analysis were then carried out on highly potent compounds with new scaffolds,which led to the discovery of 2-((5-benzyl-5H-[1,2,4]triazino[5,6-b]indol-3-yl)thio)-N-(naphthalen-1-yl)acetamide(SR86).This compound showed good activity against SIRT2 with an IC50 value of 1.3 μM.SR86 did not exhibit activity against SIRT1 and SIRT3,implying a good selectivity for SIRT2.In in vitro cellular assays,SR86 displayed very good antiviability activity against breast cancer cell line MCF-7.In Western blot assays,SR86 showed considerable activity in blocking the deacetylation of α-tubulin,which is a typical substrate of SIRT2.Collectively,because of the new scaffold structure and good selectivity of SR86,it could serve as a promising lead compound,hence deserving further studies.