Sirtuin proteins (SIRTs) are histone deacetylases (HDACs) involved in cellular processes such as gene transcription and cell cycle regulation. Recently, their chemical modulation was found to be beneficial against aging-related and neglected tropical diseases. In this manuscript, computational tools coupled with enzymatic and cellular assays provided (i) new insight on SIRT structures, describing for the first time the structural features of the SIRT2-c-Src complex; (ii) novel compounds with therapeutic potential able to inhibit SIRT activities.