A family of nitrogen-containing heterocycles as sirtuin inhibitors: synthesis and invitro biological evaluation

Sirtuins (SIRTs) are a family of NAD+-dependent deacetylases including seven members, named from SIRT-1 to SIRT-7 and characterized by diverse subcellular localizations and distinct enzymatic activities. The SIRT family is involved in translation, metabolism, and genome stability. Hence, their dysregulation is closely associated with several diseases such as cancer, diabetes, and neurological illnesses. The availability of different X-ray crystallographic structures of SIRT-2−ligand complexes made it possible to build up a structure-based investigation in the hunt for SIRT-2 inhibitors (SIRTIs). A series of in-house pyrazolo[3,4-d]pyrimidine derivatives as a class of SIRT-2 inhibitors were evaluated in silico and in vitro, leading to the identification of two effective compounds, 1 and 2. Then, further modeling studies drove the synthesis of a library of analogue compounds. The identified derivatives have been tested in vitro, and an accurate structure-activity relationship study was carried out. Interestingly, few compounds showed a low micromolar/nanomolar activity towards SIRT-2. The synthesis and the biological results will be discussed.