Sirtuin 1-Activating Compounds: Discovery of a Class of Thiazole-Based Derivatives

Abstract

Sirtuin 1 (SIRT1) is a NAD+-dependent deacetylase implicated in various biological and pathological processes, including cancer, diabetes, and cardiovascular diseases. In recent years, SIRT1-activating compounds have been demonstrated to exert cardioprotective effects. Therefore, this enzyme has become a feasible target to treat cardiovascular diseases, and many SIRT1 activators, of a natural or synthetic origin, have been identified. In the present work, we developed thiazole-based SIRT1 activators, which showed remarkably higher SIRT1 activation potencies compared with those of the reference compound resveratrol when tested in enzymatic assays. Thiazole 8, a representative compound of this series, was also subjected to further pharmacological investigations, where it was proven to reduce myocardial damage induced by an in vivo occlusion/reperfusion event, thus confirming its cardioprotective properties. In addition, the cardioprotective effect of compound 8 was significantly higher than that of resveratrol. Molecular modeling studies suggest the binding mode of these derivatives within SIRT1 in the presence of the p53-AMC peptide. These promising results could pave the way to further expand and optimize this chemical class of new and potent SIRT1 activators as potential cardioprotective agents.

Resveratrol-like Compounds as SIRT1 Activators

“…In the cell-free assay, resveratrol (Resv, 100 µM) was used as a reference activator (positive control) [ 12 , 43 , 50 ] while sirtinol (Sirt, 10 µM) as a known sirtuin inhibitor (negative control). The effects of the screened compounds on isolated SIRT1 enzyme activity were evaluated as a percentage of SIRT1 activation.…”

Sirtuin 1-activating derivatives belonging to the anilinopyridine class displaying in vivo cardioprotective activities

“…In this direction, several SIRT1-activators have been developed by us and other groups, demonstrating interesting cardioprotective profiles against IR injury in in vivo and ex vivo models. 14,15 In this regard, recently we published two papers in which, starting from the stilbenic structure of resveratrol, thiazole-derivatives were obtained and were demonstrated to have promising SIRT1-activating activities in occlusion/reperfusion models. 14,15…”

“…14,15 In this regard, recently we published two papers in which, starting from the stilbenic structure of resveratrol, thiazole-derivatives were obtained and were demonstrated to have promising SIRT1-activating activities in occlusion/reperfusion models. 14,15…”

“…1) predicted in our previous study. 14 The docking calculations were performed with GOLD software, using the GoldScore fitness function. The ligand was subjected to two different docking studies related to the two different receptor sub-sites (Fig.…”

“…1), which showed very promising results in IR models. [13][14][15] Considering our previously published series of SIRT1 activators (compounds 6 and 7 are the most representative examples), 14,15 we were intrigued by the possibility of substituting the central phenyl or thiazole portions with pyridine rings, varying the position of the nitrogen atom with respect to the double phenolic substitution, considering that pyridine moieties are often used in drug candidates thanks to their favourable features such as basicity, water solubility, and hydrogen bond-forming ability. 16 In this context, we synthesized four new subclasses of compounds belonging to four different scaffolds (scaffolds 1-4, Fig.…”