The role of SIRT-1 in various physiological processes, such as ageing and metabolism, has garnered significant interest in scientific research. The pharmacological activation of SIRT-1 is widely recognized for its health benefits, with plant-derived molecules being key candidates in drug discovery. Pterocarpus santalinus is rich in sesquiterpenes, polyphenols, terpenes, and santalins, which are well-documented for their pharmacological potential. Nevertheless, it has been explored for the first time for neuroprotection and cellular health effects. Here, in an effort to identify SIRT-1 activating molecules from P. santalinus , we isolated sixteen compounds of different classes. The compound 1 is isolated from a natural source for the first time, and the stereochemistry and relative configuration of compound 2 are determined for the first time. Moreover, the compound 7 is reported for the first time in the Pterocarpus genus, with 10 compounds identified for the first time in this species. Compounds (1-6) were characterized as sesquiterpenoids sharing a similar skeleton but with distinct stereochemical features. Further (1-6) were investigated for cytotoxicity study in cultured astrocytes, confirming their safety up to 100 µM. Additionally, live-cell analysis revealed significant improvement in cellular processes, such as an increase in lysosomal pH and mitochondrial membrane potential. In vitro , western blot analyses showed significant upregulation of SIRT-1 and SIRT-2. Additionally, p-AMPK, LC3-1/2 and SOD-2, known for regulating energy homeostasis and antioxidant machinery, were also upregulated. Further, in silico studies indicated a strong binding affinity of (1-6) with the active site of human SIRT-1, linked with the cellular health benefits of sesquiterpenes. The findings of this study identified sesquiterpenoids of P. santalinus as potent SIRT-1 activators with improved cellular health effects through in-silico binding affinity and in vitro analysis, offering the potential for further exploration in anti-aging and neuroprotective metabolic research.
Lone et al. (Sun,) studied this question.