ABSTRACT Background Parkinson's disease (PD) is a neurodegenerative disease closely related to neuroinflammation and with obvious age characteristics. Existing therapeutic drugs have problems such as insufficient efficacy and side effects. Cycloastragenol (CAG) is a known natural telomerase activator, and previous studies have found that it has a good improvement effect on PD. As a lead compound, there is significant room for improvement in pharmacological activity. Therefore, we further explore safe and efficient small molecules for PD drug exploration through structural optimization. Methods We introduced carboxylic acid small molecules into the CAG structure and evaluated the pharmacological effects of the derivatives using a PD in vitro model and a neuroinflammatory model. The structure–activity relationship analysis was used to screen the derivatives with the best activity for subsequent in vivo animal experiments. Utilize metabolomics and subsequent validation experiments to elucidate the potential mechanisms by which the derivatives exert their effects. Result We screened and obtained compound R2 from 29 derivatives, which can significantly enhance anti‐inflammatory activity and cell protection. In the MPTP induced PD mouse model, R2 can improve motor dysfunction, restore the number of TH positive neurons in the substantia nigra, and reduce inflammation levels in brain tissue and serum. Metabolomics analysis showed that R2 intervenes in PD progression by regulating the tyrosine metabolism pathway, and further validated the mechanism of compound R2 around the TLR4/NF‐κB/TERT signaling pathway. This study provides a new strategy for the development of anti PD drugs based on CAG, while expanding the potential application of carboxylic acid modification in natural product structure optimization. Conclusions This study focuses on the potential mechanism of CAG derivative R2 in treating PD through “inflammation‐aging” research. By inhibiting inflammation and restoring telomerase activity, it breaks the vicious cycle and provides new ideas for the treatment of PD, laying a foundation for the development of drugs using CAG for PD.
Xiao et al. (Sun,) studied this question.