Novel flavonoid 1,3,4-oxadiazole derivatives ameliorate MPTP-induced Parkinson's disease via Nrf2/NF-κB signaling pathway.

Parkinson's disease (PD) is a progressive neurodegenerative disorder with a complex etiology. Neuroinflammation and oxidative stress are important factors driving the progression of PD. It has been reported that 1,3,4-oxadiazole and flavone derivatives have numerous biological functions, especially in the aspect of anti-inflammatory and antioxidant. Based on the strategy of pharmacodynamic combination, we introduced 1,3,4-oxadiazole moiety into the flavonoid backbone, designed and synthesized a series of novel flavonoid 1,3,4-oxadiazole derivatives. Further, we evaluated their toxicity, anti-inflammatory and antioxidant activities using BV2 microglia. Following a comprehensive analysis, compound F12 showed the best pharmacological activity. In vivo, we induced the classical PD animal model by intraperitoneal injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) into C57/BL6J mice. Our results showed that compound F12 ameliorated MPTP-induced dysfunction in mice. Further, compound F12 reduced oxidative stress by promoting the nucleation of nuclear factor erythroid 2-related factor 2 (Nrf2) and decreased the inflammatory response by inhibiting the nuclear translocation of nuclear factor-κB (NF-κB) in vivo and in vitro. Meanwhile, compound F12 inhibited the mitochondrial apoptotic pathway to rescue microglia inflammation-mediated loss of dopaminergic neurons. In conclusion, compound F12 reduced oxidative stress and inflammation and could be as a potential agent for PD treatment.

Design, synthesis, and SAR study of novel flavone 1,2,4-oxadiazole derivatives with anti-inflammatory activities for the treatment of Parkinson's disease.

Inflammation is one of a major feature of Parkinson's disease (PD) which poses a threat to people's health in the world. It has been reported that antioxidation and anti-inflammation have significant effects on the treatment of PD. 1,2,4-oxadiazole and flavone derivatives have remarkable antioxidant and anti-inflammatory activities. In order to find highly effective drugs for PD treatment, based on the remarkable anti-inflammatory and antioxidant activities of the 1,2,4-oxadiazole pharmacophore and the flavonoid pharmacophore, we designed and synthesized a novel series of 3-methyl-8-(3-methyl-1,2,4-oxadiazol-5-yl)-2-phenyl-4H-chromen-4-one derivatives by pharmacophore combination, and evaluated their anti-inflammatory and antioxidation activities for PD treatment. Preliminary structure-activity relationship (SAR) analysis was conducted by their inhibitory activities against reactive oxygen species (ROS) and NO release in LPS-induced BV2 Microglia cells, and the optimal compound Flo8 exhibited the most potent anti-inflammatory and antioxidant activities. Both in vivo and in vitro results showed that Flo8 inhibited neuronal apoptosis by inhibiting inflammatory and apoptotic signaling pathways. In vivo studies also showed that the compound Flo8 ameliorated motor and behavioral deficits and increased serum dopamine levels in MPTP-induced PD model mice. Taken together, this study demonstrated the compound Flo8 could be a promising agent for the treatment of PD.