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.

Automated summary

Inflammation is a major feature of Parkinson's disease (PD), and antioxidation and anti-inflammation have significant effects for PD treatment. 1,2,4-oxadiazole and flavone derivatives have remarkable antioxidant and anti-inflammatory activities. In this study, a novel series of 3-methyl-8-(3-methyl-1,2,4-oxadiazol-5-yl)-2-phenyl-4H-chromen-4-one derivatives were designed and synthesized. The compound Flo8 showed the most potent anti-inflammatory and antioxidant activities, inhibiting neuronal apoptosis and improving motor and behavioral deficits in PD model mice. Overall, this study highlights Flo8 as a promising agent for PD treatment.