Synthesis and antioxidant activity of paeoniflorin derivatives

Paeoniflorin has multiple protective effects on the nervous system. However, its low bioavailability limits the exertion of its efficacy. In this study, a series of esterified derivatives of the alkyl groups of paeoniflorin were designed and synthesized through the strategies of group protection and alkyl acylation. The aim was to enhance the bioavailability of paeoniflorin, thereby improving its antioxidant activity. Through activity screening, we found that 2',6'-Bis-O-o-Fluorobenzoyl- paeoniflorin (15) has good antioxidant activity. It introduces o-fluorobenzoyl groups to the 2' and 6' of paeoniflorin. This group can increase the lipophilicity of the molecule. It also changes the electron cloud distribution of paeoniflorin, making the core hydroxyl group(4-OH) of paeoniflorin's antioxidant function more likely to combine with free radicals, thereby more effectively exerting its antioxidant effect. Detailed SAR studies indicated that derivative 15 exhibited significant antioxidant activity. Compared with paeoniflorin, it not only has better free radical scavenging activities in DPPH (0.739 ± 0.025 μM/L) and ABTS (0.557 ± 0.049 μM/L), but also shows better activity in cell experiments: It has a good cytoprotective effect, can effectively reduce the level of MDA, increase the activity of SOD, and also shows a significant effect in the experiment of ROS clearance. Moreover, it can exert an antioxidant effect by regulating Nrf2.