Design, Green Synthesis of Piperlongumine Analogs and Their Antioxidant Activity against Cerebral Ischemia-reperfusion Injury.

The supplementation of exogenous antioxidants to scavenge excessive reactive oxygen species (ROS) is an effective treatment for cerebral ischemia reperfusion injury (CIRI). Piperlongumine (PL) is a kind of natural product which has a great potential as neuroprotective agents, but it also has obvious neurotoxicity. Moreover, its neuroprotective effects remain to be improved. In this study, a series of novel PL analogs were designed on the foundation of the screened low-toxic diketene skeleton with antioxidation and the 3,4,5-trimethoxyphenyl group, which maybe increase the antioxidant activity of PL. The cytotoxicity and activity tests on a series of PL analogs which were synthesized by a novel green synthesis method indicated that all of these compounds without obvious toxicity have remarkable antioxidant effects, especially compared with diketene skeletons and PL. The cytoprotection of the active compound also decreased significantly when the carbon-carbon double bonds of the molecular skeleton were reduced. More importantly, further study revealed that compound A9 which has the best activity can confer protection for cells against oxidative stress and attenuate brain injury in rats. Overall, our findings would provide a promising drug candidate for the treatment of CIRI and guide the further development of drug research in oxidative stress-mediated diseases.