The
supplementation of exogenous antioxidants to scavenge excessive
reactive oxygen species (ROS) is an effective treatment for cerebral
ischemia-reperfusion injury (CIRI) in stroke. Piperlongumine (PL),
a natural alkaloid, has a great potential as a neuroprotective agent,
but it also has obvious toxicity. Moreover, its neuroprotective effects
remain to be improved. In this study, we designed a series of novel
PL analogs by hybridizing the screened low-toxicity diketene skeleton
with antioxidant effect and the 3,4,5-trimethoxyphenyl group, which
may increase the antioxidant activity of PL. The intermediate was
synthesized by a novel green synthesis method, and 34 compounds were
obtained. The compounds without obvious cytotoxicity have remarkable
antioxidant effects, especially compared with diketene skeletons and
PL. The cytoprotection of the active compound decreased significantly
by reduction of the carbon–carbon double bonds of the Michael
acceptor in the diketene skeleton. 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 vivo. Overall, this study provided a promising drug
candidate for the treatment of CIRI and guided the further development
of drug research in oxidative stress-mediated diseases.
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