Design, synthesis and biological evaluation of 2-arylbenzo[b]furan-4-vinylcarbonyl derivatives based on Salvianolic acid C as antioxidant neuroprotective agents for the treatment of ischemic stroke.

Ischemic stroke is a globally recognized disease characterized by high mortality and disability rates, with limited clinical treatment options available. The development of neuroprotective agents with antioxidant properties continues to be a focal point of current research. In this study, we designed and synthesized 42 derivatives using α, β-unsaturated carbonyl and 2-arylbenzo[b]furan in Salvianolic acid C as the core skeleton, and evaluated their biological activities. Among these, compound 6p demonstrated notable antioxidant neuroprotective activity and low cytotoxicity. Furthermore, it exhibited the most potent cell protective activity and ROS scavenging capacity in t-BHP-induced PC12 cells. In a rat model of ischemia-reperfusion injury, 6p was found to reduce ROS levels and neuronal apoptosis in brain tissue, enhance neurological function, and decrease the size of cerebral infarction in rats. Additionally, 6p promotes the nuclear translocation of NRF2 and elevates the expression of the antioxidant protein HO-1. Molecular docking results indicated that 6p can bind to key sites within KEAP1 complex. In conclusion, these findings suggest that compound 6p serves as a potential neuroprotective agent for the treatment of ischemic stroke.