Design, green synthesis, and anti-glutamate damage screening of chalcone derivatives with spiro-heterocyclic structures as potential anti-ischemic brain and eye damage agents.

Antagonizing excessive glutamate-induced neuroexcitatory toxicity is one of the treatments for brain and retinal nerve damage in ischemic stroke patients. In this work, a series of 3-benzoyl-4-phenyl-spiropyrrolidone (spiroheterocyclic) compounds were designed and synthesized by modifying the Michael receptor of chalcone to reduce its toxicity. Several compounds with superior protective effects on PC12 cells were screened through an experimental model of glutamate-induced damage, and a quantitative evaluation of the structure-activity relationship (QSAR) model with a regression coefficient of R2 = 0.90723 was established through the random forest (RF) algorithm. Among these compounds, E38 significantly increased the survival rate of damaged cells, promoted colony formation, and inhibited LDH release and apoptosis, and the protective effect of E38 was possibly partly through the HO-1/SIRT1 pathway. More importantly, in mice model of middle cerebral artery occlusion (MCAO), E38 decreased cerebral infarct size, improved neurological scores, and mitigated retinal damage. In conclusion, this work presents a novel class of chalcone derivatives with neuroprotective activity and offers potential compounds for the treatment of ischemic stroke.