Synthesis, target analysis, and cerebroprotective effects of novel imide antioxidants via the Nrf2/HO-1 pathway in cerebral ischemia-reperfusion injury

• DOI: 10.3389/fphar.2025.1552717
• Publication Date: 2025-05-02T11:47:58Z
• Authors: Lili Huang; Yinqi Chen; Hua Zhou; Huihui Chen; Xiping Wu; Zhuochao Wu; Zhoudi Liu; Zhiwei Zheng
• Keywords: Imide

Background Cerebral ischemia-reperfusion injury (CIRI) is a secondary brain that occurs after thrombolysis and primary cause of death in ischemic stroke patients. Antioxidants effectively reduce oxidative stress are an efficient treatment approach for CIRI. Here, novel diimide compound was synthesized using the chemical structure previously designed anti-inflammatory skeletons. Methods results The antioxidant activities five compounds (Z1–Z5) were preliminarily evaluated hydrogen peroxide-induced PC12 cell damage model, which Z3 exhibited best effect, even exceeding positive control (tert-butylhydroquinone). Enrichment analysis network targeting pharmacology methods predicted seven candidate core target genes Of these targets, computer molecular docking has strongest binding affinity nuclear factor erythroid 2-related (Nrf2). MTT colony formation assays, reactive oxygen species analysis, immunofluorescence, immunoblotting experiments verified reduced to play protective role via Nrf2/hemoxygenase 1 (HO-1) pathway. effect vivo explored through TTC staining neurobehavioral scoring CIRI model mice. Conclusion This study provides new drug development strategy CIRI, offering ideas design antioxidants.