Design, synthesis, and biological evaluation of a multi-layer-linked idebenone derivative targeting mitochondrial dysfunction and neuroinflammation for ischemic stroke.

Ischemic stroke is driven by oxidative stress, mitochondrial dysfunction, and neuroinflammation during ischemia-reperfusion. Although idebenone shows antioxidant potential, its clinical utility is limited by suboptimal efficacy. Here, we report the design, synthesis, and biological evaluation of a novel multi-layer-linked idebenone derivative (compound 8) that incorporates a redox-active pharmacophore into a rigid three-dimensional scaffold. Compound 8 was synthesized via dual Suzuki-Miyaura coupling. Biological studies demonstrated that compound 8 exhibits significantly greater neuroprotective activity than idebenone in glutamate-injured HT22 cells, with reduced cytotoxicity. Mechanistically, compound 8 suppresses mitochondrial reactive oxygen species production, preserves mitochondrial membrane potential, and restores ATP levels. In a mouse model of cerebral ischemia-reperfusion injury, compound 8 markedly reduced infarct volume and improved neurological outcomes. Multi-omics analyses further revealed that compound 8 attenuates neuroinflammation, in part, by inhibiting the SerpinA3N/NF-κB signaling axis and suppressing astrocyte activation. These findings demonstrate that multi-layer molecular engineering of idebenone enhances its pharmacological profile and represents a promising strategy for developing neuroprotective agents targeting mitochondrial dysfunction and neuroinflammation.