Discovery of a novel idebenone-rhein hybrid 4c with enhanced NQO1 expression for neuroprotection against cerebral ischemia-reperfusion injury.

Authors

Zheyi Wang, Yize Sun, Zetai Bai, Liying Meng, Mei Li, Jianwei Lou, Chuanzhu Yan, Guanzhao Wu

Published in

European journal of medicinal chemistry. Volume 318. Pages 119209. Aug 03, 2026. Epub Aug 03, 2026.

Abstract

Cerebral ischemia-reperfusion (I/R) injury remains a major therapeutic challenge due to excessive mitochondrial oxidative stress and limited neuroprotective interventions. Although idebenone exhibits mitochondrial protective activity, its efficacy is strongly dependent on NAD(P)H:quinone oxidoreductase 1 (NQO1), whose expression is often heterogeneous and insufficient in neuronal tissues. To address this limitation, we designed and synthesized a series of novel idebenone-rhein conjugates (4a-4f) that integrate the mitochondrial electron-transfer capability of idebenone with the antioxidant and NQO1-inducing properties of rhein. Among these derivatives, compound 4c demonstrated the most potent neuroprotective activity against glutamate-induced excitotoxicity in HT22 hippocampal neurons, exhibiting an EC₅₀ of 0.75 μM, markedly superior to idebenone (EC₅₀ = 3.11 μM). Molecular docking predicted a favorable docking score of 4c toward NQO1 (-10.8 kcal/mol), supporting a possible ligand-NQO1 interaction. Mechanistic investigations showed that 4c attenuated mitochondrial oxidative stress by reducing mitochondrial reactive oxygen species, restoring ATP production, preserving mitochondrial membrane potential, and enhancing mitochondrial integrity. Notably, lentiviral NQO1 knockdown experiments demonstrated that 4c retained substantial neuroprotective efficacy under reduced NQO1 expression, unlike idebenone. In a mouse middle cerebral artery occlusion/reperfusion (MCAO/R) model, intraperitoneal administration of 4c significantly reduced infarct volume, improved neurological outcomes, increased hippocampal NQO1 expression. In addition, 4c showed favorable in vitro PAMPA-BBB permeability, and H&E staining of major organs showed no obvious short-term histopathological abnormalities under the present experimental conditions. Collectively, these findings identify 4c as a promising idebenone-rhein conjugate with neuroprotective activity, which may involve NQO1 expression modulation and additional mitochondrial protective mechanisms, highlighting its potential value for further investigation in ischemic stroke and other oxidative stress-related neurological disorders.

PMID:
42556023
Bibliographic data and abstract were imported from PubMed on 06 Aug 2026.

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