Authors
Jialun Zou, Feng Gao, Yilin Luo, Xinyue Bai, Yuan Ru, Wanyi Cen, Mengdi Lv, Jia Wang, Ning Zhang, Qianqian Hu, Xiaolong Liu
Published in
Journal of medicinal chemistry. Volume 69. Issue 21. Pages 25181-25202. Nov 12, 2026.
Abstract
Ischemic stroke (IS) is a major public health burden due to its high mortality and disability rates. Neuroinflammation and ferroptosis are two key drivers of IS progression. α-Lipoic acid (ALA) exhibits both anti-ferroptosis and anti-inflammatory activities; however, its anti-ferroptosis efficacy is suboptimal. In this study, we designed and synthesized 23 ALA derivatives. Among them, D14 exhibited the most potent anti-ferroptosis activity, with an EC50 value of 0.00247 μM, an approximately 16,000-fold improvement over ALA, while retaining comparable anti-inflammatory activity (IC50 = 13.6 μM). Mechanistically, D14 scavenged free radicals and activated the Nrf2/GPX4 pathway to restore GSH levels and reduce MDA, Fe2+, and ROS accumulation, thereby inhibiting ferroptosis. D14 also suppressed NF-κB activation by preventing IκBα degradation and p65 phosphorylation, and it reduced IL-1β, IL-6, and TNF-α secretion. In a rat middle cerebral artery occlusion (MCAO) model, D14 reduced cerebral infarct volume and ameliorated neurological deficits, surpassing ALA and the clinically used drug edaravone. Preliminary toxicity evaluation of D14 indicated a favorable safety profile. Overall, D14 is a promising multi-target lead compound for the treatment of IS.
PMID:
43018563
Bibliographic data and abstract were imported from PubMed on 12 Nov 2026.
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