2. Academic Validation
  3. Design, synthesis, and biological evaluation of hybrids from both nitrones with eNOS-mimicking activity and selective iNOS inhibitors for the treatment of ischemic stroke

Design, synthesis, and biological evaluation of hybrids from both nitrones with eNOS-mimicking activity and selective iNOS inhibitors for the treatment of ischemic stroke

  • Eur J Med Chem. 2026 Feb 5:303:118428. doi: 10.1016/j.ejmech.2025.118428.
Weijie Jiao 1,  Hui Ye 2,  Duorui Ji 2,  Mengshuang Huang 2,  Ruichen Li 3,  Jian Jia 2,  Bowen Wang 2,  Shurui Wang 4,  Zhen Lei 4,  Nan Qin 4,  Hong Wu 4,  Xiaokun Li 3,  Guiyue Wu 4,  Yinglin Cui 4,  Yihua Zhang 2,  Jianbing Wu 2,  Zhangjian Huang 5
Affiliations

Affiliations

  • 1 State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 211198, PR China; Henan Province Hospital of Traditional Chinese Medicine, The Second Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, 450002, PR China.
  • 2 State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 211198, PR China.
  • 3 Xinxiang Municipal Hospital of Traditional Chinese Medicine, Xinxiang, 453000, PR China.
  • 4 Henan Province Hospital of Traditional Chinese Medicine, The Second Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, 450002, PR China.
  • 5 State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 211198, PR China; School of Pharmacy, Xinjiang Key Laboratory of Biopharmaceuticals and Medical Devices, Key Laboratory of Active Components of Xinjiang Natural Medicine and Drug Release Technology, Engineering Research Center of Xinjiang and Central Asian Medicine Resources, Xinjiang Medical University, Urumqi, 830054, PR China. Electronic address: zhangjianhuang@cpu.edu.cn.
PMID: 41386204 DOI: 10.1016/j.ejmech.2025.118428
Abstract

Ischemic stroke (IS) involves complex pathologies such as excitotoxicity, oxidative stress, and inflammation. Targeting inducible nitric oxide synthase (iNOS) which produces damaging levels of NO, while sparing neuroprotective endothelial NOS (eNOS) activity, represents a promising therapeutic strategy. We designed and synthesized a series of hybrids from both nitrones with eNOS-mimicking activity and iNOS inhibitors. Among them, compound 13h exhibited selectivity for iNOS (49.2- and 43.3-fold selectivity over nNOS and eNOS, respectively). And 13h demonstrated significant neuroprotective effects across multiple in vitro models, including oxygen-glucose deprivation/reoxygenation (OGD/R) and H2O2-induced damage in neuronal and endothelial cells. In a transient middle cerebral artery occlusion (tMCAO) rat model, 13h (30 mg/kg, i.v.) markedly reduced cerebral infarction volume (>80 %) and improved neurological function. Mechanistic studies suggest its efficacy stems from anti-oxidant, selective iNOS inhibition, and 3-nitrotyrosine (3-NT) suppression activities. Thus, 13h serves as a novel compound with a multi-target activity against IS.

Keywords

Ischemic stroke; Multi-target; Neuroprotection; Nitric oxide; Nitrone; iNOS.

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