2. Academic Validation
  3. Design, synthesis and biological evaluation of N-salicyloyl tryptamine derivatives as multifunctional neuroprotectants for the treatment of ischemic stroke

Design, synthesis and biological evaluation of N-salicyloyl tryptamine derivatives as multifunctional neuroprotectants for the treatment of ischemic stroke

  • Eur J Med Chem. 2024 Nov 15:278:116795. doi: 10.1016/j.ejmech.2024.116795.
Genping Wu 1,  Bo Li 1,  Xiuzhen Wei 1,  Yaxin Chen 1,  Yuting Zhao 1,  Yan Peng 1,  Jianhui Su 1,  Zecheng Hu 1,  Linsheng Zhuo 1,  Ying Tian 2,  Zhen Wang 3,  Xue Peng 4
Affiliations

Affiliations

  • 1 The Affiliated Nanhua Hospital, School of Pharmaceutical Science, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China.
  • 2 The Affiliated Nanhua Hospital, School of Pharmaceutical Science, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China. Electronic address: uscty@usc.edu.cn.
  • 3 The Affiliated Nanhua Hospital, School of Pharmaceutical Science, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China; National Health Commission Key Laboratory of Birth Defect Research and Prevention Hunan Provincial Maternal and Child Health Care Hospital, Changsha, Hunan, 410008, China; MOE Key Lab of Rare Pediatric Diseases, School of Life Sciences, Central South University, Changsha, 410000, China. Electronic address: zhenw@usc.edu.cn.
  • 4 The Affiliated Nanhua Hospital, School of Pharmaceutical Science, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China. Electronic address: pengxue@usc.edu.cn.
PMID: 39216381 DOI: 10.1016/j.ejmech.2024.116795
Abstract

Ischemic stroke (IS) is a disease of high death and disability worldwide with few medications in clinical treatment. Neuroinflammation and oxidative stress are considered as crucial factors in the progression of IS. In our previous studies, N-salicyloyl tryptamine derivative (NST) L7 exhibited promising anti-inflammatory properties and is considered a potential clinical therapy for IS but had limited antioxidant capacity. Here, we have designed, synthesized, and biologically evaluated 30 novel NSTs for their neuroprotective effects against cerebral ischemia-reperfusion (CI/R) injury. To identify a multifunctional neuroprotectant with enhanced antioxidant and anti-inflammatory capacity, as well as an effective therapeutic agent for CI/R damage. Among them, M11 exhibited synergistic highly anti-oxidant, anti-inflammatory, anti-ferroptosis, and anti-apoptosis effects and surpassed the parent compound L7. Further studies demonstrated that the synergistic and efficient neuroprotective role of M11 was mainly achieved by activating Nrf2 and stimulating its downstream target HO-1/GCLC/NQO1/GPX4. In addition, M11 possessed good blood-brain barrier permeability. Moreover, M11 effectively reduced cerebral infarct volume and improved neurological deficits in MCAO/R mice. Its hydrochloride form, M11·HCl, exhibited better pharmacokinetic properties, high safety, and a significant reduction in infarct volume, which is comparable to Edaravone. In conclusion, our findings suggested that M11 capable of activating Nrf2, could represent a promising candidate agent for IS.

Keywords

Ferroptosis; Ischemic stroke; N-salicyloyl tryptamine derivatives; Neuroinflammation; Nrf2; Oxidative stress.

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