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, -salicyloyl tryptamine derivative (NST) 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, exhibited synergistic highly anti-oxidant, anti-inflammatory, anti-ferroptosis, and anti-apoptosis effects and surpassed the parent compound . Further studies demonstrated that the synergistic and efficient neuroprotective role of was mainly achieved by activating Nrf2 and stimulating its downstream target HO-1/GCLC/NQO1/GPX4. In addition, possessed good blood-brain barrier permeability. Moreover, effectively reduced cerebral infarct volume and improved neurological deficits in MCAO/R mice. Its hydrochloride form, , exhibited better pharmacokinetic properties, high safety, and a significant reduction in infarct volume, which is comparable to Edaravone. In conclusion, our findings suggested that capable of activating Nrf2, could represent a promising candidate agent for IS.

中文翻译：

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N-水杨酰色胺衍生物作为治疗缺血性中风的多功能神经保护剂的设计、合成和生物学评价


缺血性中风（IS）是一种全球死亡率和致残率较高的疾病，临床治疗药物很少。神经炎症和氧化应激被认为是 IS 进展的关键因素。在我们之前的研究中，β-水杨酰色胺衍生物（NST）表现出有前景的抗炎特性，被认为是一种潜在的 IS 临床治疗方法，但抗氧化能力有限。在这里，我们设计、合成了 30 种新型 NST，并对其对脑缺血再灌注 (CI/R) 损伤的神经保护作用进行了生物学评估。寻找一种具有增强抗氧化和抗炎能力的多功能神经保护剂，以及一种有效治疗 CI/R 损伤的药物。其中，表现出协同的高度抗氧化、抗炎、抗铁死亡和抗细胞凋亡作用，并超越了母体化合物。进一步研究表明，协同高效的神经保护作用主要是通过激活Nrf2并刺激其下游靶点HO-1/GCLC/NQO1/GPX4来实现的。此外，还具有良好的血脑屏障通透性。此外，有效减少MCAO/R小鼠的脑梗塞体积并改善神经功能缺损。其盐酸盐形式表现出更好的药代动力学特性，安全性高，并且能显着减少梗塞体积，与依达拉奉相当。总之，我们的研究结果表明，能够激活 Nrf2，可能是一种有前途的 IS 候选药物。