Improving the Efficacy of Quinolylnitrones for Ischemic Stroke Therapy, QN4 and QN15 as New Neuroprotective Agents after Oxygen-Glucose Deprivation/Reoxygenation-Induced Neuronal Injury.

José M Alonso, Alejandro Escobar-Peso, Israel Fernández, Alberto Alcázar, José Marco-Contelles
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Abstract

In our search for new neuroprotective agents for stroke therapy to improve the pharmacological profile of the compound quinolylnitrone QN23, we have prepared and studied sixteen new, related and easily available quinolylnitrones. As a result, we have identified compounds QN4 and QN15 as promising candidates showing high neuroprotection power in a cellular experimental model of ischemia. Even though they were found to be less active than our current lead compound QN23, QN4 and QN15 provide an improved potency and, particularly for QN4, an expanded range of tolerability and improved solubility compared to the parent compound. A computational DFT-based analysis has been carried out to understand the antioxidant power of quinolylnitrones QN23, QN4 and QN15. Altogether, these results show that subtle, simple modifications of the quinolylnitrone scaffold are tolerated, providing high neuroprotective activity and optimization of the pharmacological potency required for an improved design and future drug developments in the field.

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提高喹诺酮类药物治疗缺血性脑卒中的疗效,QN4和QN15作为氧-糖剥夺/再氧诱导神经元损伤后新的神经保护剂。
为了寻找新的脑卒中治疗神经保护剂,以改善化合物喹酰尼酮QN23的药理特征,我们制备和研究了16种新的、相关的、容易获得的喹酰尼酮。因此,我们已经确定了化合物QN4和QN15作为有希望的候选者,在缺血细胞实验模型中显示出高的神经保护能力。尽管发现它们的活性低于我们目前的先导化合物QN23,但QN4和QN15提供了更好的效力,特别是QN4,与母体化合物相比,耐受性范围扩大,溶解度提高。采用基于dft的计算方法对喹酰亚硝基酮QN23、QN4和QN15的抗氧化能力进行了分析。总之,这些结果表明,对喹啉尼酮支架进行细微的、简单的修饰是耐受的,提供了高神经保护活性,并优化了该领域改进设计和未来药物开发所需的药理学效力。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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