Abstract:
NADPH oxidase (NOX2) is responsible for reactive oxygen species (ROS) production in neutrophils and has been recognized as a key mediator in inflammatory and cardiovascular pathologies. Nevertheless, there is a lack of specific NOX2 pharmacological inhibitors. In medicinal chemistry, heterocyclic compounds are essential scaffolds for drug design, and among them, indole is a very versatile pharmacophore. We tested the hypothesis that indole heteroaryl-acrylonitrile derivatives may serve as NOX2 inhibitors by evaluating the capacity of 19 of these molecules to inhibit NOX2-derived ROS production in human neutrophils (HL-60 cells). Of these compounds, C6 and C14 exhibited concentration-dependent inhibition of NOX2 (IC50~1 µM). These molecules also reduced NOX2-derived oxidative stress in cardiomyocytes and prevented cardiac damage induced by ischemia-reperfusion. Compound C6 significantly reduced the membrane translocation of p47phox, a cytosolic subunit that is required for NOX2 activation. Molecular docking analyses of the binding modes of these molecules with p47phox indicated that C6 and C14 interact with specific residues in the inner part of the groove of p47phox, the binding cavity for p22phox. This combination of methods showed that novel indole heteroaryl acrylonitriles represent interesting lead compounds for developing specific and potent NOX2 inhibitors.
摘要:
NADPH氧化酶(NOX2)负责中性粒细胞中活性氧(ROS)的产生,并已被认为是炎症和心血管疾病的关键介质。然而,缺乏特异性的NOX2药物抑制剂。在药物化学中,杂环化合物是药物设计必不可少的支架,其中,吲哚是一种用途广泛的药效团。我们通过评估19种这些分子抑制人嗜中性粒细胞(HL-60细胞)中NOX2衍生的ROS产生的能力,测试了吲哚杂芳基-丙烯腈衍生物可以用作NOX2抑制剂的假设。在这些化合物中,C6和C14表现出浓度依赖性的NOX2抑制作用(IC50~1μM)。这些分子还减少心肌细胞中N0X2衍生的氧化应激并防止由缺血再灌注诱导的心脏损伤。化合物C6显著降低p47phox的膜转位,NOX2激活所需的细胞溶质亚基。这些分子与p47phox的结合模式的分子对接分析表明,C6和C14与p47phox凹槽内部的特定残基相互作用,p22phox的结合腔。这种方法的组合表明,新型吲哚杂芳基丙烯腈代表了开发特定且有效的NOX2抑制剂的有趣先导化合物。