BACKGROUND Many neurodegenerative disorders include oxidative stress-mediated pathology. Melatonin and its metabolites act as endogenous reactive oxygen species (ROS) scavengers and antioxidants. N,N'-Disubstituted benzimidazole-2-thiones with extended side chains could exert antioxidant and neuroprotective properties due to structural similarities to melatonin. METHODS The toxicological potential of the compounds was evaluated by monitoring the synaptosomal viability and the levels of reduced glutathione (GSH) in isolated rat brain synaptosomes. The neuroprotective effects were assessed in vitro in a model of 6-hydroxydopamine (6-OHDA)-induced neurotoxicity. The capability to decrease superoxide anion radical and hypochlorite was evaluated by luminol-dependent chemiluminescent assays. RESULTS Compounds 5-7 containing residues of veratraldehyde, vanillin, and syringaldehyde at concentration 250 μM, preserved at the highest degree the synaptosomal viability and GSH levels. Further screening of compounds 5-7 at lower concentrations of 100 μM, 10 μM, and 1 μM, respectively, demonstrated that 6 and 7 do not show any toxicity within this concentration range. In the model of 6-OHDA-induced oxidative stress, 6 revealed concentration-dependent, neuroprotective, and antioxidant activities similar to melatonin. All the three compounds demonstrated ability to decrease the chemiluminescent scavenging index (CL-SI) in the hypochlorite containing system. In the superoxide system, the hydrazones exhibited different effects on the signal. CONCLUSIONS Our studies suggest that the benzimidazole-aldehyde hybrids act as direct ROS scavengers and membranes' stabilizers against free radicals. Thus, they play a role in the antioxidative defense system and have a promising potential as therapeutic neuroprotective agents for the treatment of neurodegenerative disorders.

中文翻译：

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新型苯并咪唑-醛杂化物作为具有次氯酸盐和超氧化物自由基清除活性的神经保护剂。

背景技术许多神经退行性疾病包括氧化应激介导的病理。褪黑素及其代谢产物可作为内源性活性氧（ROS）清除剂和抗氧化剂。N，N'-二取代的苯并咪唑-2-硫酮具有延长的侧链，由于其与褪黑激素的结构相似性，因此可以发挥抗氧化和神经保护作用。方法通过监测突触体的生存力和分离的大鼠脑突触体中还原型谷胱甘肽（GSH）的水平来评估该化合物的毒理学潜力。在6-羟基多巴胺（6-OHDA）诱导的神经毒性模型中体外评估了神经保护作用。通过鲁米诺依赖性化学发光测定法评估了减少超氧阴离子自由基和次氯酸盐的能力。结果含有浓度为250μM的藜芦醛，香兰素和丁香醛残基的化合物5-7最高程度地保存了突触体的活力和GSH水平。分别以100μM，10μM和1μM的较低浓度进一步筛选化合物5-7，表明6和7在此浓度范围内未显示任何毒性。在6-OHDA诱导的氧化应激模型中，有6种具有类似于褪黑激素的浓度依赖性，神经保护和抗氧化活性。这三种化合物均具有降低含有次氯酸盐的系统中化学发光清除指数（CL-SI）的能力。在超氧化物系统中，对信号表现出不同的影响。结论我们的研究表明，苯并咪唑-醛杂化物可作为直接的ROS清除剂和膜的抗自由基稳定剂。因此，它们在抗氧化防御系统中发挥作用，作为治疗神经退行性疾病的治疗性神经保护剂具有广阔的潜力。