Institute of Organic Chemistry With Center of Phytochemistry, Bulgarian Academy of Sciences, Acad. G. Bonchev Str., Building 9, 1113, Sofia, Bulgaria.
Department of Medical Physics and Biophysics, Faculty of Medicine, Medical University of Sofia, 2 Zdrave Str., 1431, Sofia, Bulgaria.
Pharmacol Rep. 2020 Aug;72(4):846-856. doi: 10.1007/s43440-020-00077-3. Epub 2020 Mar 3.
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.
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.
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.
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.
许多神经退行性疾病包括氧化应激介导的病理学。褪黑素及其代谢物作为内源性活性氧（ROS）清除剂和抗氧化剂。具有扩展侧链的 N，N'-二取代苯并咪唑-2-硫酮由于与褪黑素的结构相似，可能具有抗氧化和神经保护特性。
通过监测分离大鼠脑突触体中的突触体活力和还原型谷胱甘肽（GSH）水平来评估化合物的毒理学潜力。在 6-羟多巴胺（6-OHDA）诱导的神经毒性模型中评估了体外神经保护作用。通过依赖鲁米诺的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。
含有藜芦醛、香草醛和丁香醛残基的化合物 5-7 在 250 μM 浓度下，最高程度地保留了突触体活力和 GSH 水平。在较低浓度 100 μM、10 μM 和 1 μM 下进一步筛选化合物 5-7，结果表明 6 和 7 在该浓度范围内没有任何毒性。在 6-OHDA 诱导的氧化应激模型中，6 表现出浓度依赖性、神经保护和与褪黑素相似的抗氧化活性。所有三种化合物均表现出降低含次氯酸盐体系中化学发光清除指数（CL-SI）的能力。在超氧体系中，腙对信号表现出不同的影响。
我们的研究表明，苯并咪唑-醛杂合体作为直接的 ROS 清除剂和自由基的膜稳定剂。因此，它们在抗氧化防御系统中发挥作用，具有作为治疗神经退行性疾病的治疗神经保护剂的潜在前景。
