Anastassova Neda, Kondeva-Burdina Magdalena, Hristova-Avakumova Nadya, Stefanova Denitsa, Rangelov Miroslav, Todorova Nadezhda, Yancheva Denitsa
Institute of Organic Chemistry with Centre of Phytochemistry, Bulgarian Academy of Sciences, Acad. G. Bonchev Str., Building 9, 1113 Sofia, Bulgaria.
Department of Organic Chemistry, University of Chemical Technology and Metallurgy, 8 Kliment Ohridski Blvd., 1756 Sofia, Bulgaria.
ACS Chem Neurosci. 2025 Mar 19;16(6):1161-1181. doi: 10.1021/acschemneuro.4c00838. Epub 2025 Mar 11.
In the current study, a small series of five indole-3-acetic acid-derived arylhydrazone hybrids were synthesized and subjected to comprehensive evaluation of their neuropharmacological and radical-scavenging properties. Minimal neurotoxic effects were observed across diverse subcellular fractions, with particular emphasis on the compound bearing a 2,3-dihydroxy moiety, exhibiting superior neuroprotective effects against HO-induced oxidative stress by preserving the cell viability up to 68%. Noteworthy neuroprotection was observed in 6-OHDA-induced neurotoxicity using isolated rat brain synaptosomes, with compounds and displaying prominent effects. Compound demonstrated robust neuroprotective and antioxidant effects in models of -butyl hydroperoxide-induced oxidative stress on isolated rat brain mitochondria and nonenzyme-induced lipid peroxidation using isolated rat brain microsomes (Fe/AA). All compounds exhibited MAOB inhibition within the range of 0.130-0.493 μM, with compounds , , and showing notable selectivity against hMAOB. Molecular docking studies further validated ligand binding within MAOB active sites. The derivatives demonstrated scavenging activity and antioxidant effects against various ROS types, with compound consistently exhibiting the most potent activity. Structural modifications exerted discernible effects on scavenging capabilities and antioxidant effects, underscoring their potential therapeutic implications in neuroprotection and oxidative stress mitigation.
在当前研究中，合成了一小系列五个吲哚 - 3 - 乙酸衍生的芳基腙杂化物，并对其神经药理学和自由基清除特性进行了全面评估。在不同的亚细胞组分中观察到最小的神经毒性作用，特别强调带有2,3 - 二羟基部分的化合物，通过将细胞活力保持高达68%，对HO诱导的氧化应激表现出优异的神经保护作用。在使用分离的大鼠脑突触体的6 - OHDA诱导的神经毒性中观察到显著的神经保护作用，化合物 和 表现出突出的效果。化合物 在叔丁基过氧化氢诱导的分离大鼠脑线粒体氧化应激模型和使用分离大鼠脑微粒体（Fe/AA）的非酶诱导脂质过氧化模型中表现出强大的神经保护和抗氧化作用。所有化合物在0.130 - 0.493 μM范围内均表现出对MAOB的抑制作用，化合物 、 和 对hMAOB表现出显著的选择性。分子对接研究进一步验证了配体在MAOB活性位点内的结合。这些衍生物对各种ROS类型表现出清除活性和抗氧化作用，化合物 始终表现出最有效的活性。结构修饰对清除能力和抗氧化作用产生了明显影响，突出了它们在神经保护和减轻氧化应激方面的潜在治疗意义。
