Inhibition of cholinesterases, combined with antioxidant activity, metal-chelating capacity, and neuroprotection, is recognized as an effective multitarget therapy for the treatment of Alzheimer's disease (AD). Based on our in-house thiosemicarbazone-acridine compounds, this study recognized these derivatives as possible multi-target-directed ligand (MTDL). Initial screening against cholinesterases identified CL-01, which exhibited a promising IC50 value of 0.71 μM against butyrylcholinesterase (BChE). Twelve new derivatives were designed based on CL-01 aiming to retain the BChE inhibitory activity while incorporating a MTDL profile, including antioxidant properties and metal-complexing abilities. Among the new derivatives, CL-13 maintained a good BChE inhibition (IC50 = 1.15 μM) with improved selective index against acetylcholinesterase (SI = 9.2). The acridine nucleus was important for the activity, as its saturated tetrahydroacridine analogue (TA-01) showed a decrease in cholinesterases inhibition potencies and altered the mode of inhibition, revealing for the first time distinct functional roles for the two nuclei. Moreover, CL-13 emerged as a promising lead compound, demonstrating interesting antioxidant activity (DPPH EC50 = 47.01 μM), chelating capacity of biometals involved in Aβ aggregation and/or oxidative stress, and a lack of neurotoxicity at 50 μM in SH-SY5Y cells. It also exhibited neuroprotective effects in an in vitro oxidative stress model induced by H2O2. Finally, in vivo experiments confirmed that CL-13 effectively reversed scopolamine-induced cognitive impairment, without affecting locomotor activity in the mice.

中文翻译：

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发现靶向丁酰胆碱酯酶的新型巯代氨基甲酸酯酶，具有抗氧化、金属络合和神经保护能力，可作为阿尔茨海默病的潜在治疗方法：体外、体内和计算机研究


胆碱酯酶的抑制与抗氧化活性、金属螯合能力和神经保护相结合，被认为是治疗阿尔茨海默病 （AD） 的有效多靶点疗法。基于我们内部的巯代氨基脲-吖啶化合物，本研究将这些衍生物识别为可能的多靶点定向配体 （MTDL）。针对胆碱酯酶的初步筛选确定了 CL-01，其对丁酰胆碱酯酶 （BChE） 的 IC50 值为 0.71 μM。基于 CL-01 设计了 12 种新衍生物，旨在保留 BChE 抑制活性，同时结合 MTDL 谱，包括抗氧化特性和金属络合能力。在新衍生物中，CL-13 保持良好的 BChE 抑制 （IC50 = 1.15 μM），对乙酰胆碱酯酶的选择性指数提高 （SI = 9.2）。吖啶核对活性很重要，因为其饱和的四氢吖啶类似物 （TA-01） 显示胆碱酯酶抑制效力降低并改变了抑制模式，首次揭示了两个细胞核的不同功能作用。此外，CL-13 成为一种有前途的先导化合物，表现出有趣的抗氧化活性 （DPPH EC50 = 47.01 μM）、参与 Aβ 聚集和/或氧化应激的生物金属的螯合能力，以及 SH-SY5Y 细胞中 50 μM 时缺乏神经毒性。它还在 H 2 O 2 诱导的体外氧化应激模型中表现出神经保护作用。最后，体内实验证实 CL-13 有效逆转东莨菪碱诱导的认知障碍，而不影响小鼠的运动活动。