Du Hongtao, Ma Fang, Cao Yuanyuan, Bai Miaoyan, Gao Xinyi, Yang Ziyi, Xu Yang, Yan Yan
Shaanxi Key Laboratory of Chinese Jujube, College of Life Sciences, Yan'an University, Yan'an, Shaanxi, China.
Shaanxi Qi Yuan Kang Bo Biotechnology Co., Ltd., Tongchuan, Shaanxi, China.
Front Chem. 2025 Jan 29;13:1545908. doi: 10.3389/fchem.2025.1545908. eCollection 2025.
The multi-targeted ligands (MTDL) strategy has been recognized as a promising Approach for the development of effective treatments against Alzheimer's disease (AD), due to the presence of multiple pathological mechanisms in AD. In this study, a series of bis(7)-harmine derivatives were designed and synthesized as multifunctional drugs for the treatment of AD.
The derivatives were synthesized by chemical methods and their structure was confirmed by nuclear magnetic resonance (NMR). The Ellman's assay was utilized to assess the inhibitory potential of derivatives against AChE and BuChE. The inhibitory activity of these derivatives on both MAO-A and MAO-B was assessed using a fluorescence-based method. The thioflavin T (Th-T) fluorescence assay was used to assess the inhibition of A self-aggregation. The cytotoxicity was evaluated using the MTT assay. The Surflex-Dock program in Sybyl-X2.0 Software was employed for molecular docking.
studies revealed that numerous synthesized compounds exhibited potent inhibitory activity against AChE, and MAO-B (IC < 1 μM), as well as A aggregation (IC < 20 μM). Importantly, the multitarget compounds , , and exhibited remarkable efficacy in simultaneously mitigating A-induced toxicity in SH-SY5Y cells while demonstrating minimal cytotoxicity. Furthermore, predicted ADMET results suggested that , , and possessed favorable pharmacokinetic properties and demonstrated low toxicity levels. Additionally, molecular docking studies of 6d within the activesites of AChE, MAO-B, and A elucidated the inhibition mechanism.
Based on these findings, it is evident that , , and hold potential as promising multi-functional drugs for AD treatment.
由于阿尔茨海默病（AD）存在多种病理机制，多靶点配体（MTDL）策略已被认为是开发有效治疗AD方法的一种有前景的途径。在本研究中，设计并合成了一系列双（7）-哈尔明衍生物作为治疗AD的多功能药物。
通过化学方法合成衍生物，并通过核磁共振（NMR）确认其结构。采用Ellman法评估衍生物对乙酰胆碱酯酶（AChE）和丁酰胆碱酯酶（BuChE）的抑制潜力。使用基于荧光的方法评估这些衍生物对单胺氧化酶A（MAO-A）和单胺氧化酶B（MAO-B）的抑制活性。采用硫黄素T（Th-T）荧光测定法评估对Aβ自我聚集的抑制作用。使用MTT测定法评估细胞毒性。使用Sybyl-X2.0软件中的Surflex-Dock程序进行分子对接。
研究表明，许多合成化合物对AChE、MAO-B（IC<1μM）以及Aβ聚集（IC<20μM）表现出强效抑制活性。重要的是，多靶点化合物6d、6e和6f在减轻SH-SY5Y细胞中Aβ诱导的毒性方面同时表现出显著疗效，同时显示出最小的细胞毒性。此外，预测的ADMET结果表明，6d、6e和6f具有良好的药代动力学性质，并显示出低毒性水平。此外，对6d在AChE、MAO-B和Aβ活性位点内的分子对接研究阐明了抑制机制。
基于这些发现，显然6d、6e和6f作为有前景的AD治疗多功能药物具有潜力。
