Soliman Aya M, Abd El-Wahab Hend A A, Eissa Rana G, Baraka Nourhan M, Omar Farghaly A
Department of Medicinal Chemistry, Faculty of Pharmacy, Assiut University, Assiut 71526, Egypt; School of Chemistry, University of New South Wales (UNSW), Sydney, NSW 2052, Australia.
Department of Medicinal Chemistry, Faculty of Pharmacy, Assiut University, Assiut 71526, Egypt.
Bioorg Chem. 2025 Aug;163:108750. doi: 10.1016/j.bioorg.2025.108750. Epub 2025 Jul 14.
Recently, we reported a series of donepezil-based piperazine-2-carboxylic acid derivatives, essentially designed as MTDLs anti- Alzheimer's agents, with nanomolar to sub micromolar dual inhibitory activity against acetylcholinesterase and butyrylcholinesterase. Herein, we report the evaluation of selected series of the designed compounds 4(c, d), 5(b, c), 7(a-f), 8(a, b, f), for potential activity against further clinical traits involved in the pathogenesis of Alzheimer's disease (AD). The results revealed compounds 7b and 8f with promising in vitro inhibitory effect against Aβ aggregation (IC = 1.15 ± 0.05 and 1.10 ± 0.05 μM, respectively) as compared to the reference drug, curcumin (IC = 6.54 ± 0.31 μM). Meanwhile, compounds 7b, 7e and 8f exhibited comparable in vitro inhibitory activity against HDAC1, (IC = 0.30 ± 0.01, 0.14 ± 0.01 and 0.15 ± 0.01 μM respectively), relative to the reference drugs SAHA (IC = 0.046 ± 0.002 μM) and entinostat, (IC = 0.05 ± 0.002 μM). Additionally, the investigated compounds displayed radical scavenging effect comparable to DPPH, and metal chelating ability towards Cu (II) and Zn (II) metals. The neuroprotective characteristics have been established in vivo through several analytical assessments of the potential effects against AlCl-induced AD, in comparison to donepezil as reference drug. Explicitly, the studies involve behavioural tests, oxidative stress, neuroinflammatory markers, amyloid-beta (Aβ) aggregation, acetylcholine and acetylcholinesterase levels. The results displayed in vivo activity comparable to the reference drug. Docking studies, in the binding sites of Aβ peptide (PDB code 1IYT) and HDAC1 (PDB code 4BKX), demonstrate binding modes analogous to that elicited by the native ligands, respectively. These findings confirm of the neuroprotective activity of the designed compounds and establish their validity as MTDLs candidates for further investigation against Alzheimer's disease.
最近，我们报道了一系列基于多奈哌齐的哌嗪 - 2 - 羧酸衍生物，它们主要被设计为多靶点导向配体（MTDLs）抗阿尔茨海默病药物，对乙酰胆碱酯酶和丁酰胆碱酯酶具有纳摩尔至亚微摩尔的双重抑制活性。在此，我们报告了对选定系列的设计化合物4（c，d）、5（b，c）、7（a - f）、8（a，b，f）针对阿尔茨海默病（AD）发病机制中涉及的其他临床特征的潜在活性评估。结果显示，与参考药物姜黄素（IC = 6.54 ± 0.31 μM）相比，化合物7b和8f对Aβ聚集具有有前景的体外抑制作用（IC分别为1.15 ± 0.05和1.10 ± 0.05 μM）。同时，化合物7b、7e和8f相对于参考药物SAHA（IC = 0.046 ± 0.002 μM）和恩替诺特（IC = 0.05 ± 0.002 μM），对HDAC1表现出相当的体外抑制活性（IC分别为0.30 ± 0.01、0.14 ± 0.01和0.15 ± 0.01 μM）。此外，所研究的化合物表现出与DPPH相当的自由基清除作用，以及对Cu（II）和Zn（II）金属的金属螯合能力。与作为参考药物的多奈哌齐相比，通过对AlCl₃诱导的AD的潜在影响进行的多项分析评估，在体内确立了这些化合物的神经保护特性。具体而言，这些研究涉及行为测试、氧化应激、神经炎症标志物、淀粉样β（Aβ）聚集、乙酰胆碱和乙酰胆碱酯酶水平。结果显示其体内活性与参考药物相当。在Aβ肽（PDB代码1IYT）和HDAC1（PDB代码4BKX）的结合位点进行的对接研究表明，其结合模式分别类似于天然配体引发的结合模式。这些发现证实了所设计化合物的神经保护活性，并确立了它们作为多靶点导向配体候选物用于进一步研究抗阿尔茨海默病的有效性。
