Molecular Diversity ( IF 3.9 ) Pub Date : 2021-07-17 , DOI: 10.1007/s11030-021-10248-w Arezoo Rastegari 1 , Maliheh Safavi 2 , Fahimeh Vafadarnejad 3 , Zahra Najafi 4 , Roshanak Hariri 3 , Syed Nasir Abbas Bukhari 5 , Aida Iraji 6, 7 , Najmeh Edraki 8 , Omidreza Firuzi 8 , Mina Saeedi 1, 9 , Mohammad Mahdavi 10 , Tahmineh Akbarzadeh 1, 3
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Abstract
Alzheimer’s disease (AD) is now ranked as the third leading cause of death after heart disease and cancer. There is no definite cure for AD due to the multi-factorial nature of the disease, hence, multi-target-directed ligands (MTDLs) have attracted lots of attention. In this work, focusing on the efficient cholinesterase inhibitory activity of tacrine, design and synthesis of novel arylisoxazole-tacrine analogues was developed. In vitro acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibition assay confirmed high potency of the title compounds. Among them, compounds 7l and 7b demonstrated high activity toward AChE and BChE with IC50 values of 0.050 and 0.039 μM, respectively. Both compounds showed very good self-induced Aβ aggregation and AChE-induced inhibitory activity (79.4 and 71.4% for compound 7l and 61.8 and 58.6% for compound 7b, respectively). Also, 7l showed good anti-BACE1 activity with IC50 value of 1.65 µM. The metal chelation test indicated the ability of compounds 7l and 7b to chelate biometals (Zn2+, Cu2+, and Fe2+). However, they showed no significant neuroprotectivity against Aβ-induced damage in PC12 cells. Evaluation of in vitro hepatotoxicity revealed comparable toxicity of compounds 7l and 7b with tacrine. In vivo studies by Morris water maze (MWM) task demonstrated that compound 7l significantly reversed scopolamine-induced memory deficit in rats. Finally, molecular docking studies of compounds 7l and 7b confirmed establishment of desired interactions with the AChE, BChE, and BACE1 active sites.
Graphic Abstract
中文翻译：
与他克林部分相关的新型芳基异恶唑的合成和评价：针对阿尔茨海默病的体外和体内生物活性
摘要
阿尔茨海默病 (AD) 现在被列为仅次于心脏病和癌症的第三大死因。由于AD的多因素性质，AD没有明确的治愈方法，因此，多靶点定向配体（MTDLs）引起了很多关注。在这项工作中，围绕他克林的有效胆碱酯酶抑制活性，开发了新型芳基异恶唑-他克林类似物的设计和合成。体外乙酰胆碱酯酶 (AChE) 和丁酰胆碱酯酶 (BChE) 抑制试验证实了标题化合物的高效力。其中，化合物7l和7b对 AChE 和 BChE 表现出高活性，IC 50值分别为 0.050 和 0.039 μM。两种化合物都显示出非常好的自诱导Aβ聚集和AChE诱导的抑制活性（化合物7l分别为79.4和71.4%，化合物7b分别为61.8和58.6% ）。此外，7l显示出良好的抗 BACE1 活性，IC 50值为 1.65 µM。金属螯合试验表明化合物7l和7b螯合生物金属（Zn 2+、Cu 2+和Fe 2+）的能力。然而，它们对 PC12 细胞中 Aβ 诱导的损伤没有显示出显着的神经保护作用。体外肝毒性评估显示化合物7l的毒性相当和7b与他克林。莫里斯水迷宫 (MWM) 任务的体内研究表明，化合物7l显着逆转了东莨菪碱诱导的大鼠记忆缺陷。最后，化合物7l和7b的分子对接研究证实了与 AChE、BChE 和 BACE1 活性位点的所需相互作用的建立。
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