Saeedi Mina, Felegari Peyman, Iraji Aida, Hariri Roshanak, Rastegari Arezoo, Mirfazli S Sara, Edraki Najmeh, Firuzi Omidreza, Mahdavi Mohammad, Akbarzadeh Tahmineh
Medicinal Plants Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.
Persian Medicine and Pharmacy Research Center, Tehran University of Medical Sciences, Tehran, Iran.
Arch Pharm (Weinheim). 2021 Mar;354(3):e2000258. doi: 10.1002/ardp.202000258. Epub 2020 Nov 23.
The complex pathophysiology of Alzheimer's disease (AD) has prompted researchers to develop multitarget-directed molecules to find an effective therapy against the disease. In this context, a novel series of N-(1-benzylpiperidin-4-yl)-5-arylisoxazole-3-carboxamide derivatives were designed, synthesized, and evaluated against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). In vitro biological evaluation demonstrated that compound 4e was the best AChE (IC = 16.07 μM) and BuChE inhibitor (IC = 15.16 μM). A kinetic study of 4e was also conducted, which presented a mixed-type inhibition for both enzymes. Molecular docking studies revealed that compound 4e fitted well into the active sites of AChE and BuChE, forming stable and strong interactions with key residues Glu199, Trp84, Asp72, Tyr121, and Phe288 in AChE and His438, Trp82, Ala328, Tyr332, Phe329, Thr120, and Pro285 in BuChE. Besides, the inhibition of BACE1 by 4e and the biometal chelation activity of 4e were measured. The neuroprotective assessment revealed that 4e exhibited 23.2% protection at 50 µM toward amyloid-beta-induced PC12 neuronal cells. Overall, this study exhibited that compound 4e was a promising compound targeting multiple factors associated with AD.
阿尔茨海默病（AD）复杂的病理生理学促使研究人员开发多靶点导向分子，以寻找针对该疾病的有效治疗方法。在此背景下，设计、合成了一系列新型的N-(1-苄基哌啶-4-基)-5-芳基异恶唑-3-甲酰胺衍生物，并对其进行了乙酰胆碱酯酶（AChE）和丁酰胆碱酯酶（BuChE）抑制活性评估。体外生物学评估表明，化合物4e是最佳的AChE抑制剂（IC = 16.07 μM）和BuChE抑制剂（IC = 15.16 μM）。还对4e进行了动力学研究，结果表明其对两种酶均表现为混合型抑制。分子对接研究表明，化合物4e能很好地契合AChE和BuChE的活性位点，与AChE中的关键残基Glu199、Trp84、Asp72、Tyr121和Phe288以及BuChE中的His438、Trp82、Ala328、Tyr332、Phe329、Thr120和Pro285形成稳定而强烈的相互作用。此外，还测定了4e对β-分泌酶1（BACE1）的抑制作用以及4e的生物金属螯合活性。神经保护评估显示，在50 μM浓度下，4e对淀粉样β蛋白诱导的PC12神经细胞具有23.2%的保护作用。总体而言，本研究表明化合物4e是一种有前景的针对与AD相关多种因素的化合物。
