N-(1-Benzylpiperidin-4-yl)-2-((5-phenyl-1,3,4-oxadiazol-2-yl)thio) 的一些分子杂化物的开发和评价作为对抗阿尔茨海默病的多功能药物,ACS Omega

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N-(1-Benzylpiperidin-4-yl)-2-((5-phenyl-1,3,4-oxadiazol-2-yl)thio) 的一些分子杂化物的开发和评价作为对抗阿尔茨海默病的多功能药物
ACS Omega ( IF 3.7 ) Pub Date : 2023-03-02 , DOI: 10.1021/acsomega.2c08061
Digambar Kumar Waiker ₁ , Akash Verma ₁ , Poorvi Saraf ₁ , Gajendra T A ₂ , Sairam Krishnamurthy ₂ , Rameshwar Nath Chaurasia ₃ , Sushant Kumar Shrivastava ₁

Affiliation

一系列新化合物 ( SD-1–17 ) 是按照分子杂交方法设计、合成和生物学测试的 hAChE、hBChE、hBACE-1 和 Aβ 聚集抑制潜力，以改善与阿尔茨海默氏病相关的认知和记忆功能. 化合物SD-4和SD-6在体外显示出针对 hAChE、hBChE 和 hBACE-1 酶的多功能抑制特性。化合物SD-4和SD-6在自身和乙酰胆碱酯酶 (AChE) 诱导的硫黄素 T 测定中也显示出抗 Aβ 聚集潜力。这两种化合物都显示出显着的碘化丙锭 (PI) 从胆碱酯酶-外周活性位点 (ChE-PAS) 区域的置换，具有出色的血脑屏障 (BBB) 渗透性并且没有神经毒性倾向。化合物SD-6改善东莨菪碱和 Aβ 诱导的阿尔茨海默病 (AD) 行为大鼠模型的认知和记忆功能。离体生化估计显示丙二醛 (MDA) 和 AChE 水平显着降低，而在海马脑匀浆中观察到超氧化物歧化酶 (SOD)、过氧化氢酶、谷胱甘肽 (GSH) 和 ACh 水平显着增加。脑切片的组织病理学检查也显示在SD-6处理的实验动物中没有神经元或任何组织损伤的迹象。化合物SD-4和SD-6的计算机分子对接结果表明它们与 hChE 催化阴离子位点 (CAS)、PAS 和 hBACE-1 酶的催化二元残基结合。两种化合物与 ChE 和 hBACE-1 酶的 100 ns 分子动力学模拟研究也证实了配体-蛋白质复合物的稳定性，而 quikprop 分析表明化合物具有类似药物的特性。

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Development and Evaluation of Some Molecular Hybrids of N-(1-Benzylpiperidin-4-yl)-2-((5-phenyl-1,3,4-oxadiazol-2-yl)thio) as Multifunctional Agents to Combat Alzheimer’s Disease

A series of some novel compounds (SD-1–17) were designed following a molecular hybridization approach, synthesized, and biologically tested for hAChE, hBChE, hBACE-1, and Aβ aggregation inhibition potential to improve cognition and memory functions associated with Alzheimer’s disease. Compounds SD-4 and SD-6 have shown multifunctional inhibitory profiles against hAChE, hBChE, and hBACE-1 enzymes in vitro. Compounds SD-4 and SD-6 have also shown anti-Aβ aggregation potential in self- and acetylcholinesterase (AChE)-induced thioflavin T assay. Both compounds have shown a significant propidium iodide (PI) displacement from the cholinesterase-peripheral active site (ChE-PAS) region with excellent blood–brain barrier (BBB) permeability and devoid of neurotoxic liabilities. Compound SD-6 ameliorates cognition and memory functions in scopolamine- and Aβ-induced behavioral rat models of Alzheimer’s disease (AD). Ex vivo biochemical estimation revealed a significant decrease in malonaldehyde (MDA) and AChE levels, while a substantial increase of superoxide dismutase (SOD), catalase, glutathione (GSH), and ACh levels is seen in the hippocampal brain homogenates. The histopathological examination of brain slices also revealed no sign of neuronal or any tissue damage in the SD-6-treated experimental animals. The in silico molecular docking results of compounds SD-4 and SD-6 showed their binding with hChE-catalytic anionic site (CAS), PAS, and the catalytic dyad residues of the hBACE-1 enzymes. A 100 ns molecular dynamic simulation study of both compounds with ChE and hBACE-1 enzymes also confirmed the ligand–protein complex’s stability, while quikprop analysis suggested drug-like properties of the compounds.

更新日期：2023-03-02

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