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从 4-氧代-N-4-二苯丁酰胺中发现具有抗乙酰胆碱酯酶活性的可还原选择性单胺氧化酶 B 抑制剂。

Discovery of reversible selective monoamine oxidase B inhibitors with anti-acetylcholinesterase activity derived from 4-oxo-N-4-diphenyl butanamides.

机构信息

Pharmaceutical Chemistry Research Laboratory, Department of Pharmaceutical Engineering & Technology, Indian Institute of Technology (Banaras Hindu University), Varanasi, 221005, India.

出版信息

Future Med Chem. 2023 Jan;15(2):189-210. doi: 10.4155/fmc-2022-0169. Epub 2023 Feb 17.

Abstract

Multitargeted drugs are essential for the treatment of various neurodegenerative disorders, because of their complex nature. This study aimed to develop novel small molecules as selective monoamine oxidase B (MAO-B) inhibitors with cholinesterase inhibition. With the help of fragment-based drug design, some 4-oxo-N-4-diphenyl butanamides were designed and synthesized as MAO-B inhibitors with anti-acetylcholinesterase (AChE) activity. Compound showed the best neuroprotection, with reversible selective MAO-B inhibition activity (IC = 11.54 ± 0.64 nM). Compounds , , , and (IC = 20.90 ± 0.50, 17.25 ± 0.90, 15.85 ± 0.16, 16.81 ± 0.85 and 25.19 ± 0.17 nM, respectively) also appeared as potent and selective MAO-B inhibitors with anti-AChE activity. The present study suggests potent, neuroprotective and nontoxic lead compounds as selective MAO-B inhibitors with anti-AChE activity.

摘要

多靶点药物对于治疗各种神经退行性疾病至关重要,因为这些疾病的性质非常复杂。本研究旨在开发新型小分子作为选择性单胺氧化酶 B(MAO-B)抑制剂,同时具有胆碱酯酶抑制作用。借助基于片段的药物设计,设计并合成了一些 4-氧代-N-4-二苯基丁酰胺类化合物作为具有抗乙酰胆碱酯酶(AChE)活性的 MAO-B 抑制剂。化合物 表现出最佳的神经保护作用,具有可逆的选择性 MAO-B 抑制活性(IC = 11.54 ± 0.64 nM)。化合物 、 、 、 和 (IC = 20.90 ± 0.50、17.25 ± 0.90、15.85 ± 0.16、16.81 ± 0.85 和 25.19 ± 0.17 nM)也表现出较强的选择性 MAO-B 抑制作用和抗 AChE 活性。本研究提供了一些有潜力的、具有神经保护作用且毒性低的先导化合物,作为具有抗 AChE 活性的选择性 MAO-B 抑制剂。

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