丁酰胆碱酯酶
乙酰胆碱酯酶
单胺氧化酶
药理学
单胺类神经递质
单胺氧化酶B
化学
胆碱酯酶
单胺氧化酶A
酶
体内
塞莱吉林
阿切
体外
舍曲林
氟西汀
生物化学
抗抑郁药
医学
生物
血清素
帕金森病
内科学
疾病
受体
海马体
生物技术
作者
Muhammad Shahid Nadeem,Jalaluddin A. Khan,Umer Rashid
标识
DOI:10.1016/j.ijbiomac.2021.10.102
摘要
For the potential therapy of Alzheimer's disease (AD), cholinesterases (ChE) and monoamine oxidase (MAO) are key enzymes that regulate the level of acetylcholinesterase (AChE)/butyrylcholinesterase (BChE) and monoamines. The aim of current research is the synthesis of multi-target compounds that can concomitantly inhibit ChEs and MAO. A series of fluoxetine and sertraline hybrids was designed and evaluated as multi-target inhibitors of ChEs and hMAO. In-vitro enzyme inhibition studies demonstrated that a number of compounds displayed excellent inhibition in submicromolar to nanomolar range. However, compounds 17, 22, 38-40 possess excellent concomitant inhibitory activity against ChEs and hMAO-A/B enzymes and thus emerged as optimal multi-target hybrids. In-vivo acute toxicity study showed the safety of synthesized compounds up to 2000 mg/kg dose. The examinations of brain tissue in Swiss albino mice suggested that selected most active MAO-B inhibitors 17 and 22 have a propensity to block the MAO-B activity that could be responsible for their neurodegenerative effect in mice. The in-vitro inhibitory manner of interaction of these multipotent compounds on all four targets were confirmed by molecular docking investigations.
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