Donepezil‐indolyl hybrids as multipotent cholinesterase/monoamine oxidase inhibitors for the potential treatment of Alzheimer’s disease

拉萨吉林 单胺氧化酶 化学 丁酰胆碱酯酶 药理学 乙酰胆碱酯酶 多奈哌齐 塞莱吉林 单胺氧化酶B 胆碱酯酶 生物化学 阿切 医学 帕金森病 疾病 内科学 痴呆
作者
Kaloyan Yuliyanov Krastev
出处
期刊:Alzheimers & Dementia [Wiley]
卷期号:19 (S24)
标识
DOI:10.1002/alz.082645
摘要

Abstract Background Numerous laboratory and clinical studies have evidenced that MAO‐B inhibitors are a potential therapeutic approach for the treatment of AD. Thus, drugs used to inhibit activated MAO, including rasagiline, ladostigil and selegiline, may provide neuroprotection against AD by improving cognitive impairment, modulating the proteolytic cleavage of APP and decreasing levels of Aβ protein fragments that accumulate in the brain. Future clinical studies on MAO inhibitors for the treatment of AD may provide further insights into the mechanism of action of antioxidants as therapeutic agents for AD. Method Series of donepezil‐indolyl hybrids were prepared and characterized via highresolution mass spectrometry, 1 H nuclear magnetic resonance and 13 C nuclear magnetic resonance techniques. In vitro fluorometric assay (by Amplex® UltraRed reagent to detect hydrogen peroxide or peroxidase activity in biological samples or enzymes.) was used to investigate the activity of the synthesized compounds on both MAO‐A and MAO‐B isozymes as well as acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) by Ellman method with modifications. Result The biological evaluation of molecules 1‐30 showed that most of these compounds are potent, in the nanomolar range, and selective AChEI, with moderate and equipotent selectivity for MAO‐A and MAO‐B inhibition. In overall, compound 11, as a potent and selective dual AChEI, showing a moderate MAO inhibitory profile, can be considered as an attractive multipotent drug for further development on two key pharmacological targets playing key roles in the therapy of Alzheimer’s disease. Conclusion The pharmacological profile of compound 11, as well as the fact that it is a readily available compound in a short synthetic sequence, in good chemical yields, prompts us to select it as a lead‐compound for further optimization in our current research programme targeted to the preparation of new molecules for the potential treatment of AD.

科研通智能强力驱动
Strongly Powered by AbleSci AI
科研通是完全免费的文献互助平台,具备全网最快的应助速度,最高的求助完成率。 对每一个文献求助,科研通都将尽心尽力,给求助人一个满意的交代。
实时播报
刚刚
西北望发布了新的文献求助10
1秒前
waayu完成签到 ,获得积分10
1秒前
小武丁发布了新的文献求助10
2秒前
2秒前
FashionBoy应助LLB采纳,获得10
2秒前
2秒前
2秒前
3秒前
隐形曼青应助柚子采纳,获得10
3秒前
逃跑计划完成签到,获得积分10
5秒前
务实幻露完成签到,获得积分10
5秒前
6秒前
西北望完成签到,获得积分10
6秒前
7秒前
zhang值发布了新的文献求助10
7秒前
8秒前
丘比特应助自觉平露采纳,获得10
8秒前
lqiqivv发布了新的文献求助10
8秒前
10秒前
奔跑石小猛完成签到,获得积分10
10秒前
11秒前
11秒前
hhhheyyyyo完成签到,获得积分10
11秒前
细腻天蓝完成签到 ,获得积分10
12秒前
12秒前
ambitiouslu发布了新的文献求助10
13秒前
13秒前
nykal发布了新的文献求助10
13秒前
朴实浩宇完成签到,获得积分10
14秒前
十点十分发布了新的文献求助10
14秒前
南信第一深情完成签到,获得积分10
14秒前
北落完成签到 ,获得积分20
15秒前
吃肯德基发布了新的文献求助30
15秒前
16秒前
16秒前
piaoyingzhiyu发布了新的文献求助10
17秒前
17秒前
所所应助科研通管家采纳,获得10
17秒前
ding应助科研通管家采纳,获得10
17秒前
高分求助中
Continuum Thermodynamics and Material Modelling 3000
Production Logging: Theoretical and Interpretive Elements 2700
Les Mantodea de Guyane Insecta, Polyneoptera 1000
Structural Load Modelling and Combination for Performance and Safety Evaluation 1000
Conference Record, IAS Annual Meeting 1977 820
England and the Discovery of America, 1481-1620 600
電気学会論文誌D(産業応用部門誌), 141 巻, 11 号 510
热门求助领域 (近24小时)
化学 材料科学 生物 医学 工程类 有机化学 生物化学 物理 纳米技术 计算机科学 内科学 化学工程 复合材料 基因 遗传学 物理化学 催化作用 量子力学 光电子学 冶金
热门帖子
关注 科研通微信公众号,转发送积分 3572795
求助须知:如何正确求助?哪些是违规求助? 3142958
关于积分的说明 9449441
捐赠科研通 2844307
什么是DOI,文献DOI怎么找? 1563431
邀请新用户注册赠送积分活动 731771
科研通“疑难数据库(出版商)”最低求助积分说明 718695