香豆素
多奈哌齐
化学
乙酰胆碱酯酶
胆碱酯酶
塔克林
查尔酮
药理学
乙酰胆碱酯酶抑制剂
血脑屏障
阿切
酶
生物化学
立体化学
有机化学
痴呆
生物
医学
中枢神经系统
神经科学
病理
疾病
作者
Ankita Sharma,Vijay K. Nuthakki,Sumeet Gairola,Bikarma Singh,Sandip B. Bharate
出处
期刊:ChemMedChem
[Wiley]
日期:2022-08-16
卷期号:17 (18)
被引量:4
标识
DOI:10.1002/cmdc.202200300
摘要
Plants have immensely contributed to the drug discovery for neurodegenerative diseases. Herein, we undertook the phytochemical investigation of Nardostachys jatamansi (D.Don) DC. rhizomes followed by semisynthetic modifications to discover cholinesterase (ChE) and beta-site amyloid precursor protein cleaving enzyme 1 (BACE-1) inhibitors. The 8-acetyl-7-hydroxycoumarin isolated from the bioactive extract moderately inhibits acetylcholinesterase (AChE) and BACE-1 with IC50 values of 22.1 and 17.7 μM, respectively. The semisynthetic trifluoromethyl substituted coumarin chalcone display a 5-fold improvement in BACE-1 inhibition (IC50 3.3 μM). Another semisynthetic derivative, a coumarin-donepezil hybrid, exhibits dual inhibition of both ChEs with IC50 values of 1.22 and 3.09 μM, respectively. Molecular modeling and enzyme kinetics revealed that the coumarin-donepezil hybrid is a non-competitive inhibitor of AChE. It crosses the blood-brain barrier and also inhibits Aβ self-aggregation. The results presented herein warrant a detailed investigation of the coumarin-donepezil hybrid in preclinical models of Alzheimer's disease.
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