期刊
BIOORGANIC & MEDICINAL CHEMISTRY
卷 25, 期 2, 页码 633-645出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2016.11.032
关键词
Multitarget-directed ligands; Butyrylcholinesterase inhibitors; MAO-B inhibitors; Alzheimer's disease
资金
- Slovenian Research Agency
- France-Alzheimer Foundation [FA-AAP-2013-65-101349]
- Agence Nationale de la Recherche [ANR-12-BS07-0008-03]
- Institut Francais
- Agence Nationale de la Recherche (ANR) [ANR-12-BS07-0008] Funding Source: Agence Nationale de la Recherche (ANR)
In the brains of patients with Alzheimer's disease, the enzymatic activities of butyrylcholinesterase (BChE) and monoamine oxidase B (MAO-B) are increased. While BChE is a viable therapeutic target for alleviation of symptoms caused by cholinergic hypofunction, MAO-B is a potential therapeutic target for prevention of neurodegeneration in Alzheimer's disease. Starting with piperidine-based selective human (h)BChE inhibitors and propargylamine-based MAO inhibitors, we have designed, synthesized and biochemically evaluated a series of N-propargylpiperidines. All of these compounds inhibited hBChE with good selectivity over the related enzyme, acetylcholinesterase, and crossed the blood-brain barrier in a parallel artificial membrane permeation assay. The crystal structure of one of the inhibitors (compound 3) in complex with hBChE revealed its binding mode. Three compounds (4, 5, 6) showed con-comitant inhibition of MAO-B. Additionally, the most potent hBChE inhibitor 7 and dual BChE and MAO-B inhibitor 6 were non-cytotoxic and protected neuronal SH-SY5Y cells from toxic amyloid beta-peptide species. (C) 2016 Elsevier Ltd. All rights reserved.
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