Rational Design of Novel Selective Dual-Target Inhibitors of Acetylcholinesterase and Monoamine Oxidase B as Potential Anti-Alzheimer’s Disease Agents

Multifunctional agents aiming at cholinesterases (ChEs) and monoamine oxidases (MAOs) are promising therapy for Alzheimer’s disease (AD). Herein, a series of novel propargylamine-modified pyrimidinylthiourea derivatives (1–4) were designed and synthesized as dual inhibitors of ChEs and MAOs with oth...

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Published in:ACS chemical neuroscience 2019-01, Vol.10 (1), p.482-496
Main Authors: Xu, Yixiang, Zhang, Jian, Wang, Huan, Mao, Fei, Bao, Keting, Liu, Wenwen, Zhu, Jin, Li, Xiaokang, Zhang, Haiyan, Li, Jian
Format: Article
Language:English
Subjects:
Acetylcholinesterase - metabolism
Alzheimer Disease - drug therapy
Alzheimer Disease - enzymology
Animals
Blood-Brain Barrier - drug effects
Blood-Brain Barrier - metabolism
Cholinesterase Inhibitors - administration & dosage
Cholinesterase Inhibitors - chemistry
Cholinesterase Inhibitors - metabolism
Drug Delivery Systems - methods
Drug Design
Mice
Mice, Inbred ICR
Monoamine Oxidase - metabolism
Monoamine Oxidase Inhibitors - administration & dosage
Monoamine Oxidase Inhibitors - chemistry
Monoamine Oxidase Inhibitors - metabolism
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Summary:Multifunctional agents aiming at cholinesterases (ChEs) and monoamine oxidases (MAOs) are promising therapy for Alzheimer’s disease (AD). Herein, a series of novel propargylamine-modified pyrimidinylthiourea derivatives (1–4) were designed and synthesized as dual inhibitors of ChEs and MAOs with other functions against AD. Most of these derivatives inhibited ChEs and MAOs with IC50 values in the micro- or nanomolar ranges. Compound 1c displayed the dual functional profile of targeting the AChE (IC50 = 0.032 ± 0.007 μM) and MAO-B (IC50 = 2.117 ± 0.061 μM), along with the improved blood-brain barrier (BBB) permeability, antioxidant ability, and good copper chelating property in vitro. Animal studies showed that compound 1c·HCl could inhibit the cerebral AChE/MAO-B activities and alleviate scopolamine-induced cognitive impairment in mice. Combined with good oral bioavailability (F = 45.55%), these findings demonstrated that compound 1c may be a potent brain permeable multifunctional candidate for the treatment of AD.
ISSN:1948-7193
1948-7193
DOI:10.1021/acschemneuro.8b00357