Design, Synthesis, and Evaluation of Acetylcholinesterase and Butyrylcholinesterase Dual-Target Inhibitors against Alzheimer’s Diseases

Guo, Yan; Yang, Hongyu; Huang, Zhongwei; Tian, Sen; Li, Qihang; Du, Chenxi; Chen, Tingkai; Liu, Yang; Sun, Haopeng; Liu, Zongliang

doi:10.3390/molecules25030489

Cited by 15 publications

(12 citation statements)

References 37 publications

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“…After incubation for another 15 min at 37 °C, SDS (30 μL, 0.4 %) was added to stop the reaction. The absorbance was measured at 405 nm using a microplate reader [43] . The data were analyzed using Origin 2018.…”

Section: Methodsmentioning

confidence: 99%

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Design, Synthesis and Biological Evaluation of Xanthone Derivatives for Possible Treatment of Alzheimer's Disease Based on Multi‐Target Strategy

Yang

Qiao

Hui

et al. 2020

Chemistry & Biodiversity

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Four xanthone derivatives were synthesized and evaluated as acetylcholinesterase inhibitors (AChEIs) with metal chelating ability and antioxidant ability against Alzheimer's disease (AD). Most of them exhibited potential acetylcholinesterase (AChE), butylcholinesterase (BuChE) inhibitory, antioxidant and metal chelating properties. Among them, 1-hydroxy-3-[2-(pyrrolidin-1-yl)ethoxy]-9H-xanthen-9-one had the highest ability to inhibit AChE and displayed high selectivity towards AChE (IC 50 = 2.403 � 0.002 μM for AChE and IC 50 = 31.221 � 0.002 μM for BuChE), and it was also a good antioxidant (IC 50 = 2.662 � 0.003 μM). Enzyme kinetic studies showed that this compound was a mixed-type inhibitor, which could interact simultaneously with the catalytic anionic site (CAS) and the peripheral anionic site (PAS) of AChE. Interestingly, its copper complex showed more significant inhibitory activity for AChE (IC 50 = 0.934 � 0.002 μM) and antioxidant activity (IC 50 = 1.064 � 0.003 μM). Molecular dockings were carried out for the four xanthone derivatives in order to further investigate the binding modes. Finally, the blood-brain barrier (BBB) penetration prediction indicated that all compounds might penetrate BBB. These results suggested that 1-hydroxy-3-[2-(pyrrolidin-1-yl)ethoxy]-9H-xanthen-9-one was promising AChEI with metal chelating ability and antioxidant ability for the further investigation.

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Section: Methodsmentioning

confidence: 99%

“…The absorbance was measured at 405 nm using a microplate reader. [43] The data were analyzed using Origin 2018.…”

Section: Kinetic Of Ache Inhibitionmentioning

confidence: 99%

Design, Synthesis and Biological Evaluation of Xanthone Derivatives for Possible Treatment of Alzheimer's Disease Based on Multi‐Target Strategy

Yang

Qiao

Hui

et al. 2020

Chemistry & Biodiversity

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“…The Chinese Center for Disease Control and Prevention estimated that there are more than 9 million AD patients in China at present, and it is expected that 40 million could be affected by 2050. AD not only brings a heavy mental burden and economic pressure to the family members and friends of patients but also places a very large burden on the social economy [ 3 ]. At present, the typical events in AD pathogenesis are considered to be the formation of extracellular amyloid-β (Aβ) plaques, intracellular accumulation of abnormally phosphorylated tau, neuronal synaptic dysfunction, and neuronal loss [ 4 , 5 , 6 , 7 ].…”

Section: Introductionmentioning

confidence: 99%

The Main Alkaloids in Uncaria rhynchophylla and Their Anti-Alzheimer’s Disease Mechanism Determined by a Network Pharmacology Approach

Zeng

Wang

et al. 2021

IJMS

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Alzheimer’s disease (AD) is a growing concern in modern society, and effective drugs for its treatment are lacking. Uncaria rhynchophylla (UR) and its main alkaloids have been studied to treat neurodegenerative diseases such as AD. This study aimed to uncover the key components and mechanism of the anti-AD effect of UR alkaloids through a network pharmacology approach. The analysis identified 10 alkaloids from UR based on HPLC that corresponded to 90 anti-AD targets. A potential alkaloid target-AD target network indicated that corynoxine, corynantheine, isorhynchophylline, dihydrocorynatheine, and isocorynoxeine are likely to become key components for AD treatment. KEGG pathway enrichment analysis revealed the Alzheimers disease (hsa05010) was the pathway most significantly enriched in alkaloids against AD. Further analysis revealed that 28 out of 90 targets were significantly correlated with Aβ and tau pathology. These targets were validated using a Gene Expression Omnibus (GEO) dataset. Molecular docking studies were carried out to verify the binding of corynoxine and corynantheine to core targets related to Aβ and tau pathology. In addition, the cholinergic synapse (hsa04725) and dopaminergic synapse (hsa04728) pathways were significantly enriched. Our findings indicate that UR alkaloids directly exert an AD treatment effect by acting on multiple pathological processes in AD.

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“…PAS can facilitate the movement of ACh towards CAS and therefore contribute to improving the catalytic efficiency of ACh (Guo et al. 2020 ). Molecular docking showed that aaptamine can interact with key amino acid residues in the CAS and PAS sites of AChE and BuChE through hydrogen bonds or π–π stacking interactions.…”

Section: Discussionmentioning

confidence: 99%

Aaptamine – a dual acetyl – and butyrylcholinesterase inhibitor as potential anti-Alzheimer’s disease agent

Miao

et al. 2022

Pharmaceutical Biology

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Context Alzheimer’s disease (AD) is a neurodegenerative disorder that affects millions of people worldwide. Acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) are promising therapeutic targets for AD. Objective To evaluate the inhibitory effects of aaptamine on two cholinesterases and investigate the in vivo therapeutic effect on AD in a zebrafish model. Materials and methods Aaptamine was isolated from the sponge Aaptos suberitoides Brøndsted (Suberitidae). Enzyme inhibition, kinetic analysis, surface plasmon resonance (SPR) and molecular docking assays were used to determine its inhibitory effect on AChE and BuChE in vitro . Zebrafish were divided into six groups: control, model, 8 μM donepezil, 5 , 10 and 20 μM aaptamine. After three days of drug treatment, the behaviour assay was performed. Results The IC 50 values of aaptamine towards AChE and BuChE were 16.0 and 4.6 μM. And aaptamine directly inhibited the two cholinesterases in the mixed inhibition type, with K i values of 6.96 ± 0.04 and 6.35 ± 0.02 μM, with K d values of 87.6 and 10.7 μM. Besides, aaptamine interacts with the crucial anionic sites of AChE and BuChE. In vivo studies indicated that the dyskinesia recovery rates of 5 , 10 and 20 μM aaptamine group were 34.8, 58.8 and 60.0%, respectively, and that of donepezil was 63.7%. Discussion and conclusions Aaptamine showed great potential to exert its anti-AD effects by directly inhibiting the activities of AChE and BuChE. Therefore, this study identified a novel medicinal application of aaptamine and provided a new structural scaffold for the development of anti-AD drugs.

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Design, Synthesis, and Evaluation of Acetylcholinesterase and Butyrylcholinesterase Dual-Target Inhibitors against Alzheimer’s Diseases

Cited by 15 publications

References 37 publications

Design, Synthesis and Biological Evaluation of Xanthone Derivatives for Possible Treatment of Alzheimer's Disease Based on Multi‐Target Strategy

Design, Synthesis and Biological Evaluation of Xanthone Derivatives for Possible Treatment of Alzheimer's Disease Based on Multi‐Target Strategy

The Main Alkaloids in Uncaria rhynchophylla and Their Anti-Alzheimer’s Disease Mechanism Determined by a Network Pharmacology Approach

Aaptamine – a dual acetyl – and butyrylcholinesterase inhibitor as potential anti-Alzheimer’s disease agent

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