Synthesis of derivatives of cleistopholine and their anti-acetylcholinesterase and anti-β-amyloid aggregation activity

Wu, Zhenhua; Liao, Wenxia; Chen, Kelin; Qin, Jingfang; Tang, Huang

doi:10.1016/j.bioorg.2017.11.011

Cited by 7 publications

(5 citation statements)

References 43 publications

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“…Its activity may indirectly reflect the severity of oxidative stress damage in AD [ 42 ]. Previous studies have reported the alleviation of Aβ deposition by increasing SOD activity and inhibiting AChE activity in AD mice and in vitro cells [ 43 , 44 ]. Clostridium butyricum has been demonstrated to increase SOD levels by regulating the p62-Keap1-Nrf2 signaling pathway and the intestinal microbial community [ 45 ].…”

Section: Discussionmentioning

confidence: 99%

Impact of Donepezil Supplementation on Alzheimer’s Disease-like Pathology and Gut Microbiome in APP/PS1 Mice

Li,

Wu,

Kong

et al. 2023

Microorganisms

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Based on published information, the occurrence and development of Alzheimer’s disease (AD) are potentially related to gut microbiota changes. Donepezil hydrochloride (DH), which enhances cholinergic activity by blocking acetylcholinesterase (AChE), is one of the first-line drugs for AD treatment approved by the Food and Drug Administration (FDA) of the USA. However, the potential link between the effects of DH on the pathophysiological processes of AD and the gut microbiota remains unclear. In this study, pathological changes in the brain and colon, the activities of superoxide dismutase (SOD) and AChE, and changes in intestinal flora were observed. The results showed that Aβ deposition in the prefrontal cortex and hippocampus of AD mice was significantly decreased, while colonic inflammation was significantly alleviated by DH treatment. Concomitantly, SOD activity was significantly improved, while AChE was significantly reduced after DH administration. In addition, the gut microbiota community composition of AD mice was significantly altered after DH treatment. The relative abundance of Akkermansia in the AD group was 54.8% higher than that in the N group. The relative abundance of Akkermansia was increased by 18.3% and 53.8% in the AD_G group and the N_G group, respectively. Interestingly, Akkermansia showed a potential predictive value and might be a biomarker for AD. Molecular docking revealed the binding mode and major forces between DH and membrane proteins of Akkermansia. The overall results suggest a novel therapeutic mechanism for treating AD and highlight the critical role of gut microbiota in AD pathology.

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Section: Discussionmentioning

confidence: 99%

Impact of Donepezil Supplementation on Alzheimer’s Disease-like Pathology and Gut Microbiome in APP/PS1 Mice

Li,

Wu,

Kong

et al. 2023

Microorganisms

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“…There is also some evidence that AChE may help in aβ plaque assembly, through binding to the PAS. 15 In this study, we employed a machine learning approach with literature data followed by a high-throughput screening strategy for the detection of AChE inhibitors and then a docking approach to visualize the molecular interactions with the most promising inhibitor identified. We were able to generate Bayesian machine learning models for eel and human AChE using literature data along with Assay Central or alternative machine learning algorithms.…”

Section: ■ Discussionmentioning

confidence: 99%

“…The cholinergic hypothesis of AD argues that the cognitive decline associated with the disease is due to the gradual loss of these cholinergic neurons, and three of the five FDA-approved treatments for AD are cholinesterase inhibitors. There is also some evidence that AChE may help in aβ plaque assembly, through binding to the PAS …”

Section: Discussionmentioning

confidence: 99%

“…12,13 Synthetic analogs and derivatives of these natural products have also been synthesized in an effort to find more AChE inhibitors. Derivatives from active compounds in peppers 14 trees 15,16 have been produced as well as derivatives of whole chemical classes of compounds like diterpenoids, 17 flavonoids, 18,19 and coumarins. 20,21 Additionally, compounds either derived from or incorporating the commercial inhibitors donepezil, 22,23 galantamine, 24 or tacrine 25−28 have been developed.…”

Section: ■ Introductionmentioning

confidence: 99%

“…AChE inhibitors have therefore continued to be found in the extracts of plants , and marine sponges. , Synthetic analogs and derivatives of these natural products have also been synthesized in an effort to find more AChE inhibitors. Derivatives from active compounds in peppers and trees , have been produced as well as derivatives of whole chemical classes of compounds like diterpenoids, flavonoids, , and coumarins. , Additionally, compounds either derived from or incorporating the commercial inhibitors donepezil, , galantamine, or tacrine − have been developed. Other approaches have focused on molecules designed to interact with key parts of the AChE enzyme binding site, like the peripheral anionic site (PAS). , …”

Section: Introductionmentioning

confidence: 99%

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The Antiviral Drug Tilorone Is a Potent and Selective Inhibitor of Acetylcholinesterase

Vignaux

Minerali

Lane

et al. 2021

Chem. Res. Toxicol.

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Acetylcholinesterase (AChE) is an important drug target in neurological disorders like Alzheimer’s disease, Lewy body dementia, and Parkinson’s disease dementia as well as for other conditions like myasthenia gravis and anticholinergic poisoning. In this study, we have used a combination of high-throughput screening, machine learning, and docking to identify new inhibitors of this enzyme. Bayesian machine learning models were generated with literature data from ChEMBL for eel and human AChE inhibitors as well as butyrylcholinesterase inhibitors (BuChE) and compared with other machine learning methods. High-throughput screens for the eel AChE inhibitor model identified several molecules including tilorone, an antiviral drug that is well-established outside of the United States, as a newly identified nanomolar AChE inhibitor. We have described how tilorone inhibits both eel and human AChE with IC50’s of 14.4 nM and 64.4 nM, respectively, but does not inhibit the closely related BuChE IC50 > 50 μM. We have docked tilorone into the human AChE crystal structure and shown that this selectivity is likely due to the reliance on a specific interaction with a hydrophobic residue in the peripheral anionic site of AChE that is absent in BuChE. We also conducted a pharmacological safety profile (SafetyScreen44) and kinase selectivity screen (SelectScreen) that showed tilorone (1 μM) only inhibited AChE out of 44 toxicology target proteins evaluated and did not appreciably inhibit any of the 485 kinases tested. This study suggests there may be a potential role for repurposing tilorone or its derivatives in conditions that benefit from AChE inhibition.

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Synthesis and biological evaluation of novel 8- substituted sampangine derivatives as potent inhibitor of Zn2+-Aβ complex mediated toxicity, oxidative stress and inflammation

Xie

et al. 2021

Bioorganic Chemistry

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Synthesis of derivatives of cleistopholine and their anti-acetylcholinesterase and anti-β-amyloid aggregation activity

Cited by 7 publications

References 43 publications

Impact of Donepezil Supplementation on Alzheimer’s Disease-like Pathology and Gut Microbiome in APP/PS1 Mice

Impact of Donepezil Supplementation on Alzheimer’s Disease-like Pathology and Gut Microbiome in APP/PS1 Mice

The Antiviral Drug Tilorone Is a Potent and Selective Inhibitor of Acetylcholinesterase

Synthesis and biological evaluation of novel 8- substituted sampangine derivatives as potent inhibitor of Zn2+-Aβ complex mediated toxicity, oxidative stress and inflammation

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