Targeting beta-amyloid pathogenesis through acetylcholinesterase inhibitors

Castro, Ana; Martinez, Ana

doi:10.2174/138161206778792985

Cited by 256Cholinesterase and Neurodegenerative DiseasesAlzheimer's disease research and treatmentsEnzyme function and inhibition

Targeting beta-amyloid pathogenesis through acetylcholinesterase inhibitors

Castro, Ana, Martinez, Ana·2006·Current Pharmaceutical Design

DOI 10.2174/138161206778792985

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Abstract

Although the hallmarks of neurodegeneration in Alzheimer's brains are well known, one of the current difficulties is related to the lack of solid evidence about the ultimate factors that give rise to the pathogenesis of this disease, creating a great challenge for the definition of efficient treatments for Alzheimer's disease (AD). Current therapeutic option for AD patients is the use of acetylcholinesterase (AChE) inhibitors, which gives only a symptomatic relief. However, recent studies show a long-lasting effect in a certain percentage of patients. In fact, there is accumulating evidence that an AChE has secondary non-cholinergic functions including the processing and deposition of beta-amyloid (Abeta). AChE could play a role in the Abeta metabolism and during an early step in the development of the senile plaque, as revealed by the finding that AChE accelerates Abeta deposition. Considering the non-classical AChE functions, their relationships with AD hallmarks, and the putative role of peripheral anionic site in all these functions, the dual binding site AChE inhibitors may acquire importance for AD treatment. On the other hand, the interference of AChE inhibitors with Abeta processing is not a general rule for this class of compounds with the involvement of other features such as chemical structure and/or genetic regulation. This review highlights the collection of several compounds with an outstanding profile against AChE-induced amyloid aggregation and potent AChE inhibitory activity, indicating the possibility of targeting Abeta through the inhibition of AChE and reveals the emergence of a new generation of AChE inhibitors aiming to be excellent candidate drugs for the future cure of Alzheimer's disease.

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Conformational changes due to AChE-Aβ complex formation enhance Aβ metabolism and senile plaque generation.
“Moreover, the conformational changes due to AChE-Aβ complex formation also enhanced the metabolism of Aβ and senile plaque generation [30].”
From Acetylcholinesterase Inhibitory Potential of Various Sesquiterpene Analogues for Alzheimer’s Disease Therapy (2021) · cites this paper as [30]

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Synthesis, Biological Evaluation, and Molecular Modeling of Donepezil and N-[(5-(Benzyloxy)-1-methyl-1H-indol-2-yl)methyl]-N-methylprop-2-yn-1-amine Hybrids as New Multipotent Cholinesterase/Monoamine Oxidase Inhibitors for the Treatment of Alzheimer’s Disease
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Cholinesterase Inhibitors and Beyond
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Oxidative Stress in Alzheimer’s Disease: Are We Connecting the Dots?
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Pyrano[3,2-c]quinoline−6-Chlorotacrine Hybrids as a Novel Family of Acetylcholinesterase- and β-Amyloid-Directed Anti-Alzheimer Compounds
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Tacrine–Melatonin Hybrids as Multifunctional Agents for Alzheimer's Disease, with Cholinergic, Antioxidant, and Neuroprotective Properties
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Synthesis and Multitarget Biological Profiling of a Novel Family of Rhein Derivatives As Disease-Modifying Anti-Alzheimer Agents
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Donepezil + propargylamine + 8-hydroxyquinoline hybrids as new multifunctional metal-chelators, ChE and MAO inhibitors for the potential treatment of Alzheimer's disease
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Tacripyrines, the First Tacrine−Dihydropyridine Hybrids, as Multitarget-Directed Ligands for the Treatment of Alzheimer’s Disease
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Novel Tacrine–Benzofuran Hybrids as Potent Multitarget-Directed Ligands for the Treatment of Alzheimer’s Disease: Design, Synthesis, Biological Evaluation, and X-ray Crystallography
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Synthesis and evaluation of 7-substituted coumarin derivatives as multimodal monoamine oxidase-B and cholinesterase inhibitors for the treatment of Alzheimer's disease
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Boom in the development of non‐peptidic β‐secretase (BACE1) inhibitors for the treatment of Alzheimer's disease
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Memoquin: A Multi-Target–Directed Ligand as an Innovative Therapeutic Opportunity for Alzheimer's Disease
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Synthesis of new donepezil analogues and investigation of their effects on cholinesterase enzymes
Sağlık, B. N., Ilgın, S., & Özkay, Y. (2016) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2016.10.042 · Cited by 116 · see citing works
Acetylcholinesterase Inhibitory Potential of Various Sesquiterpene Analogues for Alzheimer’s Disease Therapy
Arya, A., Chahal, R., Rao, R., Rahman, M. H., Kaushik, D., Akhtar, M. F., Saleem, A., Khalifa, S. M. A., El-Seedi, H. R., Kamel, M., et al. (2021) · Biomolecules · doi:10.3390/biom11030350 · Cited by 111 · see citing works
“Moreover, the conformational changes due to AChE-Aβ complex formation also enhanced the metabolism of Aβ and senile plaque generation [30].”
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A review of pharmacological and pharmacokinetic properties of Forsythiaside A
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Synergistic Effects of Curcumin and Piperine as Potent Acetylcholine and Amyloidogenic Inhibitors With Significant Neuroprotective Activity in SH-SY5Y Cells via Computational Molecular Modeling and in vitro Assay
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Combined QSAR, molecular docking and molecular dynamics study on new Acetylcholinesterase and Butyrylcholinesterase inhibitors
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Neuroprotective and Cholinergic Properties of Multifunctional Glutamic Acid Derivatives for the Treatment of Alzheimer’s Disease
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Tacrine-6-Ferulic Acid, a Novel Multifunctional Dimer, Inhibits Amyloid-β-Mediated Alzheimer's Disease-Associated Pathogenesis In Vitro and In Vivo
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Donepezil-Based Central Acetylcholinesterase Inhibitors by Means of a “Bio-Oxidizable” Prodrug Strategy: Design, Synthesis, and in Vitro Biological Evaluation
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Design, synthesis and evaluation of novel tacrine–rhein hybrids as multifunctional agents for the treatment of Alzheimer's disease
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Multi-target Design Strategies in the Context of Alzheimer’s Disease: Acetylcholinesterase Inhibition and NMDA Receptor Antagonism as the Driving Forces
Rosini, M., Simoni, E., Minarini, A., & Melchiorre, C. (2014) · Neurochemical Research · doi:10.1007/s11064-014-1250-1 · Cited by 94 · see citing works
Pinus halepensis essential oil attenuates the toxic Alzheimer’s amyloid beta (1-42)-induced memory impairment and oxidative stress in the rat hippocampus
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A multifunctional therapeutic approach: Synthesis, biological evaluation, crystal structure and molecular docking of diversified 1H-pyrazolo[3,4-b]pyridine derivatives against Alzheimer's disease
Umar, T., Shalini, S., Raza, M. K., Gusain, S., Kumar, J., Seth, P., Tiwari, M., & Hoda, N. (2019) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2019.04.038 · Cited by 89 · see citing works
Current Pharmacotherapy and Multi-Target Approaches for Alzheimer’s Disease
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Natural acetylcholinesterase inhibitors: A multi-targeted therapeutic potential in Alzheimer's disease
Kumar, G., K., P. G., Poornima, D. V., Shantaram, M., & Ranjita, G. (2024) · European Journal of Medicinal Chemistry Reports · doi:10.1016/j.ejmcr.2024.100154 · Cited by 88 · see citing works
Synthesis and evaluation of dihydropyrimidinone-derived selenoesters as multi-targeted directed compounds against Alzheimer’s disease
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Oxidative Stress, Mitochondrial Abnormalities and Proteins Deposition: Multitarget Approaches in Alzheimer's Disease
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Cystamine-tacrine dimer: A new multi-target-directed ligand as potential therapeutic agent for Alzheimer’s disease treatment
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Discovery of Novel Tacrine–Pyrimidone Hybrids as Potent Dual AChE/GSK-3 Inhibitors for the Treatment of Alzheimer’s Disease
Yao, H., Uras, G., Zhang, P., Xu, S., Yin, Y., Liu, J., Qin, S., Li, X., Allen, S., Bai, R., et al. (2021) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.1c00160 · Cited by 82 · see citing works
RETRACTED ARTICLE: Neuroprotective effect of ipriflavone against scopolamine-induced memory impairment in rats
Hafez, H. S., Ghareeb, D. A., Saleh, S. R., Abady, M. M., Demellawy, M. E., Hussien, H. M., & Abdel-Monem, N. M. (2017) · Psychopharmacology · doi:10.1007/s00213-017-4690-x · Cited by 82 · see citing works
Retracted
Synthesis, Inhibitory Activity of Cholinesterases, and Neuroprotective Profile of Novel 1,8-Naphthyridine Derivatives
Rı́os, C. D. L., Egea, J., Marco, J. L., Leon, R. M., Samadi, A., Iriepa, I., Moraleda, I., Galvez‐Ruano, E., Garcı́a, A. G., López, M. G., et al. (2010) · Journal of Medicinal Chemistry · doi:10.1021/jm901902w · Cited by 79 · see citing works
Multitarget Strategies in Alzheimer’S Disease: Benefits and Challenges on the Road to Therapeutics
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Design, synthesis and biological evaluation of novel coumarin- N -benzyl pyridinium hybrids as multi-target agents for the treatment of Alzheimer's disease
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BDNF-, IGF-1- and GDNF-Secreting Human Neural Progenitor Cells Rescue Amyloid β-Induced Toxicity in Cultured Rat Septal Neurons
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Dual Inhibitors of β-Amyloid Aggregation and Acetylcholinesterase as Multi-Target Anti-Alzheimer Drug Candidates
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Discovery of novel rivastigmine-hydroxycinnamic acid hybrids as multi-targeted agents for Alzheimer's disease
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Multipotent MAO and cholinesterase inhibitors for the treatment of Alzheimer's disease: Synthesis, pharmacological analysis and molecular modeling of heterocyclic substituted alkyl and cycloalkyl propargyl amine
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Synthesis and evaluation of novel 1,2,3-triazole-based acetylcholinesterase inhibitors with neuroprotective activity
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Synthesis, biological assessment and molecular modeling of new multipotent MAO and cholinesterase inhibitors as potential drugs for the treatment of Alzheimer’s disease
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Synthesis, biological assessment, and molecular modeling of racemic 7-aryl-9,10,11,12-tetrahydro-7H-benzo[7,8]chromeno[2,3-b]quinolin-8-amines as potential drugs for the treatment of Alzheimer's disease
Maalej, E., Chabchoub, F., Oset‐Gasque, M. J., Esquivias-Pérez, M., González, M. P., Monjas, L., Pérez, C., Rı́os, C. D. L., Rodrı́guez-Franco, M. I., Iriepa, I., et al. (2012) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2012.06.038 · Cited by 69 · see citing works
N-Methyl-N-((1-methyl-5-(3-(1-(2-methylbenzyl)piperidin-4-yl)propoxy)-1H-indol-2-yl)methyl)prop-2-yn-1-amine, a New Cholinesterase and Monoamine Oxidase Dual Inhibitor
Bautista‐Aguilera, Ó. M., Samadi, A., Chioua, M., Nikolic, K. M., Filipić, S., Agbaba, D., Soriano, E., de Andrés, L., Rodrı́guez-Franco, M. I., Alcaro, S., et al. (2014) · Journal of Medicinal Chemistry · doi:10.1021/jm501501a · Cited by 67 · see citing works
Protective effects of low molecular weight chondroitin sulfate on amyloid beta (Aβ)-induced damage in vitro and in vivo
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Alzheimer's disease and related neurodegenerative disorders: implication and counteracting of melatonin
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Novel Triazole-Quinoline Derivatives as Selective Dual Binding Site Acetylcholinesterase Inhibitors
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Synthesis and pharmacological assessment of diversely substituted pyrazolo[3,4-b]quinoline, and benzo[b]pyrazolo[4,3-g][1,8]naphthyridine derivatives
SILVA, D. N. N. D., Chioua, M., Samadi, A., Carreiras, M. C., Jimeno, M. L., Mendes, E., Rı́os, C. D. L., Romero, A., Villarroya, M., López, M. G., et al. (2011) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2011.05.068 · Cited by 61 · see citing works
Latest advances in dual inhibitors of acetylcholinesterase and monoamine oxidase B against Alzheimer’s disease
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Cholinergic System and Post-translational Modifications: An Insight on the Role in Alzheimer's Disease
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Drug repurposing for Alzheimer’s disease: in silico and in vitro investigation of FDA-approved drugs as acetylcholinesterase inhibitors
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Toxicological and pharmacological evaluation, antioxidant, ADMET and molecular modeling of selected racemic chromenotacrines {11-amino-12-aryl-8,9,10,12-tetrahydro-7H-chromeno[2,3-b]quinolin-3-ols} for the potential prevention and treatment of Alzheimer's disease
Oset‐Gasque, M. J., González, M. P., Pérez‐Peña, J., García-Font, N., Romero, A., del Pino, J., Ramos, E., Hadjipavlou‐Litina, D., Soriano, E., Chioua, M., et al. (2014) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2013.12.021 · Cited by 55 · see citing works
Multipotent drugs with cholinergic and neuroprotective properties for the treatment of Alzheimer and neuronal vascular diseases. I. Synthesis, biological assessment, and molecular modeling of simple and readily available 2-aminopyridine-, and 2-chloropyridine-3,5-dicarbonitriles
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Phenserine
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Multi-Target-Directed Ligands as an Effective Strategy for the Treatment of Alzheimer’s Disease
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Novel oxoisoaporphine-based inhibitors of acetyl- and butyrylcholinesterase and acetylcholinesterase-induced beta-amyloid aggregation
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Synthesis and AChE Inhibitory Activity of Novel Thiazolylhydrazone Derivatives
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Dual-Acting Cholinesterase–Human Cannabinoid Receptor 2 Ligands Show Pronounced Neuroprotection in Vitro and Overadditive and Disease-Modifying Neuroprotective Effects in Vivo
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Study of the interactions of forsythiaside and rutin with acetylcholinesterase (AChE)
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Authors: Castro, A., & Martinez, A.
ORCID: Castro, Ana
Venue: Current Pharmaceutical Design
Publisher: Bentham Science Publishers Ltd.
Published: 2006-11-01
Volume: 12
Issue: 33
Pages: 4377-4387
ISSN: 1381-6128 (ISSN-L)
DOI: 10.2174/138161206778792985
OpenAlex: W1976042714
Cited by: 207
References: 75
Citations by year: 2026: 7 · 2025: 5 · 2024: 12 · 2023: 7 · 2022: 13 · 2021: 13 · 2020: 12 · 2019: 10 · 2018: 7 · 2017: 16 · 2016: 16 · 2015: 11 · 2014: 9 · 2013: 8 · 2012: 15
FWCI: 5.22
Type: journal article
Language: en
Open access: closed
Locations: Current Pharmaceutical Design (publishedVersion)
PubMed (publishedVersion)
Topics: Health Sciences › Medicine › Pharmacology › Cholinesterase and Neurodegenerative Diseases
Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Enzyme function and inhibition
Keywords: Alzheimer's disease, amyloid-beta, acetylcholinesterase inhibitors, amyloid fibril formation, peripheral anionic site, dual binding site inhibitors, amyloid plaques, amyloid deposition
MeSH terms: Alzheimer Disease, Cholinesterase Inhibitors, Humans, Amyloid beta-Peptides

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Targeting beta-amyloid pathogenesis through acetylcholinesterase inhibitors

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