Highly Selective Butyrylcholinesterase Inhibitors With Tunable Duration of Action by Chemical Modification of Transferable Carbamate Units Exhibit Pronounced Neuroprotective Effect in an Alzheimer’s Disease Mouse Model
Abstract
In this study, the carbamate structure of pseudo-irreversible butyrylcholinesterase (BChE) inhibitors was optimized with regard to a longer binding to the enzyme. A set of compounds bearing different heterocycles (e.g., morpholine, tetrahydroisoquinoline, benzimidazole, piperidine) and alkylene spacers (2 to 10 methylene groups between carbamate and heterocycle) in the carbamate residue was synthesized and characterized in vitro for their binding affinity, binding kinetics, and carbamate hydrolysis. These novel BChE inhibitors are highly selective for h BChE over human acetycholinesterase ( h AChE), yielding short-, medium-, and long-acting nanomolar h BChE inhibitors (with a half-life of the carbamoylated enzyme ranging from 1 to 28 h). The inhibitors show neuroprotective properties in a murine hippocampal cell line and a pharmacological mouse model of Alzheimer’s disease (AD), suggesting a significant benefit of BChE inhibition for a disease-modifying treatment of AD.
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During Alzheimer's disease progression, BChE activity can increase significantly, potentially contributing to aggregation of amyloid beta-peptides and formation of senile plaques.
“Notably, during the progression of AD, BChE activity can increase significantly, potentially contributing to the aggregation of amyloid beta-peptides and the formation of senile plaques, which are characteristic of the disease [90,91].”
From Cholinesterase Inhibitors from Plants and Their Potential in Alzheimer’s Treatment: Systematic Review (2025) · cites this paper as [91]
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Memantine Derivatives as Multitarget Agents in Alzheimer’s Disease
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“Notably, during the progression of AD, BChE activity can increase significantly, potentially contributing to the aggregation of amyloid beta-peptides and the formation of senile plaques, which are characteristic of the disease [90,91].”
- Authors
- Hoffmann, M., Stiller, C., Endres, E., Scheiner, M., Gunesch, S., Sotriffer, C., Maurice, T., & Decker, M.
- Affiliations
- University of Würzburg (DE)
- Inserm (FR)
- Corresponding author
- Decker, Michael
- ORCID
- Venue
- Journal of Medicinal Chemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2019-10-14
- Volume
- 62
- Issue
- 20
- Pages
- 9116-9140
- ISSN
- 0022-2623 (ISSN-L)
- 1520-4804
- OpenAlex
- W2980601903
- Cited by
- 105
- References
- 84
- Citations by year
- 2026: 11 · 2025: 17 · 2024: 18 · 2023: 11 · 2022: 20 · 2021: 14 · 2020: 14
- FWCI
- 8.83
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Journal of Medicinal Chemistry (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Funders
- Bundesministerium f??r Bildung und Forschung
- Deutscher Akademischer Austauschdienst
- Campus France
- Bayerisches Staatsministerium f??r Bildung und Kultus, Wissenschaft und Kunst
- Deutsche Forschungsgemeinschaft (DE 1546/6-3)
- Studienstiftung des Deutschen Volkes
- 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
- butyrylcholinesterase inhibitors, enzyme selectivity, duration of action, carbamate hydrolysis, binding kinetics, morpholine, tetrahydroisoquinolines, benzimidazole, piperidine, neuroprotection, Alzheimer's disease, disease-modifying therapy, hippocampal cells
- MeSH terms
- Alzheimer Disease, Animals, Butyrylcholinesterase, Carbamates, Cholinesterase Inhibitors, Disease Models, Animal, Neuroprotective Agents, Mice
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