Functionalized aromatic esters of the Amaryllidaceae alkaloid haemanthamine and their in vitro and in silico biological activity connected to Alzheimer's disease
Language English Country United States Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
32450384
DOI
10.1016/j.bioorg.2020.103928
PII: S0045-2068(19)32125-X
Knihovny.cz E-resources
- Keywords
- Acetylcholinesterase, Alzheimer’s disease, Amaryllidaceae, Butyrylcholinesterase, Docking studies, Haemanthamine,
- MeSH
- Acetylcholinesterase chemistry metabolism MeSH
- Amaryllidaceae Alkaloids chemistry metabolism therapeutic use MeSH
- Alzheimer Disease drug therapy pathology MeSH
- Amaryllidaceae chemistry metabolism MeSH
- Butyrylcholinesterase chemistry metabolism MeSH
- Cholinesterase Inhibitors chemical synthesis metabolism therapeutic use MeSH
- Esters chemistry MeSH
- Phenanthridines chemistry metabolism therapeutic use MeSH
- Blood-Brain Barrier drug effects metabolism MeSH
- Kinetics MeSH
- Humans MeSH
- Molecular Docking Simulation MeSH
- Binding Sites MeSH
- Structure-Activity Relationship MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Acetylcholinesterase MeSH
- Amaryllidaceae Alkaloids MeSH
- Butyrylcholinesterase MeSH
- Cholinesterase Inhibitors MeSH
- Esters MeSH
- Phenanthridines MeSH
- hemanthamine MeSH Browser
A novel series of aromatic esters (1a-1m) related to the Amaryllidaceae alkaloid (AA) haemanthamine were designed, synthesized and tested in vitro with particular emphasis on the treatment of neurodegenerative diseases. Some of the synthesized compounds revealed promising acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitory profile. Significant human AChE (hAChE) inhibition was demonstrated by 11-O-(3-nitrobenzoyl)haemanthamine (1j) with IC50value of 4.0 ± 0.3 µM. The strongest human BuChE (hBuChE) inhibition generated 1-O-(2-methoxybenzoyl)haemanthamine (1g) with IC50 value 3.3 ± 0.4 µM. Moreover, 11-O-(2-chlorbenzoyl)haemanthamine (1m) was able to inhibit both enzymes in dose-dependent manner. The mode of hAChE and hBuChE inhibition was minutely inspected using enzyme kinetic analysis in tandem with in silico experiments, the latter elucidating crucial interaction in 1j-, 1m-hAChE and 1g-, 1m-hBuChE complexes. The blood-brain barrier (BBB) permeability was investigated applying the parallel artificial membrane permeation assay (PAMPA) to predict the CNS availability of the compounds.
Centro de Investigaciones Biológicas CSIC Avenida Ramiro de Maeztu 9 28040 Madrid Spain
Department for Life Quality Studies University of Bologna Corso D'Augusto 237 47921 Rimini Italy
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