Derivatives of montanine-type alkaloids and their implication for the treatment of Alzheimer's disease: Synthesis, biological activity and in silico study
Language English Country Great Britain, England Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
34555506
DOI
10.1016/j.bmcl.2021.128374
PII: S0960-894X(21)00601-6
Knihovny.cz E-resources
- Keywords
- Acetylcholinesterase, Alzheimeŕs disease, Amaryllidaceae alkaloid, Butyrylcholinesterase, Docking studies, Montanine-type,
- MeSH
- Acetylcholinesterase metabolism MeSH
- Alkaloids chemical synthesis chemistry pharmacology MeSH
- Alzheimer Disease drug therapy metabolism MeSH
- Butyrylcholinesterase metabolism MeSH
- Cholinesterase Inhibitors chemical synthesis chemistry pharmacology MeSH
- Blood-Brain Barrier drug effects metabolism MeSH
- Isoquinolines chemical synthesis chemistry pharmacology MeSH
- Humans MeSH
- Molecular Structure MeSH
- Molecular Docking Simulation * MeSH
- Dose-Response Relationship, Drug 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
- Alkaloids MeSH
- Butyrylcholinesterase MeSH
- Cholinesterase Inhibitors MeSH
- Isoquinolines MeSH
- montanine MeSH Browser
Alzheimeŕs disease (AD) is the most common neurodegenerative disorder, characterized by neuronal loss and cognitive impairment. Currently, very few drugs are available for AD treatment, and a search for new therapeutics is urgently needed. Thus, in the current study, twenty-eight new derivatives of montanine-type Amaryllidaceae alkaloids were synthesized and evaluated for their ability to inhibit human recombinant acetylcholinesterase (hAChE) and butyrylcholinesterase (hBuChE). Three derivatives (1n, 1o, and 1p) with different substitution patterns demonstrated significant selective inhibitory potency for hAChE (IC50 < 5 µM), and one analog, 1v, showed selective hBuChE inhibition activity (IC50 = 1.73 ± 0.05 µM). The prediction of CNS availability, as disclosed by the BBB score, suggests that the active compounds in this survey should be able pass through the blood-brain barrier (BBB). Cytotoxicity screening and docking studies were carried out for the two most pronounced cholinesterase inhibitors, 1n and 1v.
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