Aromatic Esters of the Crinane Amaryllidaceae Alkaloid Ambelline as Selective Inhibitors of Butyrylcholinesterase
Language English Country United States Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
- MeSH
- Amaryllidaceae Alkaloids chemical synthesis pharmacokinetics pharmacology MeSH
- Amaryllidaceae chemistry MeSH
- Butyrylcholinesterase drug effects MeSH
- Cholinesterase Inhibitors chemical synthesis pharmacokinetics pharmacology MeSH
- Esters MeSH
- Blood-Brain Barrier MeSH
- Humans MeSH
- Models, Molecular MeSH
- Molecular Structure MeSH
- Molecular Docking Simulation MeSH
- Substrate Specificity MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Amaryllidaceae Alkaloids MeSH
- Butyrylcholinesterase MeSH
- Cholinesterase Inhibitors MeSH
- Esters MeSH
A total of 20 derivatives (1-20) of the crinane-type alkaloid ambelline were synthesized. These semisynthetic derivatives were assessed for their potency to inhibit both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). To predict central nervous system (CNS) availability, logBB was calculated, and the data correlated well with those obtained from the parallel artificial membrane permeability assay (PAMPA). All compounds should be able to permeate the blood-brain barrier (BBB) according to the obtained results. A total of 7 aromatic derivatives (5, 6, 7, 9, 10, 12, and 16) with different substitution patterns showed inhibitory potency against human serum BuChE (IC50 < 5 μM), highlighting the three top-ranked compounds as follows: 11-O-(1-naphthoyl)ambelline (16), 11-O-(2-methylbenzoyl)ambelline (6), and 11-O-(2-methoxybenzoyl)ambelline (9) with IC50 values of 0.10 ± 0.01, 0.28 ± 0.02, and 0.43 ± 0.04 μM, respectively. Notably, derivatives 6, 7, 9, and 16 displayed selective human BuChE (hBuChE) inhibition profiles with a selectivity index > 100. The in vitro results were supported by computational studies predicting plausible binding modes of the compounds in the active sites of hBuChE.
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