Novel propargylamine-based inhibitors of cholinesterases and monoamine oxidases: Synthesis, biological evaluation and docking study
Language English Country United States Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
34492558
DOI
10.1016/j.bioorg.2021.105301
PII: S0045-2068(21)00678-7
Knihovny.cz E-resources
- Keywords
- Acetylcholinesterase, Butyrylcholinesterase, Enzyme inhibition, Molecular docking, Monoamine oxidases, Multitargeting ligands, Propargylamine, Salicylic scaffold,
- MeSH
- Antioxidants chemical synthesis chemistry pharmacology MeSH
- Butyrylcholinesterase metabolism MeSH
- Cholinesterase Inhibitors chemical synthesis chemistry pharmacology MeSH
- Cholinesterases metabolism MeSH
- Electrophorus MeSH
- Hepatocytes drug effects metabolism MeSH
- Monoamine Oxidase Inhibitors chemical synthesis chemistry pharmacology MeSH
- Horses MeSH
- Rats MeSH
- Cells, Cultured MeSH
- Humans MeSH
- Molecular Structure MeSH
- Monoamine Oxidase metabolism MeSH
- Pargyline analogs & derivatives chemical synthesis chemistry pharmacology MeSH
- Rats, Wistar MeSH
- Propylamines chemical synthesis chemistry pharmacology MeSH
- Reactive Oxygen Species metabolism MeSH
- Molecular Docking Simulation * MeSH
- Dose-Response Relationship, Drug MeSH
- Structure-Activity Relationship MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Humans MeSH
- Male MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Antioxidants MeSH
- Butyrylcholinesterase MeSH
- Cholinesterase Inhibitors MeSH
- Cholinesterases MeSH
- Monoamine Oxidase Inhibitors MeSH
- Monoamine Oxidase MeSH
- Pargyline MeSH
- propargylamine MeSH Browser
- Propylamines MeSH
- Reactive Oxygen Species MeSH
A combination of several pharmacophores in one molecule has been successfully used for multi-target-directed ligands (MTDL) design. New propargylamine substituted derivatives combined with salicylic and cinnamic scaffolds were designed and synthesized as potential cholinesterases and monoamine oxidases (MAOs) inhibitors. They were evaluated invitro for inhibition of acetyl- (AChE) and butyrylcholinesterase (BuChE) using Ellman's method. All the compounds act as dual inhibitors. Most of the derivatives are stronger inhibitors of AChE, the best activity showed 5-bromo-N-(prop-2-yn-1-yl)salicylamide 1e (IC50 = 8.05 µM). Carbamates (4-bromo-2-[(prop-2-yn-1-yl)carbamoyl]phenyl ethyl(methyl)carbamate 2d and 2,4-dibromo-6-[(prop-2-yn-1-yl)carbamoyl]phenyl ethyl(methyl)carbamate 2e were selective and the most active for BuChE (25.10 and 26.09 µM). 4-Bromo-2-[(prop-2-yn-1-ylimino)methyl]phenol 4a was the most potent inhibitor of MAOs (IC50 of 3.95 and ≈10 µM for MAO-B and MAO-A, respectively) along with a balanced inhibition of both cholinesterases being a real MTDL. The mechanism of action was proposed, and binding modes of the hits were studied by molecular docking on human enzymes. Some of the derivatives also exhibited antioxidant properties. Insilico prediction of physicochemical parameters affirm that the molecules would be active after oral administration and able to reach brain tissue.
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