Synthesis and characterization of new inhibitors of cholinesterases based on N-phenylcarbamates: In vitro study of inhibitory effect, type of inhibition, lipophilicity and molecular docking
Language English Country United States Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
29621640
DOI
10.1016/j.bioorg.2018.03.012
PII: S0045-2068(18)30020-8
Knihovny.cz E-resources
- Keywords
- Carbamates, Cholinesterases, IC(50), Molecular modeling, Monosaccharide derivatives, Water bridge,
- MeSH
- Acetylcholinesterase metabolism MeSH
- Butyrylcholinesterase metabolism MeSH
- Cholinesterase Inhibitors chemical synthesis chemistry pharmacology MeSH
- Electrophorus MeSH
- Phenylcarbamates chemical synthesis chemistry pharmacology MeSH
- Hydrophobic and Hydrophilic Interactions MeSH
- Horses MeSH
- Ligands MeSH
- Models, Molecular MeSH
- Molecular Structure MeSH
- Dose-Response Relationship, Drug MeSH
- Structure-Activity Relationship MeSH
- Animals MeSH
- Check Tag
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Acetylcholinesterase MeSH
- Butyrylcholinesterase MeSH
- Cholinesterase Inhibitors MeSH
- Phenylcarbamates MeSH
- Ligands MeSH
Based on current treatment of Alzheimer's disease, where the carbamate inhibitor Rivastigmine is used, two series of carbamate derivatives were prepared: (i) N-phenylcarbamates with additional carbamate group (1-12) and (ii) N-phenylcarbamates with monosaccharide moiety (13-24). All compounds were tested for the inhibitory effect on both of the cholinesterases, electric eel acetylcholinesterase (eeAChE) and butyrylcholinesterase from equine serum (eqBChE) and the inhibitory activity (expressed as IC50 values) was compared with that of the established drugs Galanthamine and Rivastigmine. The compounds with two carbamate groups 1-12 revealed higher inhibitory efficiency on both cholinesterases in compared with monosaccharide derived carbamates 13-24 and with Rivastigmine. The significant decrease of inhibitory efficiency on eqBChE (also for eeAChE but in less manner) was observed after deacetalization of monosaccharide. Moreover, the type of inhibitory mechanism of five chosen compounds was studied. It was found, that compounds with two carbamate groups act presumably via a mixed inhibitory mechanism and the compounds with monosaccharide moiety act as non-competitive inhibitors. The lipophilicity of tested compounds was determined using partition coefficient. Specific positions of the inhibitors in the binding sites of cholinesterases were determined using molecular modeling and the results indicate the importance of phenylcarbamate orientation in the catalytic gorges of both enzymes.
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