Preparation, in vitro evaluation and molecular modelling of pyridinium-quinolinium/isoquinolinium non-symmetrical bisquaternary cholinesterase inhibitors
Language English Country Great Britain, England Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
24220173
DOI
10.1016/j.bmcl.2013.10.043
PII: S0960-894X(13)01249-3
Knihovny.cz E-resources
- Keywords
- Cholinesterase, In vitro, Inhibitor, Molecular modelling, Myasthenia gravis,
- MeSH
- Acetylcholinesterase chemistry genetics metabolism MeSH
- Enzyme Activation drug effects MeSH
- Benzenaminium, 4,4'-(3-oxo-1,5-pentanediyl)bis(N,N-dimethyl-N-2-propenyl-), Dibromide chemistry metabolism pharmacology MeSH
- Butyrylcholinesterase chemistry genetics metabolism MeSH
- Quinolinium Compounds chemistry pharmacology MeSH
- Cholinesterase Inhibitors chemical synthesis chemistry metabolism pharmacology MeSH
- Humans MeSH
- Models, Molecular * MeSH
- Pyridinium Compounds chemistry pharmacology MeSH
- Recombinant Proteins biosynthesis chemistry genetics MeSH
- Protein Structure, Tertiary MeSH
- Protein Binding 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
- Benzenaminium, 4,4'-(3-oxo-1,5-pentanediyl)bis(N,N-dimethyl-N-2-propenyl-), Dibromide MeSH
- Butyrylcholinesterase MeSH
- Quinolinium Compounds MeSH
- Cholinesterase Inhibitors MeSH
- Pyridinium Compounds MeSH
- Recombinant Proteins MeSH
Two series of non-symmetrical bisquaternary pyridinium-quinolinium and pyridinium-isoquinolinium compounds were prepared as molecules potentially applicable in myasthenia gravis treatment. Their inhibitory ability towards human recombinant acetylcholinesterase and human plasmatic butyrylcholinesterase was determined and the results were compared to the known effective inhibitors such as ambenonium dichloride, edrophonium bromide and experimental compound BW284C51. Two compounds, 1-(10-(pyridinium-1-yl)decyl)quinolinium dibromide and 1-(12-(pyridinium-1-yl)dodecyl)quinolinium dibromide, showed very promising affinity for acetylcholinesterase with their IC50 values reaching nM inhibition of acetylcholinesterase. These most active compounds also showed satisfactory selectivity towards acetylcholinesterase and they seem to be very promising as leading structures for further modifications and optimization. Two of the most promising compounds were examined in the molecular modelling study in order to find the possible interactions between the ligand and tested enzyme.
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