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Preparation, in vitro screening and molecular modelling of symmetrical bis-quinolinium cholinesterase inhibitors--implications for early myasthenia gravis treatment
M. Komloova, K. Musilek, A. Horova, O. Holas, V. Dohnal, F. Gunn-Moore, K. Kuca,
Language English Country England, Great Britain
Document type Journal Article, Research Support, Non-U.S. Gov't
- MeSH
- Acetylcholinesterase chemistry genetics metabolism MeSH
- Ambenonium Chloride chemistry pharmacology MeSH
- Benzenaminium, 4,4'-(3-oxo-1,5-pentanediyl)bis(N,N-dimethyl-N-2-propenyl-), Dibromide chemistry pharmacology MeSH
- Butyrylcholinesterase chemistry genetics metabolism MeSH
- Quinolinium Compounds chemistry pharmacology therapeutic use MeSH
- Cholinesterase Inhibitors chemistry pharmacology therapeutic use MeSH
- Edrophonium chemistry pharmacology MeSH
- Kinetics MeSH
- Humans MeSH
- Myasthenia Gravis drug therapy MeSH
- Recombinant Proteins chemistry genetics metabolism MeSH
- Molecular Dynamics Simulation 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
This paper describes the preparation and in vitro evaluation of 18 newly prepared bis-quinolinium inhibitors on human recombinant acetylcholinesterase (AChE) and human plasmatic butyrylcholinesterase (BChE). Their inhibitory (IC(50)) and was compared to the chosen standards ambenonium dichloride, edrophonium chloride, BW284c51 and ethopropazine hydrochloride. One novel compound was found to be a promising inhibitor of hAChE (in nM range) and was better than edrophonium chloride or BW284c51, but was worse than ambenonium chloride. This compound also showed selectivity towards hAChE and it was confirmed as a non-competitive inhibitor of hAChE by kinetic analysis. A molecular modelling study further confirmed its binding to the peripheral active site of hAChE via apparent π-π or π-cationic interactions.
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