Novel tacrine/acridine anticholinesterase inhibitors with piperazine and thiourea linkers
Language English Country Netherlands Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
25036600
DOI
10.1016/j.ijbiomac.2014.06.064
PII: S0141-8130(14)00482-6
Knihovny.cz E-resources
- Keywords
- Alzheimer's disease, Cholinesterase, Cholinesterase inhibitors, Coumarin, Tacrine, β-Amyloid aggregation,
- MeSH
- Acetylcholinesterase chemistry metabolism MeSH
- Acridines chemistry MeSH
- Enzyme Activation drug effects MeSH
- Butyrylcholinesterase chemistry metabolism MeSH
- Cholinesterase Inhibitors chemistry pharmacology MeSH
- Humans MeSH
- Molecular Conformation MeSH
- Models, Molecular MeSH
- Piperazine MeSH
- Piperazines chemistry MeSH
- Tacrine chemistry MeSH
- Thiourea chemistry MeSH
- Protein Binding MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Acetylcholinesterase MeSH
- Acridines MeSH
- Butyrylcholinesterase MeSH
- Cholinesterase Inhibitors MeSH
- Piperazine MeSH
- Piperazines MeSH
- Tacrine MeSH
- Thiourea MeSH
A new series of substituted tacrine/acridine and tacrine/tacrine dimers with aliphatic or alkylene-thiourea linkers was synthesized and the potential of these compounds as novel human acetylcholinesterase (hAChE) and human butyrylcholinesterase (hBChE) inhibitors with nanomolar inhibition activity was evaluated. The most potent AChE inhibitor was found to be homodimeric tacrine derivative 14a, which demonstrated an IC50 value of 2 nM; this value indicates an activity rate which is 250-times higher than that of tacrine 1 and 7500-times higher than 7-MEOTA 15, the compounds which were used as standards in the study. IC50 values of derivatives 1, 9, 10, 14b and 15 were compared with the dissociation constants of the enzyme-inhibitor complex, Ki1, and the enzyme-substrate-inhibitor complex, Ki2, for. A dual binding site is presumed for the synthesized compounds which possess two tacrines or tacrine and acridine as terminal moieties show evidence of dual site binding. DFT calculations of theoretical desolvation free energies, ΔΔGtheor, and docking studies elucidate these suggestions in more detail.
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