Novel tacrine/acridine anticholinesterase inhibitors with piperazine and thiourea linkers
Jazyk angličtina Země Nizozemsko Médium print-electronic
Typ dokumentu časopisecké články, práce podpořená grantem
PubMed
25036600
DOI
10.1016/j.ijbiomac.2014.06.064
PII: S0141-8130(14)00482-6
Knihovny.cz E-zdroje
- Klíčová slova
- Alzheimer's disease, Cholinesterase, Cholinesterase inhibitors, Coumarin, Tacrine, β-Amyloid aggregation,
- MeSH
- acetylcholinesterasa chemie metabolismus MeSH
- akridiny chemie MeSH
- aktivace enzymů účinky léků MeSH
- butyrylcholinesterasa chemie metabolismus MeSH
- cholinesterasové inhibitory chemie farmakologie MeSH
- lidé MeSH
- molekulární konformace MeSH
- molekulární modely MeSH
- piperazin MeSH
- piperaziny chemie MeSH
- takrin chemie MeSH
- thiomočovina chemie MeSH
- vazba proteinů MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- acetylcholinesterasa MeSH
- akridiny MeSH
- butyrylcholinesterasa MeSH
- cholinesterasové inhibitory MeSH
- piperazin MeSH
- piperaziny MeSH
- takrin MeSH
- thiomočovina 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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