Novel tacrine-tryptophan hybrids: Multi-target directed ligands as potential treatment for Alzheimer's disease
Jazyk angličtina Země Francie Médium print-electronic
Typ dokumentu časopisecké články
PubMed
30851693
DOI
10.1016/j.ejmech.2019.02.021
PII: S0223-5234(19)30135-7
Knihovny.cz E-zdroje
- Klíčová slova
- Acetylcholinesterase, Alzheimer's disease, Aβ42 self-aggregation, Blood-brain barrier, Multi-target directed ligands, Tacrine-tryptophan hybrids, X-ray crystallographic analysis, hAChEinduced Aβ40 aggregation,
- MeSH
- acetylcholinesterasa metabolismus MeSH
- Alzheimerova nemoc farmakoterapie metabolismus MeSH
- amyloidní beta-protein antagonisté a inhibitory metabolismus MeSH
- bludiště - učení účinky léků MeSH
- butyrylcholinesterasa metabolismus MeSH
- cholinesterasové inhibitory chemická syntéza chemie farmakologie MeSH
- krysa rodu Rattus MeSH
- lidé MeSH
- ligandy MeSH
- molekulární struktura MeSH
- neuroprotektivní látky chemická syntéza chemie farmakologie MeSH
- potkani Wistar MeSH
- proteinové agregáty účinky léků MeSH
- takrin chemie farmakologie MeSH
- tryptofan chemie farmakologie MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- vztahy mezi strukturou a aktivitou MeSH
- zvířata MeSH
- Check Tag
- krysa rodu Rattus MeSH
- lidé MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- acetylcholinesterasa MeSH
- amyloidní beta-protein MeSH
- butyrylcholinesterasa MeSH
- cholinesterasové inhibitory MeSH
- ligandy MeSH
- neuroprotektivní látky MeSH
- proteinové agregáty MeSH
- takrin MeSH
- tryptofan MeSH
A combination of tacrine and tryptophan led to the development of a new family of heterodimers as multi-target agents with potential to treat Alzheimer's disease. Based on the in vitro biological profile, compound S-K1035 was found to be the most potent inhibitor of human acetylcholinesterase (hAChE) and human butyrylcholinesterase (hBChE), demonstrating balanced IC50 values of 6.3 and 9.1 nM, respectively. For all the tacrine-tryptophan heterodimers, favorable inhibitory effect on hAChE as well as on hBChE was coined to the optimal spacer length ranging from five to eight carbon atoms between these two pharmacophores. S-K1035 also showed good ability to inhibit Aβ42 self-aggregation (58.6 ± 5.1% at 50 μM) as well as hAChE-induced Aβ40 aggregation (48.3 ± 6.3% at 100 μM). The X-ray crystallographic analysis of TcAChE in complex with S-K1035 pinpointed the utility of the hybridization strategy applied and the structures determined with the two K1035 enantiomers in complex with hBChE could explain the higher inhibition potency of S-K1035. Other in vitro evaluations predicted the ability of S-K1035 to cross blood-brain barrier and to exert a moderate inhibition potency against neuronal nitric oxide synthase. Based on the initial promising biochemical data and a safer in vivo toxicity compared to tacrine, S-K1035 was administered to scopolamine-treated rats being able to dose-dependently revert amnesia.
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