Novel tacrine-tryptophan hybrids: Multi-target directed ligands as potential treatment for Alzheimer's disease
Language English Country France Media print-electronic
Document type Journal Article
PubMed
30851693
DOI
10.1016/j.ejmech.2019.02.021
PII: S0223-5234(19)30135-7
Knihovny.cz E-resources
- Keywords
- 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
- Acetylcholinesterase metabolism MeSH
- Alzheimer Disease drug therapy metabolism MeSH
- Amyloid beta-Peptides antagonists & inhibitors metabolism MeSH
- Maze Learning drug effects MeSH
- Butyrylcholinesterase metabolism MeSH
- Cholinesterase Inhibitors chemical synthesis chemistry pharmacology MeSH
- Rats MeSH
- Humans MeSH
- Ligands MeSH
- Molecular Structure MeSH
- Neuroprotective Agents chemical synthesis chemistry pharmacology MeSH
- Rats, Wistar MeSH
- Protein Aggregates drug effects MeSH
- Tacrine chemistry pharmacology MeSH
- Tryptophan chemistry pharmacology MeSH
- Dose-Response Relationship, Drug MeSH
- Structure-Activity Relationship MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Humans MeSH
- Male MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- Acetylcholinesterase MeSH
- Amyloid beta-Peptides MeSH
- Butyrylcholinesterase MeSH
- Cholinesterase Inhibitors MeSH
- Ligands MeSH
- Neuroprotective Agents MeSH
- Protein Aggregates MeSH
- Tacrine MeSH
- Tryptophan 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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