Novel tacrine-tryptophan hybrids: Multi-target directed ligands as potential treatment for Alzheimer's disease
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F60162694%3AG44__%2F19%3A00536671" target="_blank" >RIV/60162694:G44__/19:00536671 - isvavai.cz</a>
Alternative codes found
RIV/67985823:_____/19:00504524 RIV/60461373:22340/19:43918832 RIV/62690094:18470/19:50015604 RIV/00216208:11150/19:10393731 and 3 more
Result on the web
<a href="https://www.sciencedirect.com/science/article/pii/S0223523419301357" target="_blank" >https://www.sciencedirect.com/science/article/pii/S0223523419301357</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1016/j.ejmech.2019.02.021" target="_blank" >10.1016/j.ejmech.2019.02.021</a>
Alternative languages
Result language
angličtina
Original language name
Novel tacrine-tryptophan hybrids: Multi-target directed ligands as potential treatment for Alzheimer's disease
Original language description
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 A beta 42 self-aggregation (58.6 +/- 5.1% at 50 mu M) as well as hAChE-induced A beta(40) aggregation (483 +/- 6.3% at 100 mu M). 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.
Czech name
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Czech description
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Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
30107 - Medicinal chemistry
Result continuities
Project
Result was created during the realization of more than one project. More information in the Projects tab.
Continuities
I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace
Others
Publication year
2019
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
European Journal of Medicinal Chemistry
ISSN
0223-5234
e-ISSN
1768-3254
Volume of the periodical
168
Issue of the periodical within the volume
Apr
Country of publishing house
FR - FRANCE
Number of pages
24
Pages from-to
491-514
UT code for WoS article
000463120300038
EID of the result in the Scopus database
2-s2.0-85062424287