Novel tacrine-based multi-target directed Ligands: Enhancing cholinesterase inhibition, NMDA receptor antagonism, and CNS bioavailability for Alzheimer's disease treatment
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388963%3A_____%2F25%3A00619819" target="_blank" >RIV/61388963:_____/25:00619819 - isvavai.cz</a>
Alternative codes found
RIV/68378041:_____/25:00619819 RIV/00179906:_____/25:10498808 RIV/60162694:G44__/26:00564527 RIV/00216208:11160/25:10498808 and 2 more
Result on the web
<a href="https://www.sciencedirect.com/science/article/pii/S022352342500443X?via%3Dihub" target="_blank" >https://www.sciencedirect.com/science/article/pii/S022352342500443X?via%3Dihub</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1016/j.ejmech.2025.117678" target="_blank" >10.1016/j.ejmech.2025.117678</a>
Alternative languages
Result language
angličtina
Original language name
Novel tacrine-based multi-target directed Ligands: Enhancing cholinesterase inhibition, NMDA receptor antagonism, and CNS bioavailability for Alzheimer's disease treatment
Original language description
Alzheimer's disease (AD) is a multifaceted neurodegenerative disorder for which current treatments provide only symptomatic relief, primarily through cholinesterase (ChE) inhibition and N-methyl-d-aspartate receptor (NMDAR) antagonism. To improve therapeutic efficacy and safety, we designed and synthesized 16 novel tacrine derivatives modified at position 7 with various (hetero)aryl groups or deuterium substitution. Initially, in silico screening predicted favorable CNS permeability and oral bioavailability. Subsequent in vitro evaluations demonstrated significant inhibitory potency against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), with derivatives 5i and 5m displaying particularly promising profiles. Metabolic stability assessed using human liver microsomes revealed enhanced stability for compound 5e, whereas 5i and 5m underwent rapid metabolism. Notably, compound 7 showed improved metabolic stability attributed to deuterium incorporation. The newly synthesized compounds were further tested for antagonistic activity on the GluN1/GluN2B subtype of NMDAR, with compound 5m exhibiting the most potent and voltage-independent inhibition. The ability of these compounds to permeate the blood-brain barrier (BBB) was confirmed through in vitro PAMPA assays. In preliminary hepatotoxicity screening (HepG2 cells), most derivatives exhibited higher cytotoxicity than tacrine, emphasizing the ongoing challenge in hepatotoxicity management. Based on its overall favorable profile, compound 5m advanced to in vivo pharmacokinetic studies in mice, demonstrating efficient CNS penetration, with brain concentrations exceeding plasma levels (brain-to-plasma ratio 2.36), indicating active transport across the BBB. These findings highlight compound 5m as a promising tacrine-based multi-target-directed ligand, supporting further preclinical development as a potential therapeutic candidate for AD.
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
2025
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
292
Issue of the periodical within the volume
August
Country of publishing house
FR - FRANCE
Number of pages
19
Pages from-to
117678
UT code for WoS article
001483938000001
EID of the result in the Scopus database
2-s2.0-105003390938