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Tacrine - Benzothiazoles: Novel class of potential multitarget anti-Alzheimeŕs drugs dealing with cholinergic, amyloid and mitochondrial systems
E. Nepovimova, L. Svobodova, R. Dolezal, V. Hepnarova, L. Junova, D. Jun, J. Korabecny, T. Kucera, Z. Gazova, K. Motykova, J. Kubackova, Z. Bednarikova, J. Janockova, C. Jesus, L. Cortes, J. Pina, D. Rostohar, C. Serpa, O. Soukup, L. Aitken, RE....
Bioorganic chemistry.
2021 ;
107 (-) :
104596.
[pub] 20201228
Jazyk angličtina Země Spojené státy americké
Typ dokumentu časopisecké články, práce podpořená grantem
Perzistentní odkaz
https://www.medvik.cz/link/bmc21026098
Grantová podpora
204821/Z/16/Z
Wellcome Trust - United Kingdom
- MeSH
- 3-hydroxyacyl-CoA-dehydrogenasy antagonisté a inhibitory metabolismus MeSH
- acetylcholinesterasa metabolismus MeSH
- Alzheimerova nemoc farmakoterapie metabolismus MeSH
- amyloidní beta-protein antagonisté a inhibitory metabolismus MeSH
- benzothiazoly chemie farmakologie MeSH
- cholinergní látky chemická syntéza chemie farmakologie MeSH
- inhibitory enzymů chemická syntéza chemie farmakologie MeSH
- lidé MeSH
- mitochondrie účinky léků metabolismus MeSH
- molekulární struktura MeSH
- neuroprotektivní látky chemická syntéza chemie farmakologie MeSH
- proteinové agregáty účinky léků MeSH
- takrin chemie farmakologie MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
A series of tacrine - benzothiazole hybrids incorporate inhibitors of acetylcholinesterase (AChE), amyloid β (Aβ) aggregation and mitochondrial enzyme ABAD, whose interaction with Aβ leads to mitochondrial dysfunction, into a single molecule. In vitro, several of 25 final compounds exerted excellent anti-AChE properties and interesting capabilities to block Aβ aggregation. The best derivative of the series could be considered 10w that was found to be highly potent and selective towards AChE with the IC50 value in nanomolar range. Moreover, the same drug candidate exerted absolutely the best results of the series against ABAD, decreasing its activity by 23% at 100 μM concentration. Regarding the cytotoxicity profile of highlighted compound, it roughly matched that of its parent compound - 6-chlorotacrine. Finally, 10w was forwarded for in vivo scopolamine-induced amnesia experiment consisting of Morris Water Maze test, where it demonstrated mild procognitive effect. Taking into account all in vitro and in vivo data, highlighted derivative 10w could be considered as the lead structure worthy of further investigation.
Center for Neuroscience and Cell Biology University of Coimbra 3004 504 Coimbra Portugal
Centro de Quimica de Coimbra Department of Chemistry University of Coimbra 3044 535 Coimbra Portugal
National Institute of Mental Health Topolova 748 250 67 Klecany Czech Republic
Citace poskytuje Crossref.org
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