Tacrine - Benzothiazoles: Novel class of potential multitarget anti-Alzheimeŕs drugs dealing with cholinergic, amyloid and mitochondrial systems
Language English Country United States Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
Grant support
204821/Z/16/Z
Wellcome Trust - United Kingdom
PubMed
33421953
DOI
10.1016/j.bioorg.2020.104596
PII: S0045-2068(20)31894-0
Knihovny.cz E-resources
- Keywords
- ABAD, Acetylcholinesterase Inhibitors, Alzheimer’s disease, Amyloid β, Benzothiazole, MTDLs, Tacrine,
- MeSH
- 3-Hydroxyacyl CoA Dehydrogenases antagonists & inhibitors metabolism MeSH
- Acetylcholinesterase metabolism MeSH
- Alzheimer Disease drug therapy metabolism MeSH
- Amyloid beta-Peptides antagonists & inhibitors metabolism MeSH
- Benzothiazoles chemistry pharmacology MeSH
- Cholinergic Agents chemical synthesis chemistry pharmacology MeSH
- Enzyme Inhibitors chemical synthesis chemistry pharmacology MeSH
- Humans MeSH
- Mitochondria drug effects metabolism MeSH
- Molecular Structure MeSH
- Neuroprotective Agents chemical synthesis chemistry pharmacology MeSH
- Protein Aggregates drug effects MeSH
- Tacrine chemistry pharmacology MeSH
- Dose-Response Relationship, Drug MeSH
- Structure-Activity Relationship MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- 3-Hydroxyacyl CoA Dehydrogenases MeSH
- Acetylcholinesterase MeSH
- Amyloid beta-Peptides MeSH
- Benzothiazoles MeSH
- Cholinergic Agents MeSH
- HSD17B10 protein, human MeSH Browser
- Enzyme Inhibitors MeSH
- Neuroprotective Agents MeSH
- Protein Aggregates MeSH
- Tacrine 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
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