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Privileged multi-target directed propargyl-tacrines combining cholinesterase and monoamine oxidase inhibition activities
Z. Chrienova, E. Nepovimova, R. Andrys, R. Dolezal, J. Janockova, L. Muckova, L. Fabova, O. Soukup, P. Oleksak, M. Valis, J. Korabecny, J. Marco-Contelles, K. Kuca
Jazyk angličtina Země Anglie, Velká Británie
Typ dokumentu časopisecké články
NLK
Directory of Open Access Journals
od 2017
PubMed Central
od 2017
ProQuest Central
od 2022-01-01
Taylor & Francis Open Access
od 2002-01-01
Medline Complete (EBSCOhost)
od 2007-02-01
Health & Medicine (ProQuest)
od 2022-01-01
- MeSH
- acetylcholinesterasa metabolismus MeSH
- Alzheimerova nemoc * farmakoterapie MeSH
- aminy MeSH
- butyrylcholinesterasa * metabolismus MeSH
- cholinesterasové inhibitory farmakologie terapeutické užití MeSH
- inhibitory MAO farmakologie MeSH
- lidé MeSH
- ligandy MeSH
- monoaminoxidasa MeSH
- oxidoreduktasy MeSH
- racionální návrh léčiv MeSH
- takrin terapeutické užití MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Twenty-four novel compounds bearing tetrahydroacridine and N-propargyl moieties have been designed, synthesised, and evaluated in vitro for their anti-cholinesterase and anti-monoamine oxidase activities. Propargyltacrine 23 (IC50 = 21 nM) was the most potent acetylcholinesterase (AChE) inhibitor, compound 20 (IC50 = 78 nM) showed the best inhibitory human butyrylcholinesterase (hBChE) profile, and ligand 21 afforded equipotent and significant values on both ChEs (human AChE [hAChE]: IC50 = 0.095 ± 0.001 μM; hBChE: IC50 = 0.093 ± 0.003 μM). Regarding MAO inhibition, compounds 7, 15, and 25 demonstrated the highest inhibitory potential towards hMAO-B (IC50 = 163, 40, and 170 nM, respectively). In all, compounds 7, 15, 20, 21, 23, and 25 exhibiting the most balanced pharmacological profile, were submitted to permeability and cell viability tests. As a result, 7-phenoxy-N-(prop-2-yn-1-yl)-1,2,3,4-tetrahydroacridin-9-amine hydrochloride (15) has been identified as a permeable agent that shows a balanced pharmacological profile [IC50 (hAChE) = 1.472 ± 0.024 μM; IC50 (hBChE) = 0.659 ± 0.077 μM; IC50 (hMAO-B) = 40.39 ± 5.98 nM], and consequently, as a new hit-ligand that deserves further investigation, in particular in vivo analyses, as the preliminary cell viability test results reported here suggest that this is a relatively safe therapeutic agent.
Faculty of Medicine in Hradec Kralove Charles University Prague Hradec Kralove Czech Republic
Institute of General Organic Chemistry Laboratory of Medicinal Chemistry Madrid Spain
Citace poskytuje Crossref.org
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- $a Twenty-four novel compounds bearing tetrahydroacridine and N-propargyl moieties have been designed, synthesised, and evaluated in vitro for their anti-cholinesterase and anti-monoamine oxidase activities. Propargyltacrine 23 (IC50 = 21 nM) was the most potent acetylcholinesterase (AChE) inhibitor, compound 20 (IC50 = 78 nM) showed the best inhibitory human butyrylcholinesterase (hBChE) profile, and ligand 21 afforded equipotent and significant values on both ChEs (human AChE [hAChE]: IC50 = 0.095 ± 0.001 μM; hBChE: IC50 = 0.093 ± 0.003 μM). Regarding MAO inhibition, compounds 7, 15, and 25 demonstrated the highest inhibitory potential towards hMAO-B (IC50 = 163, 40, and 170 nM, respectively). In all, compounds 7, 15, 20, 21, 23, and 25 exhibiting the most balanced pharmacological profile, were submitted to permeability and cell viability tests. As a result, 7-phenoxy-N-(prop-2-yn-1-yl)-1,2,3,4-tetrahydroacridin-9-amine hydrochloride (15) has been identified as a permeable agent that shows a balanced pharmacological profile [IC50 (hAChE) = 1.472 ± 0.024 μM; IC50 (hBChE) = 0.659 ± 0.077 μM; IC50 (hMAO-B) = 40.39 ± 5.98 nM], and consequently, as a new hit-ligand that deserves further investigation, in particular in vivo analyses, as the preliminary cell viability test results reported here suggest that this is a relatively safe therapeutic agent.
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