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Design, Synthesis and in vitro Evaluation of Indolotacrine Analogues as Multitarget-Directed Ligands for the Treatment of Alzheimer's Disease
O. Benek, O. Soukup, M. Pasdiorova, L. Hroch, V. Sepsova, P. Jost, M. Hrabinova, D. Jun, K. Kuca, D. Zala, RR. Ramsay, J. Marco-Contelles, K. Musilek,
Jazyk angličtina Země Německo
Typ dokumentu časopisecké články, Research Support, N.I.H., Extramural, práce podpořená grantem
PubMed
26427608
DOI
10.1002/cmdc.201500383
Knihovny.cz E-zdroje
- MeSH
- acetylcholinesterasa chemie metabolismus MeSH
- Alzheimerova nemoc farmakoterapie MeSH
- buňky Hep G2 MeSH
- chinoliny chemická syntéza chemie metabolismus terapeutické užití toxicita MeSH
- cholinesterasové inhibitory chemická syntéza metabolismus terapeutické užití toxicita MeSH
- hematoencefalická bariéra metabolismus MeSH
- indoly chemická syntéza chemie metabolismus terapeutické užití toxicita MeSH
- inhibiční koncentrace 50 MeSH
- inhibitory MAO chemická syntéza metabolismus terapeutické užití toxicita MeSH
- lidé MeSH
- ligandy MeSH
- monoaminoxidasa chemie metabolismus MeSH
- racionální návrh léčiv * MeSH
- takrin chemie metabolismus terapeutické užití toxicita MeSH
- viabilita buněk účinky léků MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
Novel indolotacrine analogues were designed, synthesized, and evaluated as potential drugs for the treatment of Alzheimer's disease. By using a multitarget-directed ligand approach, compounds were designed to act simultaneously as cholinesterase (ChE) and monoamine oxidase (MAO) inhibitors. The compounds were also evaluated for antioxidant, cytotoxic, hepatotoxic, and blood-brain barrier (BBB) permeability properties. Indolotacrine 9 b (9-methoxy-2,3,4,6-tetrahydro-1H-indolo[2,3-b]quinolin-11-amine) showed the most promising results in the in vitro assessment; it is a potent inhibitor of acetylcholinesterase (AChE IC50 : 1.5 μm), butyrylcholinesterase (BChE IC50 : 2.4 μm) and MAO A (IC50 : 0.49 μm), and it is also a weak inhibitor of MAO B (IC50 : 53.9 μm). Although its cytotoxic (IC50 : 5.5±0.4 μm) and hepatotoxic (IC50 : 1.22±0.11 μm) profiles are not as good as those of the standard 7-methoxytacrine (IC50 : 63±4 and 11.50±0.77 μm, respectively), the overall improvement in the inhibitory activities and potential to cross the BBB make indolotacrine 9 b a promising lead compound for further development and investigation.
Citace poskytuje Crossref.org
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- $a Benek, Ondrej $u Department of Toxicology and Military Pharmacy, Department of Epidemiology, Faculty of Military Health Sciences, University of Defense, Trebesska 1575, 500 01, Hradec Kralove, Czech Republic. National Institute of Mental Health, Topolova 748, 250 67, Klecany, Czech Republic. University Hospital, Sokolska 581, 500 05, Hradec Kralove, Czech Republic.
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