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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,
Language English Country Germany
Document type Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't
Persistent link
https://www.medvik.cz/link/bmc17014250
- MeSH
- Acetylcholinesterase chemistry metabolism MeSH
- Alzheimer Disease drug therapy MeSH
- Hep G2 Cells MeSH
- Quinolines chemical synthesis chemistry metabolism therapeutic use toxicity MeSH
- Cholinesterase Inhibitors chemical synthesis metabolism therapeutic use toxicity MeSH
- Blood-Brain Barrier metabolism MeSH
- Indoles chemical synthesis chemistry metabolism therapeutic use toxicity MeSH
- Inhibitory Concentration 50 MeSH
- Monoamine Oxidase Inhibitors chemical synthesis metabolism therapeutic use toxicity MeSH
- Humans MeSH
- Ligands MeSH
- Monoamine Oxidase chemistry metabolism MeSH
- Drug Design * MeSH
- Tacrine chemistry metabolism therapeutic use toxicity MeSH
- Cell Survival drug effects MeSH
- Structure-Activity Relationship MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't 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.
References provided by 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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- $a Hroch, Lukas $u University Hospital, Sokolska 581, 500 05, Hradec Kralove, Czech Republic. Department of Pharmaceutical Chemistry and Drug Control, Faculty of Pharmacy in Hradec Kralove, Charles University in Prague, Akademika Heyrovskeho 1203, 500 05, Hradec Kralove, Czech Republic.
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- $a Sepsova, Vendula $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. University Hospital, Sokolska 581, 500 05, Hradec Kralove, Czech Republic.
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