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Novel Tacrine-Scutellarin Hybrids as Multipotent Anti-Alzheimer's Agents: Design, Synthesis and Biological Evaluation

K. Spilovska, J. Korabecny, V. Sepsova, D. Jun, M. Hrabinova, P. Jost, L. Muckova, O. Soukup, J. Janockova, T. Kucera, R. Dolezal, E. Mezeiova, D. Kaping, K. Kuca,

. 2017 ; 22 (6) : . [pub] 20170616

Jazyk angličtina Země Švýcarsko

Typ dokumentu časopisecké články

Perzistentní odkaz   https://www.medvik.cz/link/bmc18010482

A novel series of 6-chlorotacrine-scutellarin hybrids was designed, synthesized and the biological activity as potential anti-Alzheimer's agents was assessed. Their inhibitory activity towards human acetylcholinesterase (hAChE) and human butyrylcholinesterase (hBChE), antioxidant activity, ability to cross the blood-brain barrier (BBB) and hepatotoxic profile were evaluated in vitro. Among these compounds, hybridK1383, bearing two methylene tether between two basic scaffolds, was found to be very potenthAChE inhibitor (IC50= 1.63 nM). Unfortunately, none of the hybrids displayed any antioxidant activity (EC50≥ 500 μM). Preliminary data also suggests a comparable hepatotoxic profile with 6-Cl-THA (established on a HepG2 cell line). Kinetic studies performed onhAChE with the most active compound in the study,K1383, pointed out to a mixed, non-competitive enzyme inhibition. These findings were further corroborated by docking studies.

Citace poskytuje Crossref.org

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$a A novel series of 6-chlorotacrine-scutellarin hybrids was designed, synthesized and the biological activity as potential anti-Alzheimer's agents was assessed. Their inhibitory activity towards human acetylcholinesterase (hAChE) and human butyrylcholinesterase (hBChE), antioxidant activity, ability to cross the blood-brain barrier (BBB) and hepatotoxic profile were evaluated in vitro. Among these compounds, hybridK1383, bearing two methylene tether between two basic scaffolds, was found to be very potenthAChE inhibitor (IC50= 1.63 nM). Unfortunately, none of the hybrids displayed any antioxidant activity (EC50≥ 500 μM). Preliminary data also suggests a comparable hepatotoxic profile with 6-Cl-THA (established on a HepG2 cell line). Kinetic studies performed onhAChE with the most active compound in the study,K1383, pointed out to a mixed, non-competitive enzyme inhibition. These findings were further corroborated by docking studies.
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$a Korabecny, Jan $u Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic. korabecny.jan@gmail.com. Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic. korabecny.jan@gmail.com.
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$a Sepsova, Vendula $u Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic. vsepsova@gmail.com. Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic. vsepsova@gmail.com.
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$a Hrabinova, Martina $u Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic. martina.hrabinova@unob.cz. Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic. martina.hrabinova@unob.cz.
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$a Soukup, Ondrej $u National Institute of Mental Health, Topolova 748, 250 67 Klecany, Czech Republic. ondrej.soukup@fnhk.cz. Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic. ondrej.soukup@fnhk.cz.
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$a Janockova, Jana $u Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic. jana.janockova@gmail.com.
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$a Kucera, Tomas $u Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic. Tomas.kucera2@unob.cz.
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$a Dolezal, Rafael $u Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic. rafael.dolezal@centrum.cz.
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$a Mezeiova, Eva $u National Institute of Mental Health, Topolova 748, 250 67 Klecany, Czech Republic. eva.mezeiova@gmail.com. Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic. eva.mezeiova@gmail.com.
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$a Kaping, Daniel $u National Institute of Mental Health, Topolova 748, 250 67 Klecany, Czech Republic. Daniel.Kaping@nudz.cz.
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