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Tacrine-resveratrol fused hybrids as multi-target-directed ligands against Alzheimer's disease

J. Jeřábek, E. Uliassi, L. Guidotti, J. Korábečný, O. Soukup, V. Sepsova, M. Hrabinova, K. Kuča, M. Bartolini, LE. Peña-Altamira, S. Petralla, B. Monti, M. Roberti, ML. Bolognesi,

. 2017 ; 127 (-) : 250-262. [pub] 20161226

Language English Country France

Document type Journal Article

Persistent link   https://www.medvik.cz/link/bmc17013312

Grant support
NV15-30954A MZ0 CEP Register

Multi-target drug discovery is one of the most followed approaches in the active central nervous system (CNS) therapeutic area, especially in the search for new drugs against Alzheimer's disease (AD). This is because innovative multi-target-directed ligands (MTDLs) could more adequately address the complexity of this pathological condition. In a continuation of our efforts aimed at a new series of anti-AD MTDLs, we combined the structural features of the cholinesterase inhibitor drug tacrine with that of resveratrol, which is known for its purported antioxidant and anti-neuroinflammatory activities. The most interesting hybrid compounds (5, 8, 9 and 12) inhibited human acetylcholinesterase at micromolar concentrations and effectively modulated Aβ self-aggregation in vitro. In addition, 12 showed intriguing anti-inflammatory and immuno-modulatory properties in neuronal and glial AD cell models. Importantly, the MTDL profile is accompanied by high-predicted blood-brain barrier permeability, and low cytotoxicity on primary neurons.

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$a Jeřábek, Jakub $u Department of Pharmacy and Biotechnology, University of Bologna, Via Belmeloro 6/Selmi 3, 40126 Bologna, Italy; Department of Pharmaceutical Chemistry and Drug Control, Faculty of Pharmacy in Hradec Kralove, Charles University in Prague, Heyrovskeho 1203, 500 05 Hradec Kralove, Czechia.
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$a Tacrine-resveratrol fused hybrids as multi-target-directed ligands against Alzheimer's disease / $c J. Jeřábek, E. Uliassi, L. Guidotti, J. Korábečný, O. Soukup, V. Sepsova, M. Hrabinova, K. Kuča, M. Bartolini, LE. Peña-Altamira, S. Petralla, B. Monti, M. Roberti, ML. Bolognesi,
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$a Multi-target drug discovery is one of the most followed approaches in the active central nervous system (CNS) therapeutic area, especially in the search for new drugs against Alzheimer's disease (AD). This is because innovative multi-target-directed ligands (MTDLs) could more adequately address the complexity of this pathological condition. In a continuation of our efforts aimed at a new series of anti-AD MTDLs, we combined the structural features of the cholinesterase inhibitor drug tacrine with that of resveratrol, which is known for its purported antioxidant and anti-neuroinflammatory activities. The most interesting hybrid compounds (5, 8, 9 and 12) inhibited human acetylcholinesterase at micromolar concentrations and effectively modulated Aβ self-aggregation in vitro. In addition, 12 showed intriguing anti-inflammatory and immuno-modulatory properties in neuronal and glial AD cell models. Importantly, the MTDL profile is accompanied by high-predicted blood-brain barrier permeability, and low cytotoxicity on primary neurons.
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$a Uliassi, Elisa $u Department of Pharmacy and Biotechnology, University of Bologna, Via Belmeloro 6/Selmi 3, 40126 Bologna, Italy.
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$a Guidotti, Laura $u Department of Pharmacy and Biotechnology, University of Bologna, Via Belmeloro 6/Selmi 3, 40126 Bologna, Italy.
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$a Korábečný, Jan $u Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czechia; National Institute of Mental Health, Topolova 748, 250 67 Klecany, Czechia.
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$a Soukup, Ondřej $u Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czechia; National Institute of Mental Health, Topolova 748, 250 67 Klecany, Czechia.
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$a Sepsova, Vendula $u Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, University of Defence, Trebesska 1575, 500 01 Hradec Kralove, Czechia.
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$a Hrabinova, Martina $u Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, University of Defence, Trebesska 1575, 500 01 Hradec Kralove, Czechia.
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$a Kuča, Kamil $u Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czechia; National Institute of Mental Health, Topolova 748, 250 67 Klecany, Czechia.
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$a Bartolini, Manuela $u Department of Pharmacy and Biotechnology, University of Bologna, Via Belmeloro 6/Selmi 3, 40126 Bologna, Italy.
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$a Peña-Altamira, Luis Emiliano $u Department of Pharmacy and Biotechnology, University of Bologna, Via Belmeloro 6/Selmi 3, 40126 Bologna, Italy.
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$a Roberti, Marinella $u Department of Pharmacy and Biotechnology, University of Bologna, Via Belmeloro 6/Selmi 3, 40126 Bologna, Italy. Electronic address: marinella.roberti@unibo.it.
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$a Bolognesi, Maria Laura $u Department of Pharmacy and Biotechnology, University of Bologna, Via Belmeloro 6/Selmi 3, 40126 Bologna, Italy. Electronic address: marialaura.bolognesi@unibo.it.
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