title: Tacrine-resveratrol fused hybrids as multi-target-directed ligands against Alzheimer's disease.
abstract: 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.
authors.affiliation: 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.
authors.forename: Jakub
authors.initials: J
authors.lastname: Jeřábek
authors.affiliation: Department of Pharmacy and Biotechnology, University of Bologna, Via Belmeloro 6/Selmi 3, 40126 Bologna, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Uliassi
authors.affiliation: Department of Pharmacy and Biotechnology, University of Bologna, Via Belmeloro 6/Selmi 3, 40126 Bologna, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Guidotti
authors.affiliation: 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.
authors.forename: Jan
authors.initials: J
authors.lastname: Korábečný
authors.affiliation: 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.
authors.forename: Ondřej
authors.initials: O
authors.lastname: Soukup
authors.affiliation: Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, University of Defence, Trebesska 1575, 500 01 Hradec Kralove, Czechia.
authors.forename: Vendula
authors.initials: V
authors.lastname: Sepsova
authors.affiliation: Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, University of Defence, Trebesska 1575, 500 01 Hradec Kralove, Czechia.
authors.forename: Martina
authors.initials: M
authors.lastname: Hrabinova
authors.affiliation: 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.
authors.forename: Kamil
authors.initials: K
authors.lastname: Kuča
authors.affiliation: Department of Pharmacy and Biotechnology, University of Bologna, Via Belmeloro 6/Selmi 3, 40126 Bologna, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Bartolini
authors.affiliation: Department of Pharmacy and Biotechnology, University of Bologna, Via Belmeloro 6/Selmi 3, 40126 Bologna, Italy.
authors.forename: Luis Emiliano
authors.initials: LE
authors.lastname: Peña-Altamira
authors.affiliation: Department of Pharmacy and Biotechnology, University of Bologna, Via Belmeloro 6/Selmi 3, 40126 Bologna, Italy.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Petralla
authors.affiliation: Department of Pharmacy and Biotechnology, University of Bologna, Via Belmeloro 6/Selmi 3, 40126 Bologna, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Monti
authors.affiliation: Department of Pharmacy and Biotechnology, University of Bologna, Via Belmeloro 6/Selmi 3, 40126 Bologna, Italy. Electronic address: marinella.roberti@unibo.it.
authors.forename: Marinella
authors.initials: M
authors.lastname: Roberti
authors.affiliation: Department of Pharmacy and Biotechnology, University of Bologna, Via Belmeloro 6/Selmi 3, 40126 Bologna, Italy. Electronic address: marialaura.bolognesi@unibo.it.
authors.forename: Maria Laura
authors.initials: ML
authors.lastname: Bolognesi
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000737:chemistry; D000818:Animals; D000975:Antioxidants / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D001812:Blood-Brain Barrier / Q000378:metabolism; D002091:Butyrylcholinesterase / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D015195:Drug Design; D006801:Humans; D008024:Ligands; D008099:Liver / Q000187:drug effects; D058990:Molecular Targeted Therapy; D018696:Neuroprotective Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D010446:Peptide Fragments / Q000737:chemistry; D066329:Protein Aggregates / Q000187:drug effects; D051381:Rats; D000077185:Resveratrol; D013267:Stilbenes / Q000737:chemistry*; D013619:Tacrine / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D016229:Amyloid beta-Peptides; D000975:Antioxidants; D002800:Cholinesterase Inhibitors; D008024:Ligands; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D066329:Protein Aggregates; D013267:Stilbenes; C075222:amyloid beta-protein (1-42); D013619:Tacrine; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase; D000077185:Resveratrol
keywords: Acetylcholinesterase; Alzheimer's disease; Amyloid; Multitarget compounds; Neuroinflammation