title: 7-Methoxytacrine-p-Anisidine Hybrids as Novel Dual Binding Site Acetylcholinesterase Inhibitors for Alzheimer's Disease Treatment.
abstract: Alzheimer's disease (AD) is a debilitating progressive neurodegenerative disorder that ultimately leads to the patient's death. Despite the fact that novel pharmacological approaches endeavoring to block the neurodegenerative process are still emerging, none of them have reached use in clinical practice yet. Thus, palliative treatment represented by acetylcholinesterase inhibitors (AChEIs) and memantine are still the only therapeutics used. Following the multi-target directed ligands (MTDLs) strategy, herein we describe the synthesis, biological evaluation and docking studies for novel 7-methoxytacrine-p-anisidine hybrids designed to purposely target both cholinesterases and the amyloid cascade. Indeed, the novel derivatives proved to be effective non-specific cholinesterase inhibitors showing non-competitive AChE inhibition patterns. This compounds' behavior was confirmed in the subsequent molecular modeling studies.
authors.affiliation: Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic. jan.korabecny@fnhk.cz.|Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic. jan.korabecny@fnhk.cz.|National Institute of Mental Health, Topolova 748, 250 67 Klecany, Czech Republic. jan.korabecny@fnhk.cz.
authors.forename: Jan
authors.initials: J
authors.lastname: Korabecny
authors.affiliation: Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic. martin.andrs@unob.cz.|Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic. martin.andrs@unob.cz.
authors.forename: Martin
authors.initials: M
authors.lastname: Andrs
authors.affiliation: Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic. Eugenie.nepovimova@unob.cz.|Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic. Eugenie.nepovimova@unob.cz.
authors.forename: Eugenie
authors.initials: E
authors.lastname: Nepovimova
authors.affiliation: Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic. Rafael.dolezal@fnhk.cz.
authors.forename: Rafael
authors.initials: R
authors.lastname: Dolezal
authors.affiliation: Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic. katerina.babkova@unob.cz.|Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic. katerina.babkova@unob.cz.
authors.forename: Katerina
authors.initials: K
authors.lastname: Babkova
authors.affiliation: Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic. anna.horova@unob.cz.|Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic. anna.horova@unob.cz.
authors.forename: Anna
authors.initials: A
authors.lastname: Horova
authors.affiliation: Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic. david.malinak@gmail.com.
authors.forename: David
authors.initials: D
authors.lastname: Malinak
authors.affiliation: Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic. eva.mezeiova@gmail.com.
authors.forename: Eva
authors.initials: E
authors.lastname: Mezeiova
authors.affiliation: Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic. lukasgorecki@seznam.cz.|Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic. lukasgorecki@seznam.cz.
authors.forename: Lukas
authors.initials: L
authors.lastname: Gorecki
authors.affiliation: Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic. vendula.sepsova@unob.cz.|Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic. vendula.sepsova@unob.cz.
authors.forename: Vendula
authors.initials: V
authors.lastname: Sepsova
authors.affiliation: Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic. martina.hrabinova@unob.cz.|Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic. martina.hrabinova@unob.cz.
authors.forename: Martina
authors.initials: M
authors.lastname: Hrabinova
authors.affiliation: Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic. ondrej.soukup@fnhk.cz.|Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic. ondrej.soukup@fnhk.cz.|National Institute of Mental Health, Topolova 748, 250 67 Klecany, Czech Republic. ondrej.soukup@fnhk.cz.
authors.forename: Ondrej
authors.initials: O
authors.lastname: Soukup
authors.affiliation: Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic. daniel.jun@unob.cz.|Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic. daniel.jun@unob.cz.
authors.forename: Daniel
authors.initials: D
authors.lastname: Jun
authors.affiliation: Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic. kamil.kuca@unob.cz.|Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic. kamil.kuca@unob.cz.|National Institute of Mental Health, Topolova 748, 250 67 Klecany, Czech Republic. kamil.kuca@unob.cz.
authors.forename: Kamil
authors.initials: K
authors.lastname: Kuca
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry*; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000814:Aniline Compounds / Q000138:chemical synthesis / Q000737:chemistry*; D001665:Binding Sites; D002491:Central Nervous System Agents / Q000138:chemical synthesis / Q000737:chemistry*; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry*; D006801:Humans; D007700:Kinetics; D062105:Molecular Docking Simulation; D011994:Recombinant Proteins / Q000737:chemistry; D013329:Structure-Activity Relationship; D013619:Tacrine / Q000031:analogs & derivatives*
chemical_list: D016229:Amyloid beta-Peptides; D000814:Aniline Compounds; D002491:Central Nervous System Agents; D002800:Cholinesterase Inhibitors; D011994:Recombinant Proteins; D013619:Tacrine; D000110:Acetylcholinesterase
keywords: 7-methoxy-tacrine; Alzheimer’s disease; MTDLs; acetylcholinesterase; butyrylcholinesterase; tacrine