title: Design, Synthesis and in vitro Evaluation of Indolotacrine Analogues as Multitarget-Directed Ligands for the Treatment of Alzheimer's Disease.
abstract: 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.
authors.affiliation: 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.
authors.forename: Ondrej
authors.initials: O
authors.lastname: Benek
authors.affiliation: National Institute of Mental Health, Topolova 748, 250 67, Klecany, Czech Republic.|University Hospital, Sokolska 581, 500 05, Hradec Kralove, Czech Republic.
authors.forename: Ondrej
authors.initials: O
authors.lastname: Soukup
authors.affiliation: 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.
authors.forename: Marketa
authors.initials: M
authors.lastname: Pasdiorova
authors.affiliation: 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.
authors.forename: Lukas
authors.initials: L
authors.lastname: Hroch
authors.affiliation: 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.
authors.forename: Vendula
authors.initials: V
authors.lastname: Sepsova
authors.affiliation: 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.
authors.forename: Petr
authors.initials: P
authors.lastname: Jost
authors.affiliation: 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.
authors.forename: Martina
authors.initials: M
authors.lastname: Hrabinova
authors.affiliation: 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.
authors.forename: Daniel
authors.initials: D
authors.lastname: Jun
authors.affiliation: University Hospital, Sokolska 581, 500 05, Hradec Kralove, Czech Republic.|Department of Chemistry, Faculty of Science, University of Hradec Kralove, Rokitanskeho 62, 500 03, Hradec Kralove, Czech Republic.
authors.forename: Kamil
authors.initials: K
authors.lastname: Kuca
authors.affiliation: School of Biology, Biomolecular Sciences Building, University of St. Andrews, North Haugh, St. Andrews, KY16 9ST, UK.
authors.forename: Dominykas
authors.initials: D
authors.lastname: Zala
authors.affiliation: School of Biology, Biomolecular Sciences Building, University of St. Andrews, North Haugh, St. Andrews, KY16 9ST, UK.
authors.forename: Rona R
authors.initials: RR
authors.lastname: Ramsay
authors.affiliation: Laboratory of Medicinal Chemistry, (IQOG, CSIC), Juan de la Cierva 3, 28006, Madrid, Spain. iqoc21@iqog.csic.es.
authors.forename: José
authors.initials: J
authors.lastname: Marco-Contelles
authors.affiliation: University Hospital, Sokolska 581, 500 05, Hradec Kralove, Czech Republic. kamil.musilek@gmail.com.|Department of Chemistry, Faculty of Science, University of Hradec Kralove, Rokitanskeho 62, 500 03, Hradec Kralove, Czech Republic. kamil.musilek@gmail.com.
authors.forename: Kamil
authors.initials: K
authors.lastname: Musilek
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry / Q000378:metabolism; D000544:Alzheimer Disease / Q000188:drug therapy*; D001812:Blood-Brain Barrier / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000378:metabolism / Q000627:therapeutic use* / Q000633:toxicity; D015195:Drug Design; D056945:Hep G2 Cells; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use / Q000633:toxicity; D020128:Inhibitory Concentration 50; D008024:Ligands; D008995:Monoamine Oxidase / Q000737:chemistry / Q000378:metabolism; D008996:Monoamine Oxidase Inhibitors / Q000138:chemical synthesis / Q000378:metabolism / Q000627:therapeutic use* / Q000633:toxicity; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use / Q000633:toxicity; D013329:Structure-Activity Relationship; D013619:Tacrine / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use / Q000633:toxicity
chemical_list: C000616073:9-methoxy-2,3,4,6-tetrahydro-1H-indolo(2,3-b)quinolin-11-amine; D002800:Cholinesterase Inhibitors; D007211:Indoles; D008024:Ligands; D008996:Monoamine Oxidase Inhibitors; D011804:Quinolines; C000609949:indolo(2,3-b)quinoline; D013619:Tacrine; D008995:Monoamine Oxidase; D000110:Acetylcholinesterase
keywords: Alzheimer's disease; cholinesterases; cytotoxicity; inhibitors; monoamine oxidase; multitarget-directed ligands