title: Synthesis, biological evaluation and molecular modeling of new tetrahydroacridine derivatives as potential multifunctional agents for the treatment of Alzheimer's disease.
abstract: A novel series of 9-amino-1,2,3,4-tetrahydroacridine derivatives with 4-dimethylaminobenzoic acid moiety was synthesized and tested towards inhibition of cholinesterases and amyloid β aggregation. Target compounds were designed as dual binding site cholinesterase inhibitors able to bind to both the catalytic and the peripheral site of the enzyme and therefore potentially endowed with other properties. The obtained derivatives were very potent inhibitors of both cholinesterases (EeAChE, EqBChE) with IC50 values ranging from sub-nanomolar to nanomolar range, and the inhibitory potency of the most promising agents was higher than that of the reference drugs (rivastigmine and tacrine). The kinetic studies of the most active compound 3a revealed competitive type of AChE inhibition. Moreover, all target compounds were more potent inhibitors of human AChE than tacrine with the most active compound 3b (IC50 = 19 nM). Compound 3a was also tested and displayed inhibitory potency against AChE-induced Aβ 1-42 aggregation (80.6% and 91.3% at 50 μM and 100 μM screening concentration, respectively). Moreover, cytotoxicity assay performed on A549 cells did not indicate toxicity of this agent. Compound 3a is a promising candidate for further development of novel multi-functional agents in the therapy of AD.
authors.affiliation: Department of Physicochemical Drug Analysis, Chair of Pharmaceutical Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, 30-688 Kraków, Medyczna 9, Poland. Electronic address: marek.bajda@uj.edu.pl.
authors.forename: Marek
authors.initials: M
authors.lastname: Bajda
authors.affiliation: Department of Physicochemical Drug Analysis, Chair of Pharmaceutical Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, 30-688 Kraków, Medyczna 9, Poland.
authors.forename: Jakub
authors.initials: J
authors.lastname: Jończyk
authors.affiliation: Department of Physicochemical Drug Analysis, Chair of Pharmaceutical Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, 30-688 Kraków, Medyczna 9, Poland.
authors.forename: Barbara
authors.initials: B
authors.lastname: Malawska
authors.affiliation: Laboratory of Radiopharmacy, Department of Pharmaceutical Chemistry, Drug Analyses and Radiopharmacy, Medical University, 90-151 Łódź, Muszyńskiego 1, Poland.
authors.forename: Kamila
authors.initials: K
authors.lastname: Czarnecka
authors.affiliation: Laboratory of Radiopharmacy, Department of Pharmaceutical Chemistry, Drug Analyses and Radiopharmacy, Medical University, 90-151 Łódź, Muszyńskiego 1, Poland.
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Girek
authors.affiliation: Department of Pharmaceutical Chemistry, Drug Analyses and Radiopharmacy, Medical University, 90-151 Łódź, Muszyńskiego 1, Poland.
authors.forename: Paulina
authors.initials: P
authors.lastname: Olszewska
authors.affiliation: Department of Pharmaceutical Chemistry, Drug Analyses and Radiopharmacy, Medical University, 90-151 Łódź, Muszyńskiego 1, Poland.
authors.forename: Joanna
authors.initials: J
authors.lastname: Sikora
authors.affiliation: Department of Pharmaceutical Chemistry, Drug Analyses and Radiopharmacy, Medical University, 90-151 Łódź, Muszyńskiego 1, Poland.
authors.forename: Elżbieta
authors.initials: E
authors.lastname: Mikiciuk-Olasik
authors.affiliation: Department of Medicinal Chemistry, Pharmaceutical Faculty, Medical University of Lublin, 20-090 Lublin, Jaczewskiego 4, Poland.
authors.forename: Robert
authors.initials: R
authors.lastname: Skibiński
authors.affiliation: Department of Medicinal Chemistry, Pharmaceutical Faculty, Medical University of Lublin, 20-090 Lublin, Jaczewskiego 4, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Gumieniczek
authors.affiliation: Laboratory of Radiopharmacy, Department of Pharmaceutical Chemistry, Drug Analyses and Radiopharmacy, Medical University, 90-151 Łódź, Muszyńskiego 1, Poland. Electronic address: pawel.szymanski@umed.lodz.pl.
authors.forename: Paweł
authors.initials: P
authors.lastname: Szymański
mesh_terms: D000166:Acridines / Q000138:chemical synthesis* / Q000737:chemistry; D000544:Alzheimer Disease / Q000188:drug therapy*; D002800:Cholinesterase Inhibitors / Q000737:chemistry / Q000627:therapeutic use*; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D013329:Structure-Activity Relationship
chemical_list: D000166:Acridines; D002800:Cholinesterase Inhibitors
keywords: Acetylcholinesterase inhibitors; Alzheimer’s disease; Inhibitors of Aβ aggregation; Molecular modeling; Multifunctional ligands; Tetrahydroacridines