title: Novel tacrine/acridine anticholinesterase inhibitors with piperazine and thiourea linkers.
abstract: A new series of substituted tacrine/acridine and tacrine/tacrine dimers with aliphatic or alkylene-thiourea linkers was synthesized and the potential of these compounds as novel human acetylcholinesterase (hAChE) and human butyrylcholinesterase (hBChE) inhibitors with nanomolar inhibition activity was evaluated. The most potent AChE inhibitor was found to be homodimeric tacrine derivative 14a, which demonstrated an IC50 value of 2 nM; this value indicates an activity rate which is 250-times higher than that of tacrine 1 and 7500-times higher than 7-MEOTA 15, the compounds which were used as standards in the study. IC50 values of derivatives 1, 9, 10, 14b and 15 were compared with the dissociation constants of the enzyme-inhibitor complex, Ki1, and the enzyme-substrate-inhibitor complex, Ki2, for. A dual binding site is presumed for the synthesized compounds which possess two tacrines or tacrine and acridine as terminal moieties show evidence of dual site binding. DFT calculations of theoretical desolvation free energies, ΔΔGtheor, and docking studies elucidate these suggestions in more detail.
authors.affiliation: Institute of Chemistry, Department of Organic Chemistry, P. J. Šafárik University, Faculty of Science, Moyzesova 11, 040 01 Kosice, Slovak Republic. Electronic address: slavka.hamulakova@upjs.sk.
authors.forename: Slavka
authors.initials: S
authors.lastname: Hamulakova
authors.affiliation: Institute of Chemistry, Department of Organic Chemistry, P. J. Šafárik University, Faculty of Science, Moyzesova 11, 040 01 Kosice, Slovak Republic.
authors.forename: Jan
authors.initials: J
authors.lastname: Imrich
authors.affiliation: Institute of Chemistry, Department of Organic Chemistry, P. J. Šafárik University, Faculty of Science, Moyzesova 11, 040 01 Kosice, Slovak Republic.
authors.forename: Ladislav
authors.initials: L
authors.lastname: Janovec
authors.affiliation: Institute of Chemistry, Department of Organic Chemistry, P. J. Šafárik University, Faculty of Science, Moyzesova 11, 040 01 Kosice, Slovak Republic.
authors.forename: Pavol
authors.initials: P
authors.lastname: Kristian
authors.affiliation: Institute of Chemistry, Department of Organic Chemistry, P. J. Šafárik University, Faculty of Science, Moyzesova 11, 040 01 Kosice, Slovak Republic.
authors.forename: Ivan
authors.initials: I
authors.lastname: Danihel
authors.affiliation: Charles University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry and Drug Control, Heyrovskeho 1203, 50005 Hradec Kralove, Czech Republic.
authors.forename: Ondrej
authors.initials: O
authors.lastname: Holas
authors.affiliation: Center for Advanced Studies, University of Defence, Faculty of Military Health Sciences, Trebesska 1575, 50001 Hradec Kralove, Czech Republic.
authors.forename: Miroslav
authors.initials: M
authors.lastname: Pohanka
authors.affiliation: Institute of Chemical Technology, Department of Organic Chemistry, Technicka 5, 166 28 Prague, Czech Republic.
authors.forename: Stanislav
authors.initials: S
authors.lastname: Böhm
authors.affiliation: Institute of Chemistry, Department of Organic Chemistry, P. J. Šafárik University, Faculty of Science, Moyzesova 11, 040 01 Kosice, Slovak Republic.
authors.forename: Maria
authors.initials: M
authors.lastname: Kozurkova
authors.affiliation: Center for Advanced Studies, University of Defence, Faculty of Military Health Sciences, Trebesska 1575, 50001 Hradec Kralove, Czech Republic; Center for Biomedical Research, University Hospital, Sokolska 581, 500 05 Hradec Kralove, Czech Republic.
authors.forename: Kamil
authors.initials: K
authors.lastname: Kuca
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry / Q000378:metabolism; D000166:Acridines / Q000737:chemistry*; D002091:Butyrylcholinesterase / Q000737:chemistry / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D000077489:Piperazine; D010879:Piperazines / Q000737:chemistry*; D011485:Protein Binding; D013619:Tacrine / Q000737:chemistry*; D013890:Thiourea / Q000737:chemistry*
chemical_list: D000166:Acridines; D002800:Cholinesterase Inhibitors; D010879:Piperazines; D000077489:Piperazine; D013619:Tacrine; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase; D013890:Thiourea
keywords: Alzheimer's disease; Cholinesterase; Cholinesterase inhibitors; Coumarin; Tacrine; β-Amyloid aggregation