title: Identification and characterization of diarylimidazoles as hybrid inhibitors of butyrylcholinesterase and amyloid beta fibril formation.
abstract: In this contribution, a chemical collection of aromatic compounds was screened for inhibition on butyrylcholinesterase (BChE)'s hydrolase activity using Ellman's reaction. A set of diarylimidazoles was identified as highly selective inhibitors of BChE hydrolase activity and amyloid β (Aβ) fibril formation. New derivatives were synthesized resulting in several additional hits, from which the most active was 6c, 4-(3-ethylthiophenyl)-2-(3-thienyl)-1H-imidazole, an uncompetitive inhibitor of BChE hydrolase activity (IC₅₀ BChE=0.10 μM; K(i)=0.073 ± 0.011 μM) acting also on Aβ fibril formation (IC₅₀=5.8 μM). With the aid of structure-activity relationship (SAR) studies, chemical motifs influencing the BChE inhibitory activity of these imidazoles were proposed. These bifunctional inhibitors represent good tools in basic studies of BChE and/or promising lead molecules for AD therapy.
authors: Pharmaceutical Sciences, Department of Biosciences, Abo Akademi University, BioCity, Artillerigatan 6A, FI-20520 Turku, Finland.
authors: Daniela
authors: D
authors: Karlsson
authors: Adyary
authors: A
authors: Fallarero
authors: Gerda
authors: G
authors: Brunhofer
authors: Przemyslaw
authors: P
authors: Guzik
authors: Michaela
authors: M
authors: Prinz
authors: Ulrike
authors: U
authors: Holzgrabe
authors: Thomas
authors: T
authors: Erker
authors: Pia
authors: P
authors: Vuorela
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy; D000682:Amyloid / Q000037:antagonists & inhibitors*; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors; D000818:Animals; D002091:Butyrylcholinesterase / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002800:Cholinesterase Inhibitors / Q000009:adverse effects / Q000737:chemistry* / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D004593:Electrophorus; D006736:Horses; D006801:Humans; D007093:Imidazoles / Q000009:adverse effects / Q000737:chemistry* / Q000494:pharmacology*; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D058990:Molecular Targeted Therapy; D011994:Recombinant Proteins; D054852:Small Molecule Libraries; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology
chemical_list: C571822:4-(3-ethylthiophenyl)-2-(3-thienyl)-1H-imidazole; D000682:Amyloid; D016229:Amyloid beta-Peptides; D002800:Cholinesterase Inhibitors; D007093:Imidazoles; D011994:Recombinant Proteins; D054852:Small Molecule Libraries; D013876:Thiophenes; D002091:Butyrylcholinesterase