title: Design and synthesis of N-substituted-2-hydroxyiminoacetamides and interactions with cholinesterases.
abstract: Within this study, we designed and synthesized four new oxime compounds of the N-substituted 2-hydroxyiminoacetamide structure and evaluated their interactions with acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Our aim was to explore the possibility of extending the dual-binding mode of interaction between the enzyme and the inhibitor to a so-called triple-binding mode of interaction through the introduction of an additional binding moiety. N-substituted 2-hydroxyiminoacetamide 1 was prepared via BOP catalyzed amidation of hydroxyiminoacetic acid with 3-azido-1-phenylpropylamine. An azide group enabled us to prepare more elaborate structures 2-4 by the copper-catalyzed azide-alkyne cycloaddition. The new compounds 1-4 differed in their presumed AChE peripheral site binding moiety, which ranged from an azide group to functionalized heterocycles. Molecular docking studies revealed that all three binding moieties are involved in the non-covalent interactions with ChEs for all of the four compounds, albeit not always in the complete accordance with the proposed hypothesis. All of the four compounds reversibly inhibited the ChEs with their inhibition potency increasing in the same order for both enzymes (1 < 2 < 4 < 3). A higher preference for binding to BChE (KIfrom 0.30 μmol/L to 130 μmol/L) over AChE (KIfrom 50 μmol/L to 1200 μmol/L) was observed for all of the compounds. Compounds were screened for reactivation of cyclosarin-, sarin- and VX-inhibited AChE and BChE.
authors.affiliation: Institute for Medical Research and Occupational Health, Ksaverska cesta 2, HR-10 000 Zagreb, Croatia.
authors.forename: Nikola
authors.initials: N
authors.lastname: Maraković
authors.affiliation: Ruđer Bošković Institute, Bijenička cesta 54, HR-10 000 Zagreb, Croatia.
authors.forename: Anamarija
authors.initials: A
authors.lastname: Knežević
authors.affiliation: Ruđer Bošković Institute, Bijenička cesta 54, HR-10 000 Zagreb, Croatia.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Vinković
authors.affiliation: Institute for Medical Research and Occupational Health, Ksaverska cesta 2, HR-10 000 Zagreb, Croatia.
authors.forename: Zrinka
authors.initials: Z
authors.lastname: Kovarik
authors.affiliation: Institute for Medical Research and Occupational Health, Ksaverska cesta 2, HR-10 000 Zagreb, Croatia. Electronic address: gsinko@imi.hr.
authors.forename: Goran
authors.initials: G
authors.lastname: Šinko
mesh_terms: D000081:Acetamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D000110:Acetylcholinesterase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D002091:Butyrylcholinesterase / Q000097:blood / Q000737:chemistry* / Q000378:metabolism; D020134:Catalytic Domain; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D015195:Drug Design; D006736:Horses; D006801:Humans; D007700:Kinetics; D062105:Molecular Docking Simulation; D010091:Oximes / Q000737:chemistry; D011485:Protein Binding; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000737:chemistry
chemical_list: D000081:Acetamides; D002800:Cholinesterase Inhibitors; D010091:Oximes; D011994:Recombinant Proteins; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase
keywords: Azide-alkyne cycloaddition; Inhibition; Organophosphorus compounds; Oxime antidotes; Selectivity