Design and synthesis of N-substituted-2-hydroxyiminoacetamides and interactions with cholinesterases. (25th November 2016)

• Record Type: Journal Article
• Authors: Maraković, Nikola; Knežević, Anamarija; Vinković, Vladimir; Kovarik, Zrinka; Šinko, Goran
• Is Part Of: Chemico-biological interactions. Volume 259:Part B(2016)
• Page Start: 122
• Page End: 132
• Publication Date: 2016-11-25
• Subjects: Oxime antidotes -- Azide-alkyne cycloaddition -- Organophosphorus compounds -- Inhibition -- Selectivity; Biochemistry -- Periodicals; Toxicological chemistry -- Periodicals; Biochemistry -- Periodicals; Biologie moléculaire -- Périodiques; Biochimie -- Périodiques; Toxicologie biochimique -- Périodiques; 572
• DOI: 10.1016/j.cbi.2016.05.035
• Languages: English
• ISSNs: 0009-2797

Abstract

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-hydroxyiminoacetamide1 was prepared via BOP catalyzed amidation of hydroxyiminoacetic acid with 3-azido-1-phenylpropylamine. An azide group enabled us to prepare more elaborate structures2 –4 by the copper-catalyzed azide-alkyne cycloaddition. The new compounds1 –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 ( K I from 0.30 μmol/L to 130 μmol/L) over AChE ( K I from 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. Graphical abstract: Highlights: Four new oxime compounds of the N -substituted 2-hydroxyiminoacetamide structure were prepared. All of the four oxime compounds reversibly inhibited the cholinesterases. A higher preference for binding to BChE was observed for of the four oxime compounds. Molecular docking studies predicted binding in the AChE active site of a so-called triple-binding mode.