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Design and synthesis of N-substituted-2-hydroxyiminoacetamides and interactions with cholinesterases

Maraković, Nikola; Knežević, Anamarija; Vinković, Vladimir; Kovarik, Zrinka; Šinko, Goran (2016) Design and synthesis of N-substituted-2-hydroxyiminoacetamides and interactions with cholinesterases. Chemico-Biological Interactions, 259 (B). pp. 122-132. ISSN 0009-2797

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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 (KI from 0.30 μmol/L to 130 μmol/L) over AChE (KI 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.

Item Type: Article
Uncontrolled Keywords: oxime antidotes ; azide-alkyne cycloaddition ; organophosphorus compounds ; Inhibition ; selectivity
Subjects: NATURAL SCIENCES > Chemistry
NATURAL SCIENCES > Chemistry > Organic Chemistry
Divisions: Division of Organic Chemistry and Biochemistry
Project titleProject leaderProject codeProject type
Dizajn, sinteza i evaluacija novih protuotrova kod trovanja živčanim bojnim otrovima i pesticidima-CHOLINESTERASEZrinka KovarikIP-2013-11-4307HRZZ
Depositing User: Anamarija Knežević
Date Deposited: 07 Nov 2017 14:22
DOI: 10.1016/j.cbi.2016.05.035

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