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Pregled bibliografske jedinice broj: 818400

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


Maraković, Nikola; Knežević, Anamarija; Vinković, Vladimir; Kovarik, Zrinka; Šinko, Goran
Design and synthesis of N-substituted-2-hydroxyiminoacetamides and interactions with cholinesterases // Chemico-biological interactions, 259 (2016), Part B; 122-132 doi:10.1016/j.cbi.2016.05.035 (međunarodna recenzija, članak, znanstveni)


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

Autori
Maraković, Nikola ; Knežević, Anamarija ; Vinković, Vladimir ; Kovarik, Zrinka ; Šinko, Goran

Izvornik
Chemico-biological interactions (0009-2797) 259 (2016), Part B; 122-132

Vrsta, podvrsta i kategorija rada
Radovi u časopisima, članak, znanstveni

Ključne riječi
Oxime antidotes ; Azide-alkyne cycloaddition ; Organophosphorus compounds ; Inhibition ; Selectivity

Sažetak
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.

Izvorni jezik
Engleski

Znanstvena područja
Kemija, Temeljne medicinske znanosti, Farmacija



POVEZANOST RADA


Projekt / tema
HRZZ-IP-2013-11-4307 - Dizajn, sinteza i evaluacija novih protuotrova kod trovanja živčanim bojnim otrovima i pesticidima (Zrinka Kovarik, )

Ustanove
Institut za medicinska istraživanja i medicinu rada, Zagreb,
Institut "Ruđer Bošković", Zagreb

Časopis indeksira:


  • Current Contents Connect (CCC)
  • Web of Science Core Collection (WoSCC)
    • Science Citation Index Expanded (SCI-EXP)
    • SCI-EXP, SSCI i/ili A&HCI
  • Scopus
  • MEDLINE


Uključenost u ostale bibliografske baze podataka:


  • CA Search (Chemical Abstracts)
  • EMBASE (Excerpta Medica)
  • BIOBASE
  • EMBiology
  • PASCAL M


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