Naslov
Design, synthesis, and reactivation efficiency of chiral N-substituted 2-hydroxyiminoacetamides

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

Vrsta, podvrsta i kategorija rada
Sažeci sa skupova, sažetak, znanstveni

Izvornik
Workshop on “Reactivators and Medical Countermeasures against Nerve Agents and Pesticides” : Meeting abstract, u Arhiv za higijenu rada i toksikologiju Vol.69(3) / - , 2018, A37-A37

Skup
Workshop on Reactivators and Medical Countermeasures against Nerve Agents and Pesticides

Mjesto i datum
Zagreb, Hrvatska, 14.05.2018. - 15.05.2018

Vrsta sudjelovanja
Predavanje

Vrsta recenzije
Domaća recenzija

Ključne riječi
acetylcholinesterase ; butyrylcholinesterase ; nerve agents ; oximes ; reactivators

Sažetak
Using computational methods of molecular modelling, we investigated conformational changes in the active site of acetylcholinesterase (AChE) upon binding various ligands and defined structural characteristics of efficient oxime reactivators of AChE inhibited with warfare nerve agents and defined guidelines for their synthesis. Four new chiral oxime reactivators from the N- substituted 2-hydroxiiminoacetamide group were prepared starting from racemic 1- phenylallylamine prepared from cinnamyl alcohol. Enantiomers of oximes were separated using high performance liquid chromatography on polysaharidic chiral stationary phases. New oximes were tested for inhibition of AChE and butyrylcholinesterase (BChE) and reactivation of cholinesterases inhibited with tabun, cyclosarin, sarin, and VX. New oximes reversibly inhibit both enzymes with inhibition constant (KI) in micromolar range. Both enzymes showed greatest affinity toward 2-hydroxyimino- N-(3-(4-((2- methylimidazol-1-yl)methyl)-1, 2, 3- triazol-1-yl)-1- phenylpropyl)acetamide towards which BChE displays significant selectivity and stereoselectivity. All of the new oximes showed reactivation efficiency against cyclosarin-, sarin-, and VX-inhibited BChE, while only oximes with more elaborate structure of structural element binding to peripheral allosteric site showed reactivation efficiency against inhibited AChE. Molecular docking studies concluded that differences in binding of new oximes in AChE and BChE largely result from differences in amino acids at the position of Tyr72, Tyr124, Phe297, and Tyr337 in the AChE active site.

Izvorni jezik
Engleski

Znanstvena područja
Kemija, Temeljne medicinske znanosti

POVEZANOST RADA