Design, synthesis, and reactivation efficiency of chiral N-substituted 2-hydroxyiminoacetamides (CROSBI ID 672125)
Prilog sa skupa u časopisu | sažetak izlaganja sa skupa | domaća recenzija
Podaci o odgovornosti
Maraković, Nikola ; Vinković, Vladimir ; Kovarik, Zrinka ; Šinko, Goran
engleski
Design, synthesis, and reactivation efficiency of chiral N-substituted 2-hydroxyiminoacetamides
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.
acetylcholinesterase ; butyrylcholinesterase ; nerve agents ; oximes ; reactivators
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Podaci o prilogu
A37-A37.
2018.
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objavljeno
Podaci o matičnoj publikaciji
Arhiv za higijenu rada i toksikologiju
0004-1254
1848-6312
Podaci o skupu
Workshop on Reactivators and Medical Countermeasures against Nerve Agents and Pesticides
predavanje
14.05.2018-15.05.2018
Zagreb, Hrvatska
Povezanost rada
Kemija, Temeljne medicinske znanosti