Synthesis of new pyridinium oximes and evaluation of their potency to reactivate tabun-phosphorylated acetylcholinesterase (CROSBI ID 527568)
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Podaci o odgovornosti
Kovarik, Zrinka ; Odžak, Renata ; Čalić, Maja ; Tomić, Srđanka
engleski
Synthesis of new pyridinium oximes and evaluation of their potency to reactivate tabun-phosphorylated acetylcholinesterase
The increased concern about terrorist use of nerve agents prompted us to search for new, more effective oximes against tabun poisoning. Five monoquaternary oximes, N-benzyl-4-hydroxyiminomethylpyridinium bromide (I), N-(p-bromo)benzyl-4-hydroxyiminome-thylpyridinium bromide (II), N-(p-nitro)benzyl-4-hydroxyiminomethylpyridinium bromide (III), N-(p-methyl)benzyl-4-hydroxyiminomethylpyridinium bromide (IV) and N-(p-chloro)benzyl-4-hydroxyiminomethylpyridinium bromide (V) were synthesized to examine their potency as reactivators of tabun-inhibited human erythrocyte acetylcholinesterase (AChE ; EC 3.1.1.7). Oximes were prepared by the addition of appropriate reagents for quaternization in equimolar quantities to the solution of 4-hydroxyiminomethylpyridine (100 mg, 0.819 mmol) in dry acetone (2 mL). The reaction mixtures were kept at room temperature in the dark for 2-3 days. The crystallizations were spontaneous. Acetones were removed and white crystalline compounds were washed with dry diethyl ether and were obtained in very good yields. All synthesized monoquaternary oximes were identified by IR, 1D (1H and 13C (APT)) and 2D (HETCOR) NMR spectroscopies and X-ray analysis. Inhibition of human erythrocyte AChE by tabun proceeded for 30 min, afterwards the extraction of the excess of tabun by hexane was performed. Reactivation of tabun-inhibited AChE was measured spectrophotometrically using acetylthiocholine as a substrate. Various concentrations of the oximes (0.1-1.0 mM) were used. In 24 hours the reactivation of tabun-inhibited AChE by 1 mM of the oxime reached 60% with II, III and IV, 30% with III, and less than 20 % with I. Evaluated potency of oximes as tabun-inhibited AChE reactivators were in increasing order I > III > II > V > IV based on the extent of the reactivation after 30 min. The overall reactivation rate constants were below 10 min-1M-1 for all oximes. All studied oximes were also reversible inhibitors of native AChE with increasing inhibition potency in order IV ≥ II > V > III > I. Therefore, although oxime I did not show significant reactivation ability, this oxime might be of interest as a pre-treatment drug due to its high affinity for the native AChE.
pyridinum oximes; acetylcholinesterase
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Podaci o prilogu
232-232-x.
2007.
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objavljeno
Podaci o matičnoj publikaciji
Toxicology
Szinicz, Ladislaus ; Reiner, Elsa ; Eyer, Peter
0300-483X
Podaci o skupu
New Strategies in Medical Protection Against Organophosphorus Compounds. Tenth International Medical Chemical Defence Conference (MCDC) 2006
poster
26.04.2007-27.04.2007
München, Njemačka