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Synthesis of new pyridinium oximes and evaluation of their potency to reactivate tabun-phosphorylated acetylcholinesterase


Kovarik, Zrinka; Odžak, Renata; Čalić, Maja; Tomić, Srđanka
Synthesis of new pyridinium oximes and evaluation of their potency to reactivate tabun-phosphorylated acetylcholinesterase // Toxycology Vol. 233, Issues 1-3. Tenth International Medical Chemical Defence Conference 2006 "New strategies in medical protection against organophosphorus compounds". Abstracts / Szinicz, Ladislaus ; Reiner, Elsa ; Eyer, Peter (ur.).
Muenchen, Njemačka, 2007. str. 232-232 (poster, nije recenziran, sažetak, znanstveni)


Naslov
Synthesis of new pyridinium oximes and evaluation of their potency to reactivate tabun-phosphorylated acetylcholinesterase

Autori
Kovarik, Zrinka ; Odžak, Renata ; Čalić, Maja ; Tomić, Srđanka

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

Izvornik
Toxycology Vol. 233, Issues 1-3. Tenth International Medical Chemical Defence Conference 2006 "New strategies in medical protection against organophosphorus compounds". Abstracts / Szinicz, Ladislaus ; Reiner, Elsa ; Eyer, Peter - , 2007, 232-232

Skup
New Strategies in Medical Protection Against Organophosphorus Compounds. Tenth International Medical Chemical Defence Conference (MCDC) 2006

Mjesto i datum
Muenchen, Njemačka, 26.4.-27.4.2006

Vrsta sudjelovanja
Poster

Vrsta recenzije
Nije recenziran

Ključne riječi
Pyridinum oximes; acetylcholinesterase

Sažetak
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.

Izvorni jezik
Engleski

Znanstvena područja
Kemija



POVEZANOST RADA


Projekt / tema
022-0222148-2889 - Interakcije organofosfata, karbamata i određenih liganada s esterazama (Zrinka Kovarik, )
119-1191344-3121 - Sinteze i enzimske transformacije biološki aktivnih spojeva (Srđanka Tomić-Pisarović, )

Ustanove
Institut za medicinska istraživanja i medicinu rada, Zagreb,
Prirodoslovno-matematički fakultet, 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