The effect of neutral oximes on the reactivation of human acetylcholinesterase inhibited with paraoxon

Abstract

Importantes agentes para defesa contra armas de guerra química são reativadores da acetilcolinesterase humana (huAChE) inibida por compostos organofosforados neurotóxicos (OP), e precisam de uma permeabilidade razoável pela barreira hematoencefálica (HB). Neste trabalho, oximas neutras, que penetram HB melhor do que as oximas catiônicas atualmente utilizadas como agentes de defesa, foram testadas como reativadores da huAChE inibida com paraoxon usando o método de Ellman modificado e pralidoxima (2-PAM) como padrão positivo. A oxima neutra mais ativa foi a 2-tiofenoaldoxima, que reativou 93% da huAChE inibida, sendo 12% mais eficiente do que a 2-PAM. Os resultados mostraram que oximas neutras simples possuem potencial para atuarem como antídotos para intoxicação com OPs neurotóxicos, sugerindo maior investigação no desenvolvimento de agentes de defesa neutros.Important defense agents against chemical warfare weapons, which are reactivators of human acetylcholinesterase (huAChE) inhibited by neurotoxic organophosphorus compounds (OP), need a reasonable permeation of the hematoencephalic barrier (HB). In this work, neutral oximes, which permeate HB better than the cationic oximes currently used as defense agents, were tested as reactivators of huAChE inhibited with paraoxon using the modified Ellman test with pralidoxime (2-PAM) as positive standard. The most active neutral oxime was (thiophen-2-yl)aldoxime, which reactivated 93% of the inhibited huAChE and was 12% more effective than 2-PAM. The results showed that simple neutral oximes have potential to function as antidotes for intoxication with neurotoxic OPs, suggesting further research on the development of neutral defense agents.Keywords: neutral oximes, huAChE reactivation, paraoxon, chemical warfare, (thiophen-2-yl)aldoxime IntroductionIntoxication with neurotoxic organophosphorus compounds is a serious problem caused by some pesticides used in agriculture, such as paraoxon (1) and malathion (2) ( Figure 1) and chemical warfare agents. [1][2][3][4][5][6][7][8][9][10][11] According to the World Health Organization, there are about 220,000 intoxications with organophosphorus pesticides throughout the world every year, leading to approximately 20,000 deaths. 1,[12][13][14] The most dangerous neurotoxic compounds are the chemical warfare agents soman (3), sarin (4), tabun (5) and VX (6) ( Figure 1). Though their use is prohibited by the United Nations, these agents have been employed as weapons by terrorist groups and by countries that did not sign the Chemical Weapon Convention administered by the Organization for the Prohibition of Chemical Weapons (OPCW).The principal target for the action of neurotoxic organophosphorus compounds is the enzyme acetylcholinesterase (AChE), a serine hydrolase that controls the nerve impulses at the cholinergic receptors in the central and peripheral nervous systems. 1,15-20 As shown in Ribeiro et al. 1217 Vol. 23, No. 7, 2012 Figure 2, the function of AChE (7) is the hydrolysis of the nerve impulse transmitter acetylcholine...

Ruthenium Complexes for Catalytic Dehydrogenation of Hydrazine and Transfer Hydrogenation Reactions

“…Synthesis and X‐ray structure of ruthenium‐arene complexes . To perform ruthenium catalyzed dehydrogenation of hydrazine, Ru II –arene complexes, [( η 6 ‐benzene)Ru( N ‐hydroxy‐iminopyridine)Cl] + ( [Ru]‐1 ), [( η 6 ‐benzene)Ru( N ‐methoxy‐iminopyridine)Cl] + ( [Ru]‐2 ), and [( η 6 ‐benzene)Ru( N ‐isopropyl‐iminopyridine)Cl] + ( [Ru]‐3 ), were synthesized following earlier reports (Figure a) . Recrystallization of [Ru]‐2 gave orange colour crystals suitable for single‐crystal structure determination (Figure b).…”

Design, synthesis, and evaluation of guanylhydrazones as potential inhibitors or reactivators of acetylcholinesterase

“…Reactions were monitored by TLC using DCAlufolien Kieselgel 60 F254 (Merck, Darmstadt, Germany). The NMR spectra were determined on a Varian 600 MHz spectrometer, using dimethyl sulfoxide-d6 (DMSO-d 6 ) as solvent and tetramethylsilane as internal standard. The infrared (IR) spectra were measured using a Spectrum 100 spectrometer.…”

“…IR (cm À1 ): 3291 (amine N-H), 3119 (aromatic C-H), 1628-1505 (C ¼ N and C ¼ C), 1293 and 1247 (C-N), 780 (C-H out of plane (Di-1,2) General procedure for guanylhydrazones (3)(4)(5)(6)(7)(8)(9)(10)(11)(12) Aminoguanidine hydrochloride (1.4 mmol) dissolved in 20 mL of 95% ethanol, the corresponding aldehyde (1 mmol) and two drops of HCl (0.6 M) were added to a 50.0 mL round-bottom flask. The solution was stirred and heated under reflux.…”

“…These agents lead to the phosphorylation of Ser203, which is the most important active amino acid involved in ACh hydrolysis, at the active site of AChE, leading to complete inhibition of this enzyme 5 . Despite the use of chemical warfare agents being prohibited by the United Nations, these agents constitute one of the greatest threats in the modern world 6 . In parallel, many organophosphorus pesticides are used by all countries for agricultural production, a process that sometimes causes several toxic problems.…”

Oxime functionality in surfactant self-assembly: An overview on combating toxicity of organophosphates

“…A simple and straightforward method for the detoxification of OPCs involves their reactions with α-nucleophiles. Different α-nucleophiles like hydroxamic acid [26][27], o-iodosyl carboxylates [28][29], hydroxyl benzotriazoles [30][31], hydroxylamine [32][33], hydrazine [34], and hypochlorite [35] have been used to detoxify OPCs and nerve agents.…”