Organophosphorus derivatives inhibit the enzyme acetylcholinesterase promoting cholinergic hyperstimulation, irreversible damage and death. These compounds are used by civil and military organizations as pesticides or chemical weapons, respectively, and are responsible for over three million annual cases of poisoning, as well as more than 250,000 deaths per year from intentional self-poisoning, accounting 30% of suicides in the world. The organophosphorus sarin, soman, tabun and VX are been employed as weapons of war by different terrorist groups. Oxime derivatives (pralidoxime and obidoxima) have been used as antidote in detoxification step, but the results are still not satisfactory, because these drugs have low penetration into blood-brain barrier and an inefficient nucleophilic action against organophosphorus. Thus, different analytical methods can be used to monitor the efficiency of drugs with property to reactivate or inhibit the acetylcholinesterase enzyme. This paper provides an overview of the derivatives of oximes currently used as potential reactivators and inhibitors, as well as of the main methodologies used in monitoring or reactivation or inhibition of acetylcholinesterase.Keywords: Organophosphorus; reactivation; acetylcholinesterase; oxime; inhibition. ResumoDerivados organofosforados (OPs) inibem a enzima acetilcolinesterase (AChE) acarretando hiperestimulação colinérgica, danos irreversíveis e morte. Estes compostos são utilizados no âmbito civil e militar, como pesticida e armas químicas, respectivamente, e são responsáveis por mais de três milhões de casos anuais de intoxicações, assim como mais de 250.000 mortes por ano a partir de auto-intoxicações intencionais, representando 30% dos suicídios no mundo. Os OPs sarin, soman, tabun e VX vêm sendo empregados como armas de guerra por diferentes grupos terroristas. Derivados de oxima (pralidoxima e obidoxima) agem como antídoto na etapa de detoxificação, porém os resultados ainda não são satisfatórios, pois estes fármacos possuem baixa penetração na barreira hematoencefálica e uma ação nucleofílica ineficiente frente a OPs. Assim, diferentes métodos analíticos podem ser utilizados para monitorar a eficiência de fármacos com propriedade de reativar ou inibir a enzima AChE. Este trabalho oferece uma visão geral dos derivados de oximas atualmente usados como potenciais reativadores e inibidores, assim como das principais metodologias utilizadas no monitoramento de reativação ou inibição de AChE. O principal alvo para a ação desses agentes neurotóxicos é a enzima AChE, que controla as ações centrais e periféricas do neurotransmissor acetilcolina (ACh). Os agentes OPs inibem irreversivelmente a AChE, que deixa de hidrolisar a ACh, levando a um acúmulo desta nas sinapses centrais e periféricas, promovendo hiperestimulação colinérgica, que resulta em broncorreia, fasciculação muscular e cardíaca, convulsões, depressão respiratória e morte. 5,6 O tratamento médico é difícil, uma vez que a melhor estratégia terapêutica não funciona para al...
Organophosphorus (OP) compounds are irreversible inhibitors of acetylcholinesterase (AChE) commonly used as pesticides and, unfortunately, as nerve agents in terrorist attacks. These compounds are highly soluble easily crossing the blood-brain barrier (BBB). Clinically, oximes such as pralidoxime and obidoxime are used for the reactivation of AChE. These oximes are not effective to reactivate AChE inhibited by different OPs besides the fact that they are permanently charged and do not readily cross the BBB. This work evaluated the ability of ten neutral oximes to reactivate parathion-inhibited eel AChE. Because oximes can bind to AChE as reversible inhibitors, this property was also evaluated, with pralidoxime (2-PAM) used as a reference compound. Unlike 2-PAM, which inhibited AChE in a concentration-dependent way, neutral oximes did not follow the linear order of AChE inhibition. Neutral ligands can present affinity for the periferic anionic site (PAS) site. Neutral oximes 1 and 2 (200 µM) reactivated parathion-inhibited eel AChE by 9 per cent and 11 per cent, respectively; but neither of them surpassed the reactivation efficacy of 2-PAM (25 per cent). Neutral oximes 1 and 2 reactivated AChE at a safe concentration for humans. Both neutral oximes 1 and 2 are good non-quaternary moieties for the synthesis of conjugates with enhanced reactivation potency and BBB penetration.Keywords: Acetylcholinesterase; Eel AChE; Reactivator; Oxime; Pralidoxime; Parathion RESEARCH PAPERDefence Life Science Journal, Vol. 2, No. 3, July 2017, pp. 363-369, DOI : 10.14429 LIMA, et al.: DEf. LIfE SCI. J., VOL. 2, NO. 3, JULy 2017, DOI : 10.14429/dlsj.2.10730 or allosteric) 14 . Although approved as antidotes, these oximes are not sufficiently effective to reactivate AChE inhibited by the different OPs 15,16 . The mono-quaternary oxime 2-PAM is very efficient in reactivating AChE inhibited with sarin or VX 17 but is not effective against tabun or soman 18 . Obidoxime is the most potent and most efficacious oxime in reactivating AChE inhibited by various classes of OP insecticides and tabun, but was inferior to oxime HI-6 against soman, sarin, cyclosarin and VX 19. A significant drawback to these oximes is they are permanently charged and do not readily cross the blood brain barrier (BBB) 20 . As a result, they show only limited activity in the CNS, which is a major target of OPs. Thus, effective reactivators as antidotes are increasingly needed against a broader spectrum of nerve agents 21 . Introducing non-quaternary organic compounds has been a novel method of efficiently penetrate the BBB for reactivation of brain AChE 22. Non-charged oximes have previously been developed with improved BBB penetration [23][24][25][26][27][28][29] and sufficient reactivation of AChE inhibited by nerve agents and insecticides 24,30 . Even with improved BBB penetration and reactivation of AChE, the specific oxime structures with superior reactivating potency to those in use remain unknown.The work proposed here evaluated the ability of...
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