Os agentes de guerra química constituem uma das maiores ameaças do mundo moderno. Dentre estes, destacam-se os agentes neurotóxicos, em virtude de sua alta letalidade e periculosidade. Eles são compostos organofosforados que atuam pela inibição da enzima acetilcolinesterase, a qual é fundamental no processo de transmissão de impulsos nervosos. Existem várias formas de tratamento para a intoxicação por organofosforados, mas nenhuma delas é eficaz contra todos os agentes conhecidos ou contra todos os seus efeitos. Esta revisão tem como foco o uso de compostos organofosforados como agentes neurotóxicos de guerra química. Após uma breve introdução histórica, será feita uma discussão sobre as principais características estruturais e biológicas da acetilcolinesterase, seguida por uma revisão das propriedades dos compostos organofosforados e da sua aplicação como agentes de guerra química. Por fim, serão discutidas as formas de tratamento contra estes agentes, com ênfase nas oximas usadas para reativar a acetilcolinesterase inibida.Chemical warfare agents constitute one of the greatest threats in the modern world. Among them, the neurotoxic agents are of special interest due to their high lethality and danger. Neurotoxic agents are organophosphorus compounds that act by inhibiting the enzyme acetylcholinesterase, which is fundamental for the control of transmission of nervous impulses. There are several ways of treating intoxication by organophosphorus compounds, but none of them is efficient against all the known neurotoxic agents or against all of their effects. This review focus on the use of organophosphorus compounds as neurotoxic chemical warfare agents. After a brief historical introduction, it will be done a discussion about the structural and biological characteristics of acetylcholinesterase, followed by a review of the properties of organophosphorus compounds and their application as chemical warfare agents. Finally, the ways of treatment against intoxication with these agents will be discussed, with emphasis on the oximes used for reactivating the inhibited acetylcholinesterase.

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Oximes have been used as reactivators for organophosphorus-inhibited acetylcholinesterase (AChE). However, it is still not clear why oximes are more efficient than other nucleophiles, since the reactivation consists of a simple nucleophilic substitution. In an attempt to answer this question, we have modeled the sarin-inhibited AChE reactivation by other nucleophiles (with and without the so-called alpha-effect) by applying the B3LYP/6-311G(d,p) level of theory. We have concluded that oximes reactivate AChE by a three-step mechanism in opposition to the four-step processes of the other modeled nucleophiles. In addition, our model suggests that oximes react with AChE in the deprotonated form (oximate). Our results also indicate that other nucleophiles may be used as AChE reactivators. We propose the use of hydrazones and hydrazonates for further evaluation as antidotes for intoxication by chemical warfare agents.

Cerca de 40% da população mundial está exposta à malária, o que resulta na morte de mais de dois milhões de pessoas por ano na África, América Latina, Ásia Meridional e Oceania. A forma mais grave de malária em humanos é causada pelo protozoário Plasmodium falciparum. A quimioterapia ainda é uma das principais estratégias de controle deste parasita. Muitos dos antimalariais atuam inibindo a enzima di-hidrofolato redutase (DHFR), o que resulta na morte do protozoário. Contudo, o desenvolvimento de resistência tem reduzido a eficiência dos antifolatos como antimalariais. Este fenômeno foi relacionado à ocorrência de mutações na di-hidrofolato redutase do parasita. Este artigo faz uma revisão rapida de algumas características da malária falciparum, seguida de uma revisão extensiva da di-hidrofolato redutase do P. falciparum e das mutações relacionadas à resistência a antifolatos. About 40% of the world population is exposed to malaria, which results in the death of over 2 million people per year in Africa, Latin America, Southern Asia and Oceania. The most severe type of malaria in humans is caused by the protozoan parasite Plasmodium falciparum. Chemotherapy is still one of the main control strategies for this parasite. Many of the antimalarials act by inhibiting the enzyme dihydrofolate reductase (DHFR), resulting in protozoan death. However, the development of drug resistance is reducing the efficiency of antifolates as antimalarials. This phenomenon has been linked to the occurrence of mutations in the dihydrofolate reductase of the parasite. This article includes a preliminary review of some of the features of falciparum malaria, followed by a more extensive review of the dihydrofolate reductase of P. falciparum and the mutations related to antifolate resistance.

Neurotoxic organophosphorus compounds (OPs), which are used as pesticides and chemical warfare agents lead to more than 700,000 intoxications worldwide every year. The main target of OPs is the inhibition of acetylcholinesterase (AChE), an enzyme necessary for the control of the neurotransmitter acetylcholine (ACh). The control of ACh function is performed by its hydrolysis with AChE, a process that can be completely interrupted by inhibition of the enzyme by phosphylation with OPs. Compounds used for reactivation of the phosphylated AChE are cationic oximes, which usually possess low membrane and hematoencephalic barrier permeation. Neutral oximes possess a better capacity for hematoencephalic barrier permeation. NMR spectroscopy is a very confident method for monitoring the inhibition and reactivation of enzymes, different from the Ellman test, which is the common method for evaluation of inhibition and reactivation of AChE. In this work (1)H NMR was used to test the effect of neutral oximes on inhibition of AChE and reactivation of AChE inhibited with ethyl-paraoxon. The results confirmed that NMR is a very efficient method for monitoring the action of AChE, showing that neutral oximes, which display a significant AChE inhibition activity, are potential drugs for Alzheimer disease. The NMR method showed that a neutral oxime, previously indicated by the Ellman test as better in vitro reactivator of AChE inhibited with paraoxon than pralidoxime (2-PAM), was much less efficient than 2-PAM, confirming that NMR is a better method than the Ellman test.