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.

In the past two decades, a large body of evidence has established a causative role for the beta-amyloid peptide (Abeta) in Alzheimer's disease (AD). However, recent debate has focused on whether amyloid fibrils or soluble oligomers of Abeta are the main neurotoxic species that contribute to neurodegeneration and dementia. Considerable early evidence has indicated that amyloid fibrils are toxic, but some recent studies support the notion that Abeta oligomers are the primary neurotoxins. While this crucial aspect of AD pathogenesis remains controversial, effective therapeutic strategies should ideally target both oligomeric and fibrillar species of Abeta. Here, we describe the anti-amyloidogenic and neuroprotective actions of some di- and tri-substituted aromatic compounds. Inhibition of the formation of soluble Abeta oligomers was monitored using a specific antibody-based assay that discriminates between Abeta oligomers and monomers. Thioflavin T and electron microscopy were used to screen for inhibitors of fibril formation. Taken together, these results led to the identification of compounds that more effectively block Abeta oligomerization than fibrillization. It is significant that such compounds completely blocked the neurotoxicity of Abeta to rat hippocampal neurons in culture. These findings provide a basis for the development of novel small molecule Abeta inhibitors with potential applications in AD.

We carried out Hartree-Fock (HF) and density functional theory calculations for 61 compounds, the conjugated bases of carboxylic acids, phenols, and alcohols, and analyzed their acid-base behavior using molecular orbital (MO) energies and their dependence on solvent effects. Despite the well-known correlation between highest-occupied MO (HOMO) energies and pKa, we observed that HOMO energies are inadequate to describe the acid-base behavior of these compounds. Therefore, we established a criterion to identify the best frontier MO for describing pKa values and also to understand why the HOMO approach fails. The MO that fits our criterion provided very good correlations with pKa values, much better than those obtained by HOMO energies. Since they are the frontier molecular orbitals that drive the acid-base reactions in each compound, they were called frontier effective-for-reaction MOs, or FERMOs. By use of the FERMO concept, the reactions that are HOMO driven, and those that are not, can be better explained, independently from the calculation method used, as both HF and Kohn-Sham methodologies lead to the same FERMO.

Protein amyloid aggregation is associated with a number of important human pathologies, but the precise mechanisms underlying the toxicity of amyloid aggregates are still incompletely understood. In this context, drugs capable of blocking or interfering with the aggregation of amyloidogenic proteins should be considered in strategies aimed at the development of novel therapeutic agents. Human lysozyme variants have been shown to form massive amyloid deposits in the livers and kidneys of individuals affected by hereditary systemic amyloidosis. Currently, there are no clinical treatments available to prevent or reverse formation of such amyloid deposits. We have recently described a number of di- and trisubstituted aromatic compounds that block the formation of soluble oligomers and amyloid fibrils of the beta-amyloid peptide (Abeta) and protect hippocampal neurons in culture from Abeta-induced toxicity. Here, we show that some of those compounds inhibit the formation and disrupt preformed amyloid fibrils from both human and hen egg white lysozyme. These results suggest that these small molecule compounds may serve as prototypes for the development of drugs for the prevention or treatment of different types of amyloidoses.

ABSTRACT:A detailed structural study of pralidoxime (2-PAM), the main antidote against organophosphate intoxication, was performed using Hartree-Fock, Möller-Plesset (MP2), and density functional theory (Becke, Lee, Yang, and Paar [B3LYP]) methods. Rotational barriers, equilibrium geometries, and charge distributions were calculated, showing important differences between the two forms available in physiological conditions, namely with the oxime group protonated or unprotonated. For the protonated form, conjugation between the side chain and the pyridinium ring, although present, has little importance, resulting in a flexible structure. On the other hand, the unprotonated form has a more rigid structure and a smaller charge density on the oxime oxygen. Contrary to the common belief, those results strongly suggest that it may be the protonated form of 2-PAM, instead of the unprotonated form, that is responsible for the antidote activity of this compound.

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O conceito FERMO foi empregado com sucesso ao princípio ácido-base de dureza e moleza de Pearson para quatro ligantes ambidentados. Usando um postulado intuitivo basedo em argumentos HOMO-LUMO para a dureza e moleza, as diferenças de energia FERMO-LUMO descrevem corretamente os sítios duros e moles para os sistemas estudados. Além disso, os orbitais de Kohn-Sham e Hartree-Fock levam às mesmas conclusões. The FERMO concept was successfully applied to the Pearson´s Hard and Soft acid-base principle for four ambidentate ligands. Using an intuitive statement based on the HOMO-LUMO approach to the hardness and softness, the FERMO-LUMO gaps correctly describe the soft and hard sites in the studied systems. Moreover, Kohn-Sham and Hartree-Fock MOs lead to same conclusions.

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