José Daniel Figueroa-Villar

Organophosphorus compounds as chemical warfare agents: a review

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.

Molecular Dynamics Simulations and QM/MM Studies of the Reactivation by 2-PAM of Tabun Inhibited Human Acethylcolinesterase

A elucidacao das rotas de reativacao da acetilcolinesterase humana (HuAChE) inibida por organofosforados e de crucial importância para o desenvolvimento de antidotos eficientes contra a intoxicacao causada por agentes de guerra quimica. Com o objetivo de contribuir para uma melhor compreensao do mecanismo de reativacao, foram aplicadas neste trabalho simulacoes de dinâmica molecular (DM) classica para estudar as interacoes entre a pralidoxima e aminoacidos do sitio ativo da HuAChE inibida pelo agente neurotoxico tabun. Alem disso, metodos hibridos de mecânica quântica/mecânica molecular (QM/MM) foram usados para propor um mecanismo de reativacao para a enzima inibida. Os resultados mostraram que a DM classica manteve a pralidoxima no interior do sitio ativo da enzima, em uma regiao favoravel a ocorrencia de uma possivel reacao de desfosforilacao, que foi confirmada por metodos de QM/MM, levando a proposta de um mecanismo de reativacao, energeticamente favoravel. The elucidation of the reactivation routes of human acetylcholinesterase (HuAChE) inhibited by organophosphorous compounds is of crucial importance to the development of efficient antidotes against poisoning by chemical warfare agents. In order to contribute to a better understanding of the reactivation mechanism, we applied, in this work, classical molecular dynamics (MD) simulations to study the interactions between pralidoxime and the active sites amino acids of HuAChE inhibited by the neurotoxic agent tabun. Further, quantum mechanical/molecular mechanical (QM/MM) hybrid methods were used to propose a reactivation mechanism for the inhibited enzyme. The results showed that the classic MD kept pralidoxime inside the enzymes active site, in a favorable region to the occurrence of possible reactions of dephosphorilation, which were confirmed by QM/MM methods, and lead to the proposition of an energetically favorable mechanism of reactivation.

Molecular modeling of wild-type and antifolate resistant mutant Plasmodium falciparum DHFR

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 parasites dihydrofolate reductase (DHFR). In this way, the resistance to pyrimethamine and cycloguanil, two potent inhibitors of P. falciparum DHFR, is mainly related to mutations (single and crossed) at residues 16, 51, 59, 108 and 164 of the enzyme. In this work, we have refined a recently proposed homology-model of P. falciparum DHFR, and the resulting structure was used to obtain models for 14 mutant enzymes, employing molecular modeling. Ternary complexes of the mutant enzymes with these inhibitors have been superimposed to equivalent ternary complexes of the wild-type enzyme, allowing the proposition of hypotheses for the role of each mutation in drug resistance. Based on these results, possible reasons for antifolate resistance have been proposed.

AROMATIC GUANYL HYDRAZONES : SYNTHESIS, STRUCTURAL STUDIES AND IN VITRO ACTIVITY AGAINST TRYPANOSOMA CRUZI

Abstract A series of 22 aromatic guanyl hydrazones, prepared by condensation of several aldehydes with aminoguanidine hydrochloride, were fully characterized by NMR techniques and tested in vitro against the trypomastigote form of Trypanosoma cruzi , the causative agent of Chagas disease. Most of the compounds, especially those without hydrogen bonding groups and possessing ortho -substitution, were significantly more active than crystal violet (ID 50 536 μM). The most active compound has an ID 50 value of 17 μM (25 times more potent than gentian violet).

Molecular dynamics of the interaction of pralidoxime and deazapralidoxime with acetylcholinesterase inhibited by the neurotoxic agent tabun

Efficient acetylcholinesterase reactivators are fundamental for the development of antidotes against poisoning by neurotoxic pesticides and chemical warfare agents. However, the mechanism of the reactivation reaction and the structural characteristics of the known reactivators are poorly understood. In order to study the dynamic behavior and the effect of the antidote net charge in the reactivation of this enzyme, we carried out a molecular dynamics study of human acetylcholinesterase inhibited by tabun in complex with the antidote pralidoxime and with its deaza analogues in the neutral and anionic forms. Results show that the positive charge of pralidoxime is important for its admission and permanence inside the active site. Also, the analogues, unlike pralidoxime, when forced inside the active site, move away from the phosphorilated serine residue of the enzyme and are repelled by the electrostatic potential at the entrance of the channel that conducts to the active site.

Synthesis and structure of cadmium and zinc complexes of dehydroacetic acid

Abstract The cadmium and zinc complexes of Dehydroacetic Acid (DHA) Zn(DHA)2(H2O)2 and Cd(DHA)2(H2O)2 were synthesized and the derivatives Zn(ADH)2(DMSO)2 and Cd(ADH)2(DMSO)2 were prepared through substitution of the water ligands by DMSO. To characterize structural differences between the Cd and Zn complexes, a series of analyses were carried out: 1H, 13C, and 113Cd NMR in solution and 13C and 113Cd NMR in the solid state, infra-red spectra, thermo gravimetric analysis (TGA), differential calorimetric analysis (DSC) and elemental analysis (CHNO). The X-ray crystal structures of the complexes Zn(DHA)2(DMSO)2 and Cd(DHA)2(DMSO)2 are also reported. The coordination around the metal atoms in the solid state is best described as distorted octahedra. The two chelating DHA ligands define an equatorial plane and the axial positions are occupied by two monodentate DMSO ligands coordinated by oxygen atoms, in the trans,trans,trans configuration. Significant differences were found between the Cd and Zn coordination spheres, with the latter forming relatively looser octahedral complexes.

Synthesis of Oxadeazaflavines from Barbituric Acid and Aromatic Aldehydes

Abstract 2H-Chromeno[2,3-d]-pyrimidine-2,4(3H)-diones were prepared directly from barbituric acid and salicylaldehydes or by thermal cyclization of the condensation product of barbituric acid and 6-bromopiperonal.

A theoretical and NMR study of the tautomerism of dehydroacetic acid

Abstract A study of the tautomerism of dehydroacetic acid using 1 H, 13 C (solution and CP/MAS), gated 1 H-decoupling techniques, deuterium-induced isotope effects on 13 C chemical shifts, FUCOUP and molecular modeling with AM1, has showed that this compound exists as the 3-acetyl-4-hydroxy-6-methyl-2H-pyran-2-one in solution and in the solid state.

Conformational Analysis of Toxogonine, TMB-4 and HI-6 using PM6 and RM1 Methods

In this work, after validation by comparison with results obtained by DFT, the semi-empirical methods RM1 and PM6 were employed to perform conformational analysis of three oximes employed in chemical defense. The results suggested low energy conformations for those compounds that could be useful in further parameterizations for molecular modeling studies.

Thermodynamic evaluation of complexes of zinc and cadmium that mimetize metallic centers in transcription factors

Abstract Structure and energy calculations of the zinc and cadmium complexes of the peptide his–cys in their various provable geometries have been carried out using density functional methods (LSDA pBP DN ∗ ). It is shown that, for the same complex geometry, the zinc complexes are more stable than the cadmium complexes and that, for the octahedral and square planar complexes, the cis isomers are favored over the trans isomers. It was found that the hexa-coordinated zinc complex has a distorted octahedral geometry, which, through elongation of the two H 2 O–Zn bonds, tends to adopt a square planar geometry and finally evolve to the preferred tetrahedral geometry. On the other hand, the cadmium complexes tend to stay in the octahedral geometry. These results suggest that the substitution of Zn by Cd as a probe for NMR studies of the Zn coordination environment in metaloproteins should be used with caution.