The phenylbenzothiazole compounds show antitumor properties and are highly selective. In this paper, the (99)Tc chemical shifts based on the ((99m)Tc)(CO)3 (NNO) complex conjugated to the antitumor agent 2-(4'-aminophenyl)benzothiazole are reported. Thermal and solvent effects were studied computationally by quantum-chemical methods, using the density functional theory (DFT) (DFT level BPW91/aug-cc-pVTZ for the Tc and BPW91/IGLO-II for the other atoms) to compute the NMR parameters for the complex. We have calculated the (99)Tc NMR chemical shifts of the complex in gas phase and solution using different solvation models (polarizable continuum model and explicit solvation). To evaluate the thermal effect, molecular dynamics simulations were carried, using the atom-centered density matrix propagation method at the DFT level (BP86/LanL2dz). The results highlight that the (99)Tc NMR spectroscopy can be a promising technique for structural investigation of biomolecules, at the molecular level, in different environments.

Nerve agents are organophosphates acting as potent inhibitors of acetylcholinesterase (AChE), the enzyme responsible for the hydrolysis of acetylcholine and, consequently, the termination of the transmission of nerve impulses. The inhibition of AChE by an organophosphate can be reversed by a nucleophilic agent able to dephosphorylate a serine residue in the active site of AChE. In this sense, the oximes are compounds capable of removing the nerve agent and reactivate the enzyme. Here, we have applied a methodology involving theoretical docking and Quantum Mechanics/Molecular Mechanics, using the softwares Molegro(®) and Spartan(®), to evaluate the kinetic constants of reactivation and the interactions of the oxime BI-6 with AChE inhibited by different organophosphorus compounds in comparison to in vitro data. Results confirm that this method is suitable for the prediction of kinetic and thermodynamic parameters of oximes, which may be useful in the design and selection of new and more effective oximes.

No presente trabalho foi aplicada uma metodologia teórica desenvolvida em um trabalho anterior que utiliza os programas Molegro ® e Spartan ® para avaliar as constantes cinéticas de associação e reativação de oximas, em relação a resultados in vitro previamente reportados na literatura. Como observado antes, os resultados mostraram boa correlação entre as energias livres teóricas de ligação das oximas e os dados experimentais, corroborando a metodologia como adequada para a predição de parâmetros cinéticos e termodinâmicos, os quais podem ser úteis para o planejamento e seleção de novas e mais efetivas oximas.In this work we applied a theoretical methodology developed in a former work, using the Molegro ® and Spartan ® softwares, to evaluate the association and kinetic reactivation constants of oximes, facing in vitro data previously reported in the literature. As reported before, results showed a good agreement between the theoretical binding free energies of the oximes and experimental data, corroborating the methodology as suitable for the prediction of kinetic and thermodynamic parameters that might be helpful for the design and selection of new and more effective oximes. Keywords: acetylcholinesterase, QM/MM, chemical mechanism of reactivation, neurotoxic agents IntroductionThe action of the nerve agents 1,2 as inhibitors of the enzyme acetylcholinesterase (AChE) stops the hydrolysis of the neurotransmitter acetylcholine and can lead to an irreversible inhibition of this enzyme (aging) thus triggering the cholinergic syndrome.3 To avoid this it's necessary a nucleophile, like an oxime, whose hydroxyl group is believed to be able to remove the nerve agent from the active site and reactivate AChE (Scheme 1). This reactivation reaction (illustrated in equation 1) involves, first, the association of the oxime to the inhibited enzyme (EIOx) and then the reactivation of the enzyme by the leaving of the oxime complexed to the neurotoxic agent (I-Ox).Where K R and k r are the dissociation constants, which represent the affinity of oximes for the inhibited AChE, and the rate constant for the decomposition of the stable enzyme-inhibitor-reactivator complex, respectively. 4,5The literature reports many structurally different oximes able to perform the reactivation of AChE inhibited by several different nerve agents, but one structure able to act efficiently against all the existing neurotoxic agents has not yet been reported 4,5 and oximes that are efficient against one specific nerve agent can be completely ineffective with another.2-6 Several molecular modelling studies available in literature point out to important features on the oximes structures that could be very useful to guide experimental research on this issue. [7][8][9][10][11][12][13][14][15][16][17][18][19] In a former work 4 we have Methodology Ligands data set and docking energy calculationsThe in vitro data of K R and k r for the oximes studied in this work (Figure 1) regarding AChE inhibited by cyclosarin, were reported by Kassa et al. 5 Crystallogr...

As doenças causadas por protozoários afetam hoje em dia uma grande parcela da população mundial, provocando muitas mortes e exercendo grande influência na qualidade de vida e no desenvolvimento de muitos países. Essas doenças afetam principalmente países pobres e por isso, a pesquisa e o desenvolvimento de novos fármacos são negligenciados. De fato, a maioria das drogas usadas no tratamento dessas doenças data de décadas passadas e apresentam muitas limitações, incluindo o aparecimento da resistência às drogas. Este artigo tem como foco os mais recentes desenvolvimentos publicados no campo de patentes, entre 2001-2008, com especial atenção a promissores compostos atuando contra tripanossomíase, leishmaniose, malária, toxoplasmose, amebíase, giardíase, balantidíase e pneumocistose.Protozoan infections are parasitic diseases that affect hundreds of millions of people worldwide, but have been largely neglected for drug development because they affect poor people in poor regions of the world. Most of the current drugs used to treat these diseases are decades old and have many limitations, including the emergence of drug resistance. This review will focus on the most recent developments, from 2001 to 2008, published in the field of patents and publications, paying particular attention to promising compounds acting against trypanosomiasis, leishmaniasis, malaria, toxoplasmosis, amebiasis, giardiasis, balantidiasis and pneumocystosis, their chemistry and biological evaluation, and to new chemical and pharmaceutical processes.

During World War II, organophosphorus compounds with neurotoxic action were developed and used as the basis for the development of structures currently used as pesticides in the agricultural industry. Among the nerve agents, Tabun, Sarin, Soman and VX are the most important. The factor responsible for the high toxicity of organophosphorus (OP) is the acetylcholinesterase inhibition. However, one of the characterized enzymes capable of degrading OP is Phosphotriesterase (PTE). This enzyme has generated considerable interest for applications of rapid and complete detoxification. Due to the importance of bioremediation methods for the poisoning caused by OP, this work aims to study the interaction mode between the PTE enzyme and organophosphorus compounds, in this case, Sarin, Soman, Tabun and VX have been used, which are potent acetylcholinesterase inhibitors, taking into account the enantiomers "Rp" and " Sp" of each compound, with the Sp-enantiomers presenting the higher toxicity. With that, we were able to demonstrate the existence of the stereochemical preference by PTE in these compounds. With the purpose of increasing the speed of the hydrolysis mechanism, we have proposed a modification in the enzyme active site structure, where Zn(2+) ions were substituted by Al(3+) ions. To analyze the stability of Al(3+) ions in the wild-type PTE active site, MD simulations were also performed. This mutation brought relevant results; in this case, there was a reduction of the reaction energy barrier for all the compounds, mainly for VX in which the reaction presented lower activation energy values, and consequently, a faster hydrolysis process.

We show by quantum mechanical/molecular mechanical (QM/MM) simulations that phenylbenzothiazoles undergoing an excited-state proton transfer (ESPT) can be used to probe protein binding sites. For 2-(2′-hydroxy-4′-aminophenyl)benzothiazole (HABT) bound to a tyrosine kinase, the absolute and relative intensities of the fluorescence bands arising from the enol and keto forms are found to be strongly dependent on the active-site conformation. The emission properties are tuned by hydrogen-bonding interactions of HABT with the neighboring amino acid T766 and with active-site water. The use of ESPT tuners opens the possibility of creating two-color fluorescent markers for protein binding sites, with potential applications in the detection of mutations in cancer cell lines

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