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Drug resistance, evasion of cell death and metastasis are factors that contribute to the low cure rate and disease-free survival in osteosarcomas (OS). In this study, we demonstrated that a new class of oxime-containing organometallic complexes called Pd-BPO (O3) and Pd-BMO (O4) are more cytotoxic than cisplatin (CDDP) for SaOS-2 and U2OS cells using the MTT assay. Annexin-FITC/7-AAD staining demonstrated a greater potential for palladium-oxime complexes to induce death in SaOS-2 cells than CDDP, an event confirmed using the pan-caspase inhibitor Z-VAD-FMK. Compared to CDDP, only palladium-oxime complexes eradicated the clonogenicity of SaOS-2 cells after 7 days of treatment. The involvement of the lysosome-mitochondria axis in the cell death-inducing properties of the complexes was also evaluated. Using LysoTracker Red to label the acidic organelles of SaOS-2 cells treated with the O3 and O4 complexes, a decrease in the fluorescence intensity of this probe was observed in relation to CDDP and the control. Lysosomal membrane permeabilization (LMP) was also induced by the O3 and O4 complexes in an assay using acridine orange (A/O). The greater efficiency of the complexes in depolarizing the mitochondrial membrane compared to SaOS-2 cells treated with CDDP was also observed using TMRE (tetramethyl rhodamine, ethyl ester). For in vivo studies, C. elegans was used and demonstrated that both complexes reduce body bends and pharyngeal pumping after 24 h of treatment to the same extent as CDDP. We conclude that both palladium-oxime complexes are more effective than CDDP in inducing tumor cell death. The toxicity of these complexes to C. elegans was like that induced by CDDP. These results encourage preclinical studies aimed at developing more effective drugs for the treatment of osteosarcoma (OS). Furthermore, we propose palladium-oxime complexes as a new class of antineoplastic agents.

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Recent studies have demonstrated the antiproliferative and cytotoxic effects of aza-steroids and steroidal sapogenins on human cancer cell lines. The scientific community has shown a growing interest in these compounds as drug candidates for cancer treatment. In the current work, we report the synthesis of new diosgenin oxime derivatives as potential antiproliferative agents. From (25 R)-5α-spirost-3,5,6-triol (1), a diosgenin derivative, ketones 2, 3, 4, and 9 were obtained and used as precursors of the new oximes. A condensation reaction was carried out between the steroidal ketones (2, 3, 4, and 9) with hydroxylamine hydrochloride in 2,4,6-trimethylpyridine to produce five spirostanic oximes (four of them are not reported before) with a 42-96% yield. Also, a new spirostanic α, ß-unsaturated cyanoketone was synthesized via Beckmann fragmentation using thionyl chloride with a 62% yield. Furthermore, we proposed a reaction mechanism with the aim of explaining such transformation.

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The A-series is the most recent generation of chemical warfare nerve agents (CWA) which act directly on the inhibition of the human acetylcholinesterase (HssAChE) enzyme. These compounds lack accurate experimental data on their physicochemical properties, and there is no evidence that traditional antidotes effectively reactivate HssAChE inhibited by them. In the search for potential antidotes, we employed virtual screening, molecular docking, and molecular dynamics (MD) simulations for the theoretical assessment of the performance of a library of Mannich phenols as potential reactivators of HssAChE inhibited by the Novichok agents A-230, A-232, and A-234, in comparison with the commercial oximes pralidoxime (2-PAM), asoxime (HI-6), trimedoxime (TMB-4), and obidoxime. Following the near-attack conformation (NAC) approach, our results suggest that the compounds assessed would face difficulties in triggering the proposed nucleophilic in-line displacement mechanism. Despite this, it was observed that certain Mannich phenols presented similar or superior results to those obtained by reference oximes against A-232 and A-234 model, suggesting that these compounds can adopt more favourable conformations. Additional binding energy calculations confirmed the stability of the model/ligands complexes and the reactivating potential observed in the molecular docking and MD studies. Our findings indicate that the Mannich phenols could be alternative antidotes and that their efficacy should be evaluated experimentally against the A-series CWA.

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Organophosphorus poisoning caused by some pesticides and nerve agents is a life-threating condition that must be swiftly addressed to avoid casualties. Despite the availability of medical countermeasures, the clinically available compounds lack a broad spectrum, are not effective towards all organophosphorus toxins, and have poor pharmacokinetics properties to allow them crossing the blood-brain barrier, hampering cholinesterase reactivation at the central nervous system. In this work, we designed and synthesised novel isatin derivatives, linked to a pyridinium 4-oxime moiety by an alkyl chain with improved calculated properties, and tested their reactivation potency against paraoxon- and NEMP-inhibited acetylcholinesterase in comparison to the standard antidote pralidoxime. Our results showed that these compounds displayed comparable in vitro reactivation also pointed by the in silico studies, suggesting that they are promising compounds to tackle organophosphorus poisoning.

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BACKGROUND: Neurotoxic chemical warfare agents can be classified as some of the most dangerous chemicals for humanity. The most effective of those agents are the Organophosphates (OPs) capable of restricting the enzyme Acetylcholinesterase (AChE), which in turn, controls the nerve impulse transmission. When AChE is inhibited by OPs, its reactivation can be usually performed through cationic oximes. However, until today, it has not been developed one universal defense agent, with complete effective reactivation activity for AChE inhibited by any of the many types of existing neurotoxic OPs. For this reason, before treating people intoxicated by an OP, it is necessary to determine the neurotoxic compound that was used for contamination, in order to select the most effective oxime. Unfortunately, this task usually requires a relatively long time, raising the possibility of death. Cationic oximes also display a limited capacity of permeating the Blood-Brain Barrier (BBB). This fact compromises their capacity to reactivating AChE inside the nervous system. METHODS: We performed a comprehensive search on the data about OPs available on the scientific literature today in order to cover all the main drawbacks still faced in the research for the development of effective antidotes against those compounds. RESULTS: Therefore, this review about neurotoxic OPs and the reactivation of AChE, provides insights for the new agents' development. The most expected defense agent is a molecule without toxicity and effective to reactivate AChE inhibited by all neurotoxic OPs. CONCLUSION: To develop these new agents, the application of diverse scientific areas of research, especially theoretical procedures as computational science (computer simulation, docking and dynamics), organic synthesis, spectroscopic methodologies, biology, biochemical and biophysical information, medicinal chemistry, pharmacology and toxicology, is necessary.

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Casualties caused by organophosphorus pesticides are a burden for health systems in developing and poor countries. Such compounds are potent acetylcholinesterase irreversible inhibitors, and share the toxic profile with nerve agents. Pyridinium oximes are the only clinically available antidotes against poisoning by these substances, but their poor penetration into the blood-brain barrier hampers the efficient enzyme reactivation at the central nervous system. In searching for structural factors that may be explored in future SAR studies, we evaluated neutral aryloximes as reactivators for paraoxon-inhibited Electrophorus eel acetylcholinesterase. Our findings may result into lead compounds, useful for development of more active compounds for emergencies and supportive care.

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Intoxications caused by organophosphorus compounds (OPs) are associated with the reversible, and sometimes irreversible interaction with acetylcholinesterase (AChE). OPs are commonly used as pesticides mainly in developing countries, where the associated poisoning is a major health problem related to suicidal attempts, careless manipulation, and chemical warfare. The current antidotes are oxime-based drugs that can regenerate the AChE catalytic activity. Nevertheless, challenges associated with lack of efficiency and difficulties for crossing blood-brain barrier have motivated the design of novel alternatives. We used a validated molecular docking approach for the virtual screening of 579,890 synthetic ligands and 478 drugs against a human AChE in its apo conformation, and a murine AChE conjugated with the OP tabun. After filtering, 7 hits were selected as potential competitors due to the formation of key interactions within the active site gorge of the AChE structure, and potential reactivators based on interactions with amino acids of the catalytic triad in the presence of organophosphorus compounds. The selected candidates will be further evaluated through in vitro and in vivo assays.

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The formation of amide bonds is one of the most stimulating emerging areas in organic and medicinal chemistry. Amides are recognized as central building blocks in a plethora of interesting pharmaceuticals, proteins, peptides, polymers, natural products, functional materials, and biologically relevant carbocyclic or heterocyclic molecules, and they are also found in a variety of industrial fields. Therefore, a review of recent developments and challenges in the formation of amide bonds from carbonyl compounds is particularly important. Herein, we have scrutinized a range of metal-catalyzed and metal-free approaches for the synthesis of amides from aldehydes, ketones, and oximes. In addition, this Minireview highlights relevant mechanistic studies, as well as the potential applications of these methods in the synthesis of candidate drug molecules. We hope that the data compiled herein will encourage further progress in this notable area of chemistry research.

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Tabun is one of the most dangerous nerve agents because it has deleterious effects like inhibition of the essential enzymes acetylcholinesterase (AChE) and butyrylcholinesterase. Some oximes such HI6 as 2-PAM are nucleophiles that are capable to reactivate inhibited human AChE under some conditions. Zwitterionic and cationic species have the best chance of productive action on inhibited AChE. However uncharged oximes can give important interaction information. In order to investigate the interaction and behavior of cationic and uncharged oximes, we performed molecular docking simulations and molecular dynamics and calculated binding energies of complexes of these compounds with human AChE. The uncharged oximes of larger structure were more susceptible to the influence of the substituents on the phosphorus atom and presented low binding energies. In contrast, HI 6 and 2-PAM showed high binding energy values with great contribution of the amino acid Asp74, demonstrating the importance of the quaternary nitrogen to the affinity and interaction of the oximes/AChE tabun-inhibited complexes.

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New complexes of composition [MX(HL1)] (M = PtII, PdII, X = Cl- or I-) and [MX(L1)] (M = AuIII, X = Cl-; M = PtII, PdII, X = PPh3) have been synthesized using a potentially tridentate thiosemicarbazone (H2L1) containing an additional oxime binding site. Among other analytical methods, all the seven complexes have been structurally characterized by single crystal X-ray diffractometry. Interesting structural features such as the influence of the halide ligands on hydrogen bonds and the formation of supramolecular structures for the phosphine derivatives are discussed. The in vitro trypanocidal activity of the free ligand H2L1 and its derivatives against both extracellular trypomastigote and intracellular amastigote (IC50try/ama) forms of Trypanosoma cruzi (Tulahuen Lac-Z strain) and the cytotoxicity was assessed on LLC-MK2 cell line. The results showed that complexation of the thiosemicarbazone ligand H2L1 to PtII, PdII and AuIII metal centers enhances the in vitro trypanocidal activity and that the cytotoxicity is dependent on both the metal center and coligands. Within the studied series, the AuIII complex showed the greatest potential, being not the most active but the most selective compound with a similar selectivity index to that of the standard drug benznidazole. In order to get a preliminary insight into the mechanism of action of these compounds, in vitro experiments of fluorescence quenching and enzymatic activity were performed using the AuIII complex and Trypanosoma cruzi Old Yellow Enzyme (TcOYE) which indicated that the gold derivative was capable of abstracting the hydride from the prosthetic FMN group of the enzyme. Additionally, molecular docking studies followed by semiempirical simulations showed that the [AuCl(L1)] binds to the binary complex TcOYE/FMN, almost parallel to the FMN prosthetic group, in a close distance that an electron/proton transfer might occur among them.

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RESUMO Muitos compostos organofosforados (OP) são utilizados até hoje na agricultura como pesticidas e, infelizmente, como agentes de guerra química (ou agentes dos nervos) também. Os pesticidas organofosforados e os agentes dos nervos são moléculas extremamente tóxicas, uma vez que atuam como inibidores da enzima Acetilcolinesterase (AChE). O efeito mais preocupante da exposição a estes compostos é a toxicidade colinérgica aguda, ou seja, a perda de coordenação muscular. Uma vez que o indivíduo se contamina, o processo de intoxicação começa através da ligação do OP no sítio ativo da enzima AChE inativando-a. Os tratamentos atuais para pessoas expostas a baixas doses de OP podem ser realizados com atropina, oximas e benzodiazepínicos. Processos de remediação importantes envolvem o emprego de técnicas de biorremediação utilizando diferentes enzimas degradantes, como a Fosfotriesterase da Agrobacterium radiobacter e SMP-30. Devido ao elevado número de intoxicações anualmente, é crucial buscar métodos de tratamento mais potentes e eficazes, e nesta linha, as técnicas envolvendo biorremediação parecem ser bastante promissoras para este propósito.

ABSTRACT Many organophosphorus compounds (OP) are used until today in agriculture as pesticides and, unfortunately, they are used as chemical warfare agents (or nerve agents) as well. Organophosphorus pesticides and nerve agents are extremely toxic molecules, since they act as Acetylcholinesterase (AChE) inhibitors. The most worrying effect of the exposure to these compounds is the acute cholinergic toxicity, which is the loss of muscle coordination. Once one is contaminated, the intoxication process begins through the binding of the OP in the active site of the AChE enzyme inactivating it. Current treatments for people exposed to low doses of OP can be performed with atropine, oximes and benzodiazepines. Important remediation processes involve the employment of bioremediation techniques using different degrading enzymes, such as the Phosphotriesterase from Agrobacterium radiobacter and SMP-30. Due to the high number of intoxications annually, it is crucial to search for more potent and effective treatment methods, and in this line, the techniques involving bioremediation seem to be quite promising for this purpose.

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Butyryl cholinesterase (BChE) has been seen as a key enzyme in the search for new strategies in the treatment of poisoning by organophosphates (OPs), since human BChE (HssBChE), complexed with the appropriate oxime, can be a suitable scavenger and deactivator for OPs in the blood stream. However, the efficacy of HssBChE is limited by its strict stoichiometric scavenging, slow reactivation, and propensity for aging. The improvement of the reactivation rate by new and more efficient oximes could contribute to mitigate this problem and increase the HssBChE efficiency as scavenger. Several oximes have been synthesized and tested with this goal, some with promising results, but the mechanistic aspects of the reactivation reaction are not fully understood yet. In order to better investigate this mechanism, docking and mixed quantum and molecular mechanics combined with principal components analysis were performed here to evaluate the capacity of reactivation and determine the preferred route for the reactivation reaction of two new oximes on HssBChE inhibited by the neurotoxic agents cyclosarin and sarin. Plots of potential energies were calculated and all the transition states of the reactional mechanism were determined. Our results showed a good correlation with experimental data and pointed to the most efficient oxime with both OPs. The protocol used could be a suitable tool for a preliminary evaluation of the HssBChE reactivation rates by new oximes.

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Chemical weapons are a major worldwide problem, since they are inexpensive, easy to produce on a large scale and difficult to detect and control. Among the chemical warfare agents, we can highlight the organophosphorus compounds (OP), which contain the phosphorus element and that have a large number of applications. They affect the central nervous system and can lead to death, so there are a lot of works in order to design new effective antidotes for the intoxication caused by them. The standard treatment includes the use of an anticholinergic combined to a central nervous system depressor and an oxime. Oximes are compounds that reactivate Acetylcholinesterase (AChE), a regulatory enzyme responsible for the transmission of nerve impulses, which is one of the molecular targets most vulnerable to neurotoxic agents. Increasingly, enzymatic treatment becomes a promising alternative; therefore, other enzymes have been studied for the OP degradation function, such as phosphotriesterase (PTE) from bacteria, human serum paraoxonase 1 (HssPON1) and diisopropyl fluorophosphatase (DFPase) that showed significant performances in OP detoxification. The understanding of mechanisms by which enzymes act is of extreme importance for the projection of antidotes for warfare agents, and computational chemistry comes to aid and reduce the time and costs of the process. Molecular Docking, Molecular Dynamics and QM/MM (quantum-mechanics/molecular-mechanics) are techniques used to investigate the molecular interactions between ligands and proteins.

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Steroidal sapogenins have shown antiproliferative effects against several tumor cell lines; and their effects on human cancer cells are currently under study. Changes in the functionality on the steroidal structure make it possible to modify the biological activity of compounds. Herein, we report the synthesis and in vitro antitumor activity of two steroidal oxime compounds on cervical cancer cells. These derivatives were synthesized from the steroidal sapogenin diosgenin in good yields. The in vitro assays show that the steroidal oximes show significant antiproliferative activity compared to the one observed for diosgenin. Cell proliferation, cell death, and the cytotoxic effects were determined in both cervical cancer cells and human lymphocytes. The cancer cells showed apoptotic morphology and an increased presence of active caspase-3, providing the notion of a death pathway in the cell. Significantly, the steroidal oximes did not exert a cytotoxic effect on lymphocytes.

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Biflorin 1 is a biologically active quinone, isolated from Capraria biflora. Five new biflorin-based nitrogen derivatives were synthesized, of which two were mixtures of (E)- and (Z)- isomers: (Z)-2a, (Z)-2b, (Z)-3a, (Z)- and (E)-3b, (Z)- and (E)-3c. The antibacterial activity was investigated using the microdilution method for determining the minimum inhibitory concentration (MIC) against six bacterial strains. Tests have shown that these derivatives have potential against all bacterial strains. The cytotoxic activity was also evaluated against three strains of cancer cells, but none of the derivatives showed activity.

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In the present work, we performed docking and molecular dynamics simulations studies on two groups of long-tailored oximes designed as peripheral site binders of acetylcholinesterase (AChE) and potential penetrators on the blood brain barrier. Our studies permitted to determine how the tails anchor in the peripheral site of sarin-inhibited human AChE, and which aminoacids are important to their stabilization. Also the energy values obtained in the docking studies corroborated quite well with the experimental results obtained before for these oximes.

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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.

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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.

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Objetivo. Sintetizar y realizar la evaluación preliminar de la actividad antifúngica in vitro de oximas, éteres de oxima e isoxazoles. Materiales y métodos. Las oximas se sintetizaron a partir de aldehídos o cetonas con NH2OH.HCl y K2CO3. Los éteres de oxima se obtuvieron mediante alquilación de oximas con bromuro de propargilo o bromuro de 2-bromobencilo, empleando como base NaOH y acetona como solvente. Los isoxazoles se obtuvieron mediante cicloadiciones 1,3-dipolares empleando nitrato cérico amónico (NAC), cloramina-T (CAT) y NaOCl. Los productos fueron identificados y/o caracterizados por resonancia magnética nuclear (RMN) y espectrometría de masas (EM). Se realizaron pruebas de inhibición de crecimiento radial sobre Aspergillus niger y Fusarium roseum. Resultados. Se obtuvieron cinco oximas, siete éteres de oxima, cuatro de ellos nuevos y cuatro nuevos isoxazoles. Las sustancias evaluadas presentaron actividad antifúngica a cantidades de 1,5 mg y 3,0 mg. Conclusiones. Aunque las cicloadiciones 1,3-dipolares permitieron obtener los isoxazoles esperados, se observó que ésta metodología generó una amplia variedad de subproductos lo que disminuyó los rendimientos e hizo difícil la purificación del producto de interés. Cuatro de las sustancias evaluadas presentaron porcentajes de inhibición superiores al 80%...

Synthesis and in vitro assessment of antifungal activity of oximes, oxime ethers and isoxazoles. Objective. To synthesize and carry out a preliminary evaluation of the in vitro antifungal activity of oximes, oxime ethers and isoxazoles. Materials and methods. Oximes were synthesized from aldehydes or ketones with NH2OH.HCl and K2CO3. Oxime ethers were prepared by alkylation of oximes with propargyl bromide or 2-bromobenzyl bromide, using NaOH as base and acetone as solvent. The isoxazoles were obtained by 1,3-dipolar cycloadditions using ceric ammonium nitrate (CAN), chloramine T (CAT) and NaOCl. Products were identified or characterized using nuclear magnetic resonance (NMR) and mass spectrometry (MS). Radial growth inhibition assays against Aspergillus niger and Fusarium roseum were carried out. Results. Five oximes, seven oxime ethers, four of them new, and four new isoxazoles were obtained. The assessed substances exhibited antifungal activity in amounts of 1,5 mg and 3,0 mg. Conclusions. Although 1,3-dipolar cycloadditions allowed to obtain the desired isoxazoles, this methodology produced a wide variety of side products that reduced yields and made difficult the purification of the target products. Four of the tested compounds showed inhibition percentages greater than 80%...

Síntese e avaliação “in vitro” da atividade antifúngica de oximas, éteres de oxima e isoxazóis. Objetivo. Sintetizar e realizar a avaliação preliminar da atividade antifúngica in vitro de oximas, éteres de oxima e isoxazóis. Materiais e métodos. As oximas foram sintetizadas a partir de aldeídos ou cetonas com NH2OH.HCl e K2CO3. Os éteres de oxima foram obtidos pela alquilação de oximas com brometo de propargilo ou brometo de 2-bromobenzilo, utilizando NaOH como base e acetona como solvente. Os isoxazóis foram obtidos por cicloadição 1,3-dipolar usando nitrato cérico de amônio (NCA), cloramina-T (CAT) e NaOCl. Os produtos foram identificados e / ou caracterizados por ressonância magnética nuclear (RMN) e espectrometria de massas (EM). Foram realizados testes de inibição sobre o crescimento radial de Aspergillus niger e Fusarium roseum. Resultados. Foram obtidas cinco oximas, sete éteres de oxima, quatro deles novos e quatro novos isoxazóis. As substâncias testadas apresentaram atividade antifúngica em quantidades de 1,5 mg e 3,0 mg. Conclusões. Embora as cicloadições 1,3-dipolares permitiram obter os isoxazóis esperados, observou-se que esta metodologia resultou numa grande variedade de subprodutos que reduziram os rendimentos e tornaram difícil a purificação do produto de interesse. Quatro das substâncias testadas apresentaram porcentagens de inibição acima de 80%...

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La intoxicación por organofosforados es una de las causas más frecuentes de intoxicación en el mundo y una de las tres formas principales de suicidio, llegando a mortalidades cercanas al 15%. Esta radica en la inhibición irreversible que sus componentes hacen en la enzima acetilcolinesterasa, llevando con ello a la aparición de signos y síntomas secundarios al exceso de acetilcolina en los sistemas donde actúa. Su manejo aún es controvertido y sigue basándose en las medidas de descontaminación, utilización de atropina, oximas y benzodiacepinas, sin haber consenso en muchas de las dosis e intervalos de tiempo para la administración de estos medicamentos. En este artículo exponemos un caso en el cual se hace necesario utilizar dosis e intervalos de administración de atropina y el uso tardío de las oximas. Con este caso se puede concluir que la administración tardía de oximas y la utilización de grandes cantidades de atropina pueden ser una alternativa en el manejo de este tipo de intoxicación. [Leotau MA, Pacheco SH, Tavera CH. Intoxicación por organofosforados con necesidad de altas dosis de atropina y administración tardía de oximas. MedUNAB 2010; 13:44-50].

Organophosphate poisoning is one of the most frequent causes of poisoning in the world and one of the three main forms of suicide, reaching roughly 15% mortality, this lies in the irreversible inhibition that make components in the enzyme acetylcholinesterase, leading thus the signs and symptoms secondary to excessive acetylcholine in the systems where it operates. Its management is still controversial and remains based on the decontamination measures, use of atropine, oximes and benzodiazepines, no consensus on many of the doses and time intervals for administration of these drugs. In this article we present a case in which it becomes necessary to use dose and timing of administration of atropine and late use of oximes. In this case we can conclude that the late administration of oximes using grades and quantities of atropine may be an alternative in handling this type of poisoning. [Leotau MA, Pacheco SH, Tavera CH. Organophosphate poisoning treated with high doses of atropine and late administration of oxime. MedUNAB 2010; 13:44-50].

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