RESUMO
Insertion of sulfoxonium ylides into the S-H bond of aryl thiols without the need for a catalyst is demonstrated, furnishing ß-keto thioethers in excellent yield in most cases. The method overcomes traditional syntheses that employ metal catalysts in combination with diazo compounds or toxic and hard-prepared haloketones. The experimental setup consists of mixing the reagents in acetonitrile at room temperature. Additional experimental as well as kinetic isotopic effect studies give some insight into the mechanism of this reaction.
RESUMO
Among the different types of diazocarbonyl substrates found in the literature to date, α,ß-unsaturated diazoketones have proven to be very promising as multifunctional intermediates. Possessing a diazo group, a ketone function and a double bond all together in a single molecule, these compounds constitute versatile building blocks for synthesis. For example, double bond functionalization, followed by intramolecular insertion reactions, can be a short alternative to prepare several rings or heterocyclic compounds. Although there are many efficient methods to prepare diazoketones, very few can be extended to the synthesis of the a,ß-unsaturated diazoketones; this is likely responsible for their limited application in synthesis. Unfortunately, the classical methods to prepare saturated- or aryl-diazoketones (acylation of diazomethane with acyl chlorides or mixed anhydrides) are not suitable for preparing a,ß-unsaturated diazoketones, since pyrazolines (dipolar cycloaddition products from the reaction between diazomethane and the double bond) are formed. Although Danheiser's two-step detrifluoroacetylative procedure (starting from a,ß-unsaturated methyl ketones) is considered the best general method, it cannot be applied to the synthesis of all types of a,ß-unsaturated diazoketones. For example, the synthesis of more complex unsaturated diazoketones, as well as those with epimerizable stereocenters in the γ position, was never described before. Another point is related to the geometry of the double bond, since practically all examples described thus far refer to unsaturated diazoketones with E geometry. In recent years, our research group developed two new Horner-Wadsworth-Emmons reagents (containing a diazocarbonyl function) that could be easily applied in the one-step preparation of α,ß-unsaturated diazoketones from aldehydes. Not only were we able to selectively synthesize E- and Z-unsaturated diazoketones, but also to employ these useful platforms in the short synthesis of several nitrogen heterocycles such as indolizidines, quinolizidines, piperidines, and pyrrolidines. Our purpose in this Account is to introduce this class of diazoketone and provide a brief historical overview, culminating in how we developed a general methodology to prepare them. In continuation, we wish to call of the reader's attention to these important building blocks, showing how we could apply them to the synthesis of several nitrogen heterocycles, including the very short preparation of some popular alkaloids. The reader will also notice that the combination of these three important functions in the same molecule makes these compounds special as well as provides powerful platforms to access many important molecules in a direct fashion.
RESUMO
The leishmanicidal activity of a series of 4-aminoquinoline (AMQ) derivatives was assayed against Leishmania amazonensis. This activity against the intracellular parasite was found stronger than for L. amazonensis promastigotes. Neither compound was cytotoxic against macrophages. The compound AMQ-j, which exhibited a strong activity against promastigotes and amastigotes of L. amazonensis (IC50 values of 5.9 and 2.4 µg/mL, respectively) and similar leishmanicidal activity to reference drugs, was chosen for studies regarding its possible mechanism of action toward parasite death. The results showed that the compound AMQ-j induced depolarization of the mitochondrial membrane potential in promastigotes and in L. amazonensis-infected macrophages, but not in uninfected macrophages. Furthermore, the depolarization of the mitochondrial membrane potential was dose dependent in infected macrophages. We have established that promastigotes and L. amazonensis-infected macrophages treated with AMQ-j were submitted to oxidative stress. This is in line with the increase in the level of reactive oxygen species (ROS). Leishmania amazonensis-infected macrophages treated with AMQ-j did not show a significant increase in the production of nitric oxide. Our results indicate the effective and selective action of AMQ-j against L. amazonensis, and its mechanism of action appears to be mediated by mitochondrial dysfunction associated with ROS production.
Assuntos
Aminoquinolinas/química , Antiprotozoários/química , Antiprotozoários/farmacologia , Leishmania mexicana/efeitos dos fármacos , Animais , Morte Celular/efeitos dos fármacos , Membrana Celular/efeitos dos fármacos , Células Cultivadas , Avaliação Pré-Clínica de Medicamentos/métodos , Leishmania mexicana/citologia , Leishmania mexicana/fisiologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Macrófagos/parasitologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos Endogâmicos BALB C/parasitologia , Óxido Nítrico/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismoRESUMO
Currently, the research and development of sunscreens play an important role on the synthesis of actives that are stable in various kinds of formulations-in addition to their efficiency and broad spectrum of protection against ultraviolet radiation. Our objective here was to synthesize new sunscreening chemical agents using quinoline as a base molecule. Twelve quinoline derivatives were synthesized, four of them novel molecules, and their photoprotective activity was determined in vitro using diffuse transmittance spectrophotometry. We determined their SPF, UVAPF, UVA/UVB ratio, critical wavelength and Boots Star Rating. The quinolines derivatives presented a varied profile of photoprotection, their SPF ranging from 2 to 11 and their UVAPF from 2 to 7. In terms of the critical wavelength, all molecules were considered of broad-spectrum by different classifications. Regarding the Boots Star Rating, one compound received no rating, seven of them received a three stars rating, three received a four stars rating and three were given a five stars rating. The molecules showed in the present work have a wide range of possibilities for creating new sunscreen products, once they have good SPF or UVAPF for single molecules, and they also possess other different qualities that can act synergistically.
Assuntos
Quinolinas/síntese química , Protetores Solares/síntese química , Química Farmacêutica , Estrutura Molecular , Quinolinas/química , Espectrofotometria , Protetores Solares/químicaRESUMO
This paper describes the synthesis and in vitro biological activities of imidazolidine and hexahydropyrimidine derivatives against bacteria (Escherichia coli, Staphylococcus aureus and Mycobacterium tuberculosis) and Leishmania protozoa. Out of sixteen heterocyclic derivatives tested, none were cytotoxic against mammalian cells. The compounds showed significant bacterial effects and leishmanicidal activity. Compounds 4a and 4c were active against S. aureus and E. coli, respectively. Compounds 3a-3f, 4h and 4i presented promising results against M. tuberculosis, with MIC values ranging from 12.5 to 25.0 µg/mL, comparable to the "first and second line" drugs used to treat tuberculosis. Compounds 4a, 4c and 4e were active against L major. Three of them were structurally characterized by single-crystal X-ray diffraction.
Assuntos
Antibacterianos/síntese química , Antibacterianos/farmacologia , Antiparasitários , Bactérias/efeitos dos fármacos , Imidazolidinas , Leishmania/efeitos dos fármacos , Pirimidinas , Animais , Antibacterianos/química , Antiparasitários/síntese química , Antiparasitários/química , Antiparasitários/farmacologia , Células Cultivadas , Cristalografia por Raios X , Humanos , Imidazolidinas/síntese química , Imidazolidinas/química , Imidazolidinas/farmacologia , Camundongos , Viabilidade Microbiana/efeitos dos fármacos , Modelos Moleculares , Estrutura Molecular , Mycobacterium tuberculosis/efeitos dos fármacos , Pirimidinas/síntese química , Pirimidinas/química , Pirimidinas/farmacologiaRESUMO
Esta revisão de literatura teve como objetivo dispor informações sobre as adaptações produzidas pelo treinamento de vibração quando realizado através de plataformas vibratórias. Em consulta a base de dados Medline encontramos 25 artigos originais sobre o tema. Após uma análise criteriosa desses estudos constatamos que grande parte deles foi realizada com delineamento experimental inapropriado. Sendo assim, 13 artigos foram excluídos e, esta revisão foi baseada em 12 estudos. Em relação aos efeitos agudos e crônicos da vibração em jovens encontramos resultados controversos, o que nos permite afirmar que ainda não existem dados suficientes na literatura que comprovem a eficiência dessa estratégia nessas condições. Por outro lado, em se tratando da população idosa, parece que o treinamento de vibração pode melhorar o equilíbrio, a agilidade e a marcha. Além disso, o treinamento de vibração pode ser tão eficiente quanto o treinamento de força convencional na melhora da força e da potência. No entanto, essas conclusões ainda não podem ser consideradas definitivas, uma vez que esses resultados foram encontrados em apenas dois estudos.
The purpose of this review was to investigate the adaptations of vibration training using vibration platforms. Literature search was performed using the Medline database (25 original studies). However, the analysis of the experimental designs revealed that only 12 studies met the criteria to be included in our review. Regarding the acute and chronic effects of vibration training in young population, results were controversial and its efficiency has yet to be proven under such conditions. On the other hand, in the elderly, it seems that vibration training can improve balance, agility and gait. Moreover, vibration training seems to be as efficient as conventional strength training in the improvement of strength and power for this population. However, further evidence is still needed in order to establish such conclusions, once these results had been found in two studies only.