Submitted by Fabio Sobreira Campos da Costa (fabio.sobreira@ufpe.br) on 2016-07-28T13:21:21Z No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) TESE_Amanda Aliança_digital.pdf: 2689265 bytes, checksum: 0b25cf703fd666da539c3034a8c40823 (MD5) / Made available in DSpace on 2016-07-28T13:21:21Z (GMT). No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) TESE_Amanda Aliança_digital.pdf: 2689265 bytes, checksum: 0b25cf703fd666da539c3034a8c40823 (MD5) Previous issue date: 2016-02-25 / CAPEs / A leishmaniose é uma doença infecciosa, não contagiosa de caráter zoonótico, causada por vários tipos de protozoários do gênero Leishmania. Em humanos, a doença apresenta três principais formas clínicas, dependendo das espécies envolvidas de Leishmania: a cutânea, mucocutânea e visceral (LV), sendo esta última a forma mais grave que quando não tratada pode evoluir para óbito em mais de 90% dos casos. O agente etiológico da LV compreende Leishmania donovani na Índia e leste da África; Leishmania infantum na China, Ásia central, Europa, África, América do Sul e Central. Calcula-se que a prevalência mundial de leishmaniose esteja em torno de 12 milhões de pessoas, acometendo 80 países e com uma estimativa de 400.000 novos casos da doença por ano. O tratamento atual para a leishmaniose é baseado na utilização de antimoniais pentavalentes como o estibogluconato de sódio (Pentostan®) e o antimoniato de meglumina (Glucantime®), este apresenta várias dificuldades como toxicidade, via de administração intravenosa e tempo prolongado de tratamento, que levam a sua descontinuação. Diante deste cenário, os compostos sintéticos são de grande importância na terapêutica por representarem 85% dos fármacos disponíveis. As ftalimidas e os tiazóis são importantes classes de compostos sintéticos e apresentam amplo espectro de atividades biológicas, como ansiolítica, anti-Parkinson, anti-Alzheimer, analgésica, anti-inflamatória, imunomoduladora e antibacteriana. O presente trabalho teve como objetivo avaliar a atividade in vitro frente a L. infantum e a células de mamíferos de uma série de 15 derivados ftalimido-tiazóis. Os compostos foram avaliados frente a formas promastigotas e amastigotas de L. infantum, quanto à citotoxicidade frente a células vero, macrófagos J774 e macrófagos peritoneais, a produção de óxido nítrico e alterações sobre alvos intracelulares do parasito. Os resultados mostram que os compostos oriundos da hibridação da ftalimida com 1,3 tiazol apresentaram atividade leishmanicida contra formas promastigota de L. infantum, baixa citotoxicidade às células de mamíferos testadas e aumentaram a produção de ON em relação às células controles nos macrófagos não infectados. Os compostos 2j e 2m se mostraram como os mais potentes contra as formas promastigotas da série testada, estes foram testados frente as formas amastigotas, os compostos reduziram a sobrevivência de amastigotas intracelulares e apresentaram baixa citotoxicidade para os macrófagos peritoneais. Formas promastigotas tratadas com esses compostos apresentaram alterações ultraestruturais como: encolhimento do corpo celular, perda da integridade da membrana celular, vacuolização do citoplasma, perfis de membranas circundando organelas e inchaço da mitocôndria. Quando avaliada a marcação pelo iodeto de propídio e pela rodamina 123, formas promastigotas tratadas com os compostos 2j e 2m apresentaram aumento no número de células marcadas com o iodeto de propídio e induziram alterações significativas no potencial de membrana mitocondrial. Dessa maneira, os compostos ftalimido-tiazóis apresentam atividades leishmanicida e devem formar a base para futuros estudos experimentais. / Leishmaniasis is an infectious disease, non-contagious with zoonotic characteristic, caused by several types of protozoa of the genus Leishmania. In humans, the disease has three main clinical forms, depending on the species of Leishmania involved: cutaneous, mucocutaneous and visceral, the latter being the more severe if left untreated can lead to death in more than 90% of cases. The etiologic agent of LV comprises Leishmania donovani in India and East Africa; Leishmania infantum in China, Central Asia, Europe, Africa, South and Central America. It is estimated that the worldwide prevalence of leishmaniasis is around 12 million people in 80 countries and 400,000 new cases per year. The current treatment for leishmaniasis is based on the use of pentavalent antimonials such as stibogluconate sodium (Pentostan®) and meglumine antimonate (Glucantime®), this presents several problems such as difficulties such as toxicity, intravenous route of administration and prolonged treatment, which leads to its discontinuation of the treatment. The phthalimides and thiazoles are important classes of synthetic compounds and have a broad spectrum of biological activities such as anxiolytic, anti-Parkinsons, anti-Alzheimer, analgesic, antiinflammatory, immunomodulating and antibacterial. This study aimed to evaluate the in vitro activity against L. infantum and mammalian cells in a series of 15-phthalimido thiazoles derivatives. The present work report the in vitro activity of a phthalimido-thiazoles derivatives series. The activities were evaluated against promastigotes and amastigotes of Leishmania infantum, front of cytotoxicity to vero cells, J774 macrophages and peritoneal macrophages, the effect on production of nitric oxide (NO) and changes of intracellular targets on the parasite. The results show that the compounds arising from the hybridization of phthalimido 1, 3 thiazole showed leishmanicidal activity against promastigotes forms of L. infantum, low cytotoxicity to mammalian cells and increased the NO production compared to control cells in uninfected macrophages. The compounds 2j and 2m are shown as the most potent against promastigotes of the test series, these were tested against amastigote forms, the compounds reduced the survival of intracellular amastigotes and showed low cytotoxicity peritoneal macrophages. The promastigotes treated with these compounds exhibited ultrastructural changes such as cell body shrinkage, loss of cell membrane integrity, vacuolization of the cytoplasm membranes surrounding organelles profiles and swelling of mitochondria. The compounds 2j and 2m were the most potent of the series tested and the parasites treated with these compounds showed ultrastructural changes such as cell body shrinkage, loss of cellular membrane integrity, vacuolization of cytoplasm, membrane profiles surrounding organelles and swelling of mitochondria. When assessed by propidium iodide tag and the rhodamine 123 promastigotes treated with the compounds 2j and 2m showed an increase in the number of cells stained with propidium iodide and induced significant changes in mitochondrial membrane potential. Thus, the phthalimido-thiazoles compounds have leishmanicide activities and should form the basis for future experimental studies.

Functionalization of hydrocarbons via a free-radical based allyl transfer reaction using various allyl bromide substrates has been previously studied. The work described in this dissertation focuses on the replacement of Br by phthalimido-N-oxyl (PINO ) which helps make this chemistry environmentally friendly. To replace Br with PINO , replacement of previously used allyl-bromide substrates with new allyl-PINO substrates were necessary. Various allyl- PINO compounds were synthesized and the use of these allyl-phthalimido-N-oxyl (allyl-PINO) compounds for the functionalization of various alkyl aromatic hydrocarbons is demonstrated. Kinetic studies were performed to observe the efficiency of the new chain reaction compared to the previously reported studies with allyl-bromides. We recently discovered that these allyl substrates are useful for the functionalization of ethers and acetals. The functionalization of various cyclic and acyclic ethers was performed using these allyl transfer reactions. This reaction was also performed in-solution, which allowed us to perform these reactions at low reagent concentrations. Kinetic chain lengths were measured for these reactions. High chain lengths were observed for all used ethers. Kinetic studies to investigate the rate of radical addition-elimination processes were performed using laser flash photolysis and competition kinetics. These experiments helped us to measure the reactivity and selectivity of PINO as a chain carrier in comparison with Br. Additionally, a new competition experiment was designed to study the relative rate constant for the 􀈕-fragmentation process. For this experiment a novel substrate that contains two leaving groups, Br and PINO, was synthesized, and the relative rates of elimination of Br vs PINO were compared. / Ph. D.