O estresse tem se mostrado como um agravante de diversas patologias e transtornos psiquiátricos, como o transtorno depressivo maior (TDM). Estudos apontam que o hipocampo, bem como as vias serotonérgicas presentes neste, estão envolvidas com as respostas de estresse bem como nos efeitos deletérios causados por este. O antagonismo do receptor 5-HT 7, presente nestas vias, tem apresentado um efeito antidepressivo e ansiolítico em alguns trabalhos, porém poucos são os estudos que investigam o papel do receptor 5-HT 7 nas estruturas encefálicas em relação às repostas de estresse. Diante desse dado, o presente trabalho utilizou o modelo Labirinto em Cruz Elevado (LCE) 24 horas após a restrição para investigar o papel do receptor 5-HT 7 do hipocampo na consolidação da memória aversiva. A metodologia utilizada consistiu na injeção bilateral de SB-258741, um antagonista do receptor 5-HT7, no hipocampo dorsal de ratos Wistar machos, feita logo após o estresse de restrição de movimento com exposição ao LCE 24 horas depois. Como resultado desta metodologia, foi observado um aumento na porcentagem de entradas dos animais nos braços abertos, mas não na porcentagem de tempo em que o animal permaneceu nestes braços. Este dado mostra que a injeção de um antagonista de 5-HT 7 no hipocampo leva a uma atenuação dos efeitos comportamentais da consolidação de memória aversiva, corroborando com efeito ansiolítico consequente ao antagonismo deste receptor, observado na literatura. Nesse sentido, a investigação sobre o papel desse receptor, nas respostas de estresse, pode ser útil para o desenvolvimento de novos fármacos para os tratamentos dos efeitos prejudiciais do estresse. / Stress has been shown to be an aggravating factor for various diseases and psychiatric disorders, such as major depressive disorder (MDD). Studies suggest that the hippocampus, as well as serotonergic pathways present in this structure, are involved in stress responses as well as in the deleterious effects caused by this factor. The receptor antagonism of 5-HT 7 receptor, present in these pathways, has shown an antidepressant and anxiolytic effect in some studies, but few studies are investigating the role of 5-HT 7 receptor in brain structures related to stress responses. Given this data, this study used the Elevated Plus Maze (EPM) 24 hours after the restrain stress to investigate the role of 5-HT 7 receptor in the hippocampus consolidation of aversive memory. The methodology in this study consisted of bilateral injection of SB-258741, an antagonist of the 5-HT7 receptor, into the dorsal hippocampus of male Wistar rats, made 5 minutes after the restrain stress with exposure to EPM after 24 hours. As a result of this method, an increase in the percentage of animals entries into the open arms, but not at the percentage of time the animal remained in these arms, was observed. This data shows that the injection of a 5-HT 7 antagonist in the hippocampus leads to an attenuation of the aversive memory consolidation behavioral effects, corroborating with the consequent anxiolytic effect to the antagonism of this receptor, presented in the literature. In this sense, research on the role of this receptor in stress responses may be useful for the development of new drugs for the treatment of the harmful effects of stress.

Mon travail de thèse concerne l’étude des leucémies aiguës lymphoblastiques T (LAL-T). Il se décline en deux projets. Le premier, Le Saracatinib affecte les LAL-T humaines en ciblant la kinase LCK dans les cellules riches en radeaux lipidiques, nous a permis d’identifier une nouvelle voie métabolique importante pour la prolifération des cellules leucémiques. Nous avons montré que la kinase LCK est intégrée dans les radeaux lipidiques et impliquée dans la croissance des cellules leucémiques. L’inhibiteur de LCK Saracatinib affecte les cellules de LAL-T in vitro et in vivo en ciblant particulièrement les cellules les plus agressives ayant beaucoup de radeaux lipidiques à leur surface. Ces résultats permettent d’envisager une nouvelle stratégie thérapeutique pour traiter les LAL-T et ont fait l’objet d’une publication parue dans Leukemia en janvier 2018. Le second projet, Les leucémies aiguës lymphoblastiques T produisent l’interleukine 7 de manière autocrine, démontre pour la première fois que pour la plupart des LAL-T, les cellules sont capables de sécréter elles-mêmes la cytokine IL-7. Nous avons complété cette étude par une analyse des mécanismes épigénétiques impliqués dans la régulation de cette sécrétion autocrine. Nos résultats montrent qu’elle est activée par la fixation des facteurs de transcription IRF-1 (Interferon Regulatory Factor 1) et IRF-2 au niveau du promoteur du gène IL 7, lorsque celui-ci est peu méthylé. Grâce à l’inactivation du gène IL-7 dans un de nos modèles de LAL-T, nous avons pu démontrer que la sécrétion autocrine favorise le développement de la leucémie chez la souris xénogreffée en impactant la prise de greffe et le nombre de cellules initiatrices de leucémie. Ainsi, la régulation épigénétique de la sécrétion autocrine d’IL-7 pourrait être impliquée dans les premières étapes de la leucémogenèse des LAL-T. / My PhD work concerns T-cells acute lymphoblastic leukemia (T-ALL) and includes two projects. The first one, Saracatinib impairs maintenance of human T-ALL by targeting the LCK tyrosine kinase in cells displaying high level of lipid rafts, allow us to identify a new signaling pathway important for the proliferation of T-ALL cells. We showed that LCK is localized into lipid rafts and is involved in the growth of T-ALL cells. The LCK inhibitor Saracatinib affects T-ALL cells in vitro and in vivo by targeting the most aggressive cells displaying high level of lipid rafts. These results highlight a new therapeutic strategy to treat T-ALL and were published in Leukemia in January 2018. The second project, T cell acute lymphoblastic leukemia produces autocrine interleukin 7, demonstrated for the first time that T-ALL cells are able to produce IL-7 cytokine. We performed an analysis of epigenetic mechanisms involved in the regulation of this autocrine secretion. Our results showed that when the IL-7 gene promoter is low methylated, Interferon Regulatory Factor 1 (IRF-1) and (IRF-2) transcription factors bind IRF-E sequence and upregulate IL-7 gene transcription. Thanks to IL 7 gene inactivation in one of our T ALL models, we demonstrated that autocrine secretion promotes leukemia development on xenografted mice through increasing engraftment cells capacity and leukemia initiating cells number. Thus, epigenetic regulation of IL-7 autocrine secretion may be involved in the leukemogenesis of T-ALL.

Avec la révolution du numérique, l’usage de la vidéo a fortement évolué durant les dernières décennies, passant du cinéma à la télévision, puis au web, du récit fictionnel au documentaire et de l’éditorialisation à la création par l’utilisateur. Les médias sont les vecteurs pour échanger des informations, des connaissances, des « reportages » personnels, des émotions... L’enrichissement automatique des documents multimédias est toujours un sujet de recherche depuis l’avènement des médias. Dans ce contexte, nous proposons dans un premier temps une modélisation des différents concepts et acteurs mis en œuvre pour analyser automatiquement des documents multimédias afin de déployer dynamiquement des services interactifs en relation avec le contenu des médias. Nous définissons ainsi les concepts d’analyseur, de service interactif, de description d’un document multimédia et enfin les fonctions nécessaires pour faire interagir ceux-ci. Le modèle d’analyse obtenu se démarque de la littérature en proposant une architecture modulaire, ouverte et évolutive. Nous présentons ensuite l’implantation de ces concepts dans le cadre d’un prototype de démonstration. Ce prototype permet ainsi de mettre en avant les contributions avancées dans la description des modèles. Une implantation ainsi que des recommandations sont détaillées pour chacun des modèles. Afin de montrer les résultats d’implantation des solutions proposées sur la plateforme telles que les standards MPEG-7 pour la description, MPEG-4 BIFS pour les scènes interactives ou encore OSGI pour l’architecture générale, nous présentons différents exemples de services interactifs intégrés dans la plateforme. Ceux-ci permettent de vérifier les capacités d’adaptation aux besoins d’un ou plusieurs services interactifs. / The concept developed in this thesis is to propose an architecture model allowing automatic multimedia analysis and inserting pertinent interactive contents accordingly to multimedia content. Until nowadays, studies are mainly trying to provide tools and frameworks to generate a full description of the multimedia. It can be compared as trying to describe the world since the system must have huge description capabilities. Actually, it is not possible to represent the world through a tree of concepts and relationships due to time and computer limitations. Therefore, according to the amount of multimedia analyzers developed all over the world, this thesis proposes a platform able to host, combine and share existing multimedia analyzers. Furthermore, we only consider user’s requirements to select only required elements from multimedia platform to analyze the multimedia. In order to easily adapt the platform to the service requirements, we propose a modular architecture based on plug-in multimedia analyzers to generate the contextual description of the media. Besides, we provide an interactive scene generator to dynamically create related interactive scenes. We choose the MPEG-7 standard to implement the multimedia’s description and MPEG-4 BIFS standard to implement interactive scenes into multimedia. We also present experimental results on different kind of interactive services using video real time information extraction. The main implemented example of interactive services concerns an interactive mobile TV application related to parliament session. This application aims to provide additional information to users by inserting automatically interactive contents (complementary information, subject of the current session…) into original TV program. In addition, we demonstrate the capacity of the platform to adapt to multiple domain applications through a set of simple interactive services (goodies, games...).

La presente Tesis Doctoral se realiza en base a tres MOTIVACIONES. Una motivación personal, gestada en una curiosidad y/o asombro infantil que se perpetúa en la adultez a modo de cuestionamiento filosófico; una motivación por el estudio de la genial obra del filósofo Arthur Schopenhauer, quien a mi entender, es uno de los filósofos más honestos con la verdad y con la propia naturaleza; y una motivación por el tema de AMOR, tema que enraíza directamente con la esencia del ser humano, y que sin embargo, ha sido obviado por la mayoría de los filósofos. La investigación tiene por OBJETIVO por una parte, un estudio historiográfico del Capítulo 44 de los complementos a la obra primaria “El mundo como voluntad y representación” que porta por título “La Metafísica del amor sexual”; y por otra, un estudio filosófico en cuanto que trata de dar respuesta a una pregunta o hipótesis planteada: ¿Es cierto que el amor platónico es una mentira y que el amor propuesto por Schopenhauer es verdad? y, ¿De qué verdad y/o mentira estamos hablando? Ambos objetivos, el estudio historiográfico y el filosófico, se entrelazan entre sí dando lugar a una respuesta unitaria que se soporta en la genial filosofía de Arthur Schopenhauer. El DESARROLLO TEÓRICO de la investigación se realiza mediante una cuidada metodología cimentada en cuatro puntos primordiales: a) Estructura, b) Literatura secundaria, c) Investigaciones Empíricas, d) Osadía creativa. a) Se dota de una estructura explícita a un texto (Cap. 44 de los Complementos “Metafísica del Amor Sexual”) que parece no poseer, a priori, ningún orden prestablecido. Gracias a esta compartimentación en los diferentes temas se hace más preciso el estudio de cada una de las partes. b) Se utiliza el conjunto de la obra fundamental de Arthur Schopenhauer para matizar y ampliar lo expuesto por su capítulo, y se realiza un trabajo de consulta y utilización de literatura secundaria respecto al tema tratado. c) Se dota de mayor rigor científico al capítulo tratado incluyendo las últimas investigaciones científicas que corroboran mayoritariamente las afirmaciones y/o intuiciones del filósofo alemán. d) El conjunto de la tesis doctoral está impregnado de un ímpetu creativo del autor, tratando de dar una particular respuesta en base a todo lo incorporado en el transcurso de la investigación. Este punto se podrá intuir con mayor evidencia en los dos últimos capítulos antes de las conclusiones: Schopenhauer en el Banquete y El amor como solución (provisional) a la existencia subjetiva. La CONCLUSIÓN final y general es que se encuentran evidencias de que el amor platónico es simplemente una mentira, o alegoría, si se quiere, para no mostrar la verdadera naturaleza del amor. El amor, por muchos tintes etéreos del que se quiera revestir, no deja de ser un instinto natural especializado y dirigido a la reproducción. La reproducción no es únicamente el resultado del instinto sino que, en su vertiente metafísica, es la perpetuación (en las nuevas generaciones) de una pulsión ciega y constante que el filósofo alemán conceptualiza como Voluntad. / This Doctoral Thesis is performed on three motivations. Personal motivation, gestated in a curious and / or perpetuating childlike wonder in adulthood as a philosophical inquiry, a motivation for the study of the great works of the philosopher Arthur Schopenhauer, who in my opinion, is one of the greatest philosophers honest with the truth and with the nature, and motivated by the love theme, rooted issue directly with the essence of the human being, and yet it has been ignored by most philosophers. The research aims on the one hand, a historiographic study of Chapter 44 of the additions to the primary work "The World as Will and Representation" which carries the title "The Metaphysics of Sexual Love" and, secondly, a philosophical study As for trying to answer a question or hypothesis: Is it true that platonic love is a lie and that proposed by Schopenhauer love you? and what truth and / or lie we talking about? Both objectives, historiographical and philosophical study, intertwine with each other resulting in a united response that supports the philosophy of Arthur Schopenhauer great. The theoretical development of the research is done through a careful methodology founded on four key points: a) structure, b) secondary literature, c) empirical research, d) Daring creative. a) gives an explicit structure to a text (Cap. 44 of Supplements "Metaphysics of Sexual Love") that seems to have, a priori, any preset order. With this partitioning in different subjects is more precise study of each of the parties. b) Use the set of the seminal work of Arthur Schopenhauer to refine and expand the above for their chapter, and they do a consultation and use of secondary literature on the subject. c) It gives greater scientific rigor Chapter treaty including the latest scientific research largely corroborating statements and / or intuitions of the German philosopher. d) The entire thesis is impregnated with a creative impetus of the author, trying to give a particular response based on all built in the course of the investigation. This section may intuit more evident in the last two chapters before conclusions: Schopenhauer in the Symposium and Love as solution (provisional) to the subjective existence. The final conclusion is generally found evidence that Platonic love is just a lie, or allegory, if you will, to not show the true nature of love. Love, for many of ethereal dyes you want coated, no longer a natural instinct to run specialized and playback. Playback is not only the result of instinct but in its metaphysical aspect, is the perpetuation (new generations) of a blind instinct and constant German philosopher conceptualized as Will.

Export is a top priority for Sweden's economy but for Swedish companies it may involve uncomfortable risks of exporting without sincere consideration. When the United Nations Security Council puts an embargo against a country, this often mean an import and export restriction. The thought is to push undemocratic regimes into respecting human rights. When the embargo is in force, however, the parties are not able to fulfill their contractual obligations, which practically means that the agreement will be suspended. The problem is what happens when an embargo is in force for a longer period of time. After the embargo is withdrawn, the price on the market may have changed significantly, which indicates a financial sacrifice for a seller if he has to provide specific performance to the buyer. The question thus is whether the seller, after a prolonged economic sanctions is withdrawn, still is obliged to provide specific performance? The United Nations Convention on Contracts for the International Sale of Goods (CISG) is applicable where both parties are signatories to CISG or by rules of international private law. To require performance as a buyer is a general right in Article 46 CISG, but there are exceptions to this rule in Article 28 CISG. Article 28 CISG states that if one party is entitled to require performance of any obligation by the other party, a court is not bound to enter a judgment for specific performance unless the court would do so under its own law in respect of similar contracts of sale not governed by this Convention. Since CISG advocates a harmonized application of international trade, the right to specific performance cannot be waived just on the basis of Article 28 CISG alone. With regard to good faith in international trade in Article 7 (1) CISG, the principle of reasonableness, which is a general principle that the CISG is based upon in accordance with Article 7 (2) CISG and 7.2.2 (b) UPICC, and with the support of international usage regularity observed in the trade concerned in Article 9 CISG, the right to specific performance does not exist anymore after a prolonged embargo has been withdrawn. / Export är högprioriterat för Sveriges ekonomi men för svenska företag kan det inne-bära obekväma risker med att exportera utan eftertanke. När Förenta Nationernas säkerhetsråd går in och lägger ett embargo mot en stat innebär detta ofta en import- och export restriktion. Tanken är att pressa odemokratiska regimer att respektera mänskliga rättigheter. När embargot är i kraft kan dock parterna inte uppfylla sina avtalsförpliktelser vilket innebär att avtalet blir suspenderat. Det problematiska är vad som händer då ett embargo är i kraft under en längre tid. Efter det att ett embargo lyfts kan priset på marknaden ändrats avsevärt vilket innebär en ekonomisk uppoffring för en säljare att tvingas fullgöra i natura. Frågan blir då om säljare efter det att en långvarig ekonomisk sanktion lyfts, fortfarande är tvingen att fullgöra i natura? Lag (1987:822) om internationella köp(CISG) blir tillämplig i det fall då båda parters stater är signatärer eller genom privaträttsliga regler. Att kräva fullgörelse som köpare är en generell rätt i artikel 46 CISG men det finns ett explicit undantag till denna regel i artikel 28 CISG. Artikel 28 CISG stadgar att domstol som ska lösa tvisten, inte är skyldig att meddela dom på fullgörelse om domstol enligt egen forumlandets egen lagstiftning inte skulle ha gjort detta. Skulle tvisten lösas i Svensk domstol blir 23 § köplag (1990:931) tillämplig. Eftersom CISG förespråkar en harmoniserad tillämpning inom internationell handel är det inte tillförlitligt att mena på att rätten till fullgörelse bortfaller med stöd av endast artikel 28 CISG. Med beaktande av god sed i internationell handel i artikel 7(1) CISG, principen om rimlighet/förnuftig person som är en generell princip som CISG är baserat på i enlighet med artikel 7(2) CISG och 7.2.2 (b) UPICC, samt med stöd av handelsbruk i artikel 9 CISG, bortfaller rätten till fullgörelse i natura efter det att ett långvarigt embargo har lyfts.

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A prospecção e síntese de novos derivados de 8-hidroxiquinolina está em ascensão devido às suas diversas atividades biológicas. Neste trabalho é relatada a síntese e avaliação da atividade antimicrobiana de novos derivados contendo uma sulfonamida substituída na posição 5 da 8-hidroxiquinolina ou um grupamento aminossubstituído na posição 7 da 5-cloro-8-hidroxiquinolina ou 5-cloro-8-metoxiquinolina. Os derivados 5-sulfonamidas foram preparados por clorossulfonação seguida da reação com a amina apropriada. Os derivados 7-aminossubstituído foram sintetizados através da metilação da hidroxila da posição 8, seguida da reação de cross-coupling catalisada por paládio e desmetilação. A avaliação da atividade antimicrobiana foi realizada através do método de microdiluição em caldo. Dentre os compostos sintetizados, 5a (da série 5-sulfonamidas) foi o mais potente, sendo ativo contra todas as espécies fúngicas testadas, além de apresentar importante atividade contra cepas de Staphylococcus aureus, e baixa toxicidade contra células VERO. Isso sugere que a introdução de um grupamento retirador de elétrons em para no substituinte arila da posição 5 é importante para a atividade antimicrobiana. Ainda, a nanoemulsão preparada contendo 5a manteve a atividade antifúngica da substância contra espécies de Candida spp. A série 7-aminossubstituído também apresentou resultados muito interessantes. Desta série, o composto 5i foi o mais potente. Isso sugere que grupamentos heterocíclicos hidrofílicos na posição 7 podem favorecer a atividade antifúngica. A presença da hidroxila livre na posição 8 parece ser essencial para a atividade antifúngica, pois os derivados protegidos por uma metila foram pouco ativos. Os derivados de 8-hidroxiquinolina 5a e 5i podem ser considerados para estudos posteriores na busca de novos agentes antimicrobianos. / The synthesis and screening of new 8-hydroxyquinoline derivatives is growing, due to their various biological activities. In this work, the synthesis and antimicrobial evaluation of new derivatives containing a substituted 5-sulfonamide in the 8-hydroxyquinoline or a substituted amino group at the 7-position of the 5-chloro-8-hydroxyquinoline or 5-chloro-8-methoxyquinoline is reported. The 5-sulfonamide derivatives were prepared by chlorosulfonation followed by the reaction with the appropriate amine. The 7-amino derivatives were synthesized by methylation of the 8-hydroxyquinoline, followed by palladium-catalyzed cross-coupling reaction and demethylation. The antimicrobial evaluation was tested by the broth microdilution method. Among all the prepared compounds, 5a (from the 5-sulfonamide series) was the most potent, being active against all the fungal species tested, while also showing important activity against Staphylococcus aureus strains, and low toxicity against VERO cells. This suggests that the introduction of an electron-withdrawing group at para-position of the N-aryl substituent is important for the activity. In addition, the prepared 5a nanoemulsion maintained the antifungal activity of the compound against Candida spp. The 7-amino series has also presented interesting results. In this series, 5i was the most potent compound. This suggests that the hydrophilic heterocyclic substituent at the 7-position was favorable to antifungal activity. The presence of the free hydroxyl at the 8-position is important for the antifungal activity, since the methyl-protected derivatives were poorly active. The 8-hydroxyquinoline derivatives 5a and 5i may be considered for further studies in the search for novel antimicrobial agents.

Submitted by Renorbio (renorbioba@ufba.br) on 2018-04-26T15:58:23Z No. of bitstreams: 1 TESE DE DOUTORADO_GLÁUCIO BARROS SALDANHA.pdf: 4782886 bytes, checksum: 5487ab253c7be5687d66ef5f9581108e (MD5) / Approved for entry into archive by Delba Rosa (delba@ufba.br) on 2018-05-04T14:06:18Z (GMT) No. of bitstreams: 1 TESE DE DOUTORADO_GLÁUCIO BARROS SALDANHA.pdf: 4782886 bytes, checksum: 5487ab253c7be5687d66ef5f9581108e (MD5) / Made available in DSpace on 2018-05-04T14:06:18Z (GMT). No. of bitstreams: 1 TESE DE DOUTORADO_GLÁUCIO BARROS SALDANHA.pdf: 4782886 bytes, checksum: 5487ab253c7be5687d66ef5f9581108e (MD5) / Os neoflavonoides compreendem compostos que possuem um esqueleto básico de carbono (C6-C3-C6) e que podem ser sintetizados ou ser encontrado naturalmente em plantas superiores como das famílias Clusiaceae, Leguminosae, Rubiaceae e Rutaceae. Os neoflavonoides têm atraído grande interesse devido às suas propriedades farmacológicas e bioquímicas apresentadas em estudos in vitro e in vivo. Em relação às doenças tropicais negligenciadas (DTNs), os neoflavonoides demonstraram ser promissoras moléculas bioativas no tratamento da leishimaniose, tripanossomose americana e malária. Sendo assim, estudos adicionais são necessários para dar uma maior ênfase a sua ação farmacológica em outras doenças negligenciadas como a causada por vermes do gênero Schistosoma. Neste contexto farmacológico, o objetivo do presente trabalho foi avaliar o potencial quimioterapêutico do composto 7-acetoxi-4-aril-3,4-di-hidrocumarina, classificado como neoflavonoide, em um modelo experimental contra o Schistosoma mansoni. Além do estudo do potencial antiprotozoário, estudos não clínicos de segurança farmacológica foram realizados pela avaliação da toxicidade em dose única (14 dias) e em doses repetidas (28 dias) em camundongos Swiss fêmeas. O perfil de toxicidade aguda (300 e 2000 mg/kg) e em doses repetidas (250, 500 e 1000 mg/kg) foram realizados em camundongos Swiss fêmeas de acordo com a diretriz 423 e 407 da Organização para a Cooperação e Desenvolvimento Econômico (OECD), respectivamente, pelos parâmetros relacionados às alterações do peso corporal, consumo de alimento e água, parâmetros hematológicos e bioquímicos. Na avaliação farmacológica do 7-acetoxi-4-aril-3,4-di-hidrocumarina (6,25, 12,5, 25, 50 e 100 μg/mL) contra o S. mansoni, os parâmetros analisados foram a taxa de mortalidade, redução na atividade motora, número de ovos e alterações tegumentares. De acordo com experimentos realizados, foi demonstrado que o 7-acetoxi-4-aril-3,4-di-hidrocumarina a partir da concentração de 12.5 μg/mL induziu a mortalidade dos vermes S. mansoni, redução na atividade motora, mudanças na morfologia tegumentar e inibição na produção de ovos pela separação de todos os casais de vermes adultos tratados. A capacidade do 7-acetoxi-4-aril-3,4- di-hidrocumarina de manter os vermes adultos machos e fêmeas separados demonstra ser a principal justificativa para elevada redução na oviposição de S. mansoni. Além da atividade quimioterapêutico, os resultados da toxicidade aguda e em doses repetidas de 7-acetoxi-4-aril- 3,4-di-hidrocumarina demonstraram ausência de sinais clínicos adversos (contorções abdominais, reflexo de endireitamento, irritabilidade, piloereção), mortalidade, alterações significativas no peso corporal e dos órgãos internos, consumo de alimento e água. Os parâmetros hematológicos (eritrócitos, plaquetas e leucócitos) e bioquímicos (glicose, ureia, creatinina, ácido úrico, alanina aminotrasaminase, aspartato aminotrasaminase, colesterol, triglicerídeos) também não apresentaram alterações significativas quando comparado com os grupos controles dos estudos de toxicidade em dose única (aguda) e em doses repetidas. Em conclusão, os resultados do presente estudo demonstraram atividade anti-helmíntica do 7- acetoxi-4-aril-3,4-di-hidrocumarina e fornecem uma importante compreensão do perfil de toxicidade deste neoflavonoide, no qual pode ser considerado como sendo um composto com toxicidade superior a 2000 mg/kg em camundongos Swiss fêmeas. / The neoflavonoid group comprise compounds that have a basic carbon skeleton (C6-C3-C6) and that can be synthesized or be naturally found in families of higher plants such as the Clusiaceae, Leguminosae, Rubiaceae and Rutaceae families. Neoflavonoids have attracted great interest because of their pharmacological and biochemical properties presented in the in vitro and in vivo studies. In relation to neglected tropical diseases (NTDs), the neoflavonoids have been shown to be promising bioactive molecules in the treatment of leishmaniasis, American trypanosomiasis and malaria. Thus, additional studies are needed to give greater emphasis to their pharmacological action in other neglected diseases such as that caused by worms of Schistosoma genus. In this pharmacological context, the objective of the present study was to evaluate the chemotherapeutic potential of the 7-acetoxy-4-aryl-3,4- dihydrocoumarin, classified as neoflavonoid, using an experimental model against Schistosoma mansoni. In addition to study the antiprotozoal potential, non-clinical pharmacological safety studies were performed by evaluating single dose (14 days) and repeated doses (28 days) toxicity in female Swiss mice. The acute toxicity profile (300 and 2000 mg/kg) and repeated doses (250, 500 and 1000 mg / kg) were performed in female Swiss mice according to guidelines 423 and 407 of the Organisation for Economic Cooperation and Development (OECD), respectively, by the parameters related to changes in body weight, food and water consumption, as well as hematological and biochemical parameters. In the pharmacological evaluation of 7-acetoxy-4-aryl-3,4-dihydrocoumarin (6.25, 12.5, 25, 50 and 100 μg/ml) against S. mansoni, the parameters analyzed were the mortality rate, reduction in motor activity, number of eggs and tegumentary changes. According to experiments performed, it was demonstrated that the 7-acetoxy-4-aryl-3,4- dihydrocoumarin from the concentration of 12.5 μg/mL induced the mortality of S. mansoni worms, the reduction in motor activity and, changes in tegumentary morphology and inhibition in egg production by separation of all couples of adult worms treated. The capacity of 7-acetoxy-4-aryl-3,4-dihydrocoumarin to maintain separate male and female adult worms is shown to be the main justification for high reduction in S. mansoni oviposition. In addition to chemotherapeutic activity, the results of acute toxicity and repeated doses of 7-acetoxy-4- aryl-3,4-dihydrocoumarin demonstrated no clinical adverse symptoms (abdominal contortions, righting reflex, irritability, piloerection), mortality, significant changes in body weight and internal organs, food and water consumption. The hematological parameters (analysis of erythrocyte, platelets and leukocytes) and biochemical parameters (glucose, urea, creatinine, uric acid, aspartate aminotransferase, alanine aminotransferase, cholesterol, and triglycerides) also showed no significant changes when compared to the control groups. In conclusion, the results of the present study demonstrated in vitro anthelmintic activity of 7- acetoxy-4-aryl-3,4-dihydrocoumarin and provide an important understanding of the toxicity profile of this neoflavonoid, in which it can be considered as a compound with toxicity greater than 2000 mg/kg in female Swiss mice.

A prospecção e síntese de novos derivados de 8-hidroxiquinolina está em ascensão devido às suas diversas atividades biológicas. Neste trabalho é relatada a síntese e avaliação da atividade antimicrobiana de novos derivados contendo uma sulfonamida substituída na posição 5 da 8-hidroxiquinolina ou um grupamento aminossubstituído na posição 7 da 5-cloro-8-hidroxiquinolina ou 5-cloro-8-metoxiquinolina. Os derivados 5-sulfonamidas foram preparados por clorossulfonação seguida da reação com a amina apropriada. Os derivados 7-aminossubstituído foram sintetizados através da metilação da hidroxila da posição 8, seguida da reação de cross-coupling catalisada por paládio e desmetilação. A avaliação da atividade antimicrobiana foi realizada através do método de microdiluição em caldo. Dentre os compostos sintetizados, 5a (da série 5-sulfonamidas) foi o mais potente, sendo ativo contra todas as espécies fúngicas testadas, além de apresentar importante atividade contra cepas de Staphylococcus aureus, e baixa toxicidade contra células VERO. Isso sugere que a introdução de um grupamento retirador de elétrons em para no substituinte arila da posição 5 é importante para a atividade antimicrobiana. Ainda, a nanoemulsão preparada contendo 5a manteve a atividade antifúngica da substância contra espécies de Candida spp. A série 7-aminossubstituído também apresentou resultados muito interessantes. Desta série, o composto 5i foi o mais potente. Isso sugere que grupamentos heterocíclicos hidrofílicos na posição 7 podem favorecer a atividade antifúngica. A presença da hidroxila livre na posição 8 parece ser essencial para a atividade antifúngica, pois os derivados protegidos por uma metila foram pouco ativos. Os derivados de 8-hidroxiquinolina 5a e 5i podem ser considerados para estudos posteriores na busca de novos agentes antimicrobianos. / The synthesis and screening of new 8-hydroxyquinoline derivatives is growing, due to their various biological activities. In this work, the synthesis and antimicrobial evaluation of new derivatives containing a substituted 5-sulfonamide in the 8-hydroxyquinoline or a substituted amino group at the 7-position of the 5-chloro-8-hydroxyquinoline or 5-chloro-8-methoxyquinoline is reported. The 5-sulfonamide derivatives were prepared by chlorosulfonation followed by the reaction with the appropriate amine. The 7-amino derivatives were synthesized by methylation of the 8-hydroxyquinoline, followed by palladium-catalyzed cross-coupling reaction and demethylation. The antimicrobial evaluation was tested by the broth microdilution method. Among all the prepared compounds, 5a (from the 5-sulfonamide series) was the most potent, being active against all the fungal species tested, while also showing important activity against Staphylococcus aureus strains, and low toxicity against VERO cells. This suggests that the introduction of an electron-withdrawing group at para-position of the N-aryl substituent is important for the activity. In addition, the prepared 5a nanoemulsion maintained the antifungal activity of the compound against Candida spp. The 7-amino series has also presented interesting results. In this series, 5i was the most potent compound. This suggests that the hydrophilic heterocyclic substituent at the 7-position was favorable to antifungal activity. The presence of the free hydroxyl at the 8-position is important for the antifungal activity, since the methyl-protected derivatives were poorly active. The 8-hydroxyquinoline derivatives 5a and 5i may be considered for further studies in the search for novel antimicrobial agents.