Nesta tese são apresentados, em dois capítulos, os resultados da reatividade química de quinoxalinas e os estudos visando à síntese de quinona natural, a vegfrecina. Modificações específicas em estruturas privilegiadas, padrões estruturais relevantes para bioatividade, representam uma alternativa viável na busca de novos ligantes para alvos macromoleculares. Neste cenário, as quinoxalinas apresentam destacada importância no âmbito da química medicinal, sendo assim é de grande importância o desenvolvimento de metodologias de funcionalização que conduzam a diversidade molecular deste núcleo. Neste contexto, foram realizadas reações de ativação C - H, como uma estratégia para a síntese de derivados vinil quinoxalinicos, com base na abordagem de Fujiwara-Moritani. Os resultados obtidos com este estudo indicaram que a densidade eletrônica das olefinas utilizadas neste estudo foi determinante para o rendimento reacional. Assim, as reações envolvendo olefinas ricas em elétrons, resultaram em maior rendimento do produto alquenilado, alcançando 89%. A deoxidação ocorreu em rendimentos de 43 - 54%, levando a ampliação da coleção de compostos desenvolvidos neste projeto. Os compostos aqui desenvolvidos foram testados quanto à atividade antimicobacteriana, entretanto, nenhum deles apresentou resultados promissores. O segundo capítulo desta tese abordou a síntese da Vegfrecina, que possui seletividade de inibição dos receptores do fator de crescimento endotelial vascular (VEGFR), bloqueando a ativação de VEGFR-1 e VEGFR-2 e, consequentemente, interferindo na vascularização, proliferação e metástase tumoral. Nossa estratégia utilizou o intermediário chave 6-Bromo-5,8-dimetoxi-2,2-dimetil-2,3-dihidroquinazolin-4(1H)-ona em reações de aminação de Buchwald Hartwig com três anilinas diferentes. Embora tenhamos obtido três intermediários sintéticos inéditos, em bons rendimentos, a etapa de oxidação não foi promissora, impossibilitando a obtenção da Vegfrecina e de seus análogos. / The study of chemistry reactivity of quinoxalines and the study aiming total syntheses of natural quinone, vegfrecine, are shown in this thesis in two chapters. The specific modifications privileged scaffold represents a promising way following for new macromolecular ligands targets. Considering the great importance of quinoxaline core in medicinal chemistry, the development of efficient methodologies in orther to obtain molecular diversity have attracted large attention. In this context, using Fujiwara-Moritani approach the C-H activation reactions were performed as good strategy in synthesis of vinyl- quinoxaline derivatives. Our results indicated the importance of olefin electron density in the reaction yields. In this way, reactions involving high electron density olefines, results in the high alkenilated products, achieving 89% of yield. The deoxygenation process occurred in yields of 43 until 54. The compounds obtained were tested against Mycobacterium tuberculosis, however no primissing results were observed. The second chapter in this thesis show our attempt to total synthesis of Vegfrecine, that have inhibitory activity of vascular endothelial growth factor receptor (VEGFR), Our strategy used the 6-bromo-5,8-dimethoxy-2,2-dimethyl-2,3-dihydroquinazolin-4(1H)-one in Buchwald Hartwig reaction with three different olefins. Although these new synthetic intermediates were obtained with good yield, the last step of oxidation didn\'t work. Therefore, it was not possible to obtain the Vegfrecine and its analogous.

Résumé: Le travail rapporté dans cette thèse concerne le développement de nouvelles réactions organométalliques pour la création de liaisons C-S dans des systèmes complexes.Dans Le premier chapitre, nous rapportons une méthode originale de bioconjugation de peptides et protéines dans l'eau à température ambiante. La méthode a été appliquée avec succès à la bioconjugation de l'anticorp Trastuzumab.Le deuxième chapitre est consacré à l'étude de la réactivité des alpha ou béta thiosucres dans le couplage de Buchwald-Hartwig-Mitiga avec différent partenaires électrophiles.Dans un premier sous chapitre, nous rapportons une réaction inattendue de couplage de thiosucres avec le précatalyseur G3-Xanthphos pour conduire à de 2-aminobiphenyl glycosides bifonctionnels. La reaction a lieu à température ambiante et dans l'eau et produit des atropidiastéréomères stables.Dans une seconde partie de ce travail, nous décrivons une méthode originale d'accès à benzothiapinones et benzoxathiapinones glycosylées.Cette méthode fait intervenir un couplage de thiosucres avec des aryls iodés ayant un ester en ortho, suivi d'une lactonisation (ou lactimisation) pour conduire aux produits cyclisés.L'avant dernière partie de ce travail, concerne la synthèse de polysaccharides via une réaction de couplage de 2-iodo glycals avec des thiosucres de configuration définie.Ce travail se termine par l'application de couplage de thiosucres à la synthèse de Carbènes N-Hétérocycliques thioglycosylés (NHCs) hydrosolubles. / Abstract: The work reported in this thesis concerns the development of new organometallic reactions for the creation of C-S bonds in complex systems.In the first chapter, we report an original method of bioconjugation of peptides and proteins in water at room temperature. The method has been successfully applied to the bioconjugation of the antibody Trastuzumab.The second chapter is devoted to the study of the reactivity of alpha or beta-thiosugars in the Buchwald-Hartwig-Mitiga coupling with different electrophilic partners.In a first sub-chapter, we report an unexpected reaction of thiosugar coupling with the G3-Xanthphos precatalyst to yield bifunctional 2-aminobiphenyl glycosides. The reaction takes place at room temperature and in water and produces stable atropidiastereomers.In a second part of this work, we describe an original method of access to glycosylated benzothiapinones (and benzoxathiapinones).This method involves thiosugar coupling with iodinated aryls having an ortho ester, followed by lactonization (or lactimization) to yield cyclized products.The last part of this work concerns the synthesis of polysaccharides via a coupling reaction of 2-iodo glycals with thiosugars of defined configuration.This work ends with the application of thiosugar coupling to the synthesis of water-soluble thioglycosylated N-Heterocyclic Carbenes (NHCs) .

[pt] Neste trabalho foi desenvolvida a síntese de novos análogos do tipo N-tosil-aza-carbapterocarpanos com potencial ação antiproliferativa em linhagens de leucemia e mama.Os compostos aza-carbapterocarpanos e espiro-iso-indolinas, foram preparados através de abordagens sintéticas distintas e classificadas em Grupo I e II respectivamente. A etapa chave para obtenção dos compostos do grupo I foi a reação de aza-arilação do tipo Heck catalisada por paládio a partir de tetralonas comerciais e N-tosil-iodoanilinas substituídas previamente sintetizadas. Três moléculas deste grupo foram avaliadas quanto a sua ação antiproliferativa em linhagens de leucemia e mama. Dentre estas, o composto N-tosil-aza-carbaptercarpeno apresentou IC50 = 1,93 (mais ou menos) 0,88 micrômetros, 2,18 (mais ou menos) 1,47 micrômetros e 2.89 (mais ou menos) 0,92 micrômetros nas linhagens de leucemia K562, lucena-1 e FEPS, respectivamente, e na linhagem de mama MDA-MB-231 IC50=33.37 (mais ou menos) 3.98 micrômetros. Por outro lado, o composto aza-carbapterocarpeno foi inativo nestas mesmas linhagens, indicando que na ausência do grupo arilsulfonamida a ação antileucêmica não ocorre. Os compostos do grupo II, denominados espiro iso-indolinas, foram sintetizados através da adição diastereosseletiva de organomagnesío às N-terc-butano-sulfiniliminas quirais, seguida de uma aminação de Buchwald-Hartwig intramolecular catalisada por paládio. As N-terc-butano-sulfiniliminas foram obtidas através de tetralonas, cromanonas e tiocromanonas comerciais em uma reação de condensação com as N-tert-butanosulfinamidas comerciais em micro-ondas em uma abordagem livre de solvente utilizando tetraetóxido de titânio. Após as reações de adição nucleofílica com organomagnésio, remoção do auxiliar quiral e ciclização intramolecular, os compostos forma obtidos enantiomericamente puros e foram avaliados em linhagens de leucemia K562 e FESP. Embora estes compostos tenham apresentado baixa potência frente às linhagens testadas (IC50 entre 31,85 mais ou menos 3.0 micrômetros e 77,58 (mais ou menos) 5.76 micrômetros), pôde-se observar que há diferenças relevantes entre os enantiômeros, assim o como apresentam sensibilidade colateral, atuando em linhagens multiresitentes. / [en] In this work, the synthesis of new N-tosyl aza-carbapterocarpane analogues with potential antiproliferative action in leukemia and breast cell lines was developed. The aza-carbapterocarpanes and spiro-isoindolines compounds were prepared using different synthetic approaches and classified in Group I and II respectively. The key step for obtaining group I compounds was the palladium catalyzed Heck-type azaarylation reaction from commercially synthesized substituted tetralones and substituted N-tosyl iodoanilines. Three compounds of this group were evaluated for their antiproliferative action in leukemia cell lines and breast cancer cells lines. The compound N-tosyl-aza-carbaptercarpene presented IC50 = 1,93 0,88 , 2,18 (plus or minus) 1,47 micrometers e 2.89 (plus or minus) 0,92 micrometers. On the other hand, the aza-carbapterocarpene compound was inactive in these same lines, suggesting the role of the absence of the arylsulfonamide group for the antileukemic activity does not occur .The group II, denominated spiroisoindolines, were synthesized by diastereoselective addition of organomagnesium to chiral N-tert-butane sulfinylimines, followed by a palladium catalyzed intramolecular Buchwald-Hartwig amination. The N-tert-butane sulfinylimines were obtained through commercial tetralones, chromanones and thiochromanones by the condensation reaction with commercial N-tert-butanesulfinamides in a solvent free sistem using titanium tetraethoxide. After nucleophilic addition reactions with organomagnesium, chiral auxiliary removal and intramolecular cyclization, the compounds were obtained enantiomerically pure and were evaluated in K562 and FESP leukemia lines. Although these compounds presented low potency compared to the tested lines (IC50 between 31.85 (plus or minus) 3.0 micrometers and 77.58 (plus or minus) 5.76 micrometers), it was observed that there of them present relevant differences between enantiomers as soon as collateral sensitivity, acting in leukemia multiresistent cell lines.

This work describes the synthesis and functionalization of azoles employing different methodologies, based on organometallic catalysis or not. Firstly, we disclose the synthesis tetra-substituted 5-trifluoromethyl pyrazoles via sequential halogenation of 5-trifluoromethyl pyrazoles and palladium-catalyzed carbon–carbon and carbon–nitrogen cross-coupling reactions employing organozinc reagents and amines as coupling partners, respectively. This work allowed to achieve new pyrazolic systems in moderated to good yields. Posteriorly, we show the synthesis of 1,3-di(hetero)aryl indazoles exploring the complementary catalytic activity of nickel and copper complexes. We commenced this study evaluating different nickel pre-catalysts to perform the intramolecular amination of unprotected 2-chlorophenyl hydrazones. In a second moment, we described the N-(hetero)arylation of the in situ generated NH indazoles, using a simple catalytic system based on copper/DMEDA. This sequential one-pot fashion procedure allowed the achievement of several 1,3-di(hetero)aryl indazoles in moderate to good yields. Lastly, we disclose the formation of pyrazolo[1,5-a]quinoxalin-4(5H)-ones by the reaction between ethyl 1-(2-chlorophenyl)-1H-pyrazole-5-carboxylate and primary amines. The one-pot methodology undergoes by two sequential reactional pathways: i) amidation of the ester moiety attached to the pyrazole ring, and ii) intramolecular cyclization via nucleophilic aromatic substitution. This synthetic approach proved to be efficient only for primary aliphatic amines, allowing to achieve molecules with different substitution patterns in moderate to good yields. Key-words: Azoles, quinoxalinones, Negishi cross-coupling, Buchwald-Hartwig cross-coupling. / Este trabalho descreve a síntese e a funcionalização de azóis através de diferentes metodologias, ancoradas ou não na catálise organometálica. Primeiramente, descrevemos a síntese de 5-trifluormetil pirazóis tetrassubtituídos através de reações de acoplamento cruzado catalisadas por complexos de paládio entre 5-trifluormetil-4-halo pirazóis, reagentes organozinco e aminas. Este trabalho permitiu a obtenção de novos sistemas pirazólicos com rendimentos moderados a bons. Posteriormente realizamos a síntese de 1,3-di(hetero)aril indazóis explorando as atividades catalíticas complementares de complexos de níquel e cobre. Primeiramente avaliamos diferentes pré-catalisadores de níquel para realizar a aminação intramolecular de diferentes 2-clorofenil hidrazonas não protegidas. Em um segundo momento, realizamos a N-(hetero)arilação dos NH indazóis gerados in situ, através do emprego de um sistema catalítico baseado em cobre/DMEDA. A metodologia permitiu a obtenção de diferentes indazóis 1,3-di(hetero)aril substituídos, com rendimentos moderados a bons. Por fim, demonstramos a síntese de pirazolo[1,5-a]quinoxalin-4(5H)-onas a partir da reação entre 1-(2-clorofenil)-1H-pirazolo-5-carboxilatos de etila e aminas primárias. A metodologia one-pot envolve duas etapas sequenciais; i) amidação da função éster do pirazol e ii) ciclização intramolecular via substituição nucleofílica aromática. Esta abordagem sintética provou ser eficiente ao se empregar aminas alquílicas primárias, permitindo a obtenção de diferentes padrões de substituição com rendimentos moderados a bons.

Dissertação (mestrado)—Universidade de Brasília, Programa de Pós-Graduação em História, 2013. / Submitted by Alaíde Gonçalves dos Santos (alaide@unb.br) on 2014-06-04T13:41:46Z No. of bitstreams: 1 2013_WalkiriaOliveiraSilva.pdf: 937333 bytes, checksum: 43c619bd4e77ba2c02d85a03a5573b30 (MD5) / Approved for entry into archive by Guimaraes Jacqueline(jacqueline.guimaraes@bce.unb.br) on 2014-06-04T14:38:54Z (GMT) No. of bitstreams: 1 2013_WalkiriaOliveiraSilva.pdf: 937333 bytes, checksum: 43c619bd4e77ba2c02d85a03a5573b30 (MD5) / Made available in DSpace on 2014-06-04T14:38:54Z (GMT). No. of bitstreams: 1 2013_WalkiriaOliveiraSilva.pdf: 937333 bytes, checksum: 43c619bd4e77ba2c02d85a03a5573b30 (MD5) / Esta dissertação objetiva analisar como a obra de Ernst Kantorowicz, Kaiser Friedrich der Zweite, relaciona-se com a fundamentação da identidade nacional alemã durante os anos da República de Weimar. Ernst Kantorowicz foi membro do Círculo de Stefan George, um dos principais movimentos culturais da Alemanha durante as três primeiras décadas do século XX. Por isso, é indispensável apresentar as contribuições do Círculo de Stefan George para as discussões acerca da História e de sua escrita. A análise da obra de Kantorowicz encontra-se indissociada das propostas vinculadas pelo Círculo de Stefan George. Este trabalho está divido em três capítulos: o primeiro abarca o poeta, Stefan George, e a formação de seu Círculo. O segundo apresenta as ideias do Círculo sobre o conhecimento histórico e os principais conceitos formulados por alguns membros do Círculo de George. O último analisa a obra de Kantorowicz a fim de observar como a biografia do Imperador Frederico II contribuiu para a fundamentação e reinterpretação da identidade nacional alemã e como se relaciona com a escrita da história do Círculo de Stefan George. _______________________________________________________________________________________ ABSTRACT / The present dissertation aims to analyse Ernst Kantorowicz’s work, Kaiser Friedrich der Zweite, published in 1927, and its relation to the German national identity’s substantiation during the Weimar Republic. Ernst Kantorowicz was a member of the George Circle, one of the most important cultural movements in Germany during the first three decades of twentieth century. Taking in account his contributions to the George Circle on the debate on History and historiography, the analysis of Kantorowicz’s work should be inseparable of the ideas of the George Circle. This work is divided in three chapters: the first one presents the poet, Stefan George, and the formation’s process of his Circle. The second shows the ideas of the Circle about the historical knowledge and the main concepts formulated by some members of the George Circle. The last one analyses Kantorowicz’s work in order to observe how the biography of the Emperor Frederick II contributed to found the ground and reinterpretat the German national identity in its relation to the historiography of the George Circle.

<p>  </p> <p>Aromatic C-N bond formation is critical for synthetic chemistry in pharmaceutical, agrochemical, and natural product synthesis. Due to the prevalence of this bond class, many synthetic routes have been developed over time to meet the demand. The most recent and robust C-N bond formation reaction is the palladium catalyzed Buchwald-Hartwig amination. Considering the importance of the Buchwald-Hartwig amination, a high-throughput experimentation (HTE) campaign was devised to create a library in which chemists can refer to optimal reaction conditions and ligand/catalyst choice based on the nature of their substrates to be coupled. This study showed trends for the appropriate choice of ligand and catalyst, along with what bases, temperatures, stoichiometries, and solvents are appropriate for the selected substrate combination at hand. </p>

Les lymphomes à grandes cellules anaplasiques ou ALCL (Anaplastic Large-Cell Lymphoma) sont des cancers appartenant à la famille des lymphomes de type non-Hodgkin. La majorité des ALCL est issue d'une translocation t(2;5)(p23;q35) donnant lieu à la formation d'une protéine de fusion appelée NPM-ALK. A ce jour, peu d'inhibiteurs présentent de bonnes activités contre cette protéine chimérique. L'obésité représente un problème socio-médical d'envergure, à la fois pour ses effets directs et indirects ; le surpoids étant un facteur primaire dans de nombreuses maladies, tout particulièrement les diabètes, les accidents cardiovasculaires, le cancer, etc. A contrario, une restriction calorique (RC) est associée à des bénéfices importants en terme de santé. A l'issue de plusieurs criblages, un inhibiteur au motif 2-acylaminothiazole a montré une activité anticancéreuse sur ALK mais également la faculté de mimer la restriction calorique chez C. Elegans. Par conséquent, les travaux de recherche réalisés lors de cette thèse ont concerné la synthèse d'inhibiteurs comportant le squelette 2-acylaminothiazole. Les chromatographies d'affinité effectuées sur deux de nos inhibiteurs ont permis l'identification de cibles principales potentielles dans le cadre de la restriction calorique et des cibles secondaires possibles pour NPM-ALK. Ensuite, la présence d'un atome de brome sur le cycle aromatique a mené à la formation de liaisons C(sp2)-C(sp2), C(sp2)-C(sp) et C(sp2)- N, en utilisant les couplages catalysés par le palladium. Les différentes méthodes de modulation chimique ont conduit à mettre en place une librairie de 134 molécules. Certains d'entres eux et plus précisément ceux possédant un atome de silicium ont démontré une très bonne activité contre ALK et son mutant L1196M. Enfin, des résultats préliminaires ont également été obtenus sur le sujet de la restriction calorique avec quatre composés montrant une réduction du taux de lipides chez C. Elegans / Anaplastic Large-Cell Lymphoma (ALCL) is a type of cancer belonging to the non-Hodgkin family. The majority of ALCL arises from a translocation t(2;5) (p23;35) which leads to the formation of a fusion protein called NPM-ALK. Nowadays, few molecules are known to inhibit the activity of this chimeric protein. Obesity is a major socio-medical problem, for both direct and indirect effects, overweight is a primary factor in many diseases, especially diabetes, cardiovascular events, cancer, etc... In contrast, caloric restriction (CR) is associated with significant benefits in terms of health. After several screenings, one inhibitor based on a 2-acylaminothiazol scaffold showed anticancer activity on the protein ALK but also the ability to mimic caloric restriction in C. Elegans. The aim of this PhD was to develop the synthesis of new inhibitors including the 2-acylaminothiazol scaffold. The affinity chromatography performed on two of our inhibitors was used to identify potential major cellular targets in the process of caloric restriction and secondary cellular targets for NPM-ALK. Then, the presence of a bromo group on the aromatic ring allowed the formation of C(sp2)-C(sp2), C(sp2)- C(sp) and C(sp2)-N bonds, using palladium-catalyzed couplings. The different chemical methodologies afforded the synthesis of a library of 134 molecules. Some of them especially with a silicon atom demonstrated very good inhibitory activity and high selectivity against NPM-ALK and L1196M-NPM-ALK. Finally, preliminary results were also obtained on the subject of calorie restriction with four compounds showing a reduction of lipids in C. Elegans

Le travail s’est articulé autour de la synthèse et de l’évaluation biologique de nouveaux inhibiteurs de protéines kinases dont essentiellement de kinases dépendantes de cyclines (CDKs). La dérégulation de ces kinases est mise en cause dans l’apparition de nombreuses pathologies prolifératives telles que le cancer ou non prolifératives telles que les maladies neurodégénératives. Deux types d’inhibiteurs ont été préparés. La première famille de composés étudiée est la famille des purines, sur laquelle a été introduite des substructures de type aminodiols en position C-2. Ces aminodiols ont été préparés de manière stéréosélective via la réaction de dihydroxylation asymétrique décrite par Sharpless ou à partir de dérivés d’acides aminés. Parmi les inhibiteurs réalisés, plusieurs ont montré une inhibition envers les protéines CDK5, CDK9 et CK1 très supérieure (IC50 de l’ordre de 100 nM) à celle de la (R)-Roscovitine, molécule actuellement en phase clinique II dans plusieurs cancers. Ces inhibitions des cibles enzymatiques s’accompagnent d’un effet antiprolifératif sur plusieurs lignées tumorales. Enfin l’étude d’une des molécules a été complétée par des tests très favorables sur des enzymes de microsomes hépatiques (IC50 > 5 μM). Dans une seconde partie, des imidazo[1,2-b]pyridazines ont été préparées. Une synthèse originale conduisant aux imidazo[1,2-b]pyridazines 3,6,8-trisubstituées a été mise au point. Les produits présentent une inhibition forte envers les protéines kinases telles que CDK5 et CK1 (IC50 < 50 nM). Ils montrent également des propriétés antiprolifératives sur les cellules tumorales SH-SY5Y. Enfin, des imidazo[1,2-b]pyridazines 3,6-disubstituées se révèlent être des inhibiteurs sélectifs de la protéine CLK1 (IC50 < 100 nM). / This thesis focuses on the synthesis and biological evaluation of new kinase inhibitors. Kinase deregulation is associated with numerous diseases such as cancer or neurodegenerative diseases. In the first part of this work, 2,6,9-trisubstituted purines bearing at C-2 position aminodiols derivatives were prepared. Aminodiols were obtained either via Sharpless asymmetric dihydroxylation or by reduction of amino esters. The compounds appeared to be more potent against kinases than (R)-roscovitine which is presently undergoing phase II clinical tests. In particular, inhibition of CK1, CDK5 and CDK9 were observed with IC50 < 200 nM. The compounds prepared showed an antiproliferative effect against tumor cell-lines (SH-SY5Y). Eventually, one of the most promising compounds was assayed against a series of cyt P450 enzymes and did not showed any inhibition (IC50 > 5 μM). The second family of compounds prepared in this work is imidazo[1,2-b]pyridazines. A new route to 3,6,8-trisubstituted imidazo[1,2-b]pyridazines was first developed. These products were shown to be highly potent inhibitors of several kinases such as CDK5 and CK1 (IC50 < 50 nM). The kinase inhibitions were accompanied by antiproliferative activities against tumor cell-lines. Finally, a series of 3,6-disubtituted imidazo[1,2-b]pyridazines was also prepared and appeared to be selective inhibitors of CLK1 (IC50 < 100 nM).

This graduation thesis describes life in the border village Podmokly in the period between 1853-1918. The author presents the penetration of the Saxon capital at this time and further developing the business mostly Germans from Saxony in the chocolate industry. It focuses on chocolate, which at that time originated in the village, and the chocolate Jordan & Timaeus, Hartwig & Vogel, and Otto Rüger. Initially focused on the development of village Podmokly, the characteristic time, the amount of customs duties and surcharges on raw materials for production of chocolate and cocoa. In this work the author shows contemporary practice in the manufacture of chocolate, recipes and curiosities, which were associated with the production of chocolate. The analysis of chocolate, the author focuses on the history of chocolate on the description of the factory and its reorganization, social policy, in compliance with regulations and laws that were created at this time. Furthermore, the author explores the field of advertising, international exhibitions, sales and production of chocolate and firm structure. The work is drawn primarily from contemporary sources, or. journal of modern literature and scientific studies

Ce travail s'inscrit dans la recherche et le développement de nouvelles molécules à visée thérapeutique via la mise au point de cyclisations radicalaires oxydatives médiées par l'acétate de manganèse(III). Deux problématiques ont dirigé nos recherches. Tout d'abord, nous avons développé une stratégie de synthèse de prodrogues analogues de la pafuramidine, molécule antileishmanienne. Ainsi, une 1ère série d'amidoximes a été obtenue à partir de &#946;-cétosulfones par une synthèse multi-étapes faisant appel aux réactions i) de cyclisations radicalaires oxydatives médiées par Mn(OAc)3 et ii) de couplages pallado-catalysées de Buchwald-Hartwig et de Heck. Suite à l'évaluation biologique in vitro sur Leishmania donovani et sur des cellules humaines, une 2ème série d'amidoximes et en particulier des monoamidoximes a été réalisée, ce qui a révélé une molécule présentant un index de sélectivité 40 fois plus élevé que celui de la pentamidine, médicament utilisé comme référence. Nous avons également mis au point un double couplage "one-pot" de Buchwald-Hartwig dans le but d'obtenir des produits dicouplés dissymétriques, précurseurs éventuels de futures diamidoximes. Dans une deuxième partie, nous nous sommes focalisés sur la synthèse de composés spirocycliques pouvant constituer un pharmacophore original. De ce fait, une stratégie de synthèse conduisant à divers noyaux tels des tétralines spirocycliques, des spirolactones, des spirobenzophénanthrédin-6(5H)-ones a été mise au point. Ce travail nous a également menés vers la synthèse de dérivés thiobarbiturates, analogues de composés anesthésiques ou anticonvulsivants. / This work focuses on the research and development of new therapeutic molecules through optimized radical cyclizations mediated by manganese(III) acetate. Two problematics directed our research. First, we developed analogous prodrugs of pafuramidine, an antileishmanial molecule. Thus, a 1rst series of amidoximes was obtained from &#946;-ketosulfones by a multi-step synthesis involving i) radical oxidative cyclizations mediated by Mn(OAc)3 and ii) pallado-catalyzed Buchwald-Hartwig and Heck coupling reactions. The 1rst series being biologically evaluated in vitro, both on Leishmania donovani and human cells, a 2nd series and particularly monoamidoximes was prepared and revealed a molecule presenting a selectivity index 40 times higher than the one of pentamidine, used as reference drug compound. We also developed a one-pot double Buchwald-Hartwig coupling reaction in the aim to obtain dissymmetric dicoupled products, potential precursors of future diamidoximes. In a second time, we focused on the synthesis of spirocyclic compounds which could constitute an original pharmacophore. Therefore, we performed a synthesis allowing access to a wide variety of scaffolds such as spirocyclic tetralins, spirolactones, spirobenzophenanthridin-6(5H)-ones. This work allowed the synthesis of thiobarbiturates, analogous of anesthetic or anticonvulsive compounds.