La découverte de l'Artémisinine, un 1,2,4-trioxacyclohexane, et le fait que la liaison endoperoxide est essentielle pour son activité antimalarique, a conduit les chimistes à la synthèse de nouvelles molécules contenant le motif endoperoxide pour obtenir de nouveaux leaders. Certains de ces composés peroxidiques sont les 1,2-dioxanes et les 1,2,4,5-tetraoxanes. À cet égard, la première partie de mon travail a été réalisée dans le laboratoire du professeur Giuseppe Campiani à l'université de Sienne et a inclus la synthèse d'analogues 1,2-dioxane du produit naturel Plakortine mais aussi le développement d'une stratégie de synthèse polyvalent du produit naturel 9,10-dihydroplakortine. Une des étapes clés dans notre approche synthétique a été la stéréosélectivité des réactions ainsi que la formation du squelette chiral 1,2-dioxane. En combinant l'époxidation dissymétrique de Sharpless à l'hydroperoxysilylation régiosélective d'alcène catalysée par le cobalt (II) de Mukaiyama-Isayama, la stéréochimie désirée a été obtenue. Dans la seconde partie de mon doctorat qui a pris place dans le laboratoire du professeur Paul O'Neill à l'université de Liverpool, la conception, la synthèse et l'évaluation du potentiel antimalarique de deux nouvelles séries de 1,2,4,5-tetraoxanes ont été réalisées. La première série de tetraoxanes, appelée les Mannoxanes, est une drogue hybride qui possède un noyau tetraoxane et une chaine latérale basique insérée grâce à une réaction de mannich. La seconde série a été préparée par une approche utilisant l'amination réductrice pour inclure la chaine latérale basique sur le noyau tetraoxane. Les deux séries ont montré d'excellentes activités antimalariques (de l'ordre du nanomolaire) contre plasmodium falciparum. / The discovery of artemisinin, a 1,2,4-trioxacyclohexane, and the fact that the endoperoxide bond is essential for its antimalarial activity has led chemists to synthesize new molecules containing the endoperoxide moiety in order to find new antimalarial hits. Some of these peroxidic compounds include the 1,2-dioxanes and the 1,2,4,5-tetraoxanes. In this regard, work on the first part of the PhD (Chapter 2) has been developed in the laboratories of Prof. Giuseppe Campiani at the University of Siena and includes the synthesis of 1,2-dioxane analogues of natural product Plakortin and the development of a versatile synthetic strategy to the natural compound 9,10-dihydroplakortin. One of the key issues in our synthetic approach has been the stereoselectivity of the reactions and the formation of the chiral 1,2-dioxane skeleton. By combining Sharpless asymmetric epoxidation to the Mukaiyama-Isayama Co(II)-catalyzed regioselective hydroperoxysilylation of an alkene, the desired stereochemistry has been obtained. In the second part of the PhD (Chapter 3), which has taken place in the laboratories of Prof. Paul O'Neill at the University of Liverpool, design, synthesis and assessment of the antimalarial potency of two new series of 1,2,4,5-tetraoxanes has been achieved. The first series of novel tetraoxanes are called Mannoxanes and are hybrid drugs that include a tetraoxane and a mannich basic phenol side-chain. The second new series has been synthesized by using a reductive amination approach to include the basic side chain in the tetraoxane molecule scaffold. Both of these series have shown excellent antimalarial activities against Plasmodium falciparum in the low nanomolar range.

Submitted by Renata Lopes (renatasil82@gmail.com) on 2016-09-22T17:54:20Z No. of bitstreams: 1 lucaslopardifranco.pdf: 1498046 bytes, checksum: aa3cf634965e77b44f29d47f725c19c1 (MD5) / Approved for entry into archive by Diamantino Mayra (mayra.diamantino@ufjf.edu.br) on 2016-09-26T20:30:01Z (GMT) No. of bitstreams: 1 lucaslopardifranco.pdf: 1498046 bytes, checksum: aa3cf634965e77b44f29d47f725c19c1 (MD5) / Made available in DSpace on 2016-09-26T20:30:01Z (GMT). No. of bitstreams: 1 lucaslopardifranco.pdf: 1498046 bytes, checksum: aa3cf634965e77b44f29d47f725c19c1 (MD5) Previous issue date: 2010-12-20 / CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Este trabalho trata da síntese de diidroperóxidos e de tetraoxanos, ambos contendo um esqueleto carbônico similar àqueles das chalconas e curcuminas. Essas classes de compostos possuem um amplo espectro de ação terapêutica, o que somado ao núcleo endoperóxido pode resultar em novos candidatos a agentes antimaláricos e antiparasitários em geral. A partir de reações usando como material de partida o benzaldeído e dois de seus derivados metoxilados, foi obtida uma série de três dibenzalcetonas com estruturas similares às chalconas e curcuminas, com rendimentos que variaram de 76 a 95%. Com a finalidade de averiguar a importância da insaturação na atividade biológica dos produtos finais, foi feita a hidrogenação dessas dibenzalcetonas, gerando outras três cetonas saturadas, sendo uma delas inédita, com rendimentos que variaram de 51 a 93%. Essas seis cetonas, juntamente com a cicloexanona e a terc-butil-cicloexanona comerciais, foram usadas como materiais de partida na síntese dos diidroperóxidos e tetraoxanos. Para tal, foram testados vários métodos visando obter uma metodologia de preparação rápida, usando reagentes de baixo custo e pouco tóxicos. Nas tentativas de síntese dos diidroperóxidos foram utilizados e comparados quatro procedimentos diferentes e o mais eficiente, através do uso de peróxido de hidrogênio em fase etérea, proporcionou a obtenção de cinco diidroperóxidos, sendo três deles inéditos, com rendimentos que variaram de 51 a 89%. Nas tentativas de síntese dos tetraoxanos foram utilizados e comparados três métodos diferentes e o mais eficiente, usando a síntese “one pot”, proporcionou a obtenção de quatro tetraoxanos, sendo três deles inéditos, com rendimentos que variaram de 22 a 70%. Todos os compostos foram caracterizados através de técnicas adequadas, tais como: IV, RMN de 1H e de 13C e faixa de fusão. Esses compostos foram avaliados quanto às suas atividades tripanocidas e estão sendo avaliados quanto às suas ações antimaláricas. / This work describes the synthesis of dihydroperoxides and tetraoxanes, both with the similar structure of chalcones and curcumins. These classes of compounds have a broad spectrum of therapeutic action, which, added to the endoperoxide moiety, may result in new candidates as antimalarial and antiparasit agents. A series of three aromatic ketones were obtained from benzaldehyde and two of its methoxylated derivatives in 76 to 95% yields. These compounds contain structures similar to curcumin and chalcones. Aiming to establish the importance of unsaturation in biological activity of the final products the dibenzalketones obtained were hydrogenated, generating three more ketones in 51 to 93% yields. These six ketones, cyclohexanone and tert-butyl cyclohexanone were used in the synthesis of dihydroperoxides and tetraoxanes. For this purpose, several methods were tested aiming a fast method of preparation, using reagents of low cost and toxicity. Four different methodologies were used and compared for the synthesis of the dihydroperoxides. The most efficient provided five dihydroperoxides in 51 to 89% yields. Three different methodologies were used and compared for the synthesis of the tetraoxanes. The most efficient methodology provided four tetraoxanes in 22 to 70% yield. All compounds were characterized using appropriate techniques such as IR, 1H and 13C NMR and melting point. These compounds demonstrated low trypanocidal activity and are being evaluated for their antimalarial action.