Il y a de nos jours un besoin urgent de découvrir de nouveaux médicaments pour relever le défi de la multirésistance dans le traitement des infections bactériennes et le cancer. Dans cette perspective, des bases de Schiff dérivées de dithiocarbazates et leurs complexes métalliques correspondants sont des candidats intéressants puisqu'ils peuvent être facilement synthétisés et permettent une grande diversité de coordination. Dans cette étude, des complexes tetradentes et bidente ont été préparés. Les ligands et complexes synthétisés ont été entièrement caractérisés par différentes méthodes spectroscopiques et physico-chimiques dans le solide et en solution. L'activité antibactérienne de ces complexes a ensuite été étudiée et a permis de sélectionner un complexe " leader " (plus efficace, stable et fonctionnalisable). Ce complexe a alors été modifié afin d'augmenter sa stabilité en milieux biologique, sa solubilité dans l'eau ainsi que son activité. Il a été conjugué avec différentes entités : des peptides pénétrants, un polyéthylène glycol (PEG) et un peptide inhibiteur des pompes d'efflux bactériennes. Ces complexes ont montré une remarquable activité antibactérienne sur neuf souches de bactéries Gram-positives et Gram-négatives et en particulier, ils se sont avérés très efficaces contre S.aureus. L'activité anti-cancéreuse des complexes non-conjugués a également été étudiée et les complexes de cuivre sélectionnés et testés sur des cellules de cancer du sein ont montré une cytotoxicité élevée. Ceci met en évidence la pertinence d'utiliser les complexes métalliques, pour à la fois stabiliser les ligands et générer des composés plus actifs. / There is an urgent need to discover new drugs with novel mechanisms of action, higher activity and improved selectivity to address the severe challenge of multidrug resistance in treating bacterial infections and cancer. In view of this, Schiff bases derived from S-substituted dithiocarbazate and their corresponding metal complexes with a plethora of potentially exciting biological activities and coordination chemistry are attractive candidates. Metal complexes of tetradentate NNSS and bidentate NS ligands have been prepared. The compounds were fully characterized with various physico-chemical and spectroscopic methods in solution and solid state. Conjugation of the most promising antimicrobial compound to various moities (polyarginine, polyethylene glycol (PEG) and an bacterial efflux pump inhibitor) was achieved to prepare improved therapeutic agents. The nanoarginines (R9) derivatives showed the most encouraging synergistic effect upon conjugation and complexation to copper ion with enhanced water solubility, bacteria cell membrane permeability and bioactivity. The Cu(II) R9 derivatives possess remarkable antibacterial activity against a wide spectrum of bacteria and in particular, highly efficacious against S. aureus. This show that the conjugation of polyarginine to dithiocarbazate compounds can greatly influence their therapeutic potential. Cytotoxic assay was also carried out for selected non-conjugated compounds. All the selected Cu(II) complexes assayed against breast cancer cells lines exhibited good cytotoxicity. This work highlights the relevance of the strategy that consists of using metal complexes to stabilize the ligands and improve their bioactivity.

No presente trabalho, foram estudadas duas series de complexos mistos de cobre (II). A primeira serie de complexos, constituída pelos ligantes 3-hidroxipicolinato e 2-acetilpiridinatiossemicarbazona N(4) substituída, sendo o substituinte variado pelos grupos ciclohexil, etil e fenil, ou o 2-acetilpiridinabenzilditiocarbazato. A segunda serie, constituída pelas mesmas tiossemicarbazonas e ditiocarbazato, com o ligante 2-hidroxinicotinato no lugar do 3-hidroxipicolinato. Com a finalidade de avaliar a atividade contra Mycobacterium tuberculosis. <br /> Os complexos obtidos foram caracterizados em estado sólido, pelo ponto de fusão e por meio espectroscopia de absorção na região do infravermelho e difração de raios X em monocristais. Em solução foi utilizada a técnica de espectroscopia eletrônica. <br /> Foi feito o estudo da atividade biológica dos 8 compostos obtidos contra o Mycobacterium tuberculosis, sendo todos eles candidatos ativos e promissores no combate à bactéria, já que apresentam todos valores baixos de concentração inibitória mínima. Sendo que os complexos 2 ,3, 4 e 6 apresentam atividade melhor do que alguns dos fármacos já usados no tratamento como ciprofloxacino, ácido p-aminosalicílico, cicloserina, gentamicina, etambutol, kanamicina, tobramicina, claritromicina e tiacetazona. / In the present work were investigated two series of mixed complexes of coppe (II). The first of them is constituted by the ligands 3-hydroxypicolinate and 2-acetylpyridinedithiosemicabazate or 2-acetylpyridinethiossemicrzones N(4) substituted, were the substituted groups consist on cyclohexyl, ethyl and phenyl. The second series is formed by the same thiosemicarbazones and dithiocarbazate, but with the ligand 2-hydroxynicotinate, instead of 3-hydroxypicolinate. This, in order to evaluate the activity against Mycobaterium tuberculosis. <br /> The synthetized complexes have been characterized in solid state through the melting point and infrared spectroscopy and X-ray diffraction on single crystals. The characterization in solution was done by electronic spectroscopy. <br /> Assays were performed to determine the biological activity of the eight compounds synthetized against the Mycobacterium tuberculosis. All complexes have shown low minimal inhibitory concentration, being promising candidates for successive tests. It is observed that complex 2, 3, 4 and 6 exhibit better activity than some of the drugs used in the treatment such as ciprofloxacin, p-aminosalicylic acid, cycloserine, gentamicin, ethambutol, kanamycin, tobramycin, thiacetazone and clarithromycin.

No presente trabalho, foram estudadas duas series de complexos mistos de cobre (II). A primeira serie de complexos, constituída pelos ligantes 3-hidroxipicolinato e 2-acetilpiridinatiossemicarbazona N(4) substituída, sendo o substituinte variado pelos grupos ciclohexil, etil e fenil, ou o 2-acetilpiridinabenzilditiocarbazato. A segunda serie, constituída pelas mesmas tiossemicarbazonas e ditiocarbazato, com o ligante 2-hidroxinicotinato no lugar do 3-hidroxipicolinato. Com a finalidade de avaliar a atividade contra Mycobacterium tuberculosis. <br /> Os complexos obtidos foram caracterizados em estado sólido, pelo ponto de fusão e por meio espectroscopia de absorção na região do infravermelho e difração de raios X em monocristais. Em solução foi utilizada a técnica de espectroscopia eletrônica. <br /> Foi feito o estudo da atividade biológica dos 8 compostos obtidos contra o Mycobacterium tuberculosis, sendo todos eles candidatos ativos e promissores no combate à bactéria, já que apresentam todos valores baixos de concentração inibitória mínima. Sendo que os complexos 2 ,3, 4 e 6 apresentam atividade melhor do que alguns dos fármacos já usados no tratamento como ciprofloxacino, ácido p-aminosalicílico, cicloserina, gentamicina, etambutol, kanamicina, tobramicina, claritromicina e tiacetazona. / In the present work were investigated two series of mixed complexes of coppe (II). The first of them is constituted by the ligands 3-hydroxypicolinate and 2-acetylpyridinedithiosemicabazate or 2-acetylpyridinethiossemicrzones N(4) substituted, were the substituted groups consist on cyclohexyl, ethyl and phenyl. The second series is formed by the same thiosemicarbazones and dithiocarbazate, but with the ligand 2-hydroxynicotinate, instead of 3-hydroxypicolinate. This, in order to evaluate the activity against Mycobaterium tuberculosis. <br /> The synthetized complexes have been characterized in solid state through the melting point and infrared spectroscopy and X-ray diffraction on single crystals. The characterization in solution was done by electronic spectroscopy. <br /> Assays were performed to determine the biological activity of the eight compounds synthetized against the Mycobacterium tuberculosis. All complexes have shown low minimal inhibitory concentration, being promising candidates for successive tests. It is observed that complex 2, 3, 4 and 6 exhibit better activity than some of the drugs used in the treatment such as ciprofloxacin, p-aminosalicylic acid, cycloserine, gentamicin, ethambutol, kanamycin, tobramycin, thiacetazone and clarithromycin.

O parasita Trypanosoma cruzi (T. cruzi) é o causador da doença de Chagas e continua sendo um grave problema de saúde pública, principalmente nas regiões mais pobres da América Latina. Na busca por novas drogas terapêuticas contra T. cruzi, nós avaliamos a atividade do composto 5-hidroxi-3-metil-5-fenil-pirazolina-1-(S-benzilditiocarbazato) (H2bdtc) tanto in vitro quanto in vivo. Esta espécie foi caracterizada por análise elementar, espectroscopia UV-visível, infravermelho, RMN e espectrometria de massas. Nos experimentos biológicos, o composto H2bdtc em suspensão e/ou encapsulado em nanopartícula lipídica sólida (NLS) foi comparado com um dos medicamentos empregados atualmente, o benzonidazol (BZN). Utilizando-se o composto H2bdtc encapsulado em NLS observou-se: (a) redução de forma eficaz da parasitemia em camundongos, em concentração 100 vezes mais baixa do que aquela normalmente empregada para Benzonidazol (clinicamente aplicada a uma concentração de 400 ?mol kg-1 dia-1); (b) diminuição da inflamação e das lesões de fígado e do coração e (c) resultou em 100,0% de sobrevivência dos camundongos infectados com T. cruzi após 60 dias. Para fins de elucidação do possível mecanismo de ação do composto H2bdtc, estudo de interação com o DNA e com a albumina do soro Humano (HSA) foram realizados. Baseado nos dados relacionados à atividade tripanocida in vitro e in vivo do composto H2bdtc, este pode ser tomado como potente agente tripanocida e o estudo desenvolvido neste projeto pode concorrer ao uso de H2bdtc como possível nova droga a ser utilizada contra Doença de Chagas. / The parasite Trypanosoma cruzi causes Chagas disease, which remains a serious public health concern and continues to victimize thousands of people, primarily in the poorest regions of Latin America. In the search for new therapeutic drugs against T. cruzi, here we have evaluated both the in vitro and the in vivo activity of 5-hydroxy-3-methyl-5-phenyl-pyrazoline-1-(S-benzyldithiocarbazate) (H2bdtc). This compound was characterized by elemental analysis, UV-visible spectroscopy, infrared, NMR and mass spectrometry. Biological experiments were conducted with H2bdtc as a free compound or encapsulated into solid lipid nanoparticles; we compared the results with those achieved by using the currently employed drug, benznidazole. H2bdtc encapsulated into solid lipid nanoparticles (a) effectively reduced parasitemia in mice at concentrations 100 times lower than that normally employed for benznidazole (clinically applied at a concentration of 400 ?mol kg-1 day-1); (b) diminished inflammation and lesions of the liver and heart; and (c) resulted in 100,0% survival of mice infected with T. cruzi. Biological mechanism elucidation of H2bdtc compound was analyzed based on the interaction with DNA and Human Serum Albumin (HSA). Based on the data related to the in vitro and in vivo trypanocidal activity of H2bdtc it was taken as potent trypanocidal agent. Studies developed on this project allow concluding that H2bdtc is a possible new drug to be used against Chagas Disease.

O parasita Trypanosoma cruzi (T. cruzi) é o causador da doença de Chagas e continua sendo um grave problema de saúde pública, principalmente nas regiões mais pobres da América Latina. Na busca por novas drogas terapêuticas contra T. cruzi, nós avaliamos a atividade do composto 5-hidroxi-3-metil-5-fenil-pirazolina-1-(S-benzilditiocarbazato) (H2bdtc) tanto in vitro quanto in vivo. Esta espécie foi caracterizada por análise elementar, espectroscopia UV-visível, infravermelho, RMN e espectrometria de massas. Nos experimentos biológicos, o composto H2bdtc em suspensão e/ou encapsulado em nanopartícula lipídica sólida (NLS) foi comparado com um dos medicamentos empregados atualmente, o benzonidazol (BZN). Utilizando-se o composto H2bdtc encapsulado em NLS observou-se: (a) redução de forma eficaz da parasitemia em camundongos, em concentração 100 vezes mais baixa do que aquela normalmente empregada para Benzonidazol (clinicamente aplicada a uma concentração de 400 ?mol kg-1 dia-1); (b) diminuição da inflamação e das lesões de fígado e do coração e (c) resultou em 100,0% de sobrevivência dos camundongos infectados com T. cruzi após 60 dias. Para fins de elucidação do possível mecanismo de ação do composto H2bdtc, estudo de interação com o DNA e com a albumina do soro Humano (HSA) foram realizados. Baseado nos dados relacionados à atividade tripanocida in vitro e in vivo do composto H2bdtc, este pode ser tomado como potente agente tripanocida e o estudo desenvolvido neste projeto pode concorrer ao uso de H2bdtc como possível nova droga a ser utilizada contra Doença de Chagas. / The parasite Trypanosoma cruzi causes Chagas disease, which remains a serious public health concern and continues to victimize thousands of people, primarily in the poorest regions of Latin America. In the search for new therapeutic drugs against T. cruzi, here we have evaluated both the in vitro and the in vivo activity of 5-hydroxy-3-methyl-5-phenyl-pyrazoline-1-(S-benzyldithiocarbazate) (H2bdtc). This compound was characterized by elemental analysis, UV-visible spectroscopy, infrared, NMR and mass spectrometry. Biological experiments were conducted with H2bdtc as a free compound or encapsulated into solid lipid nanoparticles; we compared the results with those achieved by using the currently employed drug, benznidazole. H2bdtc encapsulated into solid lipid nanoparticles (a) effectively reduced parasitemia in mice at concentrations 100 times lower than that normally employed for benznidazole (clinically applied at a concentration of 400 ?mol kg-1 day-1); (b) diminished inflammation and lesions of the liver and heart; and (c) resulted in 100,0% survival of mice infected with T. cruzi. Biological mechanism elucidation of H2bdtc compound was analyzed based on the interaction with DNA and Human Serum Albumin (HSA). Based on the data related to the in vitro and in vivo trypanocidal activity of H2bdtc it was taken as potent trypanocidal agent. Studies developed on this project allow concluding that H2bdtc is a possible new drug to be used against Chagas Disease.