O presente trabalho consiste na síntese, caracterização e estudos de atividade tripanocida de doze compostos, sendo oito tiossemicarbazonas (TSCs) e quatro ditiocarbazatos (DTCs), contendo anel pirazolínico em suas estruturas, assim como no estudo da formação de complexos de um DTC com GaIII. As TSCs e os DTCs foram obtidos em reações de condensação envolvendo uma β-dicetona e uma tiossemicarbazida ou ditiocarbazato, respectivamente. A partir de 1-fenil-1,3-butanodiona (benzoilacetona) e 4-R-tiossemicarbazida, foram obtidas as TSCs de nome 5-hidroxi-3-metil-5-fenil-pirazolina-1-(4-R-tiossemicarbazona), identificados como H2bt, H2bmt, H2bet e H2bpt, com R = H, Me, Et e Ph, respectivamente. Mudando a β-dicetona para 4,4,4-trifluoro-1-fenil-1,3-butanodiona, foram obtidas as TSCs de nome 5-hidroxi-3-fenil-5-trifluorometil-pirazolina-1-(4-R-tiossemicarbazona), identificados como H2ft, H2fmt, H2fet e H2fpt, com R = H, Me, Et e Ph, respectivamente. De modo similar, os DTCs de nome 5-hidroxi-3-metil-5-fenil-pirazolina-1-(S-p-R-benzilditiocarbazato), H2bdtc e H2mbdtc, para R = H e OMe, respectivamente, foram obtidos a partir de benzoilacetona e S-p-R-benzilditiocarbazato, enquanto que os DTCs de nome 5-hidroxi-3-fenil-5-trifluorometil-pirazolina-1-(S-p-R-benzilditiocarbazato), H2fdtc e H2mfdtc, para R = H e OMe, respectivamente, formaram-se quando a 4,4,4-trifluoro-1-fenil-1,3-butanodiona foi a β-dicetona utilizada. Os compostos foram caracterizados por diversas técnicas, que incluíram análise elementar, espectroscopia na região do infravermelho (IV), espectrometria de massas, ressonância magnética nuclear de hidrogênio e flúor (RMN1H e 19F) e difração de raios X em monocristal. As TSCs e os DTCs foram avaliados quanto a suas atividades anti-T. cruzi e citotoxicidade frente a células de macrófagos J774, sendo possível avaliar as influências dos grupos periféricos substituintes. Nestes estudos, dois novos compostos, além do H2bdtc, cuja atividade é conhecida, se mostraram promissores, H2bt e H2bmt, apresentando valores de atividade tripanocida CC50try = 9,91 e 6,85 µM, respectivamente, para a cepa Y na forma tripomastigota do T. cruzi. Ambos foram superiores ao benzonidazol, utilizado como referência (CC50try = 10,6 µM). Os compostos também se mostraram seletivos, com CC50 > 100 µM para células de macrófago J774. Estudos de complexação com GaIII utilizando H2bdtc como agente complexante levaram a dois novos complexos, variando-se as condições reacionais, sendo um mononuclear, [Ga(bdtc)(Hbdtc)].CH3OH, e um dinuclear, [Ga2(bdtc)2(µOCH3)2].CH2Cl2, os quais foram caracterizados, tanto em solução quanto no estado sólido, tendo tido suas estruturas determinadas por difração de raios X em monocristal. Ambos apresentam centros de GaIII pentacoordenados, com grau de distorção diferenciado, entre uma geometria de coordenação bipiramidal trigonal e piramidal de base quadrada. Quando dianiônico, o bdtc2- coordenou-se O,N,S-tridentado, diferentemente da forma S,N-bidentada observa para o DTC, quando coordenado monoaniônico, como bdtc1-. / The present work describes the synthesis, structural characterization and trypanocidal activity studies of twelve compounds, eight thiosemicarbazones (TSCs) and four dithiocarbazates (DTCs) containing pyrazoline ring in their structures, as well as in the study of complex formation of a DTC with GaIII. The TSCs and DTCs were obtained from condensation reactions involving a & beta;-diketone and a dithiocarbazate or thiosemicarbazide, respectively. From 1-phenyl-1,3-butanedione (benzoylacetone) and 4-R-thiosemicarbazide were obtained TSCs the name 5-hydroxy-3-methyl-5-phenyl-pyrazoline-1-(4-R-thiosemicarbazone), identified as H2bt, H2bmt, H2bet and H2bpt, R = H, Me, Et, Ph, respectively. Changing the & beta;-diketone for 4,4,4-trifluoro-1-phenyl-1,3-butanedione result in TSCs the name 5-hydroxy-3-phenyl-5-trifluoromethyl-pyrazoline-1-(4-R-thiosemicarbazone), identified as H2ft, H2fmt, H2fet and H2fpt, R = H, Me, Et, Ph, respectively. Similarly, the DTCs with name 5-hydroxy-3-methyl-5-phenyl-pyrazoline-1-(S-p-R-benzyldithiocarbazate), H2bdtc and H2mbdtc to R = H and OMe, respectively, were obtained from benzoylacetone and S-p-R-benzyldithiocarbazate, while DTCs 5-hydroxy-3-phenyl-5-trifluoromethyl-pyrazoline-1-(S-p-R-benzyldithiocarbazate), H2fdtc and H2mfdtc to R = H and OMe, respectively, are formed with 4,4,4-trifluoro-1-phenyl-1,3-butanedione. The compounds were characterized by various techniques such as elemental analysis, infrared spectroscopy (IR), mass spectrometry, nuclear magnetic resonance of hydrogen and fluorine (1H and 19F NMR) and single crystals X-ray diffraction. The TSCs and DTCs were evaluated for their anti-T. cruzi activity and cytotoxicity against macrophage cells, making it possible to evaluate the effects of substituent peripheral groups. In these studies, other two new compounds than H2bdtc whose activity is known, were considered promising, H2bt and H2bmt, having superior activity, CC50try values 9.91 and 6.85 µM, respectively, compared with benznidazole used as reference (CC50try = 10.6 µM). The compounds also show selective with CC50> 100 µM for J774 macrophage cells. In the complexation studies with GaIII using H2bdtc it is possible to obtain two new complex, varying the reaction conditions, being a mononuclear, [Ga(bdtc)(Hbdtc)]·CH3OH, and other dinuclear [Ga2(bdtc)2(µ OCH3)2].CH2Cl2, which were characterized both in solution and in solid state, having their structures determined by single crystals X-ray diffraction. Both having GaIII pentacoordenate, with distortion of coordination geometry between trigonal bipyramidal and square pyramidal. When the ligand bdtc2- coordinated dianionic the form is O,N,S-tridentate, unlike the form S,N-bidentate was observed for the DTC when coordinated monoanionic as bdtc1-.The present work describes the synthesis, structural characterization and trypanocidal activity studies of twelve compounds, eight thiosemicarbazones (TSCs) and four dithiocarbazates (DTCs) containing pyrazoline ring in their structures, as well as in the study of complex formation of a DTC with GaIII. The TSCs and DTCs were obtained from condensation reactions involving a ?-diketone and a dithiocarbazate or thiosemicarbazide, respectively. From 1-phenyl-1,3-butanedione (benzoylacetone) and 4-R-thiosemicarbazide were obtained TSCs the name 5-hydroxy-3-methyl-5-phenyl-pyrazoline-1-(4-R-thiosemicarbazone), identified as H2bt, H2bmt, H2bet and H2bpt, R = H, Me, Et, Ph, respectively. Changing the ?-diketone for 4,4,4-trifluoro-1-phenyl-1,3-butanedione result in TSCs the name 5-hydroxy-3-phenyl-5-trifluoromethyl-pyrazoline-1-(4-R-thiosemicarbazone), identified as H2ft, H2fmt, H2fet and H2fpt, R = H, Me, Et, Ph, respectively. Similarly, the DTCs with name 5-hydroxy-3-methyl-5-phenyl-pyrazoline-1-(S-p-R-benzyldithiocarbazate), H2bdtc and H2mbdtc to R = H and OMe, respectively, were obtained from benzoylacetone and S-p-R-benzyldithiocarbazate, while DTCs 5-hydroxy-3-phenyl-5-trifluoromethyl-pyrazoline-1-(S-p-R-benzyldithiocarbazate), H2fdtc and H2mfdtc to R = H and OMe, respectively, are formed with 4,4,4-trifluoro-1-phenyl-1,3-butanedione. The compounds were characterized by various techniques such as elemental analysis, infrared spectroscopy (IR), mass spectrometry, nuclear magnetic resonance of hydrogen and fluorine (1H and 19F NMR) and single crystals X-ray diffraction. The TSCs and DTCs were evaluated for their anti-T. cruzi activity and cytotoxicity against macrophage cells, making it possible to evaluate the effects of substituent peripheral groups. In these studies, other two new compounds than H2bdtc whose activity is known, were considered promising, H2bt and H2bmt, having superior activity, CC50try values 9.91 and 6.85 µM, respectively, compared with benznidazole used as reference (CC50try = 10.6 µM). The compounds also show selective with CC50> 100 µM for J774 macrophage cells. In the complexation studies with GaIII using H2bdtc it is possible to obtain two new complex, varying the reaction conditions, being a mononuclear, [Ga(bdtc)(Hbdtc)]·CH3OH, and other dinuclear [Ga2(bdtc)2(?-OCH3)2]·CH2Cl2, which were characterized both in solution and in solid state, having their structures determined by single crystals X-ray diffraction. Both having GaIII pentacoordenate, with distortion of coordination geometry between trigonal bipyramidal and square pyramidal. When the ligand bdtc2- coordinated dianionic the form is O,N,S-tridentate, unlike the form S,N-bidentate was observed for the DTC when coordinated monoanionic as bdtc1-.

O presente trabalho consiste na síntese, caracterização e estudos de atividade tripanocida de doze compostos, sendo oito tiossemicarbazonas (TSCs) e quatro ditiocarbazatos (DTCs), contendo anel pirazolínico em suas estruturas, assim como no estudo da formação de complexos de um DTC com GaIII. As TSCs e os DTCs foram obtidos em reações de condensação envolvendo uma β-dicetona e uma tiossemicarbazida ou ditiocarbazato, respectivamente. A partir de 1-fenil-1,3-butanodiona (benzoilacetona) e 4-R-tiossemicarbazida, foram obtidas as TSCs de nome 5-hidroxi-3-metil-5-fenil-pirazolina-1-(4-R-tiossemicarbazona), identificados como H2bt, H2bmt, H2bet e H2bpt, com R = H, Me, Et e Ph, respectivamente. Mudando a β-dicetona para 4,4,4-trifluoro-1-fenil-1,3-butanodiona, foram obtidas as TSCs de nome 5-hidroxi-3-fenil-5-trifluorometil-pirazolina-1-(4-R-tiossemicarbazona), identificados como H2ft, H2fmt, H2fet e H2fpt, com R = H, Me, Et e Ph, respectivamente. De modo similar, os DTCs de nome 5-hidroxi-3-metil-5-fenil-pirazolina-1-(S-p-R-benzilditiocarbazato), H2bdtc e H2mbdtc, para R = H e OMe, respectivamente, foram obtidos a partir de benzoilacetona e S-p-R-benzilditiocarbazato, enquanto que os DTCs de nome 5-hidroxi-3-fenil-5-trifluorometil-pirazolina-1-(S-p-R-benzilditiocarbazato), H2fdtc e H2mfdtc, para R = H e OMe, respectivamente, formaram-se quando a 4,4,4-trifluoro-1-fenil-1,3-butanodiona foi a β-dicetona utilizada. Os compostos foram caracterizados por diversas técnicas, que incluíram análise elementar, espectroscopia na região do infravermelho (IV), espectrometria de massas, ressonância magnética nuclear de hidrogênio e flúor (RMN1H e 19F) e difração de raios X em monocristal. As TSCs e os DTCs foram avaliados quanto a suas atividades anti-T. cruzi e citotoxicidade frente a células de macrófagos J774, sendo possível avaliar as influências dos grupos periféricos substituintes. Nestes estudos, dois novos compostos, além do H2bdtc, cuja atividade é conhecida, se mostraram promissores, H2bt e H2bmt, apresentando valores de atividade tripanocida CC50try = 9,91 e 6,85 µM, respectivamente, para a cepa Y na forma tripomastigota do T. cruzi. Ambos foram superiores ao benzonidazol, utilizado como referência (CC50try = 10,6 µM). Os compostos também se mostraram seletivos, com CC50 > 100 µM para células de macrófago J774. Estudos de complexação com GaIII utilizando H2bdtc como agente complexante levaram a dois novos complexos, variando-se as condições reacionais, sendo um mononuclear, [Ga(bdtc)(Hbdtc)].CH3OH, e um dinuclear, [Ga2(bdtc)2(µOCH3)2].CH2Cl2, os quais foram caracterizados, tanto em solução quanto no estado sólido, tendo tido suas estruturas determinadas por difração de raios X em monocristal. Ambos apresentam centros de GaIII pentacoordenados, com grau de distorção diferenciado, entre uma geometria de coordenação bipiramidal trigonal e piramidal de base quadrada. Quando dianiônico, o bdtc2- coordenou-se O,N,S-tridentado, diferentemente da forma S,N-bidentada observa para o DTC, quando coordenado monoaniônico, como bdtc1-. / The present work describes the synthesis, structural characterization and trypanocidal activity studies of twelve compounds, eight thiosemicarbazones (TSCs) and four dithiocarbazates (DTCs) containing pyrazoline ring in their structures, as well as in the study of complex formation of a DTC with GaIII. The TSCs and DTCs were obtained from condensation reactions involving a & beta;-diketone and a dithiocarbazate or thiosemicarbazide, respectively. From 1-phenyl-1,3-butanedione (benzoylacetone) and 4-R-thiosemicarbazide were obtained TSCs the name 5-hydroxy-3-methyl-5-phenyl-pyrazoline-1-(4-R-thiosemicarbazone), identified as H2bt, H2bmt, H2bet and H2bpt, R = H, Me, Et, Ph, respectively. Changing the & beta;-diketone for 4,4,4-trifluoro-1-phenyl-1,3-butanedione result in TSCs the name 5-hydroxy-3-phenyl-5-trifluoromethyl-pyrazoline-1-(4-R-thiosemicarbazone), identified as H2ft, H2fmt, H2fet and H2fpt, R = H, Me, Et, Ph, respectively. Similarly, the DTCs with name 5-hydroxy-3-methyl-5-phenyl-pyrazoline-1-(S-p-R-benzyldithiocarbazate), H2bdtc and H2mbdtc to R = H and OMe, respectively, were obtained from benzoylacetone and S-p-R-benzyldithiocarbazate, while DTCs 5-hydroxy-3-phenyl-5-trifluoromethyl-pyrazoline-1-(S-p-R-benzyldithiocarbazate), H2fdtc and H2mfdtc to R = H and OMe, respectively, are formed with 4,4,4-trifluoro-1-phenyl-1,3-butanedione. The compounds were characterized by various techniques such as elemental analysis, infrared spectroscopy (IR), mass spectrometry, nuclear magnetic resonance of hydrogen and fluorine (1H and 19F NMR) and single crystals X-ray diffraction. The TSCs and DTCs were evaluated for their anti-T. cruzi activity and cytotoxicity against macrophage cells, making it possible to evaluate the effects of substituent peripheral groups. In these studies, other two new compounds than H2bdtc whose activity is known, were considered promising, H2bt and H2bmt, having superior activity, CC50try values 9.91 and 6.85 µM, respectively, compared with benznidazole used as reference (CC50try = 10.6 µM). The compounds also show selective with CC50> 100 µM for J774 macrophage cells. In the complexation studies with GaIII using H2bdtc it is possible to obtain two new complex, varying the reaction conditions, being a mononuclear, [Ga(bdtc)(Hbdtc)]·CH3OH, and other dinuclear [Ga2(bdtc)2(µ OCH3)2].CH2Cl2, which were characterized both in solution and in solid state, having their structures determined by single crystals X-ray diffraction. Both having GaIII pentacoordenate, with distortion of coordination geometry between trigonal bipyramidal and square pyramidal. When the ligand bdtc2- coordinated dianionic the form is O,N,S-tridentate, unlike the form S,N-bidentate was observed for the DTC when coordinated monoanionic as bdtc1-.The present work describes the synthesis, structural characterization and trypanocidal activity studies of twelve compounds, eight thiosemicarbazones (TSCs) and four dithiocarbazates (DTCs) containing pyrazoline ring in their structures, as well as in the study of complex formation of a DTC with GaIII. The TSCs and DTCs were obtained from condensation reactions involving a ?-diketone and a dithiocarbazate or thiosemicarbazide, respectively. From 1-phenyl-1,3-butanedione (benzoylacetone) and 4-R-thiosemicarbazide were obtained TSCs the name 5-hydroxy-3-methyl-5-phenyl-pyrazoline-1-(4-R-thiosemicarbazone), identified as H2bt, H2bmt, H2bet and H2bpt, R = H, Me, Et, Ph, respectively. Changing the ?-diketone for 4,4,4-trifluoro-1-phenyl-1,3-butanedione result in TSCs the name 5-hydroxy-3-phenyl-5-trifluoromethyl-pyrazoline-1-(4-R-thiosemicarbazone), identified as H2ft, H2fmt, H2fet and H2fpt, R = H, Me, Et, Ph, respectively. Similarly, the DTCs with name 5-hydroxy-3-methyl-5-phenyl-pyrazoline-1-(S-p-R-benzyldithiocarbazate), H2bdtc and H2mbdtc to R = H and OMe, respectively, were obtained from benzoylacetone and S-p-R-benzyldithiocarbazate, while DTCs 5-hydroxy-3-phenyl-5-trifluoromethyl-pyrazoline-1-(S-p-R-benzyldithiocarbazate), H2fdtc and H2mfdtc to R = H and OMe, respectively, are formed with 4,4,4-trifluoro-1-phenyl-1,3-butanedione. The compounds were characterized by various techniques such as elemental analysis, infrared spectroscopy (IR), mass spectrometry, nuclear magnetic resonance of hydrogen and fluorine (1H and 19F NMR) and single crystals X-ray diffraction. The TSCs and DTCs were evaluated for their anti-T. cruzi activity and cytotoxicity against macrophage cells, making it possible to evaluate the effects of substituent peripheral groups. In these studies, other two new compounds than H2bdtc whose activity is known, were considered promising, H2bt and H2bmt, having superior activity, CC50try values 9.91 and 6.85 µM, respectively, compared with benznidazole used as reference (CC50try = 10.6 µM). The compounds also show selective with CC50> 100 µM for J774 macrophage cells. In the complexation studies with GaIII using H2bdtc it is possible to obtain two new complex, varying the reaction conditions, being a mononuclear, [Ga(bdtc)(Hbdtc)]·CH3OH, and other dinuclear [Ga2(bdtc)2(?-OCH3)2]·CH2Cl2, which were characterized both in solution and in solid state, having their structures determined by single crystals X-ray diffraction. Both having GaIII pentacoordenate, with distortion of coordination geometry between trigonal bipyramidal and square pyramidal. When the ligand bdtc2- coordinated dianionic the form is O,N,S-tridentate, unlike the form S,N-bidentate was observed for the DTC when coordinated monoanionic as bdtc1-.

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / No presente trabalho é descrita a obtenção de hidrazonas derivadas de isoniazida e de seus complexos de cobre(II) e gálio(III) candidatos a protótipos de fármacos antituberculose e antitumoral. Para investigar o efeito da modificação química sobre as bioatividades do fármaco isoniazida, foram preparados cinco derivados hidrazônicos: 2-piridinocarboxaldeído isonicotinoil hidrazona (HPCIH, 1), 2-acetilpiridina isonicotinoil hidrazona (HAPIH, 2), 2-benzoilpiridina isonicotinoil hidrazona (HBPIH, 3), 2-piridinoformamida isonicotinoil hidrazona (HPAmIH, 4) e 2-pirazinoformamida isonicotinoil hidrazona (HPzAmIH, 5), sendo o composto HPAmIH (4) inédito. Análises de ponto de fusão, espectroscopia de infravermelho (IV), espectrometria de massas, ressonância magnética nuclear (RMN), análise elementar e termogravimetria confirmaram a obtenção e pureza das hidrazonas. Foi determinada ainda a estrutura de HPCIH (1) por difração de raios X de monocristal. Essas moléculas foram efetivas em inibir o crescimento de cepas de micobactérias Mycobacterium tuberculosis H37Rv (ATCC 27294) nas concentrações testadas, com exceção de HPzAmIH (5). As hidrazonas HAPIH (2) e HBPIH (3) foram os compostos orgânicos mais ativos (concentração inibitória mínima, CIM = 0,625 g/mL), apresentando atividade antimicobacteriana apenas duas vezes inferior à do fármaco isoniazida.Quanto à ação contra células tumorais, as hidrazonas HAPIH (2) e HBPIH (3) foram as mais potentes contra as linhagens OVCAR-8 (tumor de ovário - humano), HCT-116 (tumor de cólon - humano) e SF-295 (glioblastoma humano), com inibições de 34,98 a 98,63% do crescimento celular, na concentração de 5 g/mL, enquanto que a isoniazida não foi efetiva contra as linhagens estudadas. Para avaliar o efeito da coordenação a metais sobre a atividade farmacológica das hidrazonas, foram sintetizados os complexos de cobre(II) e gálio(III), sendo todos inéditos: [Cu(HPCIH)Cl2]∙H2O (6), [Cu(HAPIH)Cl2]∙H2O (7), [Cu2(HBPIH)2Cl2]Cl2∙4H2O(8), [Cu(HPAmIH)Cl2]∙H2O (9), [Cu(HPzAmIH)Cl2]∙H2O (10), [Ga(HPCIH)2](NO3)32H2O (11), [Ga(HAPIH)(APIH)](NO3)22H2O (12), [Ga(HPAmIH)(PAmIH)](NO3)22H2O(13) e [Ga(HPzAmIH)(PzAmIH)](NO3)2H2O (14). Os complexos foram caracterizados por espectroscopia de IV, análise elementar, condutivimetria, RMN e espectroscopia eletrônica. Em geral, os complexos também demonstraram ação contra M. tuberculosis, sendo que apenas para 6, 9, 10 e 14 foi verificada melhor atividade em relação às hidrazonas livres. Os complexos metálicos foram tanto quanto ou mais ativos contra as células tumorais OVCAR-8, HCT-116 e SF-295 do que as hidrazonas livres. Merecem destaque os complexos 79 e 12, que apresentaram inibição de crescimento celular de 72,2100%, na concentração de 5 g/mL. Os resultados demonstram portanto que em geral os compostos 114 são menos ativos do que a isoniazida contra M. tuberculosis, enquanto que a modificação química do fármaco, formando-se hidrazonas com posterior complexação cobre(II) e gálio(III) constituíram uma estratégia interessante na obtenção de compostos mais potentes contra células tumorais / In this work we describe the synthesis of isoniazide-derived hydrazones and their copper(II) and gallium(III) complexes candidates for drug prototypes to treat antituberculosis and cancer. Five hidrazone derivatives have been prepared in order to investigate the effect of chemical modification on the bioactivities of the drug isoniazid: 2-pyridinecarboxaldehyde isonicotinoyl hydrazone (HPCIH, 1), 2-acetylpyridine isonicotinoyl hydrazone (HAPIH, 2), 2-benzoylpyridine isonicotinoyl hydrazone (HBPIH, 3), 2-pyridineformamide isonicotinoyl hydrazone (HPAmIH, 4) and pyrazineformamide 2-isonicotinoyl hydrazone (HPzAmIH, 5), being HPAmIH (4) unpublished. Melting point, infrared spectroscopy (IR), mass spectrometry, nuclear magnetic resonance (NMR), elemental analysis and thermogravimetric analysis has confirmed the formation of hydrazones as well as its purity. All compounds have been effective in inhibiting the growth of Mycobacterium tuberculosis H37Rv (ATCC 27294) mycobacteria strains in the tested concentrations, except HPzAmIH (5). The hydrazones HAPIH (2) and HBPIH (3) have been the most active compounds (minimum inhibitory concentration, MIC = 0.625 g/mL), which have presented the antimycobacterial activity only two times lower than isoniazid drug. In relation to the action against tumor cells, the hydrazones HAPIH (2) and HBPIH (3) have been the most potent compounds against the cell lines OVCAR-8 (ovarian tumor - human), HCT-116 (colon tumor - human) and SF-295 (glioblastoma - human), with inhibitions from 34.98 to 98.63% of cellular growth at a concentration of 5 g/mL. Isoniazid, in turn, hasnt been effective against all cell lines studied. To evaluate the effect of coordinating the metal on the pharmacological activity of hydrazones, complexes of copper (II) and gallium (III) have been synthesized, being all novel compounds: [Cu(HPCIH)Cl2]∙H2O (6), [Cu(HAPIH)Cl2]∙H2O (7), [Cu2(HBPIH)2Cl2]Cl2∙4H2O(8), [Cu(HPAmIH)Cl2]∙H2O (9), [Cu(HPzAmIH)Cl2]∙H2O (10), [Ga(HPCIH)2](NO3)32H2O (11), [Ga(HAPIH)(APIH)](NO3)22H2O (12), [Ga(HPAmIH)(PAmIH)](NO3)22H2O (13) and [Ga(HPzAmIH)(PzAmIH)](NO3)2H2O (14).The complexes have been characterized by IR spectroscopy, NMR, elemental analysis, conductivimetry and electron spectroscopy. In general, these complexes have also shown action against M. tuberculosis, whereas only 6, 9, 10 and 14 have demonstrated better activity than the free hydrazones. The metal complexes have been equally or more active against human the cancer cell lines OVCAR-8, HCT-116 and SF-295 than the free hydrazones. The complexes 79 and 12 deserve to be highlighted, which have shown 72.2100% inhibition of cell growth in the 5 g/mL concentration. The results therefore demonstrate that in general compounds 114 are less active than isoniazid against M. tuberculosis, while chemical modification of the drug, forming hydrazones and subsequent complexation with the copper (II) and gallium(III) metal ions have been an interesting strategy to obtain compounds more potent against tumor cells

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / No presente trabalho é descrita a obtenção de hidrazonas derivadas de isoniazida e de seus complexos de cobre(II) e gálio(III) candidatos a protótipos de fármacos antituberculose e antitumoral. Para investigar o efeito da modificação química sobre as bioatividades do fármaco isoniazida, foram preparados cinco derivados hidrazônicos: 2-piridinocarboxaldeído isonicotinoil hidrazona (HPCIH, 1), 2-acetilpiridina isonicotinoil hidrazona (HAPIH, 2), 2-benzoilpiridina isonicotinoil hidrazona (HBPIH, 3), 2-piridinoformamida isonicotinoil hidrazona (HPAmIH, 4) e 2-pirazinoformamida isonicotinoil hidrazona (HPzAmIH, 5), sendo o composto HPAmIH (4) inédito. Análises de ponto de fusão, espectroscopia de infravermelho (IV), espectrometria de massas, ressonância magnética nuclear (RMN), análise elementar e termogravimetria confirmaram a obtenção e pureza das hidrazonas. Foi determinada ainda a estrutura de HPCIH (1) por difração de raios X de monocristal. Essas moléculas foram efetivas em inibir o crescimento de cepas de micobactérias Mycobacterium tuberculosis H37Rv (ATCC 27294) nas concentrações testadas, com exceção de HPzAmIH (5). As hidrazonas HAPIH (2) e HBPIH (3) foram os compostos orgânicos mais ativos (concentração inibitória mínima, CIM = 0,625 g/mL), apresentando atividade antimicobacteriana apenas duas vezes inferior à do fármaco isoniazida.Quanto à ação contra células tumorais, as hidrazonas HAPIH (2) e HBPIH (3) foram as mais potentes contra as linhagens OVCAR-8 (tumor de ovário - humano), HCT-116 (tumor de cólon - humano) e SF-295 (glioblastoma humano), com inibições de 34,98 a 98,63% do crescimento celular, na concentração de 5 g/mL, enquanto que a isoniazida não foi efetiva contra as linhagens estudadas. Para avaliar o efeito da coordenação a metais sobre a atividade farmacológica das hidrazonas, foram sintetizados os complexos de cobre(II) e gálio(III), sendo todos inéditos: [Cu(HPCIH)Cl2]∙H2O (6), [Cu(HAPIH)Cl2]∙H2O (7), [Cu2(HBPIH)2Cl2]Cl2∙4H2O(8), [Cu(HPAmIH)Cl2]∙H2O (9), [Cu(HPzAmIH)Cl2]∙H2O (10), [Ga(HPCIH)2](NO3)32H2O (11), [Ga(HAPIH)(APIH)](NO3)22H2O (12), [Ga(HPAmIH)(PAmIH)](NO3)22H2O(13) e [Ga(HPzAmIH)(PzAmIH)](NO3)2H2O (14). Os complexos foram caracterizados por espectroscopia de IV, análise elementar, condutivimetria, RMN e espectroscopia eletrônica. Em geral, os complexos também demonstraram ação contra M. tuberculosis, sendo que apenas para 6, 9, 10 e 14 foi verificada melhor atividade em relação às hidrazonas livres. Os complexos metálicos foram tanto quanto ou mais ativos contra as células tumorais OVCAR-8, HCT-116 e SF-295 do que as hidrazonas livres. Merecem destaque os complexos 79 e 12, que apresentaram inibição de crescimento celular de 72,2100%, na concentração de 5 g/mL. Os resultados demonstram portanto que em geral os compostos 114 são menos ativos do que a isoniazida contra M. tuberculosis, enquanto que a modificação química do fármaco, formando-se hidrazonas com posterior complexação cobre(II) e gálio(III) constituíram uma estratégia interessante na obtenção de compostos mais potentes contra células tumorais / In this work we describe the synthesis of isoniazide-derived hydrazones and their copper(II) and gallium(III) complexes candidates for drug prototypes to treat antituberculosis and cancer. Five hidrazone derivatives have been prepared in order to investigate the effect of chemical modification on the bioactivities of the drug isoniazid: 2-pyridinecarboxaldehyde isonicotinoyl hydrazone (HPCIH, 1), 2-acetylpyridine isonicotinoyl hydrazone (HAPIH, 2), 2-benzoylpyridine isonicotinoyl hydrazone (HBPIH, 3), 2-pyridineformamide isonicotinoyl hydrazone (HPAmIH, 4) and pyrazineformamide 2-isonicotinoyl hydrazone (HPzAmIH, 5), being HPAmIH (4) unpublished. Melting point, infrared spectroscopy (IR), mass spectrometry, nuclear magnetic resonance (NMR), elemental analysis and thermogravimetric analysis has confirmed the formation of hydrazones as well as its purity. All compounds have been effective in inhibiting the growth of Mycobacterium tuberculosis H37Rv (ATCC 27294) mycobacteria strains in the tested concentrations, except HPzAmIH (5). The hydrazones HAPIH (2) and HBPIH (3) have been the most active compounds (minimum inhibitory concentration, MIC = 0.625 g/mL), which have presented the antimycobacterial activity only two times lower than isoniazid drug. In relation to the action against tumor cells, the hydrazones HAPIH (2) and HBPIH (3) have been the most potent compounds against the cell lines OVCAR-8 (ovarian tumor - human), HCT-116 (colon tumor - human) and SF-295 (glioblastoma - human), with inhibitions from 34.98 to 98.63% of cellular growth at a concentration of 5 g/mL. Isoniazid, in turn, hasnt been effective against all cell lines studied. To evaluate the effect of coordinating the metal on the pharmacological activity of hydrazones, complexes of copper (II) and gallium (III) have been synthesized, being all novel compounds: [Cu(HPCIH)Cl2]∙H2O (6), [Cu(HAPIH)Cl2]∙H2O (7), [Cu2(HBPIH)2Cl2]Cl2∙4H2O(8), [Cu(HPAmIH)Cl2]∙H2O (9), [Cu(HPzAmIH)Cl2]∙H2O (10), [Ga(HPCIH)2](NO3)32H2O (11), [Ga(HAPIH)(APIH)](NO3)22H2O (12), [Ga(HPAmIH)(PAmIH)](NO3)22H2O (13) and [Ga(HPzAmIH)(PzAmIH)](NO3)2H2O (14).The complexes have been characterized by IR spectroscopy, NMR, elemental analysis, conductivimetry and electron spectroscopy. In general, these complexes have also shown action against M. tuberculosis, whereas only 6, 9, 10 and 14 have demonstrated better activity than the free hydrazones. The metal complexes have been equally or more active against human the cancer cell lines OVCAR-8, HCT-116 and SF-295 than the free hydrazones. The complexes 79 and 12 deserve to be highlighted, which have shown 72.2100% inhibition of cell growth in the 5 g/mL concentration. The results therefore demonstrate that in general compounds 114 are less active than isoniazid against M. tuberculosis, while chemical modification of the drug, forming hydrazones and subsequent complexation with the copper (II) and gallium(III) metal ions have been an interesting strategy to obtain compounds more potent against tumor cells