Síntese, caracterização e estudo da ação antituberculose e citotóxica de hidrazonas derivadas de isoniazida e de seus complexos de cobre(II) e gálio(III)
Autor(a) principal: | |
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Data de Publicação: | 2015 |
Tipo de documento: | Dissertação |
Idioma: | por |
Título da fonte: | Biblioteca Digital de Teses e Dissertações da UERJ |
Texto Completo: | http://www.bdtd.uerj.br/handle/1/15796 |
Resumo: | 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isonicotinoyl hydrazone (HPAmIH, 4) and pyrazineformamide 2-isonicotinoyl hydrazone (HPzAmIH, 5), being HPAmIH (4) unpublished.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, hasn t 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]∙½H2O (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 |
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Lessa, Josane Alveshttp://lattes.cnpq.br/8402296847454322Cruz, Mauricio Tavares de Macedohttp://lattes.cnpq.br/1753494541981720Casellato, Annelisehttp://lattes.cnpq.br/6666301937868490http://lattes.cnpq.br/7822103307743205Firmino, Gisele dos Santos Silva2021-01-07T19:03:17Z2015-05-132015-01-30FIRMINO, Gisele dos Santos Silva. Síntese, caracterização e estudo da ação antituberculose e citotóxica de hidrazonas derivadas de isoniazida e de seus complexos de cobre(II) e gálio(III). 2015. 122 f. Dissertação (Mestrado em Química ambiental; Polímeros) - Universidade do Estado do Rio de Janeiro, Rio de Janeiro, 2015.http://www.bdtd.uerj.br/handle/1/15796In 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, hasn t 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]∙½H2O (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 cellsNo 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]∙½H2O (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 tumoraisSubmitted by Boris Flegr (boris@uerj.br) on 2021-01-07T19:03:17Z No. of bitstreams: 1 Gisele dos Santos Silva Firmino.pdf: 2331486 bytes, checksum: c0d7f2a251ae9b96583c77f11f2182b5 (MD5)Made available in DSpace on 2021-01-07T19:03:17Z (GMT). No. of bitstreams: 1 Gisele dos Santos Silva Firmino.pdf: 2331486 bytes, checksum: c0d7f2a251ae9b96583c77f11f2182b5 (MD5) Previous issue date: 2015-01-30Coordenação de Aperfeiçoamento de Pessoal de Nível Superiorapplication/pdfporUniversidade do Estado do Rio de JaneiroPrograma de Pós-Graduação em QuímicaUERJBRCentro de Tecnologia e Ciências::Instituto de QuímicaHydrazonesisoniazidgallium(III) complexescopper(II) complexestuberculosiscytotoxic activityHidrazonasisoniazidacomplexos de gálio(III)complexos de cobre(II)tuberculoseatividade citotóxicaCNPQ::CIENCIAS EXATAS E DA TERRA::QUIMICA::QUIMICA INORGANICASíntese, caracterização e estudo da ação antituberculose e citotóxica de hidrazonas derivadas de isoniazida e de seus complexos de cobre(II) e gálio(III)Synthesis, characterization and study of antituberculosis and cytotoxic action of isoniazid-derived hydrazones and its copper(II) and gallium(III) complexesinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/masterThesisinfo:eu-repo/semantics/openAccessreponame:Biblioteca Digital de Teses e Dissertações da UERJinstname:Universidade do Estado do Rio de Janeiro (UERJ)instacron:UERJORIGINALGisele dos Santos Silva Firmino.pdfapplication/pdf2331486http://www.bdtd.uerj.br/bitstream/1/15796/1/Gisele+dos+Santos+Silva+Firmino.pdfc0d7f2a251ae9b96583c77f11f2182b5MD511/157962024-02-27 14:47:46.253oai:www.bdtd.uerj.br:1/15796Biblioteca Digital de Teses e Dissertaçõeshttp://www.bdtd.uerj.br/PUBhttps://www.bdtd.uerj.br:8443/oai/requestbdtd.suporte@uerj.bropendoar:29032024-02-27T17:47:46Biblioteca Digital de Teses e Dissertações da UERJ - Universidade do Estado do Rio de Janeiro (UERJ)false |
dc.title.por.fl_str_mv |
Síntese, caracterização e estudo da ação antituberculose e citotóxica de hidrazonas derivadas de isoniazida e de seus complexos de cobre(II) e gálio(III) |
dc.title.alternative.eng.fl_str_mv |
Synthesis, characterization and study of antituberculosis and cytotoxic action of isoniazid-derived hydrazones and its copper(II) and gallium(III) complexes |
title |
Síntese, caracterização e estudo da ação antituberculose e citotóxica de hidrazonas derivadas de isoniazida e de seus complexos de cobre(II) e gálio(III) |
spellingShingle |
Síntese, caracterização e estudo da ação antituberculose e citotóxica de hidrazonas derivadas de isoniazida e de seus complexos de cobre(II) e gálio(III) Firmino, Gisele dos Santos Silva Hydrazones isoniazid gallium(III) complexes copper(II) complexes tuberculosis cytotoxic activity Hidrazonas isoniazida complexos de gálio(III) complexos de cobre(II) tuberculose atividade citotóxica CNPQ::CIENCIAS EXATAS E DA TERRA::QUIMICA::QUIMICA INORGANICA |
title_short |
Síntese, caracterização e estudo da ação antituberculose e citotóxica de hidrazonas derivadas de isoniazida e de seus complexos de cobre(II) e gálio(III) |
title_full |
Síntese, caracterização e estudo da ação antituberculose e citotóxica de hidrazonas derivadas de isoniazida e de seus complexos de cobre(II) e gálio(III) |
title_fullStr |
Síntese, caracterização e estudo da ação antituberculose e citotóxica de hidrazonas derivadas de isoniazida e de seus complexos de cobre(II) e gálio(III) |
title_full_unstemmed |
Síntese, caracterização e estudo da ação antituberculose e citotóxica de hidrazonas derivadas de isoniazida e de seus complexos de cobre(II) e gálio(III) |
title_sort |
Síntese, caracterização e estudo da ação antituberculose e citotóxica de hidrazonas derivadas de isoniazida e de seus complexos de cobre(II) e gálio(III) |
author |
Firmino, Gisele dos Santos Silva |
author_facet |
Firmino, Gisele dos Santos Silva |
author_role |
author |
dc.contributor.advisor1.fl_str_mv |
Lessa, Josane Alves |
dc.contributor.advisor1Lattes.fl_str_mv |
http://lattes.cnpq.br/8402296847454322 |
dc.contributor.referee1.fl_str_mv |
Cruz, Mauricio Tavares de Macedo |
dc.contributor.referee1Lattes.fl_str_mv |
http://lattes.cnpq.br/1753494541981720 |
dc.contributor.referee2.fl_str_mv |
Casellato, Annelise |
dc.contributor.referee2Lattes.fl_str_mv |
http://lattes.cnpq.br/6666301937868490 |
dc.contributor.authorLattes.fl_str_mv |
http://lattes.cnpq.br/7822103307743205 |
dc.contributor.author.fl_str_mv |
Firmino, Gisele dos Santos Silva |
contributor_str_mv |
Lessa, Josane Alves Cruz, Mauricio Tavares de Macedo Casellato, Annelise |
dc.subject.eng.fl_str_mv |
Hydrazones isoniazid gallium(III) complexes copper(II) complexes tuberculosis cytotoxic activity |
topic |
Hydrazones isoniazid gallium(III) complexes copper(II) complexes tuberculosis cytotoxic activity Hidrazonas isoniazida complexos de gálio(III) complexos de cobre(II) tuberculose atividade citotóxica CNPQ::CIENCIAS EXATAS E DA TERRA::QUIMICA::QUIMICA INORGANICA |
dc.subject.por.fl_str_mv |
Hidrazonas isoniazida complexos de gálio(III) complexos de cobre(II) tuberculose atividade citotóxica |
dc.subject.cnpq.fl_str_mv |
CNPQ::CIENCIAS EXATAS E DA TERRA::QUIMICA::QUIMICA INORGANICA |
description |
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, hasn t 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]∙½H2O (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 |
publishDate |
2015 |
dc.date.available.fl_str_mv |
2015-05-13 |
dc.date.issued.fl_str_mv |
2015-01-30 |
dc.date.accessioned.fl_str_mv |
2021-01-07T19:03:17Z |
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info:eu-repo/semantics/publishedVersion |
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info:eu-repo/semantics/masterThesis |
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masterThesis |
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publishedVersion |
dc.identifier.citation.fl_str_mv |
FIRMINO, Gisele dos Santos Silva. Síntese, caracterização e estudo da ação antituberculose e citotóxica de hidrazonas derivadas de isoniazida e de seus complexos de cobre(II) e gálio(III). 2015. 122 f. Dissertação (Mestrado em Química ambiental; Polímeros) - Universidade do Estado do Rio de Janeiro, Rio de Janeiro, 2015. |
dc.identifier.uri.fl_str_mv |
http://www.bdtd.uerj.br/handle/1/15796 |
identifier_str_mv |
FIRMINO, Gisele dos Santos Silva. Síntese, caracterização e estudo da ação antituberculose e citotóxica de hidrazonas derivadas de isoniazida e de seus complexos de cobre(II) e gálio(III). 2015. 122 f. Dissertação (Mestrado em Química ambiental; Polímeros) - Universidade do Estado do Rio de Janeiro, Rio de Janeiro, 2015. |
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http://www.bdtd.uerj.br/handle/1/15796 |
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Universidade do Estado do Rio de Janeiro |
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BR |
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Centro de Tecnologia e Ciências::Instituto de Química |
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Universidade do Estado do Rio de Janeiro |
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