Sinapatos sintéticos como candidatos a protótipos de fármacos antifúngicos
Autor(a) principal: | |
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Data de Publicação: | 2022 |
Tipo de documento: | Dissertação |
Idioma: | por |
Título da fonte: | Biblioteca Digital de Teses e Dissertações da UFPB |
Texto Completo: | https://repositorio.ufpb.br/jspui/handle/123456789/26283 |
Resumo: | In recent years there has been an increase in studies on fungi, due to the high incidence of diseases caused by them, demonstrating that today these microorganisms are important causes of mortality in humans, reaching millions of people per year in the world. Due to the indiscriminate use of drugs indicated for the treatment of candidiasis, the occurrence of fungal resistance is observed, requiring the development of new pharmacotherapeutic alternatives. Phenolic acids, such as sinapic acid, constitute groups of aromatic carboxylic acids widely found in plants, which present structural diversity and several described biological activities, with emphasis on antimicrobial activity, such as the anti-Candida action. Thus, the present study aimed to prepare a collection of eleven synapates (1-11), structurally related, and to evaluate the antifungal activity of these compounds against two species of fungi, C. albicans and C. tropicalis, and to establish the structure-activity relationship of the substances evaluated. Synthetic derivatives were prepared via Fischer esterification, Steglich reaction, and esterifications with aryl halides in the presence of triethylamine. In the structural characterization, the spectroscopic techniques of Infrared, Nuclear Magnetic Resonance of 1H and 13C were used. Products were obtained in yields of 13.9–82.3%. Among the eleven compounds obtained, six are unpublished in the literature (5, 7-11). The antifungal test was performed by determining the minimum inhibitory concentration (MIC) and establishing the minimum fungicidal concentration (CFM), including the investigation of the mechanism of action (sorbitol and ergosterol). When analyzing the results, it can be seen that esters 4, 5 and 8 showed a fungicidal effect with values of MIC = CFM = 213.8 μM and 53,4 μM, MIC = CFM = 25.3 μM and 25.3 μM, MIC = CFM = 43.8 μM and 175,3 μM against C. albicans and C. tropicalis, respectively. It was found through the ratio (CFM/MIC<4), that the molecules exerted a fungicidal effect. Regarding the structural characteristics of the esters on the antifungal bioactivity, the importance of the medium alkyl chains and the aryl substituent with a large alkyl group in the para position of the ring was evidenced. According to the ergosterol test it is suggested that the mechanism of action occurs in the plasma membrane of the fungal cell. The in silico analysis on pharmacokinetic and toxicological prediction suggested that the compounds are not lethal, carcinogenic and multagenic, with 1 and 3 being hepatotoxic and immunotoxic, while the others showed only cytotoxicity. As for absorption, all showed good water solubility, which indicates that they can be administered orally. Therefore, it was possible to establish chemical characteristics that can serve as a reference for the advancement in the development of new antifungal compounds with better biological action against Candida species. |
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Sinapatos sintéticos como candidatos a protótipos de fármacos antifúngicosÁcido sinápicoRelação estrutura-atividadeCandidaAtividade antifúngicaSinapic acidStructure-activity relationshipAntifungal activityCNPQ::CIENCIAS BIOLOGICAS::FARMACOLOGIAIn recent years there has been an increase in studies on fungi, due to the high incidence of diseases caused by them, demonstrating that today these microorganisms are important causes of mortality in humans, reaching millions of people per year in the world. Due to the indiscriminate use of drugs indicated for the treatment of candidiasis, the occurrence of fungal resistance is observed, requiring the development of new pharmacotherapeutic alternatives. Phenolic acids, such as sinapic acid, constitute groups of aromatic carboxylic acids widely found in plants, which present structural diversity and several described biological activities, with emphasis on antimicrobial activity, such as the anti-Candida action. Thus, the present study aimed to prepare a collection of eleven synapates (1-11), structurally related, and to evaluate the antifungal activity of these compounds against two species of fungi, C. albicans and C. tropicalis, and to establish the structure-activity relationship of the substances evaluated. Synthetic derivatives were prepared via Fischer esterification, Steglich reaction, and esterifications with aryl halides in the presence of triethylamine. In the structural characterization, the spectroscopic techniques of Infrared, Nuclear Magnetic Resonance of 1H and 13C were used. Products were obtained in yields of 13.9–82.3%. Among the eleven compounds obtained, six are unpublished in the literature (5, 7-11). The antifungal test was performed by determining the minimum inhibitory concentration (MIC) and establishing the minimum fungicidal concentration (CFM), including the investigation of the mechanism of action (sorbitol and ergosterol). When analyzing the results, it can be seen that esters 4, 5 and 8 showed a fungicidal effect with values of MIC = CFM = 213.8 μM and 53,4 μM, MIC = CFM = 25.3 μM and 25.3 μM, MIC = CFM = 43.8 μM and 175,3 μM against C. albicans and C. tropicalis, respectively. It was found through the ratio (CFM/MIC<4), that the molecules exerted a fungicidal effect. Regarding the structural characteristics of the esters on the antifungal bioactivity, the importance of the medium alkyl chains and the aryl substituent with a large alkyl group in the para position of the ring was evidenced. According to the ergosterol test it is suggested that the mechanism of action occurs in the plasma membrane of the fungal cell. The in silico analysis on pharmacokinetic and toxicological prediction suggested that the compounds are not lethal, carcinogenic and multagenic, with 1 and 3 being hepatotoxic and immunotoxic, while the others showed only cytotoxicity. As for absorption, all showed good water solubility, which indicates that they can be administered orally. Therefore, it was possible to establish chemical characteristics that can serve as a reference for the advancement in the development of new antifungal compounds with better biological action against Candida species.Conselho Nacional de Pesquisa e Desenvolvimento Científico e Tecnológico - CNPqNos últimos anos houve um aumento nos estudos sobre os fungos, devido à alta incidência de doenças causadas pelos mesmos, demonstrando que hoje esses microrganismos são importantes causadores de mortalidade em humanos, atingindo milhões de pessoas por ano no mundo. Devido ao uso indiscriminado dos medicamentos indicados para tratamento de candidíase observa-se a ocorrência de resistência fúngica, sendo necessário o desenvolvimento de novas alternativas farmacoterapêuticas. Os ácidos fenólicos, como o ácido sinápico, constituem um grupo de ácidos carboxílicos aromáticos amplamente encontrados em vegetais, que apresentam diversidade estrutural e várias atividades biológicas descritas, com destaque para atividade antimicrobiana, a exemplo da ação anti-Candida. Desta maneira, o presente estudo teve o objetivo de preparar uma coleção de onze sinapatos (1-11), estruturalmente relacionados, e avaliar a atividade antifúngica desses compostos frente a duas espécies de fungos, C. albicans e C. tropicalis, e estabelecer a relação estrutura-atividade das substâncias avaliadas. Os derivados sintéticos foram preparados via esterificação de Fischer, reação de Steglich, e esterificações com haletos de arila na presença de trietilamina. Na caracterização estrutural utilizou-se as técnicas espectroscópicas de Infravermelho, Ressonância Magnética Nuclear de 1H e 13C. Os produtos foram obtidos com rendimentos de 13,9–82,3%. Dentre os onze compostos obtidos, seis são inéditos na literatura (5, 7-11). Foi realizado o teste antifúngico via determinação da concentração inibitória mínima (CIM) e estabelecida a concentração fungicida mínima (CFM), incluindo a investigação do mecanismo de ação (sorbitol e ergosterol). Ao analisar os resultados pode-se verificar que os ésteres 4, 5 e 8 demonstraram efeito fungicida com valores de CIM = CFM = 213,8 μM e 53,4 μM, CIM = CFM = 25,3 μM e 25,3 μM, CIM = CFM = 43,8 μM e 175,3 μM frente à C. albicans e C. tropicalis, respectivamente. Constatou-se por meio da razão (CFM/CIM<4), que as moléculas exerceram efeito fungicida. No tocante as características estruturais dos ésteres sobre a bioatividade antifúngica, evidenciou-se a importância das cadeias alquílicas médias e substituinte arílico com grupo alquílico volumoso na posição para do anel. De acordo com o teste de ergosterol sugere-se que o mecanismo de ação ocorre na membrana plasmática da célula fúngica. A análise in silico sobre predição farmacocinética e toxicológica sugeriu que os compostos não são letais, carcinogênicos e mutagênicos, sendo o 1 e 3 hepatotóxicos e imunotóxicos, quanto aos demais apresentaram-se apenas citotóxicos. Quanto a absorção, todos apresentaram boa solubilidade em água, o que indica que podem ser admisnistrados por via oral. Portanto, foi possível estabelecer características químicas que podem servir de referência para o avanço no desenvolvimento de novos compostos antifúngicos com melhor ação biológica contra espécies de Candida.Universidade Federal da ParaíbaBrasilFarmacologiaPrograma de Pós-Graduação em Produtos Naturais e Sintéticos BioativosUFPBSousa, Damião Pergentino dehttp://lattes.cnpq.br/3139435097016290Ferreira, Fernando Emanuel de Sousa2023-02-13T17:13:06Z2022-12-042023-02-13T17:13:06Z2022-09-30info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/masterThesishttps://repositorio.ufpb.br/jspui/handle/123456789/26283porAttribution-NoDerivs 3.0 Brazilhttp://creativecommons.org/licenses/by-nd/3.0/br/info:eu-repo/semantics/openAccessreponame:Biblioteca Digital de Teses e Dissertações da UFPBinstname:Universidade Federal da Paraíba (UFPB)instacron:UFPB2023-05-22T13:05:01Zoai:repositorio.ufpb.br:123456789/26283Biblioteca Digital de Teses e Dissertaçõeshttps://repositorio.ufpb.br/PUBhttp://tede.biblioteca.ufpb.br:8080/oai/requestdiretoria@ufpb.br|| diretoria@ufpb.bropendoar:2023-05-22T13:05:01Biblioteca Digital de Teses e Dissertações da UFPB - Universidade Federal da Paraíba (UFPB)false |
dc.title.none.fl_str_mv |
Sinapatos sintéticos como candidatos a protótipos de fármacos antifúngicos |
title |
Sinapatos sintéticos como candidatos a protótipos de fármacos antifúngicos |
spellingShingle |
Sinapatos sintéticos como candidatos a protótipos de fármacos antifúngicos Ferreira, Fernando Emanuel de Sousa Ácido sinápico Relação estrutura-atividade Candida Atividade antifúngica Sinapic acid Structure-activity relationship Antifungal activity CNPQ::CIENCIAS BIOLOGICAS::FARMACOLOGIA |
title_short |
Sinapatos sintéticos como candidatos a protótipos de fármacos antifúngicos |
title_full |
Sinapatos sintéticos como candidatos a protótipos de fármacos antifúngicos |
title_fullStr |
Sinapatos sintéticos como candidatos a protótipos de fármacos antifúngicos |
title_full_unstemmed |
Sinapatos sintéticos como candidatos a protótipos de fármacos antifúngicos |
title_sort |
Sinapatos sintéticos como candidatos a protótipos de fármacos antifúngicos |
author |
Ferreira, Fernando Emanuel de Sousa |
author_facet |
Ferreira, Fernando Emanuel de Sousa |
author_role |
author |
dc.contributor.none.fl_str_mv |
Sousa, Damião Pergentino de http://lattes.cnpq.br/3139435097016290 |
dc.contributor.author.fl_str_mv |
Ferreira, Fernando Emanuel de Sousa |
dc.subject.por.fl_str_mv |
Ácido sinápico Relação estrutura-atividade Candida Atividade antifúngica Sinapic acid Structure-activity relationship Antifungal activity CNPQ::CIENCIAS BIOLOGICAS::FARMACOLOGIA |
topic |
Ácido sinápico Relação estrutura-atividade Candida Atividade antifúngica Sinapic acid Structure-activity relationship Antifungal activity CNPQ::CIENCIAS BIOLOGICAS::FARMACOLOGIA |
description |
In recent years there has been an increase in studies on fungi, due to the high incidence of diseases caused by them, demonstrating that today these microorganisms are important causes of mortality in humans, reaching millions of people per year in the world. Due to the indiscriminate use of drugs indicated for the treatment of candidiasis, the occurrence of fungal resistance is observed, requiring the development of new pharmacotherapeutic alternatives. Phenolic acids, such as sinapic acid, constitute groups of aromatic carboxylic acids widely found in plants, which present structural diversity and several described biological activities, with emphasis on antimicrobial activity, such as the anti-Candida action. Thus, the present study aimed to prepare a collection of eleven synapates (1-11), structurally related, and to evaluate the antifungal activity of these compounds against two species of fungi, C. albicans and C. tropicalis, and to establish the structure-activity relationship of the substances evaluated. Synthetic derivatives were prepared via Fischer esterification, Steglich reaction, and esterifications with aryl halides in the presence of triethylamine. In the structural characterization, the spectroscopic techniques of Infrared, Nuclear Magnetic Resonance of 1H and 13C were used. Products were obtained in yields of 13.9–82.3%. Among the eleven compounds obtained, six are unpublished in the literature (5, 7-11). The antifungal test was performed by determining the minimum inhibitory concentration (MIC) and establishing the minimum fungicidal concentration (CFM), including the investigation of the mechanism of action (sorbitol and ergosterol). When analyzing the results, it can be seen that esters 4, 5 and 8 showed a fungicidal effect with values of MIC = CFM = 213.8 μM and 53,4 μM, MIC = CFM = 25.3 μM and 25.3 μM, MIC = CFM = 43.8 μM and 175,3 μM against C. albicans and C. tropicalis, respectively. It was found through the ratio (CFM/MIC<4), that the molecules exerted a fungicidal effect. Regarding the structural characteristics of the esters on the antifungal bioactivity, the importance of the medium alkyl chains and the aryl substituent with a large alkyl group in the para position of the ring was evidenced. According to the ergosterol test it is suggested that the mechanism of action occurs in the plasma membrane of the fungal cell. The in silico analysis on pharmacokinetic and toxicological prediction suggested that the compounds are not lethal, carcinogenic and multagenic, with 1 and 3 being hepatotoxic and immunotoxic, while the others showed only cytotoxicity. As for absorption, all showed good water solubility, which indicates that they can be administered orally. Therefore, it was possible to establish chemical characteristics that can serve as a reference for the advancement in the development of new antifungal compounds with better biological action against Candida species. |
publishDate |
2022 |
dc.date.none.fl_str_mv |
2022-12-04 2022-09-30 2023-02-13T17:13:06Z 2023-02-13T17:13:06Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/masterThesis |
format |
masterThesis |
status_str |
publishedVersion |
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https://repositorio.ufpb.br/jspui/handle/123456789/26283 |
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https://repositorio.ufpb.br/jspui/handle/123456789/26283 |
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por |
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Attribution-NoDerivs 3.0 Brazil http://creativecommons.org/licenses/by-nd/3.0/br/ info:eu-repo/semantics/openAccess |
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Attribution-NoDerivs 3.0 Brazil http://creativecommons.org/licenses/by-nd/3.0/br/ |
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openAccess |
dc.publisher.none.fl_str_mv |
Universidade Federal da Paraíba Brasil Farmacologia Programa de Pós-Graduação em Produtos Naturais e Sintéticos Bioativos UFPB |
publisher.none.fl_str_mv |
Universidade Federal da Paraíba Brasil Farmacologia Programa de Pós-Graduação em Produtos Naturais e Sintéticos Bioativos UFPB |
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UFPB |
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Biblioteca Digital de Teses e Dissertações da UFPB |
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Biblioteca Digital de Teses e Dissertações da UFPB |
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Biblioteca Digital de Teses e Dissertações da UFPB - Universidade Federal da Paraíba (UFPB) |
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