Avaliação antimicrobiana de 3-nitrobenzamidas sintéticas sobre espécies de Candida e estudos de docking molecular
Autor(a) principal: | |
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Data de Publicação: | 2021 |
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/123456789/22118 |
Resumo: | Fungal infections affect a significant part of the population. It is estimated that around 1 billion people around the world have been affected by some type of fungus. The Candida genus is responsible for several infectious diseases, especially in individuals with compromised immunity. In addition, the emergence of strains resistant to available drugs is worrying, which results in greater difficulties for treatment and association with cases of death. Therefore, the search for new pharmacotherapeutic alternatives is urgent. Nitrobenzene derivatives have several antimicrobial properties, including antifungal action. Thus, in the present study, the antifungal potential of fourteen 3- nitrobenzamide derivatives against Candida species (C. albicans, C. krusei and C. glabrata) was investigated and a structure-activity relationship of the substances evaluated was established. The 3-nitrobenzamide derivatives were prepared using the Schotten-Baumann reaction and were structurally characterized by the techniques of Infrared Spectroscopy and Nuclear Magnetic Resonance of 1H and 13C. The products obtained had yields of 25.2-72.7% and three derivatives from the collection are unprecedented (6, 8 and 10). In antifungal tests, the Minimum Inhibitory Concentration (MIC) was determined using the microdilution technique in 96-well plates and the Minimum Fungicidal Concentration (MFC) in solid culture medium. The possible mode of action was also investigated using the sorbitol and ergosterol assays. Nine compounds showed antifungal activity with MIC values ranging from 39.06 to 1250 µg/mL. Considering the analysis of the CFM/CIM ratio, which presented values in a range of 1 to 3, it can be seen that the derivatives have fungicidal action. Imide 14 showed the best fungicidal effect in the collection against strains of C. albicans, C. krusei and C. glabrata, with MIC and CFM values of 39.06 µg/mL. The data suggest that this compound does not act directly on the fungal cell membrane or through mechanisms that involve cell wall functions. Regarding the structure and antifungal activity relationship, the presence of the dicarbonyl system linked to nitrogen or methylenedioxide potentiates the inhibitory action against fungal species. The molecular docking study shows that seven out of ten targets that share higher docking scores belonging to the ergosterol biosynthetic pathway, with predicted binding to targets: GTP RHO1 binding protein, diphosphomevalonate decarboxylase, squalene monooxygenase, 24-C-sterol methyltransferase and squalene synthase; the small size of the molecule and the carbonyl groups, mainly, were ideal for stabilizing the molecule in the receptors. The analysis, formula made for C. albicans, was also done for C. krusei and C. glabrata species targets, in which there is a small mutation in C. krusei target residues, but which does not alter the compound binding in this target. Given these results, it is concluded that 3-nitrobenzamides are promising compounds for the development of new antifungal drugs against Candida spp. |
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Avaliação antimicrobiana de 3-nitrobenzamidas sintéticas sobre espécies de Candida e estudos de docking molecularAtividade antifúngicaAmidasImidaNitrocompostAntifungal activityAmidesImideNitro compoundCNPQ::CIENCIAS BIOLOGICAS::FARMACOLOGIAFungal infections affect a significant part of the population. It is estimated that around 1 billion people around the world have been affected by some type of fungus. The Candida genus is responsible for several infectious diseases, especially in individuals with compromised immunity. In addition, the emergence of strains resistant to available drugs is worrying, which results in greater difficulties for treatment and association with cases of death. Therefore, the search for new pharmacotherapeutic alternatives is urgent. Nitrobenzene derivatives have several antimicrobial properties, including antifungal action. Thus, in the present study, the antifungal potential of fourteen 3- nitrobenzamide derivatives against Candida species (C. albicans, C. krusei and C. glabrata) was investigated and a structure-activity relationship of the substances evaluated was established. The 3-nitrobenzamide derivatives were prepared using the Schotten-Baumann reaction and were structurally characterized by the techniques of Infrared Spectroscopy and Nuclear Magnetic Resonance of 1H and 13C. The products obtained had yields of 25.2-72.7% and three derivatives from the collection are unprecedented (6, 8 and 10). In antifungal tests, the Minimum Inhibitory Concentration (MIC) was determined using the microdilution technique in 96-well plates and the Minimum Fungicidal Concentration (MFC) in solid culture medium. The possible mode of action was also investigated using the sorbitol and ergosterol assays. Nine compounds showed antifungal activity with MIC values ranging from 39.06 to 1250 µg/mL. Considering the analysis of the CFM/CIM ratio, which presented values in a range of 1 to 3, it can be seen that the derivatives have fungicidal action. Imide 14 showed the best fungicidal effect in the collection against strains of C. albicans, C. krusei and C. glabrata, with MIC and CFM values of 39.06 µg/mL. The data suggest that this compound does not act directly on the fungal cell membrane or through mechanisms that involve cell wall functions. Regarding the structure and antifungal activity relationship, the presence of the dicarbonyl system linked to nitrogen or methylenedioxide potentiates the inhibitory action against fungal species. The molecular docking study shows that seven out of ten targets that share higher docking scores belonging to the ergosterol biosynthetic pathway, with predicted binding to targets: GTP RHO1 binding protein, diphosphomevalonate decarboxylase, squalene monooxygenase, 24-C-sterol methyltransferase and squalene synthase; the small size of the molecule and the carbonyl groups, mainly, were ideal for stabilizing the molecule in the receptors. The analysis, formula made for C. albicans, was also done for C. krusei and C. glabrata species targets, in which there is a small mutation in C. krusei target residues, but which does not alter the compound binding in this target. Given these results, it is concluded that 3-nitrobenzamides are promising compounds for the development of new antifungal drugs against Candida spp.Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPESAs infecções fúngicas acometem uma significativa parte da população. Estima-se que cerca de 1 bilhão de pessoas em todo o mundo já foram afetadas por algum tipo de fungo. O gênero Candida é responsável por diversas doenças infecciosas, especialmente em indivíduos com imunidade comprometida. Além disso, é preocupante o surgimento de cepas resistentes aos fármacos disponíveis, o que resulta em maiores dificuldades para o tratamento e associação a casos de óbito. Portanto, é urgente a busca por novas alternativas farmacoterapêuticas. Derivados nitrobenzenos apresentam diversas propriedades antimicrobianas, incluindo ação antifúngica. Desse modo, no presente estudo investigou-se o potencial antifúngico de catorze derivados 3-nitrobenzamidas frente às espécies do gênero Candida (C. albicans, C. krusei e C. glabrata) e estabeleceu-se uma relação estrutura-atividade das substâncias avaliadas. Os derivados 3-nitrobenzamidas foram preparados utilizando a reação de Schotten-Baumann e foram estruturalmente caracterizados pelas técnicas de Espectroscopia de Infravermelho e Ressonância Magnética Nuclear de 1H e 13C. Os produtos obtidos tiveram rendimentos de 25,2-72,7% e três derivados da coleção são inéditos (6, 8 e 10). Nos testes antifúngicos determinou-se a Concentração Inibitória Mínima (CIM) com a técnica de microdiluição em placas de 96 poços e a Concentração Fungicida Mínima (CFM) em meio de cultura sólido. Também se investigou o possível modo de ação utilizando os ensaios do sorbitol e ergosterol. Nove compostos apresentaram atividade antifúngica com valores de CIM que variaram de 39,06 a 1250 µg/mL. Considerando a análise da razão de CFM/CIM, que apresentou valores em um intervalo de 1 a 3, pode-se verificar que os derivados apresentam ação fungicida. A imida 14 demonstrou o melhor efeito fungicida da coleção frente às cepas de C. albicans, C. krusei e C. glabrata, com valores de CIM e CFM de 39,06 µg/mL. Os dados sugerem que este composto não atua de forma direta sobre membrana celular fúngica ou por mecanismos que envolvam funções da parede celular. A respeito da relação estrutura e atividade antifúngica, a presença do sistema dicarbonílico ligado ao nitrogênio ou metilenodióxido potencializam a ação inibitória frente às espécies de fungos. O estudo de docking molecular mostra que sete dos dez alvos que compartilham scores de docking mais altos pertencem à via biossintética do ergosterol, com predição de ligação aos alvos: proteína de ligação a GTP RHO1, difosfomevalonato descarboxilase, esqualeno monooxigenase, esterol 24-C-metiltransferase e esqualeno sintase; o pequeno tamanho da molécula e os grupos carbonilas, principalmente, foram ideais para estabilização da molécula nos receptores. A análise, inicialmente feita para C. albicans, também foi feita para os alvos das espécies C. krusei e C. glabrata, em que há uma pequena mutação em resíduos do alvo de C. krusei, mas que não altera a ligação do composto neste alvo. Diante desses resultados, conclui-se que os derivados 3-nitrobenzamidas apresentam-se como compostos promissores para o desenvolvimento de novos fármacos antifúngicos contra Candida spp.Universidade Federal da ParaíbaBrasilFarmacologiaPrograma de Pós-Graduação em Produtos Naturais e Sintéticos BioativosUFPBSousa, Damião Pergentino dehttp://lattes.cnpq.br/3139435097016290Ferreira Neto, Severino2022-02-16T20:12:30Z2021-10-282022-02-16T20:12:30Z2021-08-31info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/masterThesishttps://repositorio.ufpb.br/jspui/handle/123456789/22118porAttribution-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:UFPB2022-04-27T13:41:46Zoai:repositorio.ufpb.br:123456789/22118Biblioteca Digital de Teses e Dissertaçõeshttps://repositorio.ufpb.br/PUBhttp://tede.biblioteca.ufpb.br:8080/oai/requestdiretoria@ufpb.br|| diretoria@ufpb.bropendoar:2022-04-27T13:41:46Biblioteca Digital de Teses e Dissertações da UFPB - Universidade Federal da Paraíba (UFPB)false |
dc.title.none.fl_str_mv |
Avaliação antimicrobiana de 3-nitrobenzamidas sintéticas sobre espécies de Candida e estudos de docking molecular |
title |
Avaliação antimicrobiana de 3-nitrobenzamidas sintéticas sobre espécies de Candida e estudos de docking molecular |
spellingShingle |
Avaliação antimicrobiana de 3-nitrobenzamidas sintéticas sobre espécies de Candida e estudos de docking molecular Ferreira Neto, Severino Atividade antifúngica Amidas Imida Nitrocompost Antifungal activity Amides Imide Nitro compound CNPQ::CIENCIAS BIOLOGICAS::FARMACOLOGIA |
title_short |
Avaliação antimicrobiana de 3-nitrobenzamidas sintéticas sobre espécies de Candida e estudos de docking molecular |
title_full |
Avaliação antimicrobiana de 3-nitrobenzamidas sintéticas sobre espécies de Candida e estudos de docking molecular |
title_fullStr |
Avaliação antimicrobiana de 3-nitrobenzamidas sintéticas sobre espécies de Candida e estudos de docking molecular |
title_full_unstemmed |
Avaliação antimicrobiana de 3-nitrobenzamidas sintéticas sobre espécies de Candida e estudos de docking molecular |
title_sort |
Avaliação antimicrobiana de 3-nitrobenzamidas sintéticas sobre espécies de Candida e estudos de docking molecular |
author |
Ferreira Neto, Severino |
author_facet |
Ferreira Neto, Severino |
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 Neto, Severino |
dc.subject.por.fl_str_mv |
Atividade antifúngica Amidas Imida Nitrocompost Antifungal activity Amides Imide Nitro compound CNPQ::CIENCIAS BIOLOGICAS::FARMACOLOGIA |
topic |
Atividade antifúngica Amidas Imida Nitrocompost Antifungal activity Amides Imide Nitro compound CNPQ::CIENCIAS BIOLOGICAS::FARMACOLOGIA |
description |
Fungal infections affect a significant part of the population. It is estimated that around 1 billion people around the world have been affected by some type of fungus. The Candida genus is responsible for several infectious diseases, especially in individuals with compromised immunity. In addition, the emergence of strains resistant to available drugs is worrying, which results in greater difficulties for treatment and association with cases of death. Therefore, the search for new pharmacotherapeutic alternatives is urgent. Nitrobenzene derivatives have several antimicrobial properties, including antifungal action. Thus, in the present study, the antifungal potential of fourteen 3- nitrobenzamide derivatives against Candida species (C. albicans, C. krusei and C. glabrata) was investigated and a structure-activity relationship of the substances evaluated was established. The 3-nitrobenzamide derivatives were prepared using the Schotten-Baumann reaction and were structurally characterized by the techniques of Infrared Spectroscopy and Nuclear Magnetic Resonance of 1H and 13C. The products obtained had yields of 25.2-72.7% and three derivatives from the collection are unprecedented (6, 8 and 10). In antifungal tests, the Minimum Inhibitory Concentration (MIC) was determined using the microdilution technique in 96-well plates and the Minimum Fungicidal Concentration (MFC) in solid culture medium. The possible mode of action was also investigated using the sorbitol and ergosterol assays. Nine compounds showed antifungal activity with MIC values ranging from 39.06 to 1250 µg/mL. Considering the analysis of the CFM/CIM ratio, which presented values in a range of 1 to 3, it can be seen that the derivatives have fungicidal action. Imide 14 showed the best fungicidal effect in the collection against strains of C. albicans, C. krusei and C. glabrata, with MIC and CFM values of 39.06 µg/mL. The data suggest that this compound does not act directly on the fungal cell membrane or through mechanisms that involve cell wall functions. Regarding the structure and antifungal activity relationship, the presence of the dicarbonyl system linked to nitrogen or methylenedioxide potentiates the inhibitory action against fungal species. The molecular docking study shows that seven out of ten targets that share higher docking scores belonging to the ergosterol biosynthetic pathway, with predicted binding to targets: GTP RHO1 binding protein, diphosphomevalonate decarboxylase, squalene monooxygenase, 24-C-sterol methyltransferase and squalene synthase; the small size of the molecule and the carbonyl groups, mainly, were ideal for stabilizing the molecule in the receptors. The analysis, formula made for C. albicans, was also done for C. krusei and C. glabrata species targets, in which there is a small mutation in C. krusei target residues, but which does not alter the compound binding in this target. Given these results, it is concluded that 3-nitrobenzamides are promising compounds for the development of new antifungal drugs against Candida spp. |
publishDate |
2021 |
dc.date.none.fl_str_mv |
2021-10-28 2021-08-31 2022-02-16T20:12:30Z 2022-02-16T20:12:30Z |
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 |
dc.identifier.uri.fl_str_mv |
https://repositorio.ufpb.br/jspui/handle/123456789/22118 |
url |
https://repositorio.ufpb.br/jspui/handle/123456789/22118 |
dc.language.iso.fl_str_mv |
por |
language |
por |
dc.rights.driver.fl_str_mv |
Attribution-NoDerivs 3.0 Brazil http://creativecommons.org/licenses/by-nd/3.0/br/ info:eu-repo/semantics/openAccess |
rights_invalid_str_mv |
Attribution-NoDerivs 3.0 Brazil http://creativecommons.org/licenses/by-nd/3.0/br/ |
eu_rights_str_mv |
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 |
dc.source.none.fl_str_mv |
reponame:Biblioteca Digital de Teses e Dissertações da UFPB instname:Universidade Federal da Paraíba (UFPB) instacron:UFPB |
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Universidade Federal da Paraíba (UFPB) |
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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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