Estudo antifúngico de derivados benzoxazóis e benzotiazóis frente a espécies de Candida
Autor(a) principal: | |
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Data de Publicação: | 2023 |
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/123456789/30053 |
Resumo: | In recent years there has been an increase in the incidence of diseases resulting from fungal infection, currently prevailing as an important factor of morbidity and mortality in humans. Fungal resistance to pharmacological therapy has been observed in several species, especially in the genus Candida. Thus, the search for new drug candidates is important for the development of more effective drugs. Therefore, the present study aimed to prepare and evaluate the pharmacological activity of thirteen benzoxazole and benzothiazole derivatives through in vitro studies, with the perspective of obtaining biologically active compounds and investigating chemical parameters relevant to bioactivity. The compounds were prepared by means of the decarboxylation coupling of cinnamic acid derivatives with a coupler reagent and were structurally characterized by spectroscopic techniques of Infrared, Nuclear Magnetic Resonance of Hydrogen and Carbon Thirteen and High Resolution Mass Spectrometry. Among the products obtained, six compounds are unprecedented. Subsequently, the antifungal assays were performed by determining the minimum inhibitory concentration (MIC) and the minimum fungicide concentration (MFC). In addition, the mechanism of action (sorbitol and ergosterol) against C. albicans was investigated, in which it was evidenced that the antifungal action occurs targeting the plasma membrane. The CFM/MIC ratio determined that compounds 3, 6 and 7 have fungistatic activity (CFM/MIC 4), while the other compounds exert fungicidal activity (CFM/MIC 4) ≥<for the species evaluated. All compounds showed activity at the tested concentrations (1000 to 7.81 μg/mL). 2-benzyl-5-methylbenzo[d]xazole (1) showed strong bioactivity against C. krusei with MIC of 69.9 μM (15.6 μg/mL), moderate against C. albicans and weak against C. tropicalis, with MIC of 279.9 μM (62.6 μg/mL) and 559.8 μM (125.0 μg/mL), respectively. The 2-(2-fluorobenzyl)-5-methylbenzo[d]xazole (2) in turn showed moderate bioactivity with MIC equal to 250.0 μM (62.5 μg/mL) against C. krusei and showed weak activity against C. albicans and C. tropicalis with MIC of 1036.9 μM (250.0 μg/mL). The analysis of the structure-activity relationship of compounds 1-5, all with a methyl bound to carbon 5 of the benzoxazole nucleus, showed that the insertion of substituent groups in the benzyl ring reduces the pharmacological potency. Benzoazoles 6-9, with no substitution in the benzothiazole ring, and benzoxazoles 10-13, with a chlorine atom attached to carbon 5 of the benzoxazole nucleus, also exhibited bioactivity ranging from very weak to weak, regardless of the substitutions in the benzyl ring. In general, bioactive compounds may represent an important starting point in the future planning of new antifungal drug candidates. |
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Estudo antifúngico de derivados benzoxazóis e benzotiazóis frente a espécies de CandidaAgentes contra CandidaBenzoxazóisAtividade antimicrobianaÁcido cinâmicoBenzoxazolesAntimicrobial activityCinnamic acidCNPQ::CIENCIAS BIOLOGICAS::FARMACOLOGIAIn recent years there has been an increase in the incidence of diseases resulting from fungal infection, currently prevailing as an important factor of morbidity and mortality in humans. Fungal resistance to pharmacological therapy has been observed in several species, especially in the genus Candida. Thus, the search for new drug candidates is important for the development of more effective drugs. Therefore, the present study aimed to prepare and evaluate the pharmacological activity of thirteen benzoxazole and benzothiazole derivatives through in vitro studies, with the perspective of obtaining biologically active compounds and investigating chemical parameters relevant to bioactivity. The compounds were prepared by means of the decarboxylation coupling of cinnamic acid derivatives with a coupler reagent and were structurally characterized by spectroscopic techniques of Infrared, Nuclear Magnetic Resonance of Hydrogen and Carbon Thirteen and High Resolution Mass Spectrometry. Among the products obtained, six compounds are unprecedented. Subsequently, the antifungal assays were performed by determining the minimum inhibitory concentration (MIC) and the minimum fungicide concentration (MFC). In addition, the mechanism of action (sorbitol and ergosterol) against C. albicans was investigated, in which it was evidenced that the antifungal action occurs targeting the plasma membrane. The CFM/MIC ratio determined that compounds 3, 6 and 7 have fungistatic activity (CFM/MIC 4), while the other compounds exert fungicidal activity (CFM/MIC 4) ≥<for the species evaluated. All compounds showed activity at the tested concentrations (1000 to 7.81 μg/mL). 2-benzyl-5-methylbenzo[d]xazole (1) showed strong bioactivity against C. krusei with MIC of 69.9 μM (15.6 μg/mL), moderate against C. albicans and weak against C. tropicalis, with MIC of 279.9 μM (62.6 μg/mL) and 559.8 μM (125.0 μg/mL), respectively. The 2-(2-fluorobenzyl)-5-methylbenzo[d]xazole (2) in turn showed moderate bioactivity with MIC equal to 250.0 μM (62.5 μg/mL) against C. krusei and showed weak activity against C. albicans and C. tropicalis with MIC of 1036.9 μM (250.0 μg/mL). The analysis of the structure-activity relationship of compounds 1-5, all with a methyl bound to carbon 5 of the benzoxazole nucleus, showed that the insertion of substituent groups in the benzyl ring reduces the pharmacological potency. Benzoazoles 6-9, with no substitution in the benzothiazole ring, and benzoxazoles 10-13, with a chlorine atom attached to carbon 5 of the benzoxazole nucleus, also exhibited bioactivity ranging from very weak to weak, regardless of the substitutions in the benzyl ring. In general, bioactive compounds may represent an important starting point in the future planning of new antifungal drug candidates.Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPESNos últimos anos houve um aumento na incidência das doenças decorrentes de infecção fúngica, prevalecendo atualmente como importante fator de morbidade e mortalidade em humanos. A resistência fúngica à terapia farmacológica tem sido constatada em várias espécies, com destaque para o gênero Candida. Dessa forma, a busca por novos candidatos a fármacos é importante para o desenvolvimento de medicamentos mais eficazes. Diante disso, o presente trabalho teve como objetivo preparar e avaliar a atividade farmacológica de treze derivados benzoxazóis e benzotiazóis através de estudos in vitro, com a perspectiva de obter compostos biologicamente ativos e investigar parâmetros químicos relevantes para a bioatividade. Os compostos foram preparados por meio do acoplamento descarboxilativo de derivados do ácido cinâmico com um reagente acoplador e foram estruturalmente caracterizados por técnicas espectroscópicas de Infravermelho, Ressonância Magnética Nuclear de Hidrogênio e Carbono Treze e Espectrometria de Massas de Alta Resolução. Dentre os produtos obtidos, seis compostos são inéditos. Em seguida, realizou-se os ensaios antifúngicos via a determinação da concentração inibitória mínima (CIM) e a concentração fungicida mínima (CFM). Em adição, investigou-se o mecanismo de ação (sorbitol e ergosterol) frente à C. albicans, no qual evidenciou-se que a ação antifúngica ocorre tendo como alvo a membrana plasmática. A razão CFM/CIM determinou que os compostos 3, 6 e 7 possuem atividade fungistática (CFM/CIM ≥4), já os demais compostos exercem atividade fungicida (CFM/CIM <4) para as espécies avaliadas. Todos os compostos apresentaram atividade nas concentrações testadas (1000 a 7,81 μg/mL). O 2-benzil-5-metilbenzo[d]xazol (1) apresentou bioatividade forte contra C. krusei com CIM de 69,9 μM (15,6 μg/mL), moderada frente a C. albicans e fraca contra C. tropicalis, com CIM de 279,9 μM (62,6 μg/mL) e 559,8 μM (125,0 μg/mL), respectivamente. O 2-(2-fluorobenzil)-5-metilbenzo[d]xazol (2) por sua vez demonstrou bioatividade moderada com CIM igual a 250,0 μM (62,5 μg/mL) contra C. krusei e apresentou fraca atividade contra C. albicans e C. tropicalis com CIM de 1036,9 μM (250,0 μg/mL). A análise da relação estrutura-atividade dos compostos 1-5, todos com uma metila ligada ao carbono 5 do núcleo benzoxazóis, evidenciou que a inserção de grupos substituintes no anel benzílico reduz a potência farmacológica. Os benzotiazóis 6-9, sem substituição no anel benzotiazol, e os benzoxazóis 10-13, com um átomo de cloro ligado ao carbono 5 do núcleo benzoxazol, também exibiram bioatividade variando de muito fraca a fraca, independentemente das substituições no anel benzílico. De forma geral, os compostos bioativos podem representar um importante ponto de partida no planejamento futuro de novos candidatos a fármacos antifúngicos.Universidade Federal da ParaíbaBrasilFarmacologiaPrograma de Pós-Graduação em Produtos Naturais e Sintéticos BioativosUFPBSousa, Damião Pergentino dehttp://lattes.cnpq.br/3139435097016290Emídio, Jeremias Justo2024-04-19T10:52:26Z2023-09-212024-04-19T10:52:26Z2023-06-07info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/masterThesishttps://repositorio.ufpb.br/jspui/handle/123456789/30053porAttribution-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:UFPB2024-04-20T06:09:24Zoai:repositorio.ufpb.br:123456789/30053Biblioteca Digital de Teses e Dissertaçõeshttps://repositorio.ufpb.br/PUBhttp://tede.biblioteca.ufpb.br:8080/oai/requestdiretoria@ufpb.br|| diretoria@ufpb.bropendoar:2024-04-20T06:09:24Biblioteca Digital de Teses e Dissertações da UFPB - Universidade Federal da Paraíba (UFPB)false |
dc.title.none.fl_str_mv |
Estudo antifúngico de derivados benzoxazóis e benzotiazóis frente a espécies de Candida |
title |
Estudo antifúngico de derivados benzoxazóis e benzotiazóis frente a espécies de Candida |
spellingShingle |
Estudo antifúngico de derivados benzoxazóis e benzotiazóis frente a espécies de Candida Emídio, Jeremias Justo Agentes contra Candida Benzoxazóis Atividade antimicrobiana Ácido cinâmico Benzoxazoles Antimicrobial activity Cinnamic acid CNPQ::CIENCIAS BIOLOGICAS::FARMACOLOGIA |
title_short |
Estudo antifúngico de derivados benzoxazóis e benzotiazóis frente a espécies de Candida |
title_full |
Estudo antifúngico de derivados benzoxazóis e benzotiazóis frente a espécies de Candida |
title_fullStr |
Estudo antifúngico de derivados benzoxazóis e benzotiazóis frente a espécies de Candida |
title_full_unstemmed |
Estudo antifúngico de derivados benzoxazóis e benzotiazóis frente a espécies de Candida |
title_sort |
Estudo antifúngico de derivados benzoxazóis e benzotiazóis frente a espécies de Candida |
author |
Emídio, Jeremias Justo |
author_facet |
Emídio, Jeremias Justo |
author_role |
author |
dc.contributor.none.fl_str_mv |
Sousa, Damião Pergentino de http://lattes.cnpq.br/3139435097016290 |
dc.contributor.author.fl_str_mv |
Emídio, Jeremias Justo |
dc.subject.por.fl_str_mv |
Agentes contra Candida Benzoxazóis Atividade antimicrobiana Ácido cinâmico Benzoxazoles Antimicrobial activity Cinnamic acid CNPQ::CIENCIAS BIOLOGICAS::FARMACOLOGIA |
topic |
Agentes contra Candida Benzoxazóis Atividade antimicrobiana Ácido cinâmico Benzoxazoles Antimicrobial activity Cinnamic acid CNPQ::CIENCIAS BIOLOGICAS::FARMACOLOGIA |
description |
In recent years there has been an increase in the incidence of diseases resulting from fungal infection, currently prevailing as an important factor of morbidity and mortality in humans. Fungal resistance to pharmacological therapy has been observed in several species, especially in the genus Candida. Thus, the search for new drug candidates is important for the development of more effective drugs. Therefore, the present study aimed to prepare and evaluate the pharmacological activity of thirteen benzoxazole and benzothiazole derivatives through in vitro studies, with the perspective of obtaining biologically active compounds and investigating chemical parameters relevant to bioactivity. The compounds were prepared by means of the decarboxylation coupling of cinnamic acid derivatives with a coupler reagent and were structurally characterized by spectroscopic techniques of Infrared, Nuclear Magnetic Resonance of Hydrogen and Carbon Thirteen and High Resolution Mass Spectrometry. Among the products obtained, six compounds are unprecedented. Subsequently, the antifungal assays were performed by determining the minimum inhibitory concentration (MIC) and the minimum fungicide concentration (MFC). In addition, the mechanism of action (sorbitol and ergosterol) against C. albicans was investigated, in which it was evidenced that the antifungal action occurs targeting the plasma membrane. The CFM/MIC ratio determined that compounds 3, 6 and 7 have fungistatic activity (CFM/MIC 4), while the other compounds exert fungicidal activity (CFM/MIC 4) ≥<for the species evaluated. All compounds showed activity at the tested concentrations (1000 to 7.81 μg/mL). 2-benzyl-5-methylbenzo[d]xazole (1) showed strong bioactivity against C. krusei with MIC of 69.9 μM (15.6 μg/mL), moderate against C. albicans and weak against C. tropicalis, with MIC of 279.9 μM (62.6 μg/mL) and 559.8 μM (125.0 μg/mL), respectively. The 2-(2-fluorobenzyl)-5-methylbenzo[d]xazole (2) in turn showed moderate bioactivity with MIC equal to 250.0 μM (62.5 μg/mL) against C. krusei and showed weak activity against C. albicans and C. tropicalis with MIC of 1036.9 μM (250.0 μg/mL). The analysis of the structure-activity relationship of compounds 1-5, all with a methyl bound to carbon 5 of the benzoxazole nucleus, showed that the insertion of substituent groups in the benzyl ring reduces the pharmacological potency. Benzoazoles 6-9, with no substitution in the benzothiazole ring, and benzoxazoles 10-13, with a chlorine atom attached to carbon 5 of the benzoxazole nucleus, also exhibited bioactivity ranging from very weak to weak, regardless of the substitutions in the benzyl ring. In general, bioactive compounds may represent an important starting point in the future planning of new antifungal drug candidates. |
publishDate |
2023 |
dc.date.none.fl_str_mv |
2023-09-21 2023-06-07 2024-04-19T10:52:26Z 2024-04-19T10:52:26Z |
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/123456789/30053 |
url |
https://repositorio.ufpb.br/jspui/handle/123456789/30053 |
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 |
instname_str |
Universidade Federal da Paraíba (UFPB) |
instacron_str |
UFPB |
institution |
UFPB |
reponame_str |
Biblioteca Digital de Teses e Dissertações da UFPB |
collection |
Biblioteca Digital de Teses e Dissertações da UFPB |
repository.name.fl_str_mv |
Biblioteca Digital de Teses e Dissertações da UFPB - Universidade Federal da Paraíba (UFPB) |
repository.mail.fl_str_mv |
diretoria@ufpb.br|| diretoria@ufpb.br |
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1801843026118574080 |