Avaliação da atividade de compostos de guanidina, selenoglicolicamidas e espiro-acridínicos sobre leishmania infantum
Autor(a) principal: | |
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Data de Publicação: | 2022 |
Tipo de documento: | Tese |
Idioma: | por |
Título da fonte: | Biblioteca Digital de Teses e Dissertações da UFPB |
Texto Completo: | https://repositorio.ufpb.br/jspui/handle/123456789/26794 |
Resumo: | Leishmaniasis is a neglected tropical infectious disease complex with thousands of cases annually; being of major global health concern, particularly the most severe form, visceral leishmaniasis. Treatments for visceral leishmaniasis are limited and have serious adverse effects. Compounds containing guanidine, selenium, and acridines have shown biological activities, including antiparasitic. Therefore, we analyzed the cytotoxic effects of these various compounds containing guanidine, acridine derivatives, and selenoglycolicamides on Leishmania infantum in their promastigote and amastigote forms in vitro, their cytotoxicity in human cells and their effects on the production of reactive nitrogen species. As for the activity of acridine derivatives, the IC50 values ranged from 1.10 to 6.05μg/mL for promastigote forms of Leishmania (Leishmania) infantum. In the activity under axenic amastigotes of the most active compounds, there is an expressive activity of AMTAC 11 (EC50= 0.97 ± 0.2 μg/mL) and low cytotoxicity in mononuclear cells of the peripheral system (CC50= > 100 μg/mL ). For the compounds of the selenoglycolicamides group, of the 9 compounds evaluated, 8 showed inhibitory activity against L. infantum promastigotes with IC50 ranging between 1.34 and 68.96 μg/mL. In terms of cytotoxic activity for amastigotes, the most promising compound, MSe 13, showed an EC50 of 14.59 ± 1.44 μg/mL. Within the concentrations tested, none of the compounds showed toxicity in human erythrocytes. To identify the mechanisms of action, the processes of cell death were evaluated by staining with annexin V and propidium iodide and nitrite production. As for the evaluation of the cell death profile, selenoglycolicamide MSe 13 induced cell death by apoptosis in axenic amastigotes, however, MSe 13 still induced a percentage of cell death in PBMC by apoptosis, as well as the reference drug Amphotericin B. LQOFG-2, LQOFG-6 and LQOFG-7 showed IC50 values between 5.14 and 10.76 μg/mL, respectively, in promastigotes. These compounds exhibited cytotoxicity on axenic amastigotes at values of 10.59; 8.15 and 8.46 μg/ml. The guanidine derivatives showed no apparent cytotoxicity in cells from healthy donors. Compounds containing guanidine showed a significant percentage of amastigotes to apoptosis. Regardless of L. infantum infection, LQOFG-7 increased nitrite production in PBMC's suggesting a potential mechanism of action for this compound. Therefore, these data suggest that guanidine derivatives, selenoglycolicamides, and spiro-acridines are potential molecules for anti-Leishmania activity, and more research is needed to fully understand their mechanism of action. |
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Avaliação da atividade de compostos de guanidina, selenoglicolicamidas e espiro-acridínicos sobre leishmania infantumLeishmanioseAtividade anti-LeishmaniaGuanidina - DerivadosSelenoglicolicamidasEspiro-acridínicos - DerivadosApoptoseLeishmaniasisAnti-Leishmania activityQuanidine - DerivativesSelenoglycolicamidesSpiro-acridine - DerivativesApoptosisCNPQ::CIENCIAS BIOLOGICASLeishmaniasis is a neglected tropical infectious disease complex with thousands of cases annually; being of major global health concern, particularly the most severe form, visceral leishmaniasis. Treatments for visceral leishmaniasis are limited and have serious adverse effects. Compounds containing guanidine, selenium, and acridines have shown biological activities, including antiparasitic. Therefore, we analyzed the cytotoxic effects of these various compounds containing guanidine, acridine derivatives, and selenoglycolicamides on Leishmania infantum in their promastigote and amastigote forms in vitro, their cytotoxicity in human cells and their effects on the production of reactive nitrogen species. As for the activity of acridine derivatives, the IC50 values ranged from 1.10 to 6.05μg/mL for promastigote forms of Leishmania (Leishmania) infantum. In the activity under axenic amastigotes of the most active compounds, there is an expressive activity of AMTAC 11 (EC50= 0.97 ± 0.2 μg/mL) and low cytotoxicity in mononuclear cells of the peripheral system (CC50= > 100 μg/mL ). For the compounds of the selenoglycolicamides group, of the 9 compounds evaluated, 8 showed inhibitory activity against L. infantum promastigotes with IC50 ranging between 1.34 and 68.96 μg/mL. In terms of cytotoxic activity for amastigotes, the most promising compound, MSe 13, showed an EC50 of 14.59 ± 1.44 μg/mL. Within the concentrations tested, none of the compounds showed toxicity in human erythrocytes. To identify the mechanisms of action, the processes of cell death were evaluated by staining with annexin V and propidium iodide and nitrite production. As for the evaluation of the cell death profile, selenoglycolicamide MSe 13 induced cell death by apoptosis in axenic amastigotes, however, MSe 13 still induced a percentage of cell death in PBMC by apoptosis, as well as the reference drug Amphotericin B. LQOFG-2, LQOFG-6 and LQOFG-7 showed IC50 values between 5.14 and 10.76 μg/mL, respectively, in promastigotes. These compounds exhibited cytotoxicity on axenic amastigotes at values of 10.59; 8.15 and 8.46 μg/ml. The guanidine derivatives showed no apparent cytotoxicity in cells from healthy donors. Compounds containing guanidine showed a significant percentage of amastigotes to apoptosis. Regardless of L. infantum infection, LQOFG-7 increased nitrite production in PBMC's suggesting a potential mechanism of action for this compound. Therefore, these data suggest that guanidine derivatives, selenoglycolicamides, and spiro-acridines are potential molecules for anti-Leishmania activity, and more research is needed to fully understand their mechanism of action.NenhumaAs leishmanioses são um complexo de doenças infecciosas tropical negligenciada com milhares de casos anualmente; sendo de grande preocupação para a saúde global, particularmente a forma mais grave, a leishmaniose visceral. Os tratamentos da leishmaniose visceral são limitados e têm efeitos adversos graves. Os compostos contendo guanidina, selênio e acridínicos tem apresentado atividades biológicas, dentre estas, antiparasitárias. Analisou-se, portanto, os efeitos citotóxicos desses vários compostos contendo guanidina, derivados de acridina e selenoglicolicamidas em Leishmania infantum em suas formas promastigota e amastigota in vitro, sua citotoxicidade em células humanas e efeitos na produção de espécies reativas de nitrogênio. Quanto a atividade dos derivados acridínicos, os valores de CI50 foram entre 1,10 a 6,05μg/mL para formas promastigotas de Leishmania (Leishmania) infantum. Na atividade sob formas amastigotas axênicas dos compostos mais ativos, destaca-se expressiva atividade do AMTAC 11 (EC50= 0,97 ± 0,2 μg/mL) e baixa citotoxicidade em células mononucleares do sistema periférico (CC50= > 100 μg/ml). Para os compostos do grupo das selenoglicolicamidas, dos 9 compostos avaliados, 8 apresentaram atividade inibitória contra promastigotas de L. infantum com CI50 que variaram entre 1,34 e 68,96 μg/mL. Na atividade citotóxica para amastigotas, o composto mais promissor, MSe 13 apresentou CE50 de 14,59 ± 1,44 μg/mL. Dentro das concentrações testadas, nenhum dos compostos apresentaram toxicidade em eritrócitos humanos. Para identificar os mecanismos de ação, avaliou-se os processos de morte celular por coloração com anexina V e iodeto de propídio e produção de nitrito. Quanto ao avaliação do perfil de morte celular a selenoglicolicamida MSe 13 induziu morte celular por apoptose em amastigotas axênicas, todavia a MSe 13 ainda induziu um percentual de morte celular em PBMC por apoptose, assim como o fármaco de referência Anfotericina B. Já os compostos guanidinícos LQOFG-2, LQOFG-6 e LQOFG-7 apresentaram valores de CI50 entre 5,14 a 10,76 μg/mL, respectivamente, em promastigotas. Estes compostos exibiram citotoxicidade em amastigotas axênicas em valores de 10,59; 8,15 e 8,46 μg/mL. Os derivados de guanidina não apresentaram citotoxicidade aparente em células de doadores saudáveis. Compostos contendo guanidina apresentaram uma porcentagem significativa de amastigotas a apoptose. Independente da infecção por L. infantum, LQOFG-7 aumentou a produção de nitrito em PBMC’s sugerindo um potencial mecanismo de ação para este composto. Portanto, esses dados sugerem que os derivados de guanidina, selenoglicolicamidas e espiro-acridínicos são potenciais moléculas para atividade anti-Leishmania, e mais pesquisas são necessárias para o entendimento completo de seu mecanismo de ação.Universidade Federal da ParaíbaBrasilBiotecnologiaPrograma de Pós-Graduação em BiotecnologiaUFPBClemente, Tatjana Keesen de Souza Limahttp://lattes.cnpq.br/5504382837656473Almeida, Fernanda Silva2023-04-26T13:19:29Z2022-12-142023-04-26T13:19:29Z2022-09-23info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/doctoralThesishttps://repositorio.ufpb.br/jspui/handle/123456789/26794porAttribution-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:UFPB2023-04-27T06:03:40Zoai:repositorio.ufpb.br:123456789/26794Biblioteca Digital de Teses e Dissertaçõeshttps://repositorio.ufpb.br/PUBhttp://tede.biblioteca.ufpb.br:8080/oai/requestdiretoria@ufpb.br|| diretoria@ufpb.bropendoar:2023-04-27T06:03:40Biblioteca Digital de Teses e Dissertações da UFPB - Universidade Federal da Paraíba (UFPB)false |
dc.title.none.fl_str_mv |
Avaliação da atividade de compostos de guanidina, selenoglicolicamidas e espiro-acridínicos sobre leishmania infantum |
title |
Avaliação da atividade de compostos de guanidina, selenoglicolicamidas e espiro-acridínicos sobre leishmania infantum |
spellingShingle |
Avaliação da atividade de compostos de guanidina, selenoglicolicamidas e espiro-acridínicos sobre leishmania infantum Almeida, Fernanda Silva Leishmaniose Atividade anti-Leishmania Guanidina - Derivados Selenoglicolicamidas Espiro-acridínicos - Derivados Apoptose Leishmaniasis Anti-Leishmania activity Quanidine - Derivatives Selenoglycolicamides Spiro-acridine - Derivatives Apoptosis CNPQ::CIENCIAS BIOLOGICAS |
title_short |
Avaliação da atividade de compostos de guanidina, selenoglicolicamidas e espiro-acridínicos sobre leishmania infantum |
title_full |
Avaliação da atividade de compostos de guanidina, selenoglicolicamidas e espiro-acridínicos sobre leishmania infantum |
title_fullStr |
Avaliação da atividade de compostos de guanidina, selenoglicolicamidas e espiro-acridínicos sobre leishmania infantum |
title_full_unstemmed |
Avaliação da atividade de compostos de guanidina, selenoglicolicamidas e espiro-acridínicos sobre leishmania infantum |
title_sort |
Avaliação da atividade de compostos de guanidina, selenoglicolicamidas e espiro-acridínicos sobre leishmania infantum |
author |
Almeida, Fernanda Silva |
author_facet |
Almeida, Fernanda Silva |
author_role |
author |
dc.contributor.none.fl_str_mv |
Clemente, Tatjana Keesen de Souza Lima http://lattes.cnpq.br/5504382837656473 |
dc.contributor.author.fl_str_mv |
Almeida, Fernanda Silva |
dc.subject.por.fl_str_mv |
Leishmaniose Atividade anti-Leishmania Guanidina - Derivados Selenoglicolicamidas Espiro-acridínicos - Derivados Apoptose Leishmaniasis Anti-Leishmania activity Quanidine - Derivatives Selenoglycolicamides Spiro-acridine - Derivatives Apoptosis CNPQ::CIENCIAS BIOLOGICAS |
topic |
Leishmaniose Atividade anti-Leishmania Guanidina - Derivados Selenoglicolicamidas Espiro-acridínicos - Derivados Apoptose Leishmaniasis Anti-Leishmania activity Quanidine - Derivatives Selenoglycolicamides Spiro-acridine - Derivatives Apoptosis CNPQ::CIENCIAS BIOLOGICAS |
description |
Leishmaniasis is a neglected tropical infectious disease complex with thousands of cases annually; being of major global health concern, particularly the most severe form, visceral leishmaniasis. Treatments for visceral leishmaniasis are limited and have serious adverse effects. Compounds containing guanidine, selenium, and acridines have shown biological activities, including antiparasitic. Therefore, we analyzed the cytotoxic effects of these various compounds containing guanidine, acridine derivatives, and selenoglycolicamides on Leishmania infantum in their promastigote and amastigote forms in vitro, their cytotoxicity in human cells and their effects on the production of reactive nitrogen species. As for the activity of acridine derivatives, the IC50 values ranged from 1.10 to 6.05μg/mL for promastigote forms of Leishmania (Leishmania) infantum. In the activity under axenic amastigotes of the most active compounds, there is an expressive activity of AMTAC 11 (EC50= 0.97 ± 0.2 μg/mL) and low cytotoxicity in mononuclear cells of the peripheral system (CC50= > 100 μg/mL ). For the compounds of the selenoglycolicamides group, of the 9 compounds evaluated, 8 showed inhibitory activity against L. infantum promastigotes with IC50 ranging between 1.34 and 68.96 μg/mL. In terms of cytotoxic activity for amastigotes, the most promising compound, MSe 13, showed an EC50 of 14.59 ± 1.44 μg/mL. Within the concentrations tested, none of the compounds showed toxicity in human erythrocytes. To identify the mechanisms of action, the processes of cell death were evaluated by staining with annexin V and propidium iodide and nitrite production. As for the evaluation of the cell death profile, selenoglycolicamide MSe 13 induced cell death by apoptosis in axenic amastigotes, however, MSe 13 still induced a percentage of cell death in PBMC by apoptosis, as well as the reference drug Amphotericin B. LQOFG-2, LQOFG-6 and LQOFG-7 showed IC50 values between 5.14 and 10.76 μg/mL, respectively, in promastigotes. These compounds exhibited cytotoxicity on axenic amastigotes at values of 10.59; 8.15 and 8.46 μg/ml. The guanidine derivatives showed no apparent cytotoxicity in cells from healthy donors. Compounds containing guanidine showed a significant percentage of amastigotes to apoptosis. Regardless of L. infantum infection, LQOFG-7 increased nitrite production in PBMC's suggesting a potential mechanism of action for this compound. Therefore, these data suggest that guanidine derivatives, selenoglycolicamides, and spiro-acridines are potential molecules for anti-Leishmania activity, and more research is needed to fully understand their mechanism of action. |
publishDate |
2022 |
dc.date.none.fl_str_mv |
2022-12-14 2022-09-23 2023-04-26T13:19:29Z 2023-04-26T13:19:29Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/doctoralThesis |
format |
doctoralThesis |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
https://repositorio.ufpb.br/jspui/handle/123456789/26794 |
url |
https://repositorio.ufpb.br/jspui/handle/123456789/26794 |
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 Biotecnologia Programa de Pós-Graduação em Biotecnologia UFPB |
publisher.none.fl_str_mv |
Universidade Federal da Paraíba Brasil Biotecnologia Programa de Pós-Graduação em Biotecnologia UFPB |
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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 |
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) |
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diretoria@ufpb.br|| diretoria@ufpb.br |
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1801843008869498880 |