Atividade antiplasmodial in vitro de um derivado da N-metil-isatina (CH3ISACN), e sua toxicidade in silico e in vivo
Autor(a) principal: | |
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Data de Publicação: | 2020 |
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/123456789/18351 |
Resumo: | Malaria is a parasitic disease that is highly prevalent worldwide. In 2018, it reached about 228 million people and caused 405,000 deaths. This disease is caused by the parasite of the genus Plasmodium, which is transmitted by man through the bite of the infected female mosquito of the genus Anopheles. One of the main factors that hinder or control malaria is the large number of parasites that are resistant to antimalarials, including an artemisinin and used. Therefore, it is necessary to discover new drugs that have greater efficacy and low toxicity for humans. Morita-Baylis-Hillman ads have several features, including anti-parasitic activities. Thus, the target of our study is an adduct, 2- (3-hydroxy-1-methyl-2-oxoindolin-3-yl) acrylonitrile, also called CH3ISACN. Thus, the present study aimed to investigate the potential of the CH3ISACN adduct as an antimalarial through in vitro studies, and to evaluate its toxicological effects in silico and in vivo. For this, the compound CH3ISACN was exposed to the W2 strain of P.falciparum in human erythrocytes, and evaluated if it was able to reduce parasitemia. It was also verified if it was able to cause hemolysis to erythrocytes. In addition, the theoretical pharmacokinetic and toxicological characteristics of the CH3ISACN adduct were investigated through in silico tests with the software AdmetSAR and Molinspiration. In addition, an acute in vivo toxicological study was carried out, following the experimental protocols adopted at the Toxicological Testing Laboratory (LABETOX) and the OECD Guide 423 (2001). Thus, an initial dose of 300 mg / kg of the test substance was administered to Wistar rats and subsequently, with no deaths, a dose of 2000 mg / kg was administered to other rats of the same species. During the experiment, behavioral parameters, water consumption, feed and weight evolution were evaluated. After 14 days, the animals were euthanized by overdose of anesthetic, and their blood collected for evaluation of biochemical and hematological parameters. The results showed that the CH3ISACN adduct showed good antiplasmodial activity, and low cytotoxicity, with good cell viability. In addition to what was shown to have a good theoretical oral bioavailability and did not present toxicity risks in in silico studies. Furthermore, the CH3ISACN adduct did not cause death in any of the animals, thus presenting a high LD50 and being classified according to GSH in category 5, as having low toxicity. There is also no behavioral change, as well as in the other parameters applicable to the highest dose tested, without causing a significant change. Only a reduction in urea concentration, but that did not bring relevant clinical significance. Finally, either CH3ISACN has a good candidate for malaria treatment. Therefore, it is of great value to continue your study, until reaching clinical phase tests, and thus be included in the therapeutic arsenal against malaria. |
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Atividade antiplasmodial in vitro de um derivado da N-metil-isatina (CH3ISACN), e sua toxicidade in silico e in vivoMaláriaP.falciparumFarmacologiaParasitologiaToxicologiaMalariaPharmacologyParasitologyToxicologyCNPQ::CIENCIAS BIOLOGICAS::FARMACOLOGIAMalaria is a parasitic disease that is highly prevalent worldwide. In 2018, it reached about 228 million people and caused 405,000 deaths. This disease is caused by the parasite of the genus Plasmodium, which is transmitted by man through the bite of the infected female mosquito of the genus Anopheles. One of the main factors that hinder or control malaria is the large number of parasites that are resistant to antimalarials, including an artemisinin and used. Therefore, it is necessary to discover new drugs that have greater efficacy and low toxicity for humans. Morita-Baylis-Hillman ads have several features, including anti-parasitic activities. Thus, the target of our study is an adduct, 2- (3-hydroxy-1-methyl-2-oxoindolin-3-yl) acrylonitrile, also called CH3ISACN. Thus, the present study aimed to investigate the potential of the CH3ISACN adduct as an antimalarial through in vitro studies, and to evaluate its toxicological effects in silico and in vivo. For this, the compound CH3ISACN was exposed to the W2 strain of P.falciparum in human erythrocytes, and evaluated if it was able to reduce parasitemia. It was also verified if it was able to cause hemolysis to erythrocytes. In addition, the theoretical pharmacokinetic and toxicological characteristics of the CH3ISACN adduct were investigated through in silico tests with the software AdmetSAR and Molinspiration. In addition, an acute in vivo toxicological study was carried out, following the experimental protocols adopted at the Toxicological Testing Laboratory (LABETOX) and the OECD Guide 423 (2001). Thus, an initial dose of 300 mg / kg of the test substance was administered to Wistar rats and subsequently, with no deaths, a dose of 2000 mg / kg was administered to other rats of the same species. During the experiment, behavioral parameters, water consumption, feed and weight evolution were evaluated. After 14 days, the animals were euthanized by overdose of anesthetic, and their blood collected for evaluation of biochemical and hematological parameters. The results showed that the CH3ISACN adduct showed good antiplasmodial activity, and low cytotoxicity, with good cell viability. In addition to what was shown to have a good theoretical oral bioavailability and did not present toxicity risks in in silico studies. Furthermore, the CH3ISACN adduct did not cause death in any of the animals, thus presenting a high LD50 and being classified according to GSH in category 5, as having low toxicity. There is also no behavioral change, as well as in the other parameters applicable to the highest dose tested, without causing a significant change. Only a reduction in urea concentration, but that did not bring relevant clinical significance. Finally, either CH3ISACN has a good candidate for malaria treatment. Therefore, it is of great value to continue your study, until reaching clinical phase tests, and thus be included in the therapeutic arsenal against malaria.NenhumaA malária é uma doença parasitária que apresenta grande prevalência no mundo. Em 2018 chegou a acometer cerca de 228 milhões de pessoas, e causar 405.000 mortes. Esta doença é ocasionada pelo parasita do gênero Plasmodium, que é transmitido ao homem através da picada do mosquito fêmea do gênero Anopheles infectada. Um dos principais fatores que tem dificultado o controle da malária, é o grande número de parasitos que apresentam resistência aos antimaláricos usuais, incluindo a artemisinina e derivados. Portanto, é necessário a descoberta de novos medicamentos que tenham maior eficácia, e com baixa toxicidade para o ser humano. Os adutos de Morita-Baylis-Hillman apresentam diversas funcionalidades, entre elas, atividades antiparasitárias. Desta forma, o alvo de nosso estudo é um aduto, o 2- (3-hidroxi-1-metil-2-oxoindolin-3-il) acrilonitrila, também chamado por CH3ISACN. Assim, o presente estudo teve como objetivo investigar o potencial do aduto CH3ISACN como antimalárico através de estudos in vitro, e avaliar seus efeitos toxicológicos in silico e in vivo. Para isto, o composto CH3ISACN foi exposto à cepa W2 de P. falciparum em eritrócitos humanos, e avaliado se este era capaz de reduzir a parasitemia. Sendo verificado também se o mesmo era capaz de causar hemólise aos eritrócitos. Além disto, foi investigado as características farmacocinéticas e toxicológicas teóricas do aduto CH3ISACN, por meio de ensaios in silico com os softwares AdmetSAR e Molinspiration. Ainda, foi realizado o estudo toxicológico agudo in vivo, seguindo os protocolos experimentais adotados no Laboratório de Ensaios Toxicológicos (LABETOX) e o Guia da OECD 423 (2001). Desta forma, foi administrada uma dose inicial de 300 mg/kg da substância teste, em ratas Wistar e posteriormente, não havendo mortes, foi administrado em outras ratas da mesma espécie, uma dose de 2000 mg/kg. Durante o experimento foram avaliados parâmetros comportamentais, consumo de água, ração e evolução ponderal. Após 14 dias, os animais foram eutanasiados por sobredose de anestésico, e seu sangue coletado para avaliação de parâmetros bioquímicos e hematológicos. Os resultados mostraram que o aduto CH3ISACN apresentou boa atividade antiplasmodial, e baixa citotoxicidade, tendo uma boa viabilidade celular. Além do que mostrou ter uma boa biodisponibilidade oral teórica e não apresentou riscos de toxicidade nos estudos in silico. Ainda, o aduto CH3ISACN não causou morte em nenhum dos animais, apresentando assim uma alta DL50 e sendo classificado segundo a GSH na categoria 5, como tendo baixa toxicidade. Este também não ocasionou nenhuma alteração comportamental, bem como nos demais parâmetros avaliados a maior dose testada não provocou nenhuma alteração significativa. Apenas uma redução na concentração de ureia, mas que não trouxe significado clínico relevante. Por fim, o aduto CH3ISACN apresenta-se como um bom candidato à fármaco para o tratamento da malária. Sendo assim, de grande valia a continuação de seu estudo, até alcançar testes de fase clínica, e assim ser incluído no arsenal terapêutico contra a malária.Universidade Federal da ParaíbaBrasilFarmacologiaPrograma de Pós-Graduação em Produtos Naturais e Sintéticos BioativosUFPBDiniz, Margareth de Fátima Formiga Melohttp://lattes.cnpq.br/4173269414899195Lima, Caliandra Maria Bezerra Lunahttp://lattes.cnpq.br/6515725808648467Melo, Cinthia Rodrigues2020-11-04T10:46:25Z2020-11-032020-11-04T10:46:25Z2020-02-27info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/masterThesishttps://repositorio.ufpb.br/jspui/handle/123456789/18351porhttp://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:UFPB2021-09-14T13:27:52Zoai:repositorio.ufpb.br:123456789/18351Biblioteca Digital de Teses e Dissertaçõeshttps://repositorio.ufpb.br/PUBhttp://tede.biblioteca.ufpb.br:8080/oai/requestdiretoria@ufpb.br|| diretoria@ufpb.bropendoar:2021-09-14T13:27:52Biblioteca Digital de Teses e Dissertações da UFPB - Universidade Federal da Paraíba (UFPB)false |
dc.title.none.fl_str_mv |
Atividade antiplasmodial in vitro de um derivado da N-metil-isatina (CH3ISACN), e sua toxicidade in silico e in vivo |
title |
Atividade antiplasmodial in vitro de um derivado da N-metil-isatina (CH3ISACN), e sua toxicidade in silico e in vivo |
spellingShingle |
Atividade antiplasmodial in vitro de um derivado da N-metil-isatina (CH3ISACN), e sua toxicidade in silico e in vivo Melo, Cinthia Rodrigues Malária P.falciparum Farmacologia Parasitologia Toxicologia Malaria Pharmacology Parasitology Toxicology CNPQ::CIENCIAS BIOLOGICAS::FARMACOLOGIA |
title_short |
Atividade antiplasmodial in vitro de um derivado da N-metil-isatina (CH3ISACN), e sua toxicidade in silico e in vivo |
title_full |
Atividade antiplasmodial in vitro de um derivado da N-metil-isatina (CH3ISACN), e sua toxicidade in silico e in vivo |
title_fullStr |
Atividade antiplasmodial in vitro de um derivado da N-metil-isatina (CH3ISACN), e sua toxicidade in silico e in vivo |
title_full_unstemmed |
Atividade antiplasmodial in vitro de um derivado da N-metil-isatina (CH3ISACN), e sua toxicidade in silico e in vivo |
title_sort |
Atividade antiplasmodial in vitro de um derivado da N-metil-isatina (CH3ISACN), e sua toxicidade in silico e in vivo |
author |
Melo, Cinthia Rodrigues |
author_facet |
Melo, Cinthia Rodrigues |
author_role |
author |
dc.contributor.none.fl_str_mv |
Diniz, Margareth de Fátima Formiga Melo http://lattes.cnpq.br/4173269414899195 Lima, Caliandra Maria Bezerra Luna http://lattes.cnpq.br/6515725808648467 |
dc.contributor.author.fl_str_mv |
Melo, Cinthia Rodrigues |
dc.subject.por.fl_str_mv |
Malária P.falciparum Farmacologia Parasitologia Toxicologia Malaria Pharmacology Parasitology Toxicology CNPQ::CIENCIAS BIOLOGICAS::FARMACOLOGIA |
topic |
Malária P.falciparum Farmacologia Parasitologia Toxicologia Malaria Pharmacology Parasitology Toxicology CNPQ::CIENCIAS BIOLOGICAS::FARMACOLOGIA |
description |
Malaria is a parasitic disease that is highly prevalent worldwide. In 2018, it reached about 228 million people and caused 405,000 deaths. This disease is caused by the parasite of the genus Plasmodium, which is transmitted by man through the bite of the infected female mosquito of the genus Anopheles. One of the main factors that hinder or control malaria is the large number of parasites that are resistant to antimalarials, including an artemisinin and used. Therefore, it is necessary to discover new drugs that have greater efficacy and low toxicity for humans. Morita-Baylis-Hillman ads have several features, including anti-parasitic activities. Thus, the target of our study is an adduct, 2- (3-hydroxy-1-methyl-2-oxoindolin-3-yl) acrylonitrile, also called CH3ISACN. Thus, the present study aimed to investigate the potential of the CH3ISACN adduct as an antimalarial through in vitro studies, and to evaluate its toxicological effects in silico and in vivo. For this, the compound CH3ISACN was exposed to the W2 strain of P.falciparum in human erythrocytes, and evaluated if it was able to reduce parasitemia. It was also verified if it was able to cause hemolysis to erythrocytes. In addition, the theoretical pharmacokinetic and toxicological characteristics of the CH3ISACN adduct were investigated through in silico tests with the software AdmetSAR and Molinspiration. In addition, an acute in vivo toxicological study was carried out, following the experimental protocols adopted at the Toxicological Testing Laboratory (LABETOX) and the OECD Guide 423 (2001). Thus, an initial dose of 300 mg / kg of the test substance was administered to Wistar rats and subsequently, with no deaths, a dose of 2000 mg / kg was administered to other rats of the same species. During the experiment, behavioral parameters, water consumption, feed and weight evolution were evaluated. After 14 days, the animals were euthanized by overdose of anesthetic, and their blood collected for evaluation of biochemical and hematological parameters. The results showed that the CH3ISACN adduct showed good antiplasmodial activity, and low cytotoxicity, with good cell viability. In addition to what was shown to have a good theoretical oral bioavailability and did not present toxicity risks in in silico studies. Furthermore, the CH3ISACN adduct did not cause death in any of the animals, thus presenting a high LD50 and being classified according to GSH in category 5, as having low toxicity. There is also no behavioral change, as well as in the other parameters applicable to the highest dose tested, without causing a significant change. Only a reduction in urea concentration, but that did not bring relevant clinical significance. Finally, either CH3ISACN has a good candidate for malaria treatment. Therefore, it is of great value to continue your study, until reaching clinical phase tests, and thus be included in the therapeutic arsenal against malaria. |
publishDate |
2020 |
dc.date.none.fl_str_mv |
2020-11-04T10:46:25Z 2020-11-03 2020-11-04T10:46:25Z 2020-02-27 |
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/123456789/18351 |
url |
https://repositorio.ufpb.br/jspui/handle/123456789/18351 |
dc.language.iso.fl_str_mv |
por |
language |
por |
dc.rights.driver.fl_str_mv |
http://creativecommons.org/licenses/by-nd/3.0/br/ info:eu-repo/semantics/openAccess |
rights_invalid_str_mv |
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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diretoria@ufpb.br|| diretoria@ufpb.br |
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1801842961556701184 |