Investigação da toxicidade e do mecanismo de ação do aduto de morita-baylis-hillman (CH3ISACN) como um antimalárico
Autor(a) principal: | |
---|---|
Data de Publicação: | 2024 |
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/123456789/31613 |
Resumo: | Malaria is a disease caused by the bite of the female Anopheles mosquito, which is infected by species of the genus Plasmodium. Although there are different antimalarials, the resistance that parasites have shown to them is a problem, which makes the development of new medicines urgent. Thus, the present work aimed to evaluate the toxicity of repeated doses of the 2-(3-hydroxy-1-methyl-2-oxoindolin-3- yl) acrylonitrile adduct (CH3ISACN), and its ability to reduce parasitemia using the model murine Plasmodium berghei, as well as investigating its mechanism of action as an antimalarial. The subacute toxicological study was based on OECD 407 (2008). CH3ISACN was administered orally to Swiss mice for 28 days at different doses. The animals were distributed into a control group and three treated groups (75 mg/Kg, 150 mg/Kg, 300 mg/Kg). Each group contained 5 males and 5 females. Water consumption, feed, body weight, clinical signs and mortality were analyzed. After 28 days, the animals were euthanized by an overdose of anesthetic, and their blood was collected to evaluate biochemical and hematological parameters, and their organs were collected for histopathological analysis. A genotoxicity study was carried out following OECD 474 (2014). Each group contained three animals: positive control group (50 mg/kg of cyclophosphamide), negative control group (vehicle), group treated 1 and 2 with 300 mg/kg and 600 mg/kg of CH3ISACN respectively. Administration was a single dose by gavage, over 24 hours. For pharmacological evaluation, 5 mice were separated per group. Group 1: test (250 mg/kg of the adduct); Group 2: negative control (vehicle); Group 3: positive control (15 mg of chloroquine); Group 4: organ control. Initially, the animals were inoculated intraperitoneally with erythrocytes infected with P. berghei ANKA, except group 4. They received treatment for 4 consecutive days, and on the 5th/7th day after infection, blood smears were examined to determine parasitemia. Cumulative mortality was observed until the death of one of the animals in group 2. And the animals' organs were subjected to histopathological analysis. The mechanism of action of CH3ISACN as an antiplasmodial agent was investigated based on its ability to inhibit falcipains and/or berghepains. For this, a molecular modeling approach and quantum calculations were carried out, applying docking analysis, molecular dynamics, QM/MM calculations, and MFCC. The toxicological results showed that CH3ISACN did not cause behavioral, physiological or histopathological changes. Also, it did not promote genotoxicity at the doses tested. Thus, the results obtained did not show significant intoxication, ensuring greater safety for its use. CH3ISACN was active against P.berghei, reducing the parasitemia of infected animals by 49.7% and in its histopathological analysis, animals treated by CH3ISACN showed few changes. Its mechanism of action involves the inhibition of FP-2, FP-3, BP-1 and BP-2. Based on the results already obtained, CH3ISACN is promising as a prototype for a new antimalarial. It is important to continue its study, to reach the clinical phase, and thus be part of the therapeutic arsenal against malaria. |
id |
UFPB_d038ea906a1a2ac229323ff0d7b7a6b4 |
---|---|
oai_identifier_str |
oai:repositorio.ufpb.br:123456789/31613 |
network_acronym_str |
UFPB |
network_name_str |
Biblioteca Digital de Teses e Dissertações da UFPB |
repository_id_str |
|
spelling |
Investigação da toxicidade e do mecanismo de ação do aduto de morita-baylis-hillman (CH3ISACN) como um antimaláricoToxicologiaBerghepaínasFalcipaínasMaláriaPlasmodium bergheiBerghepainsFalcipainsPharmacologyMalariaPlasmodium bergheiToxicologyCNPQ::CIENCIAS BIOLOGICAS::FARMACOLOGIAMalaria is a disease caused by the bite of the female Anopheles mosquito, which is infected by species of the genus Plasmodium. Although there are different antimalarials, the resistance that parasites have shown to them is a problem, which makes the development of new medicines urgent. Thus, the present work aimed to evaluate the toxicity of repeated doses of the 2-(3-hydroxy-1-methyl-2-oxoindolin-3- yl) acrylonitrile adduct (CH3ISACN), and its ability to reduce parasitemia using the model murine Plasmodium berghei, as well as investigating its mechanism of action as an antimalarial. The subacute toxicological study was based on OECD 407 (2008). CH3ISACN was administered orally to Swiss mice for 28 days at different doses. The animals were distributed into a control group and three treated groups (75 mg/Kg, 150 mg/Kg, 300 mg/Kg). Each group contained 5 males and 5 females. Water consumption, feed, body weight, clinical signs and mortality were analyzed. After 28 days, the animals were euthanized by an overdose of anesthetic, and their blood was collected to evaluate biochemical and hematological parameters, and their organs were collected for histopathological analysis. A genotoxicity study was carried out following OECD 474 (2014). Each group contained three animals: positive control group (50 mg/kg of cyclophosphamide), negative control group (vehicle), group treated 1 and 2 with 300 mg/kg and 600 mg/kg of CH3ISACN respectively. Administration was a single dose by gavage, over 24 hours. For pharmacological evaluation, 5 mice were separated per group. Group 1: test (250 mg/kg of the adduct); Group 2: negative control (vehicle); Group 3: positive control (15 mg of chloroquine); Group 4: organ control. Initially, the animals were inoculated intraperitoneally with erythrocytes infected with P. berghei ANKA, except group 4. They received treatment for 4 consecutive days, and on the 5th/7th day after infection, blood smears were examined to determine parasitemia. Cumulative mortality was observed until the death of one of the animals in group 2. And the animals' organs were subjected to histopathological analysis. The mechanism of action of CH3ISACN as an antiplasmodial agent was investigated based on its ability to inhibit falcipains and/or berghepains. For this, a molecular modeling approach and quantum calculations were carried out, applying docking analysis, molecular dynamics, QM/MM calculations, and MFCC. The toxicological results showed that CH3ISACN did not cause behavioral, physiological or histopathological changes. Also, it did not promote genotoxicity at the doses tested. Thus, the results obtained did not show significant intoxication, ensuring greater safety for its use. CH3ISACN was active against P.berghei, reducing the parasitemia of infected animals by 49.7% and in its histopathological analysis, animals treated by CH3ISACN showed few changes. Its mechanism of action involves the inhibition of FP-2, FP-3, BP-1 and BP-2. Based on the results already obtained, CH3ISACN is promising as a prototype for a new antimalarial. It is important to continue its study, to reach the clinical phase, and thus be part of the therapeutic arsenal against malaria.Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPESA malária é uma doença causada pela picada do mosquito fêmea Anopheles, que está infectado por espécies do gênero Plasmodium. Apesar de existirem diferentes antimaláricos, a resistência que os parasitos tem apresentado a estes é uma problemática, o que torna urgente o desenvolvimento de que novos fármacos. Assim, o presente trabalho teve como objetivo avaliar a toxicidade de doses repetidas do aduto 2- (3-hidroxi-1-metil-2-oxoindolin-3-il) acrilonitrila (CH3ISACN), e sua capacidade de reduzir a parasitemia utilizando o modelo murinho Plasmodium berghei, bem como investigar seu mecanismo de ação como um antimalárico. O estudo toxicológico subagudo foi baseado na OECD 407 (2008). A CH3ISACN foi administrada nos camundongos Swiss por via oral, durante 28 dias em diferentes doses. Os animais foram distribuídos em um grupo controle e três grupos tratados (75 mg/Kg, 150 mg/Kg, 300 mg/Kg). Cada grupo continha 5 machos e 5 fêmeas. Foram analisados o consumo de água, ração, peso corporal, sinais clínicos e mortalidade. Após 28 dias, os animais foram eutanasiados por sobredose de anestésico, e seu sangue coletado para avaliação de parâmetros bioquímicos e hematológicos, e seus órgãos coletados para análise histopatológica. Foi realizado estudo de genotoxicidade seguindo a OECD 474 (2014). Cada grupo continha três animais, sendo: grupo controle positivo (50 mg/Kg de ciclofosfamida), grupo controle negativo (veículo), grupo tratado 1 e 2 com 300 mg/Kg e 600 mg/Kg de CH3ISACN respectivamente. A administração foi em dose única por gavagem, em 24 horas. Para avaliação farmacológica, foram separados 5 camundongos por grupo. Grupo 1: teste (250 mg/Kg do aduto); Grupo 2: controle negativo (veículo); Grupo 3: controle positivo (15 mg de cloroquina); Grupo 4: controle de órgãos. Inicialmente os animais foram inoculados via intraperitoneal com eritrócitos infectados com P. berghei ANKA, exceto o grupo 4. Receberam tratamento durante 4 dias consecutivos, e no 5º/7º dia após a infecção, esfregaços sanguíneos foram examinados para determinação da parasitemia. A mortalidade cumulativa foi observada até a morte de um dos animais do grupo 2. E os órgãos dos animais foram submetidos à análise histopatológica. O mecanismo de ação da CH3ISACN como antiplasmodial, foi investigado a partir de sua capacidade de inibir falcipaínas e/ou berghepaínas. Para isso foram realizados abordagem de modelagem molecular e cálculos quânticos sendo aplicado análise de docking, dinâmica molecular, cálculos QM/MM, e MFCC. Os resultados toxicológicos mostraram que a CH3ISACN não provocou alterações comportamentais, fisiológicas e histopatológicas. Também, não promoveu genotoxicidade nas doses testadas. Assim, os resultados obtidos não mostraram intoxicação significativa, garantindo maior segurança para seu uso. A CH3ISACN foi ativa contra o P.berghei, reduzindo a parasitemia dos animais infectados em 49,7% e em sua análise histopatológica os animais tratados por CH3ISACN apresentaram poucas alterações. Seu mecanismo de ação envolve a inibição das FP-2, FP-3, BP-1 e BP-2. A partir dos resultados já obtidos, a CH3ISACN é promissora como protótipo para novo antimalárico. Sendo importante a continuação de seu estudo, para alcançar a fase clínica, e assim fazer parte do arsenal terapêutico contra a malária.Universidade Federal da ParaíbaBrasilFarmacologiaPrograma de Pós-Graduação em Desenvolvimento e Inovação Tecnológica em MedicamentosUFPBDiniz, Margareth de Fátima Formiga Melohttp://lattes.cnpq.br/4173269414899195Andrade Neto, Valter Ferreira dehttp://lattes.cnpq.br/4863082845974813Melo, Cinthia Rodrigues2024-08-28T17:10:15Z2024-03-282024-08-28T17:10:15Z2024-02-20info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/doctoralThesishttps://repositorio.ufpb.br/jspui/handle/123456789/31613porAttribution-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:UFPB2024-08-29T06:06:03Zoai:repositorio.ufpb.br:123456789/31613Biblioteca Digital de Teses e Dissertaçõeshttps://repositorio.ufpb.br/PUBhttp://tede.biblioteca.ufpb.br:8080/oai/requestdiretoria@ufpb.br|| diretoria@ufpb.bropendoar:2024-08-29T06:06:03Biblioteca Digital de Teses e Dissertações da UFPB - Universidade Federal da Paraíba (UFPB)false |
dc.title.none.fl_str_mv |
Investigação da toxicidade e do mecanismo de ação do aduto de morita-baylis-hillman (CH3ISACN) como um antimalárico |
title |
Investigação da toxicidade e do mecanismo de ação do aduto de morita-baylis-hillman (CH3ISACN) como um antimalárico |
spellingShingle |
Investigação da toxicidade e do mecanismo de ação do aduto de morita-baylis-hillman (CH3ISACN) como um antimalárico Melo, Cinthia Rodrigues Toxicologia Berghepaínas Falcipaínas Malária Plasmodium berghei Berghepains Falcipains Pharmacology Malaria Plasmodium berghei Toxicology CNPQ::CIENCIAS BIOLOGICAS::FARMACOLOGIA |
title_short |
Investigação da toxicidade e do mecanismo de ação do aduto de morita-baylis-hillman (CH3ISACN) como um antimalárico |
title_full |
Investigação da toxicidade e do mecanismo de ação do aduto de morita-baylis-hillman (CH3ISACN) como um antimalárico |
title_fullStr |
Investigação da toxicidade e do mecanismo de ação do aduto de morita-baylis-hillman (CH3ISACN) como um antimalárico |
title_full_unstemmed |
Investigação da toxicidade e do mecanismo de ação do aduto de morita-baylis-hillman (CH3ISACN) como um antimalárico |
title_sort |
Investigação da toxicidade e do mecanismo de ação do aduto de morita-baylis-hillman (CH3ISACN) como um antimalárico |
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 Andrade Neto, Valter Ferreira de http://lattes.cnpq.br/4863082845974813 |
dc.contributor.author.fl_str_mv |
Melo, Cinthia Rodrigues |
dc.subject.por.fl_str_mv |
Toxicologia Berghepaínas Falcipaínas Malária Plasmodium berghei Berghepains Falcipains Pharmacology Malaria Plasmodium berghei Toxicology CNPQ::CIENCIAS BIOLOGICAS::FARMACOLOGIA |
topic |
Toxicologia Berghepaínas Falcipaínas Malária Plasmodium berghei Berghepains Falcipains Pharmacology Malaria Plasmodium berghei Toxicology CNPQ::CIENCIAS BIOLOGICAS::FARMACOLOGIA |
description |
Malaria is a disease caused by the bite of the female Anopheles mosquito, which is infected by species of the genus Plasmodium. Although there are different antimalarials, the resistance that parasites have shown to them is a problem, which makes the development of new medicines urgent. Thus, the present work aimed to evaluate the toxicity of repeated doses of the 2-(3-hydroxy-1-methyl-2-oxoindolin-3- yl) acrylonitrile adduct (CH3ISACN), and its ability to reduce parasitemia using the model murine Plasmodium berghei, as well as investigating its mechanism of action as an antimalarial. The subacute toxicological study was based on OECD 407 (2008). CH3ISACN was administered orally to Swiss mice for 28 days at different doses. The animals were distributed into a control group and three treated groups (75 mg/Kg, 150 mg/Kg, 300 mg/Kg). Each group contained 5 males and 5 females. Water consumption, feed, body weight, clinical signs and mortality were analyzed. After 28 days, the animals were euthanized by an overdose of anesthetic, and their blood was collected to evaluate biochemical and hematological parameters, and their organs were collected for histopathological analysis. A genotoxicity study was carried out following OECD 474 (2014). Each group contained three animals: positive control group (50 mg/kg of cyclophosphamide), negative control group (vehicle), group treated 1 and 2 with 300 mg/kg and 600 mg/kg of CH3ISACN respectively. Administration was a single dose by gavage, over 24 hours. For pharmacological evaluation, 5 mice were separated per group. Group 1: test (250 mg/kg of the adduct); Group 2: negative control (vehicle); Group 3: positive control (15 mg of chloroquine); Group 4: organ control. Initially, the animals were inoculated intraperitoneally with erythrocytes infected with P. berghei ANKA, except group 4. They received treatment for 4 consecutive days, and on the 5th/7th day after infection, blood smears were examined to determine parasitemia. Cumulative mortality was observed until the death of one of the animals in group 2. And the animals' organs were subjected to histopathological analysis. The mechanism of action of CH3ISACN as an antiplasmodial agent was investigated based on its ability to inhibit falcipains and/or berghepains. For this, a molecular modeling approach and quantum calculations were carried out, applying docking analysis, molecular dynamics, QM/MM calculations, and MFCC. The toxicological results showed that CH3ISACN did not cause behavioral, physiological or histopathological changes. Also, it did not promote genotoxicity at the doses tested. Thus, the results obtained did not show significant intoxication, ensuring greater safety for its use. CH3ISACN was active against P.berghei, reducing the parasitemia of infected animals by 49.7% and in its histopathological analysis, animals treated by CH3ISACN showed few changes. Its mechanism of action involves the inhibition of FP-2, FP-3, BP-1 and BP-2. Based on the results already obtained, CH3ISACN is promising as a prototype for a new antimalarial. It is important to continue its study, to reach the clinical phase, and thus be part of the therapeutic arsenal against malaria. |
publishDate |
2024 |
dc.date.none.fl_str_mv |
2024-08-28T17:10:15Z 2024-03-28 2024-08-28T17:10:15Z 2024-02-20 |
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/123456789/31613 |
url |
https://repositorio.ufpb.br/jspui/handle/123456789/31613 |
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 Desenvolvimento e Inovação Tecnológica em Medicamentos UFPB |
publisher.none.fl_str_mv |
Universidade Federal da Paraíba Brasil Farmacologia Programa de Pós-Graduação em Desenvolvimento e Inovação Tecnológica em Medicamentos 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 |
_version_ |
1809927050541137920 |