Planejamento e s?ntese de novos h?bridos 1,2,4-triazol-3-tioalquil-nitroimidaz?licos com toxicidade seletiva contra amastigotas de Trypanosoma cruzi

Detalhes bibliográficos
Ano de defesa: 2021
Autor(a) principal: Velez, Afonso Santine Magalh?es Mesquita lattes
Orientador(a): Lima, Marco Edilson Freire de lattes
Banca de defesa: Lima, Marco Edilson Freire de, Trossini, Gustavo Henrique Goulart, Carvalho, Fernando, Kummerle, Arthur Eugne, Moreno, Thiago
Tipo de documento: Dissertação
Tipo de acesso: Acesso aberto
Idioma: por
Instituição de defesa: Universidade Federal Rural do Rio de Janeiro
Programa de Pós-Graduação: Programa de P?s-Gradua??o em Qu?mica
Departamento: Instituto de Qu?mica
País: Brasil
Palavras-chave em Português:
Piperina
Heteroc?clos
Hibrida??o molecular
Palavras-chave em Inglês:
Piperine
Heterocycles
Molecular hybridization
Área do conhecimento CNPq:
Qu?mica
Link de acesso: https://tede.ufrrj.br/jspui/handle/jspui/6388
Resumo: Chagas disease (CD) is one of the main neglected tropical diseases. CD is endemic in rural areas of developing countries in South America, and to date there is no effective treatment. Given the demand for the development of new compounds with therapeutic potential for the treatment of neglected diseases, this work aims to contribute to a study in the development of new drugs with potential antiparasitic activity. Our approach involved the application of a molecular hybridization strategy, using a 1,2,4-triazole-3-thione derivative (with antiparasitic activity previously described by our group). This triazole derivative was prepared from the natural amide piperine, the main chemical component of the dried fruits of Piper nigrum, an accessible natural product that is easy to isolate. The molecular design performed involved the hybridization of the 1,2,4-triazole-3-thione derivative of piperine with different nitroimidazole cores (which stand out as important pharmacophores for the intended antiparasitic activity). The application of this molecular modification strategy, added to the other methodologies developed in this work, allowed the preparation of six novel molecules, the 1,2,4-triazol-3-thioalkyl-nitroimidazole hybrids, which explore different positions of the nitro group in the ring imidazole, with different sizes of alkyl chains. These hybrids showed very promising activity against the amastigote forms of Trypanosoma cruzi (Tulahuen strain, C2C4 LacZ), showing, in the experiments, low to moderate toxicity in the cell models tested; in addition to the fact that all hybrids present inhibitory concentration comparable to that of the reference drug used, benznidazole, especially one hybrid that was ten times more active, with activity in the nM concentration range.
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spelling Lima, Marco Edilson Freire de880.202.667-04http://lattes.cnpq.br/8392420706762318Lima, Marco Edilson Freire deTrossini, Gustavo Henrique GoulartCarvalho, FernandoKummerle, Arthur EugneMoreno, Thiago156.250.377-44http://lattes.cnpq.br/0523866937741746Velez, Afonso Santine Magalh?es Mesquita2023-03-03T17:03:21Z2021-05-27VELEZ, Afonso Santine Magalh?es Mesquita. Planejamento e s?ntese de novos h?bridos 1,2,4-triazol-3-tioalquil-nitroimidaz?licos com toxicidade seletiva contra amastigotas de Trypanosoma cruzi, 2021. 140 f. Disserta??o (Mestrado em Qu?mica) - Instituto de Qu?mica, Universidade Federal Rural do Rio de Janeiro, Serop?dica, RJ, 2021.https://tede.ufrrj.br/jspui/handle/jspui/6388Chagas disease (CD) is one of the main neglected tropical diseases. CD is endemic in rural areas of developing countries in South America, and to date there is no effective treatment. Given the demand for the development of new compounds with therapeutic potential for the treatment of neglected diseases, this work aims to contribute to a study in the development of new drugs with potential antiparasitic activity. Our approach involved the application of a molecular hybridization strategy, using a 1,2,4-triazole-3-thione derivative (with antiparasitic activity previously described by our group). This triazole derivative was prepared from the natural amide piperine, the main chemical component of the dried fruits of Piper nigrum, an accessible natural product that is easy to isolate. The molecular design performed involved the hybridization of the 1,2,4-triazole-3-thione derivative of piperine with different nitroimidazole cores (which stand out as important pharmacophores for the intended antiparasitic activity). The application of this molecular modification strategy, added to the other methodologies developed in this work, allowed the preparation of six novel molecules, the 1,2,4-triazol-3-thioalkyl-nitroimidazole hybrids, which explore different positions of the nitro group in the ring imidazole, with different sizes of alkyl chains. These hybrids showed very promising activity against the amastigote forms of Trypanosoma cruzi (Tulahuen strain, C2C4 LacZ), showing, in the experiments, low to moderate toxicity in the cell models tested; in addition to the fact that all hybrids present inhibitory concentration comparable to that of the reference drug used, benznidazole, especially one hybrid that was ten times more active, with activity in the nM concentration range.A doen?a de Chagas (DC) ? uma das principais doen?as tropicais negligenciadas. A DC ? end?mica em ?reas rurais de pa?ses em desenvolvimento da Am?rica do Sul, e at? hoje n?o conta com um tratamento efetivo. Face ? demanda de desenvolvimento de novos compostos com potencial terap?utico para o tratamento de doen?as negligenciadas, esse trabalho visa contribuir com estudo no desenvolvimento de novos f?rmacos com potencial atividade antiparasit?ria. Nossa abordagem envolveu a aplica??o da estrat?gia de hibrida??o molecular, utilizando um derivado 1,2,4-triaz?lico-3-tiona (com atividade antiparasit?ria previamente descrita por nosso grupo). Este derivado triaz?lico foi preparado a partir da amida natural piperina, principal componente qu?mico dos frutos secos de Piper nigrum, produto natural acess?vel e de f?cil isolamento. O planejamento molecular realizado envolveu a hibrida??o do derivado 1,2,4-triaz?lico-3-tiona da piperina com diferentes n?cleos nitroimidaz?licos (que se destacam como importantes farmac?foros para a atividade antiparasit?ria pretendida). A aplica??o desta estrat?gia de modifica??o molecular, somada ?s demais metodologias desenvolvidas nesse trabalho, permitiu a prepara??o de seis novas mol?culas in?ditas, os h?bridos 1,2,4-triazol-3-tioalquil-nitroimidaz?licos, que exploram diferentes posi??es do grupamento nitro no anel imidaz?lico, com diferentes tamanhos de cadeias alqu?licas. Esses h?bridos apresentaram atividade muito promissora contra as formas amastigotas do Trypanossoma cruzi (cepa Tulahuen, C2C4 LacZ), apresentando nos experimentos, de baixa a moderada toxicidade nos modelos celulares testados; al?m de todos os h?bridos apresentarem concentra??o inibit?ria compar?veis a do f?rmaco de refer?ncia utilizado, benzonidazol, com destaque para um h?brido em especial que se mostrou dez vezes mais ativo, com atividade na faixa de concentra??o de nM.Submitted by Jorge Silva (jorgelmsilva@ufrrj.br) on 2023-03-03T17:03:21Z No. of bitstreams: 1 2021 - Afonso Santine Magalh?es Mesquita Velez.Pdf: 3298126 bytes, checksum: e1275e61229cf46334681053c3f1dcca (MD5)Made available in DSpace on 2023-03-03T17:03:21Z (GMT). No. of bitstreams: 1 2021 - Afonso Santine Magalh?es Mesquita Velez.Pdf: 3298126 bytes, checksum: e1275e61229cf46334681053c3f1dcca (MD5) Previous issue date: 2021-05-27CAPES - Coordena??o de Aperfei?oamento de Pessoal de N?vel SuperiorCNPq - Conselho Nacional de Desenvolvimento Cient?fico e Tecnol?gicoFAPERJ - Funda??o Carlos Chagas Filho de Amparo ? Pesquisa do Estado do Rio de Janeiroapplication/pdfhttps://tede.ufrrj.br/retrieve/72413/2021%20-%20Afonso%20Santine%20Magalh%c3%a3es%20Mesquita%20Velez.Pdf.jpgporUniversidade Federal Rural do Rio de JaneiroPrograma de P?s-Gradua??o em Qu?micaUFRRJBrasilInstituto de Qu?micaAL-ABDULLAH, E. S.; ASIRI, H. H.; LAHSASNI, S.; HABIB, E. E.; IBRAHIM, T. M.; EL-EMAM, A. A. Synthesis, antimicrobial, and anti-inflammatory activity, o novels S-substituted and N-substituted 5-(-adamantyl)-1,2,4-triazole-3-thiols. Drug Des. Develop. Ther., 8, 505-518, 2014. ALSTON, T. A.; ABELES, R. H. 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WHO - Global distribution of cases of Chagas disease, based on official estimates, 2018. Retrieved September 1, 2020, from https://www.who.int/docs/default-source/ntds/chagas-disease/chagas-2018-cases.pdf?sfvrsn=f4e94b3b_2, 2018. WHO - Chagas disease (American trypanosomiasis). Retrieved April 16, 2020, from https://www.who.int/health-topics/chagas-disease#tab=tab_1, 2019. WHO - Celebrating World Chagas Disease Day for the first time in 2020. Retrieved September 1, 2020, from https://www.who.int/news-room/events/detail/2020/04/14/ default-calendar/celebrating-world-chagas-disease-day-for-the-first-time-in-2020, 2020. XAVIER, S. C. C.; ROQUE, A. L. M.; BILAC, D.; ARA?JO, V. A. L.; NETO, S. F. C.; LOROSA, E. S.; SILVA, L. F. C. F.; JANSEN, A. M. Distantiae Transmission of Trypanosoma cruzi: A New Epidemiological Feature of Acute Chagas Disease in Brazil. 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dc.title.por.fl_str_mv Planejamento e s?ntese de novos h?bridos 1,2,4-triazol-3-tioalquil-nitroimidaz?licos com toxicidade seletiva contra amastigotas de Trypanosoma cruzi
dc.title.alternative.eng.fl_str_mv Planning and synthesis of new 1,2,4-triazole-3-thioalkyl-nitroimidazole hybrids with selective toxicity aganist Trypanosoma cruzi amastigotes
title Planejamento e s?ntese de novos h?bridos 1,2,4-triazol-3-tioalquil-nitroimidaz?licos com toxicidade seletiva contra amastigotas de Trypanosoma cruzi
spellingShingle Planejamento e s?ntese de novos h?bridos 1,2,4-triazol-3-tioalquil-nitroimidaz?licos com toxicidade seletiva contra amastigotas de Trypanosoma cruzi
Velez, Afonso Santine Magalh?es Mesquita
Piperina
Heteroc?clos
Hibrida??o molecular
Piperine
Heterocycles
Molecular hybridization
Qu?mica
title_short Planejamento e s?ntese de novos h?bridos 1,2,4-triazol-3-tioalquil-nitroimidaz?licos com toxicidade seletiva contra amastigotas de Trypanosoma cruzi
title_full Planejamento e s?ntese de novos h?bridos 1,2,4-triazol-3-tioalquil-nitroimidaz?licos com toxicidade seletiva contra amastigotas de Trypanosoma cruzi
title_fullStr Planejamento e s?ntese de novos h?bridos 1,2,4-triazol-3-tioalquil-nitroimidaz?licos com toxicidade seletiva contra amastigotas de Trypanosoma cruzi
title_full_unstemmed Planejamento e s?ntese de novos h?bridos 1,2,4-triazol-3-tioalquil-nitroimidaz?licos com toxicidade seletiva contra amastigotas de Trypanosoma cruzi
title_sort Planejamento e s?ntese de novos h?bridos 1,2,4-triazol-3-tioalquil-nitroimidaz?licos com toxicidade seletiva contra amastigotas de Trypanosoma cruzi
author Velez, Afonso Santine Magalh?es Mesquita
author_facet Velez, Afonso Santine Magalh?es Mesquita
author_role author
dc.contributor.advisor1.fl_str_mv Lima, Marco Edilson Freire de
dc.contributor.advisor1ID.fl_str_mv 880.202.667-04
dc.contributor.advisor1Lattes.fl_str_mv http://lattes.cnpq.br/8392420706762318
dc.contributor.referee1.fl_str_mv Lima, Marco Edilson Freire de
dc.contributor.referee2.fl_str_mv Trossini, Gustavo Henrique Goulart
dc.contributor.referee3.fl_str_mv Carvalho, Fernando
dc.contributor.referee4.fl_str_mv Kummerle, Arthur Eugne
dc.contributor.referee5.fl_str_mv Moreno, Thiago
dc.contributor.authorID.fl_str_mv 156.250.377-44
dc.contributor.authorLattes.fl_str_mv http://lattes.cnpq.br/0523866937741746
dc.contributor.author.fl_str_mv Velez, Afonso Santine Magalh?es Mesquita
contributor_str_mv Lima, Marco Edilson Freire de
Lima, Marco Edilson Freire de
Trossini, Gustavo Henrique Goulart
Carvalho, Fernando
Kummerle, Arthur Eugne
Moreno, Thiago
dc.subject.por.fl_str_mv Piperina
Heteroc?clos
Hibrida??o molecular
topic Piperina
Heteroc?clos
Hibrida??o molecular
Piperine
Heterocycles
Molecular hybridization
Qu?mica
dc.subject.eng.fl_str_mv Piperine
Heterocycles
Molecular hybridization
dc.subject.cnpq.fl_str_mv Qu?mica
description Chagas disease (CD) is one of the main neglected tropical diseases. CD is endemic in rural areas of developing countries in South America, and to date there is no effective treatment. Given the demand for the development of new compounds with therapeutic potential for the treatment of neglected diseases, this work aims to contribute to a study in the development of new drugs with potential antiparasitic activity. Our approach involved the application of a molecular hybridization strategy, using a 1,2,4-triazole-3-thione derivative (with antiparasitic activity previously described by our group). This triazole derivative was prepared from the natural amide piperine, the main chemical component of the dried fruits of Piper nigrum, an accessible natural product that is easy to isolate. The molecular design performed involved the hybridization of the 1,2,4-triazole-3-thione derivative of piperine with different nitroimidazole cores (which stand out as important pharmacophores for the intended antiparasitic activity). The application of this molecular modification strategy, added to the other methodologies developed in this work, allowed the preparation of six novel molecules, the 1,2,4-triazol-3-thioalkyl-nitroimidazole hybrids, which explore different positions of the nitro group in the ring imidazole, with different sizes of alkyl chains. These hybrids showed very promising activity against the amastigote forms of Trypanosoma cruzi (Tulahuen strain, C2C4 LacZ), showing, in the experiments, low to moderate toxicity in the cell models tested; in addition to the fact that all hybrids present inhibitory concentration comparable to that of the reference drug used, benznidazole, especially one hybrid that was ten times more active, with activity in the nM concentration range.
publishDate 2021
dc.date.issued.fl_str_mv 2021-05-27
dc.date.accessioned.fl_str_mv 2023-03-03T17:03:21Z
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.citation.fl_str_mv VELEZ, Afonso Santine Magalh?es Mesquita. Planejamento e s?ntese de novos h?bridos 1,2,4-triazol-3-tioalquil-nitroimidaz?licos com toxicidade seletiva contra amastigotas de Trypanosoma cruzi, 2021. 140 f. Disserta??o (Mestrado em Qu?mica) - Instituto de Qu?mica, Universidade Federal Rural do Rio de Janeiro, Serop?dica, RJ, 2021.
dc.identifier.uri.fl_str_mv https://tede.ufrrj.br/jspui/handle/jspui/6388
identifier_str_mv VELEZ, Afonso Santine Magalh?es Mesquita. Planejamento e s?ntese de novos h?bridos 1,2,4-triazol-3-tioalquil-nitroimidaz?licos com toxicidade seletiva contra amastigotas de Trypanosoma cruzi, 2021. 140 f. Disserta??o (Mestrado em Qu?mica) - Instituto de Qu?mica, Universidade Federal Rural do Rio de Janeiro, Serop?dica, RJ, 2021.
url https://tede.ufrrj.br/jspui/handle/jspui/6388
dc.language.iso.fl_str_mv por
language por
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