Síntese de pseudo-peptídeos contendo calcogenonucleosídeos via reações de UGI como potenciais inibidores do SARS-CoV-2
Autor(a) principal: | |
---|---|
Data de Publicação: | 2023 |
Tipo de documento: | Tese |
Idioma: | por |
Título da fonte: | Manancial - Repositório Digital da UFSM |
Texto Completo: | http://repositorio.ufsm.br/handle/1/29622 |
Resumo: | In this work, a reaction protocol was developed for a new class of pseudo-peptides through multicomponent reactions (MCR) of the Ugi’s four component reaction (U-4CR) type, starting from chalcogenonucleosides. The synthetic route was planned to have a single reaction step under mild conditions. The U-4CR reactions provide great structural versatility since the four components presented groups that could be modified: amine, aldehyde, carboxylic acid, and isocyanide. This study emphasized the amine component, in which 5'-arylchalcogenyl-3-amino-thymidines 5a-f were employed. The carboxylic acid component was also explored, two types of isocyanates were studied, and only one aldehyde was used in the reactions. The synthetic route involved a one-pot reaction at room temperature using an ethanolic milieu, and the 9a-q products were obtained with yields ranging from 25 to 77%. The products were characterized by 1H and 13C NMR spectroscopy, and also HRMS. Two-dimensional 1H and 13C NMR experiments were carried out, however, the registered spectra exhibited poor resolution and no signal attribution was performed. In silico molecular docking studies were performed to evaluate the possible interactions between the obtained compounds and the main protease (Mpro) of SARS-CoV-2. The seventeen compounds were evaluated, and nine compounds exhibited favorable interactions at the stable position close to the active site of the Mpro of SARS-CoV-2, with a highlight for compounds 9b and 9h, whose binding energies with Mpro are -8.7 and -8.8 kcal mol-1, respectively, which are bigger than the exhibit by the standard drug nirmatrelvir. In concluding remarks, seventeen new molecules were synthesized in good yields, making clear the success of Ugi 4-CR reactions in forming pseudo-peptides using chalcogenonucleosides. As prospects for further studies, these molecules can be important targets for investigating biological activities, such as evaluating antitumor activity, among others. |
id |
UFSM_76e2af72a42b126b21c5792f2f1e2323 |
---|---|
oai_identifier_str |
oai:repositorio.ufsm.br:1/29622 |
network_acronym_str |
UFSM |
network_name_str |
Manancial - Repositório Digital da UFSM |
repository_id_str |
|
spelling |
Síntese de pseudo-peptídeos contendo calcogenonucleosídeos via reações de UGI como potenciais inibidores do SARS-CoV-2Synthesis of pseudo-peptides containing chalcogenonucleosides via UGI reactions as pontential SARS-CoV-2 inhibitorsPseudo-peptídeosCalcogenonucleosídeosReações de UgiSARS-CoV-2Modelagem molecularPseudo-peptidesChalcogenonucleosidesUgi reactionsMolecular dockingCNPQ::CIENCIAS EXATAS E DA TERRA::QUIMICAIn this work, a reaction protocol was developed for a new class of pseudo-peptides through multicomponent reactions (MCR) of the Ugi’s four component reaction (U-4CR) type, starting from chalcogenonucleosides. The synthetic route was planned to have a single reaction step under mild conditions. The U-4CR reactions provide great structural versatility since the four components presented groups that could be modified: amine, aldehyde, carboxylic acid, and isocyanide. This study emphasized the amine component, in which 5'-arylchalcogenyl-3-amino-thymidines 5a-f were employed. The carboxylic acid component was also explored, two types of isocyanates were studied, and only one aldehyde was used in the reactions. The synthetic route involved a one-pot reaction at room temperature using an ethanolic milieu, and the 9a-q products were obtained with yields ranging from 25 to 77%. The products were characterized by 1H and 13C NMR spectroscopy, and also HRMS. Two-dimensional 1H and 13C NMR experiments were carried out, however, the registered spectra exhibited poor resolution and no signal attribution was performed. In silico molecular docking studies were performed to evaluate the possible interactions between the obtained compounds and the main protease (Mpro) of SARS-CoV-2. The seventeen compounds were evaluated, and nine compounds exhibited favorable interactions at the stable position close to the active site of the Mpro of SARS-CoV-2, with a highlight for compounds 9b and 9h, whose binding energies with Mpro are -8.7 and -8.8 kcal mol-1, respectively, which are bigger than the exhibit by the standard drug nirmatrelvir. In concluding remarks, seventeen new molecules were synthesized in good yields, making clear the success of Ugi 4-CR reactions in forming pseudo-peptides using chalcogenonucleosides. As prospects for further studies, these molecules can be important targets for investigating biological activities, such as evaluating antitumor activity, among others.Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPESNesse trabalho, desenvolveu-se um protocolo reacional para uma nova classe de pseudo-peptídeos, através das reações multicomponentes (MCR) do tipo Ugi de quatro componentes (U-4CR), a partir de calcogenonucleosídeos. Planejou-se a elaboração de uma rota sintética envolvendo transformações simples, em condições reacionais brandas e, em uma única etapa reacional. As reações multicomponentes de Ugi possuem uma grande versatilidade estrutural, uma vez que, os quatro componentes das reações de Ugi apresentaram grupamentos passíveis de modificações: amina, aldeído, ácido carboxílico e, isocianeto. Este estudo direcionou a ênfase para o componente amina, no qual foram empregadas as 5’-arilcalcogenil-3-amino-timidinas 5a-f. O componente ácido carboxílico também foi explorado, dois tipos de isocianetos foram estudados e apenas um aldeído foi empregado nas reações. O roteiro de síntese desenvolvido envolveu uma reação one-pot à temperatura ambiente, em meio etanólico, e os produtos 9a-q foram obtidos com valores de rendimentos na faixa de 25 a 77%. Os produtos foram caracterizados por RMN de 1H e de 13C e EMAR. Foram realizados experimentos de RMN de 1H e 13C em duas dimensões, no entanto, os espectros registrados não apresentaram resolução suficiente para fazer qualquer atribuição aos sinais. Também foram avaliados estudos de ancoragem molecular in silico para prever as possíveis interações entre os compostos obtidos e a protease principal (Mpro) do SARS-CoV-2. Os dezessete compostos foram avaliados, e 9 compostos apresentaram interações favoráveis na posição mais estável na região do sítio ativo da Mpro do SARS-CoV-2, com destaque para os compostos 9b e 9h, cujos valores para a energia de ligação com a Mpro são de –8,7 e –8,8 kcal mol-1, respectivamente, no qual se mostraram superiores ao fármaco utilizado como padrão nirmatrelvir. Ao final deste trabalho, foram sintetizadas 17 novas moléculas, em bons rendimentos, deixando claro o sucesso das U-4CR na formação de pseudo-peptídeos utilizando calcogenonucleosídeos. Como perspectivas de estudos, essas moléculas podem ser alvos importantes para a investigação de atividades biológicas, como a avaliação da atividade antitumoral, entre outras.Universidade Federal de Santa MariaBrasilQuímicaUFSMPrograma de Pós-Graduação em QuímicaCentro de Ciências Naturais e ExatasRodrigues, Oscar Endrigo Dorneleshttp://lattes.cnpq.br/6536519955416085Dornelles, LucianoDacol, Ionara IrionMorel, Ademir FariasSouza, Diego deVargas, JosimarRosa, Raquel Mello da2023-07-04T13:28:51Z2023-07-04T13:28:51Z2023-03-30info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/doctoralThesisapplication/pdfhttp://repositorio.ufsm.br/handle/1/29622porAttribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessreponame:Manancial - Repositório Digital da UFSMinstname:Universidade Federal de Santa Maria (UFSM)instacron:UFSM2023-07-04T13:28:51Zoai:repositorio.ufsm.br:1/29622Biblioteca Digital de Teses e Dissertaçõeshttps://repositorio.ufsm.br/ONGhttps://repositorio.ufsm.br/oai/requestatendimento.sib@ufsm.br||tedebc@gmail.comopendoar:2023-07-04T13:28:51Manancial - Repositório Digital da UFSM - Universidade Federal de Santa Maria (UFSM)false |
dc.title.none.fl_str_mv |
Síntese de pseudo-peptídeos contendo calcogenonucleosídeos via reações de UGI como potenciais inibidores do SARS-CoV-2 Synthesis of pseudo-peptides containing chalcogenonucleosides via UGI reactions as pontential SARS-CoV-2 inhibitors |
title |
Síntese de pseudo-peptídeos contendo calcogenonucleosídeos via reações de UGI como potenciais inibidores do SARS-CoV-2 |
spellingShingle |
Síntese de pseudo-peptídeos contendo calcogenonucleosídeos via reações de UGI como potenciais inibidores do SARS-CoV-2 Rosa, Raquel Mello da Pseudo-peptídeos Calcogenonucleosídeos Reações de Ugi SARS-CoV-2 Modelagem molecular Pseudo-peptides Chalcogenonucleosides Ugi reactions Molecular docking CNPQ::CIENCIAS EXATAS E DA TERRA::QUIMICA |
title_short |
Síntese de pseudo-peptídeos contendo calcogenonucleosídeos via reações de UGI como potenciais inibidores do SARS-CoV-2 |
title_full |
Síntese de pseudo-peptídeos contendo calcogenonucleosídeos via reações de UGI como potenciais inibidores do SARS-CoV-2 |
title_fullStr |
Síntese de pseudo-peptídeos contendo calcogenonucleosídeos via reações de UGI como potenciais inibidores do SARS-CoV-2 |
title_full_unstemmed |
Síntese de pseudo-peptídeos contendo calcogenonucleosídeos via reações de UGI como potenciais inibidores do SARS-CoV-2 |
title_sort |
Síntese de pseudo-peptídeos contendo calcogenonucleosídeos via reações de UGI como potenciais inibidores do SARS-CoV-2 |
author |
Rosa, Raquel Mello da |
author_facet |
Rosa, Raquel Mello da |
author_role |
author |
dc.contributor.none.fl_str_mv |
Rodrigues, Oscar Endrigo Dorneles http://lattes.cnpq.br/6536519955416085 Dornelles, Luciano Dacol, Ionara Irion Morel, Ademir Farias Souza, Diego de Vargas, Josimar |
dc.contributor.author.fl_str_mv |
Rosa, Raquel Mello da |
dc.subject.por.fl_str_mv |
Pseudo-peptídeos Calcogenonucleosídeos Reações de Ugi SARS-CoV-2 Modelagem molecular Pseudo-peptides Chalcogenonucleosides Ugi reactions Molecular docking CNPQ::CIENCIAS EXATAS E DA TERRA::QUIMICA |
topic |
Pseudo-peptídeos Calcogenonucleosídeos Reações de Ugi SARS-CoV-2 Modelagem molecular Pseudo-peptides Chalcogenonucleosides Ugi reactions Molecular docking CNPQ::CIENCIAS EXATAS E DA TERRA::QUIMICA |
description |
In this work, a reaction protocol was developed for a new class of pseudo-peptides through multicomponent reactions (MCR) of the Ugi’s four component reaction (U-4CR) type, starting from chalcogenonucleosides. The synthetic route was planned to have a single reaction step under mild conditions. The U-4CR reactions provide great structural versatility since the four components presented groups that could be modified: amine, aldehyde, carboxylic acid, and isocyanide. This study emphasized the amine component, in which 5'-arylchalcogenyl-3-amino-thymidines 5a-f were employed. The carboxylic acid component was also explored, two types of isocyanates were studied, and only one aldehyde was used in the reactions. The synthetic route involved a one-pot reaction at room temperature using an ethanolic milieu, and the 9a-q products were obtained with yields ranging from 25 to 77%. The products were characterized by 1H and 13C NMR spectroscopy, and also HRMS. Two-dimensional 1H and 13C NMR experiments were carried out, however, the registered spectra exhibited poor resolution and no signal attribution was performed. In silico molecular docking studies were performed to evaluate the possible interactions between the obtained compounds and the main protease (Mpro) of SARS-CoV-2. The seventeen compounds were evaluated, and nine compounds exhibited favorable interactions at the stable position close to the active site of the Mpro of SARS-CoV-2, with a highlight for compounds 9b and 9h, whose binding energies with Mpro are -8.7 and -8.8 kcal mol-1, respectively, which are bigger than the exhibit by the standard drug nirmatrelvir. In concluding remarks, seventeen new molecules were synthesized in good yields, making clear the success of Ugi 4-CR reactions in forming pseudo-peptides using chalcogenonucleosides. As prospects for further studies, these molecules can be important targets for investigating biological activities, such as evaluating antitumor activity, among others. |
publishDate |
2023 |
dc.date.none.fl_str_mv |
2023-07-04T13:28:51Z 2023-07-04T13:28:51Z 2023-03-30 |
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 |
http://repositorio.ufsm.br/handle/1/29622 |
url |
http://repositorio.ufsm.br/handle/1/29622 |
dc.language.iso.fl_str_mv |
por |
language |
por |
dc.rights.driver.fl_str_mv |
Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/ info:eu-repo/semantics/openAccess |
rights_invalid_str_mv |
Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/ |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
application/pdf |
dc.publisher.none.fl_str_mv |
Universidade Federal de Santa Maria Brasil Química UFSM Programa de Pós-Graduação em Química Centro de Ciências Naturais e Exatas |
publisher.none.fl_str_mv |
Universidade Federal de Santa Maria Brasil Química UFSM Programa de Pós-Graduação em Química Centro de Ciências Naturais e Exatas |
dc.source.none.fl_str_mv |
reponame:Manancial - Repositório Digital da UFSM instname:Universidade Federal de Santa Maria (UFSM) instacron:UFSM |
instname_str |
Universidade Federal de Santa Maria (UFSM) |
instacron_str |
UFSM |
institution |
UFSM |
reponame_str |
Manancial - Repositório Digital da UFSM |
collection |
Manancial - Repositório Digital da UFSM |
repository.name.fl_str_mv |
Manancial - Repositório Digital da UFSM - Universidade Federal de Santa Maria (UFSM) |
repository.mail.fl_str_mv |
atendimento.sib@ufsm.br||tedebc@gmail.com |
_version_ |
1805922135998201856 |