Síntese, elucidação estrutural e estudos in silico de novos compostos 2-amino-tiofênicos imídicos candidatos a fármacos antifúngicos, antileishmanicida e antitumorais
Autor(a) principal: | |
---|---|
Data de Publicação: | 2019 |
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/123456789/15841 |
Resumo: | Cryptococcosis, leishmaniasis, and cervical adenocarcinoma are challenging diseases for medical chemistry. In order to bring new treatments for these diseases, the in silico studies (ADMET and molecular docking) and organic synthesis have been used to validate new molecular targets and to develop new drugs. Bearing in mind that 2-amino-thiophene and cyclic imides are shown as attractive pharmacophores for these 3 diseases, the aim of this work was to synthesize 2-amino-thiophene-imidic hybrids and perform in silico ADMET and molecular docking studies for new targets key molecules for growth and metabolism microorganisms Cryptococcus neoformans and leishmania and tumor cells like cervical adenocarcinoma, aiming the prediction of compounds potentially more active for these targets, for future conduction of biological tests. Firstly, several synthetic methodologies were tested, among which the solvent-free reaction method at 150ºC was chosen to obtain the different hybrid derivatives. Thiophene-imidic hybrids were synthesized with determined physicochemical characteristics and confirmed structures through 1H and 13C nuclear magnetic resonance spectroscopy, mass spectrometry and X-ray diffraction (for CNF08 and ESF-07). SwissADME and Osiris Property Explore software were used in the in silico ADMET studies, where it was observed that hybrids containing maleimides and phthalimides presented better bioavailability and gastrointestinal absorption profiles, with the CNMA-06 and ESMA-06 compounds showing the best value of drugscore. Most compounds have no potential for interaction with cytochrome CYP450 CYPCD6, CYPC3A4, or P-gp isoforms, especially bis-indolyl hybrids (for example ESDP-06 and IPDP-06). Only IPDP-06 and all bis-indolines may exhibit toxic effects. Molecular docking studies were conducted using Molegro Virtual docking 6.0 software, using 3 to 4 molecular targets for each disease. All molecules presented negative values of interaction energy, indicating great potential to bind with stability and affinity to the selected macromolecules. The best ligands for the targets were the isoindolinesic hybrids, especially bis-indolinic ones, which have -COOEt radical at the C-3 position of the thiophene nucleus. Relating the results in silico ADMET and molecular docking, it was observed that the compound ESFA-06 presented ideal profile for bioavailability and interaction with the macromolecules studied. In addition, bisimides, mainly IPBT-06, have a multi-target profile, for Cryptococcosis, Leishmania and cervical adenocarcinoma, which suggests a great therapeutic potential by stimulating the tests to confirm biological activities. |
id |
UFPB_f2cadca5e65198f45037cfe3603ecd8d |
---|---|
oai_identifier_str |
oai:repositorio.ufpb.br:123456789/15841 |
network_acronym_str |
UFPB |
network_name_str |
Biblioteca Digital de Teses e Dissertações da UFPB |
repository_id_str |
|
spelling |
Síntese, elucidação estrutural e estudos in silico de novos compostos 2-amino-tiofênicos imídicos candidatos a fármacos antifúngicos, antileishmanicida e antitumoraisSíntese2-amino-tiofenosImidasHibridaçãoIn silicoSynthesis2-amino-thiophenesImidesHybridizationProdutos naturaisDerivados híbridos - Síntese2-amino-tiofênicos imídicosFármacos antifúngicosAntileishmanicidaAntitumoraisCNPQ::CIENCIAS BIOLOGICAS::FARMACOLOGIACryptococcosis, leishmaniasis, and cervical adenocarcinoma are challenging diseases for medical chemistry. In order to bring new treatments for these diseases, the in silico studies (ADMET and molecular docking) and organic synthesis have been used to validate new molecular targets and to develop new drugs. Bearing in mind that 2-amino-thiophene and cyclic imides are shown as attractive pharmacophores for these 3 diseases, the aim of this work was to synthesize 2-amino-thiophene-imidic hybrids and perform in silico ADMET and molecular docking studies for new targets key molecules for growth and metabolism microorganisms Cryptococcus neoformans and leishmania and tumor cells like cervical adenocarcinoma, aiming the prediction of compounds potentially more active for these targets, for future conduction of biological tests. Firstly, several synthetic methodologies were tested, among which the solvent-free reaction method at 150ºC was chosen to obtain the different hybrid derivatives. Thiophene-imidic hybrids were synthesized with determined physicochemical characteristics and confirmed structures through 1H and 13C nuclear magnetic resonance spectroscopy, mass spectrometry and X-ray diffraction (for CNF08 and ESF-07). SwissADME and Osiris Property Explore software were used in the in silico ADMET studies, where it was observed that hybrids containing maleimides and phthalimides presented better bioavailability and gastrointestinal absorption profiles, with the CNMA-06 and ESMA-06 compounds showing the best value of drugscore. Most compounds have no potential for interaction with cytochrome CYP450 CYPCD6, CYPC3A4, or P-gp isoforms, especially bis-indolyl hybrids (for example ESDP-06 and IPDP-06). Only IPDP-06 and all bis-indolines may exhibit toxic effects. Molecular docking studies were conducted using Molegro Virtual docking 6.0 software, using 3 to 4 molecular targets for each disease. All molecules presented negative values of interaction energy, indicating great potential to bind with stability and affinity to the selected macromolecules. The best ligands for the targets were the isoindolinesic hybrids, especially bis-indolinic ones, which have -COOEt radical at the C-3 position of the thiophene nucleus. Relating the results in silico ADMET and molecular docking, it was observed that the compound ESFA-06 presented ideal profile for bioavailability and interaction with the macromolecules studied. In addition, bisimides, mainly IPBT-06, have a multi-target profile, for Cryptococcosis, Leishmania and cervical adenocarcinoma, which suggests a great therapeutic potential by stimulating the tests to confirm biological activities.Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPESCriptococose, leishmaniose e adenocarcinoma cervical são doenças desafiadoras para a química medicinal. Com o intuito de trazer novos tratamentos para essas enfermidades os estudos in silico (ADMET e docking molecular) e síntese orgânica vêm sendo empregados para validar novos alvos moleculares e desenvolver novos fármacos. Tendo em mente que os 2-amino-tiofeno e as imídas cíclicas se mostram como farmacóforos atraentes para essas 3 doenças, o objetivo desse trabalho foi sintetizar novos híbridos 2-amino-tiofênicos-imídicos e realizar estudos in silico ADMET e de docking molecular para novos alvos moleculares chaves para o crescimento e metabolismo dos microrganismo Cryptococcus neoformans e leishmania e células tumorais de adenocarcinoma cervical, visando a predição dos compostos potencialmente mais ativos para esses alvos, para condução futura de testes biológicos. Primeiramente, foram testadas diversas metodologias sintéticas, dentre as quais o método de reação sem solvente a 150ºC foi o escolhido para obtenção dos diferentes derivados híbridos. Foram síntetizados18 híbridos tiofenos-imídicos que tiveram suas características físico-químicas determinadas e estruturas comprovadas através de espectroscopia de ressonância magnética nuclear de 1H e 13C, espectrometria de massas e difratometria de raios X (para CNF-08 e ESF-07). Os softwares SwissADME e Osiris Property Explore foram utilizados nos estudos in silico ADMET, onde se observou que os híbridos contendo maleimídas e ftalimídas apresentaram melhores perfis de biodisponibilidade e absorção gastrointestinal destacando-se os compostos CNMA-06 e ESMA-06 que mostraram o melhor valor de drugscore. A maioria dos compostos não tem potencial de interação com as isoformas CYPCD6, CYPC3A4 do citocromo CYP450, nem com P-gp, especialmente os híbridos bis-indolinas (a exemplo de ESDP-06 e IPDP-06). Somente IPDP-06 e todas as bis-indolinas podem apresentar efeitos tóxicos. Os estudos de docking molecular foram conduzidos com auxílio do software Molegro Virtual docking 6.0, usando de 3 a 4 alvos moleculares para cada uma das doenças. Todas as moléculas apresentaram valores negativos de energia de interação, indicando grande potencial de se ligar com estabilidade e afinidade às macromoléculas selecionadas. Os melhores ligantes para os alvos foram os híbridos isoindolínicos e, principalmente, bis-indolínicos, que possuem radical -COOEt na posição C-3 do núcleo tiofênico. Relacionando os resultados in silico ADMET e docking molecular, notou-se que o composto ESFA-06 apresentou perfil ideal para biodisponibilidade e interação com as macromoléculas estudadas. Além disso, em sua maioria, as bis-imidas, sobretudo IPBT-06, apresenta perfil multi-target, para Criptococose, Leishmania e adenocarcinoma cervical o que sugere um grande potencial terapêutico estimulando a realização dos ensaios para comprovação das atividades biológicas.Universidade Federal da ParaíbaBrasilFarmacologiaPrograma de Pós-Graduação em Produtos Naturais e Sintéticos BioativosUFPBMendonça Júnior, Francisco Jaime Bezerrahttp://lattes.cnpq.br/5994153651109853Pereira, Ana Ligia da Costa2019-09-24T11:28:28Z2019-03-222019-09-24T11:28:28Z2019-02-18info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/masterThesishttps://repositorio.ufpb.br/jspui/handle/123456789/15841porhttp://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:UFPB2019-09-24T11:28:28Zoai:repositorio.ufpb.br:123456789/15841Biblioteca Digital de Teses e Dissertaçõeshttps://repositorio.ufpb.br/PUBhttp://tede.biblioteca.ufpb.br:8080/oai/requestdiretoria@ufpb.br|| diretoria@ufpb.bropendoar:2019-09-24T11:28:28Biblioteca Digital de Teses e Dissertações da UFPB - Universidade Federal da Paraíba (UFPB)false |
dc.title.none.fl_str_mv |
Síntese, elucidação estrutural e estudos in silico de novos compostos 2-amino-tiofênicos imídicos candidatos a fármacos antifúngicos, antileishmanicida e antitumorais |
title |
Síntese, elucidação estrutural e estudos in silico de novos compostos 2-amino-tiofênicos imídicos candidatos a fármacos antifúngicos, antileishmanicida e antitumorais |
spellingShingle |
Síntese, elucidação estrutural e estudos in silico de novos compostos 2-amino-tiofênicos imídicos candidatos a fármacos antifúngicos, antileishmanicida e antitumorais Pereira, Ana Ligia da Costa Síntese 2-amino-tiofenos Imidas Hibridação In silico Synthesis 2-amino-thiophenes Imides Hybridization Produtos naturais Derivados híbridos - Síntese 2-amino-tiofênicos imídicos Fármacos antifúngicos Antileishmanicida Antitumorais CNPQ::CIENCIAS BIOLOGICAS::FARMACOLOGIA |
title_short |
Síntese, elucidação estrutural e estudos in silico de novos compostos 2-amino-tiofênicos imídicos candidatos a fármacos antifúngicos, antileishmanicida e antitumorais |
title_full |
Síntese, elucidação estrutural e estudos in silico de novos compostos 2-amino-tiofênicos imídicos candidatos a fármacos antifúngicos, antileishmanicida e antitumorais |
title_fullStr |
Síntese, elucidação estrutural e estudos in silico de novos compostos 2-amino-tiofênicos imídicos candidatos a fármacos antifúngicos, antileishmanicida e antitumorais |
title_full_unstemmed |
Síntese, elucidação estrutural e estudos in silico de novos compostos 2-amino-tiofênicos imídicos candidatos a fármacos antifúngicos, antileishmanicida e antitumorais |
title_sort |
Síntese, elucidação estrutural e estudos in silico de novos compostos 2-amino-tiofênicos imídicos candidatos a fármacos antifúngicos, antileishmanicida e antitumorais |
author |
Pereira, Ana Ligia da Costa |
author_facet |
Pereira, Ana Ligia da Costa |
author_role |
author |
dc.contributor.none.fl_str_mv |
Mendonça Júnior, Francisco Jaime Bezerra http://lattes.cnpq.br/5994153651109853 |
dc.contributor.author.fl_str_mv |
Pereira, Ana Ligia da Costa |
dc.subject.por.fl_str_mv |
Síntese 2-amino-tiofenos Imidas Hibridação In silico Synthesis 2-amino-thiophenes Imides Hybridization Produtos naturais Derivados híbridos - Síntese 2-amino-tiofênicos imídicos Fármacos antifúngicos Antileishmanicida Antitumorais CNPQ::CIENCIAS BIOLOGICAS::FARMACOLOGIA |
topic |
Síntese 2-amino-tiofenos Imidas Hibridação In silico Synthesis 2-amino-thiophenes Imides Hybridization Produtos naturais Derivados híbridos - Síntese 2-amino-tiofênicos imídicos Fármacos antifúngicos Antileishmanicida Antitumorais CNPQ::CIENCIAS BIOLOGICAS::FARMACOLOGIA |
description |
Cryptococcosis, leishmaniasis, and cervical adenocarcinoma are challenging diseases for medical chemistry. In order to bring new treatments for these diseases, the in silico studies (ADMET and molecular docking) and organic synthesis have been used to validate new molecular targets and to develop new drugs. Bearing in mind that 2-amino-thiophene and cyclic imides are shown as attractive pharmacophores for these 3 diseases, the aim of this work was to synthesize 2-amino-thiophene-imidic hybrids and perform in silico ADMET and molecular docking studies for new targets key molecules for growth and metabolism microorganisms Cryptococcus neoformans and leishmania and tumor cells like cervical adenocarcinoma, aiming the prediction of compounds potentially more active for these targets, for future conduction of biological tests. Firstly, several synthetic methodologies were tested, among which the solvent-free reaction method at 150ºC was chosen to obtain the different hybrid derivatives. Thiophene-imidic hybrids were synthesized with determined physicochemical characteristics and confirmed structures through 1H and 13C nuclear magnetic resonance spectroscopy, mass spectrometry and X-ray diffraction (for CNF08 and ESF-07). SwissADME and Osiris Property Explore software were used in the in silico ADMET studies, where it was observed that hybrids containing maleimides and phthalimides presented better bioavailability and gastrointestinal absorption profiles, with the CNMA-06 and ESMA-06 compounds showing the best value of drugscore. Most compounds have no potential for interaction with cytochrome CYP450 CYPCD6, CYPC3A4, or P-gp isoforms, especially bis-indolyl hybrids (for example ESDP-06 and IPDP-06). Only IPDP-06 and all bis-indolines may exhibit toxic effects. Molecular docking studies were conducted using Molegro Virtual docking 6.0 software, using 3 to 4 molecular targets for each disease. All molecules presented negative values of interaction energy, indicating great potential to bind with stability and affinity to the selected macromolecules. The best ligands for the targets were the isoindolinesic hybrids, especially bis-indolinic ones, which have -COOEt radical at the C-3 position of the thiophene nucleus. Relating the results in silico ADMET and molecular docking, it was observed that the compound ESFA-06 presented ideal profile for bioavailability and interaction with the macromolecules studied. In addition, bisimides, mainly IPBT-06, have a multi-target profile, for Cryptococcosis, Leishmania and cervical adenocarcinoma, which suggests a great therapeutic potential by stimulating the tests to confirm biological activities. |
publishDate |
2019 |
dc.date.none.fl_str_mv |
2019-09-24T11:28:28Z 2019-03-22 2019-09-24T11:28:28Z 2019-02-18 |
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/123456789/15841 |
url |
https://repositorio.ufpb.br/jspui/handle/123456789/15841 |
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 |
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_ |
1801842954324672512 |