Synthesis and molecular modelling studies of pyrimidinones and pyrrolo[3,4-d]-pyrimidinodiones as new antiplasmodial compounds

Detalhes bibliográficos
Autor(a) principal: Rogerio, Kamilla Rodrigues
Data de Publicação: 2018
Outros Autores: Carvalho, Leonardo J. M., Domingues, Luiza Helena Pinto, Neves, Bruno Junior, Moreira Filho, José Teófilo, Castro, Rosane Nora, Bianco Júnior, Cesare, Daniel-Ribeiro, Cláudio Tadeu, Andrade, Carolina Horta, Graebin, Cedric Stephan
Tipo de documento: Artigo
Idioma: eng
Título da fonte: Repositório Institucional da FIOCRUZ (ARCA)
Texto Completo: https://www.arca.fiocruz.br/handle/icict/27415
Resumo: Universidade Federal Rural do Rio de Janeiro. Departamento de Química. Laboratório de Diversidade Molecular e Química Medicinal. Seropédica, RJ, Brasil.
id CRUZ_d833491d64031909ffde42dbe4ca184b
oai_identifier_str oai:www.arca.fiocruz.br:icict/27415
network_acronym_str CRUZ
network_name_str Repositório Institucional da FIOCRUZ (ARCA)
repository_id_str 2135
spelling Rogerio, Kamilla RodriguesCarvalho, Leonardo J. M.Domingues, Luiza Helena PintoNeves, Bruno JuniorMoreira Filho, José TeófiloCastro, Rosane NoraBianco Júnior, CesareDaniel-Ribeiro, Cláudio TadeuAndrade, Carolina HortaGraebin, Cedric Stephan2018-07-10T15:37:52Z2018-07-10T15:37:52Z2018ROGERIO, Kamilla Rodrigues; et al.Synthesis and molecular modelling studies of pyrimidinones and pyrrolo[3,4-d]-pyrimidinodiones as new antiplasmodial compounds. Mem Inst Oswaldo Cruz,v.113, n.8, e170452, 9p, 2018.0074-0276https://www.arca.fiocruz.br/handle/icict/2741510.1590/0074-027601704521678-8060engFundação Oswaldo Cruz. Instituto Oswaldo CruzMaláriaPlasmodium falciparumreações multicomponentesmodelagem molecularReação de BiginellipirimidinonasMalariaPlasmodium falciparummulticomponent reactionsBiginelli reactionpyrimidinonesmolecular modellingSynthesis and molecular modelling studies of pyrimidinones and pyrrolo[3,4-d]-pyrimidinodiones as new antiplasmodial compoundsinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleUniversidade Federal Rural do Rio de Janeiro. Departamento de Química. Laboratório de Diversidade Molecular e Química Medicinal. Seropédica, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz.Laboratório de Pesquisas em Malária. Rio de Janeiro, RJ, Brasil.Universidade Federal Rural do Rio de Janeiro. Departamento de Química. Laboratório de Diversidade Molecular e Química Medicinal. Seropédica, RJ, Brasil.Universidade Federal de Goiás. Faculdade de Farmácia. Laboratório de Planejamento de Fármacos e Modelagem Molecular. Goiânia, GO, Brasil / Centro Universitário de Anápolis, UniEvangélica. Laboratório de Quimioinformática. Anápolis, GO, Brasil.Universidade Federal de Goiás. Faculdade de Farmácia. Laboratório de Planejamento de Fármacos e Modelagem Molecular. Goiânia, GO, Brasil.Universidade Federal Rural do Rio de Janeiro. Instituto de Ciências Exatas. Departamento de Química. Seropédica, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz.Laboratório de Pesquisas em Malária. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz.Laboratório de Pesquisas em Malária. Rio de Janeiro, RJ, Brasil.Universidade Federal de Goiás. Faculdade de Farmácia. Laboratório de Planejamento de Fármacos e Modelagem Molecular. Goiânia, GO, Brasil / Universidade de Campinas. Instituto de Biologia. Departamento de Genética, Evolução e Bioagentes. Laboratório de Doenças Tropicais Prof. Dr. Luiz Jacintho da Silva. Campinas, SP, Brasil.Universidade Federal Rural do Rio de Janeiro. Departamento de Química. Laboratório de Diversidade Molecular e Química Medicinal. Seropédica, RJ, Brasil.BACKGROUND Malaria is responsible for 429,000 deaths per year worldwide, and more than 200 million cases were reported in 2015. Increasing parasite resistance has imposed restrictions to the currently available antimalarial drugs. Thus, the search for new, effective and safe antimalarial drugs is crucial. Heterocyclic compounds, such as dihydropyrimidinones (DHPM), synthesised via the Biginelli multicomponent reaction, as well as bicyclic compounds synthesised from DHPMs, have emerged as potential antimalarial candidates in the last few years. METHODS Thirty compounds were synthesised employing the Biginelli multicomponent reaction and subsequent one-pot substitution/cyclisation protocol; the compounds were then evaluated in vitro against chloroquine-resistant Plasmodium falciparum parasites (W2 strain). Drug cytotoxicity in baseline kidney African Green Monkey cells (BGM) was also evaluated. The most active in vitro compounds were evaluated against P. berghei parasites in mice. Additionally, we performed an in silico target fishing approach with the most active compounds, aiming to shed some light into the mechanism at a molecular level. RESULTS The synthetic route chosen was effective, leading to products with high purity and yields ranging from 10-84%. Three out of the 30 compounds tested were identified as active against the parasite and presented low toxicity. The in silico study suggested that among all the molecular targets identified by our target fishing approach, Protein Kinase 3 (PK5) and Glycogen Synthase Kinase 3β (GSK-3β) are the most likely molecular targets for the synthesised compounds. CONCLUSIONS We were able to easily obtain a collection of heterocyclic compounds with in vitro anti-P. falciparum activity that can be used as scaffolds for the design and development of new antiplasmodial drugs.info:eu-repo/semantics/openAccessreponame:Repositório Institucional da FIOCRUZ (ARCA)instname:Fundação Oswaldo Cruz (FIOCRUZ)instacron:FIOCRUZLICENSElicense.txtlicense.txttext/plain; charset=utf-82991https://www.arca.fiocruz.br/bitstream/icict/27415/1/license.txt5a560609d32a3863062d77ff32785d58MD51ORIGINALleonardo_carvalho_etal_IOC_2018.pdfleonardo_carvalho_etal_IOC_2018.pdfapplication/pdf1246557https://www.arca.fiocruz.br/bitstream/icict/27415/2/leonardo_carvalho_etal_IOC_2018.pdf48ba2ef748ce43846be623e25cbb48b4MD52TEXTleonardo_carvalho_etal_IOC_2018.pdf.txtleonardo_carvalho_etal_IOC_2018.pdf.txtExtracted texttext/plain46463https://www.arca.fiocruz.br/bitstream/icict/27415/3/leonardo_carvalho_etal_IOC_2018.pdf.txt5dbd8ecee18e2a97852042c311a8ff92MD53icict/274152020-07-17 16:14:47.838oai:www.arca.fiocruz.br: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ório InstitucionalPUBhttps://www.arca.fiocruz.br/oai/requestrepositorio.arca@fiocruz.bropendoar:21352020-07-17T19:14:47Repositório Institucional da FIOCRUZ (ARCA) - Fundação Oswaldo Cruz (FIOCRUZ)false
dc.title.pt_BR.fl_str_mv Synthesis and molecular modelling studies of pyrimidinones and pyrrolo[3,4-d]-pyrimidinodiones as new antiplasmodial compounds
title Synthesis and molecular modelling studies of pyrimidinones and pyrrolo[3,4-d]-pyrimidinodiones as new antiplasmodial compounds
spellingShingle Synthesis and molecular modelling studies of pyrimidinones and pyrrolo[3,4-d]-pyrimidinodiones as new antiplasmodial compounds
Rogerio, Kamilla Rodrigues
Malária
Plasmodium falciparum
reações multicomponentes
modelagem molecular
Reação de Biginelli
pirimidinonas
Malaria
Plasmodium falciparum
multicomponent reactions
Biginelli reaction
pyrimidinones
molecular modelling
title_short Synthesis and molecular modelling studies of pyrimidinones and pyrrolo[3,4-d]-pyrimidinodiones as new antiplasmodial compounds
title_full Synthesis and molecular modelling studies of pyrimidinones and pyrrolo[3,4-d]-pyrimidinodiones as new antiplasmodial compounds
title_fullStr Synthesis and molecular modelling studies of pyrimidinones and pyrrolo[3,4-d]-pyrimidinodiones as new antiplasmodial compounds
title_full_unstemmed Synthesis and molecular modelling studies of pyrimidinones and pyrrolo[3,4-d]-pyrimidinodiones as new antiplasmodial compounds
title_sort Synthesis and molecular modelling studies of pyrimidinones and pyrrolo[3,4-d]-pyrimidinodiones as new antiplasmodial compounds
author Rogerio, Kamilla Rodrigues
author_facet Rogerio, Kamilla Rodrigues
Carvalho, Leonardo J. M.
Domingues, Luiza Helena Pinto
Neves, Bruno Junior
Moreira Filho, José Teófilo
Castro, Rosane Nora
Bianco Júnior, Cesare
Daniel-Ribeiro, Cláudio Tadeu
Andrade, Carolina Horta
Graebin, Cedric Stephan
author_role author
author2 Carvalho, Leonardo J. M.
Domingues, Luiza Helena Pinto
Neves, Bruno Junior
Moreira Filho, José Teófilo
Castro, Rosane Nora
Bianco Júnior, Cesare
Daniel-Ribeiro, Cláudio Tadeu
Andrade, Carolina Horta
Graebin, Cedric Stephan
author2_role author
author
author
author
author
author
author
author
author
dc.contributor.author.fl_str_mv Rogerio, Kamilla Rodrigues
Carvalho, Leonardo J. M.
Domingues, Luiza Helena Pinto
Neves, Bruno Junior
Moreira Filho, José Teófilo
Castro, Rosane Nora
Bianco Júnior, Cesare
Daniel-Ribeiro, Cláudio Tadeu
Andrade, Carolina Horta
Graebin, Cedric Stephan
dc.subject.other.pt_BR.fl_str_mv Malária
Plasmodium falciparum
reações multicomponentes
modelagem molecular
Reação de Biginelli
pirimidinonas
topic Malária
Plasmodium falciparum
reações multicomponentes
modelagem molecular
Reação de Biginelli
pirimidinonas
Malaria
Plasmodium falciparum
multicomponent reactions
Biginelli reaction
pyrimidinones
molecular modelling
dc.subject.en.pt_BR.fl_str_mv Malaria
Plasmodium falciparum
multicomponent reactions
Biginelli reaction
pyrimidinones
molecular modelling
description Universidade Federal Rural do Rio de Janeiro. Departamento de Química. Laboratório de Diversidade Molecular e Química Medicinal. Seropédica, RJ, Brasil.
publishDate 2018
dc.date.accessioned.fl_str_mv 2018-07-10T15:37:52Z
dc.date.available.fl_str_mv 2018-07-10T15:37:52Z
dc.date.issued.fl_str_mv 2018
dc.type.status.fl_str_mv info:eu-repo/semantics/publishedVersion
dc.type.driver.fl_str_mv info:eu-repo/semantics/article
format article
status_str publishedVersion
dc.identifier.citation.fl_str_mv ROGERIO, Kamilla Rodrigues; et al.Synthesis and molecular modelling studies of pyrimidinones and pyrrolo[3,4-d]-pyrimidinodiones as new antiplasmodial compounds. Mem Inst Oswaldo Cruz,v.113, n.8, e170452, 9p, 2018.
dc.identifier.uri.fl_str_mv https://www.arca.fiocruz.br/handle/icict/27415
dc.identifier.issn.pt_BR.fl_str_mv 0074-0276
dc.identifier.doi.none.fl_str_mv 10.1590/0074-02760170452
dc.identifier.eissn.none.fl_str_mv 1678-8060
identifier_str_mv ROGERIO, Kamilla Rodrigues; et al.Synthesis and molecular modelling studies of pyrimidinones and pyrrolo[3,4-d]-pyrimidinodiones as new antiplasmodial compounds. Mem Inst Oswaldo Cruz,v.113, n.8, e170452, 9p, 2018.
0074-0276
10.1590/0074-02760170452
1678-8060
url https://www.arca.fiocruz.br/handle/icict/27415
dc.language.iso.fl_str_mv eng
language eng
dc.rights.driver.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Fundação Oswaldo Cruz. Instituto Oswaldo Cruz
publisher.none.fl_str_mv Fundação Oswaldo Cruz. Instituto Oswaldo Cruz
dc.source.none.fl_str_mv reponame:Repositório Institucional da FIOCRUZ (ARCA)
instname:Fundação Oswaldo Cruz (FIOCRUZ)
instacron:FIOCRUZ
instname_str Fundação Oswaldo Cruz (FIOCRUZ)
instacron_str FIOCRUZ
institution FIOCRUZ
reponame_str Repositório Institucional da FIOCRUZ (ARCA)
collection Repositório Institucional da FIOCRUZ (ARCA)
bitstream.url.fl_str_mv https://www.arca.fiocruz.br/bitstream/icict/27415/1/license.txt
https://www.arca.fiocruz.br/bitstream/icict/27415/2/leonardo_carvalho_etal_IOC_2018.pdf
https://www.arca.fiocruz.br/bitstream/icict/27415/3/leonardo_carvalho_etal_IOC_2018.pdf.txt
bitstream.checksum.fl_str_mv 5a560609d32a3863062d77ff32785d58
48ba2ef748ce43846be623e25cbb48b4
5dbd8ecee18e2a97852042c311a8ff92
bitstream.checksumAlgorithm.fl_str_mv MD5
MD5
MD5
repository.name.fl_str_mv Repositório Institucional da FIOCRUZ (ARCA) - Fundação Oswaldo Cruz (FIOCRUZ)
repository.mail.fl_str_mv repositorio.arca@fiocruz.br
_version_ 1813009273733513216