Synthesis and molecular modelling studies of pyrimidinones and pyrrolo[3,4-d]-pyrimidinodiones as new antiplasmodial compounds
| Autor(a) principal: | |
|---|---|
| Data de Publicação: | 2018 |
| Outros Autores: | , , , , , , , , |
| 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. |
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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 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| 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. |
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2018 |
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2018-07-10T15:37:52Z |
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2018-07-10T15:37:52Z |
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2018 |
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info:eu-repo/semantics/publishedVersion |
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info:eu-repo/semantics/article |
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article |
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publishedVersion |
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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 |
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https://www.arca.fiocruz.br/handle/icict/27415 |
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eng |
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eng |
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info:eu-repo/semantics/openAccess |
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openAccess |
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Fundação Oswaldo Cruz. Instituto Oswaldo Cruz |
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Fundação Oswaldo Cruz. Instituto Oswaldo Cruz |
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