Optimization of 1,4-Naphthoquinone Hit Compound: A Computational, Phenotypic, and In Vivo Screening against Trypanosoma cruzi
| Autor(a) principal: | |
|---|---|
| Data de Publicação: | 2021 |
| 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/47369 |
Resumo: | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Ultraestrutura Celular. Rio de Janeiro, RJ, Brasil. |
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Lara, Leonardo S.Lechuga, Guilherme C.Moreira, Caroline dos S.Santos, Thais B.Ferreira, Vitor F.Rocha, David R. daPereira, Miriam C. S.2021-05-25T19:50:13Z2021-05-25T19:50:13Z2021LARA, Leonardo S. et al. Optimization of 1,4-Naphthoquinone Hit Compound: A Computational, Phenotypic, and In Vivo Screening against Trypanosoma cruzi. Molecules, v. 26, n. 2, 21p, 2021.1420-3049https://www.arca.fiocruz.br/handle/icict/4736910.3390/molecules26020423engMDPITrypanosoma cruziAtividade tripanocidaNaftoquinonasQuimioterapiaOtimização compostaTrypanosoma cruziNaphthoquinonesTrypanocidal activityChemotherapyCompound optimizationOptimization of 1,4-Naphthoquinone Hit Compound: A Computational, Phenotypic, and In Vivo Screening against Trypanosoma cruziinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleFundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Ultraestrutura Celular. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Ultraestrutura Celular. Rio de Janeiro, RJ, Brasil.Universidade Federal Fluminense. Instituto de Química. Departamento de Química Orgânica. Niterói, RJ, Brasil.Universidade Federal Fluminense. Instituto de Química. Departamento de Química Orgânica. Niterói, RJ, Brasil.Universidade Federal Fluminense. Instituto de Química. Departamento de Química Orgânica. Niterói, RJ, Brasil.Universidade Federal Fluminense. Instituto de Química. Departamento de Química Orgânica. Niterói, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Ultraestrutura Celular. Rio de Janeiro, RJ, Brasil.Chagas disease (CD) still represents a serious public health problem in Latin America, even after more than 100 years of its discovery. Clinical treatments (nifurtimox and benznidazole) are considered inadequate, especially because of undesirable side effects and low efficacy in the chronic stages of the disease, highlighting the urgency for discovering new effective and safe drugs. A small library of compounds (1a–i and 2a–j) was designed based on the structural optimization of a Hit compound derived from 1,4-naphthoquinones (C2) previously identified. The biological activity, structure-activity relationship (SAR), and the in silico physicochemical profiles of the naphthoquinone derivatives were analyzed. Most modifications resulted in increased trypanocidal activity but some substitutions also increased toxicity. The data reinforce the importance of the chlorine atom in the thiophenol benzene ring for trypanocidal activity, highlighting 1g, which exhibit a drug-likeness profile, as a promising compound against Trypanosoma cruzi. SAR analysis also revealed 1g as cliff generator in the structure-activity similarity map (SAS maps). However, compounds C2 and 1g were unable to reduce parasite load, and did not prevent mouse mortality in T. cruzi acute infection. Phenotypic screening and computational analysis have provided relevant information to advance the optimization and design of new 1,4-naphthoquinone derivatives with a better pharmacological profile.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/47369/1/license.txt5a560609d32a3863062d77ff32785d58MD51ORIGINALLeonardoS_Lara_etal_IOC_2021.pdfLeonardoS_Lara_etal_IOC_2021.pdfapplication/pdf9693707https://www.arca.fiocruz.br/bitstream/icict/47369/2/LeonardoS_Lara_etal_IOC_2021.pdfea04964e0f9e0b7858db746e618a19e8MD52TEXTLeonardoS_Lara_etal_IOC_2021.pdf.txtLeonardoS_Lara_etal_IOC_2021.pdf.txtExtracted texttext/plain75127https://www.arca.fiocruz.br/bitstream/icict/47369/3/LeonardoS_Lara_etal_IOC_2021.pdf.txtdb023209aca5e568557622230f3d58f2MD53icict/473692021-05-26 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| dc.title.pt_BR.fl_str_mv |
Optimization of 1,4-Naphthoquinone Hit Compound: A Computational, Phenotypic, and In Vivo Screening against Trypanosoma cruzi |
| title |
Optimization of 1,4-Naphthoquinone Hit Compound: A Computational, Phenotypic, and In Vivo Screening against Trypanosoma cruzi |
| spellingShingle |
Optimization of 1,4-Naphthoquinone Hit Compound: A Computational, Phenotypic, and In Vivo Screening against Trypanosoma cruzi Lara, Leonardo S. Trypanosoma cruzi Atividade tripanocida Naftoquinonas Quimioterapia Otimização composta Trypanosoma cruzi Naphthoquinones Trypanocidal activity Chemotherapy Compound optimization |
| title_short |
Optimization of 1,4-Naphthoquinone Hit Compound: A Computational, Phenotypic, and In Vivo Screening against Trypanosoma cruzi |
| title_full |
Optimization of 1,4-Naphthoquinone Hit Compound: A Computational, Phenotypic, and In Vivo Screening against Trypanosoma cruzi |
| title_fullStr |
Optimization of 1,4-Naphthoquinone Hit Compound: A Computational, Phenotypic, and In Vivo Screening against Trypanosoma cruzi |
| title_full_unstemmed |
Optimization of 1,4-Naphthoquinone Hit Compound: A Computational, Phenotypic, and In Vivo Screening against Trypanosoma cruzi |
| title_sort |
Optimization of 1,4-Naphthoquinone Hit Compound: A Computational, Phenotypic, and In Vivo Screening against Trypanosoma cruzi |
| author |
Lara, Leonardo S. |
| author_facet |
Lara, Leonardo S. Lechuga, Guilherme C. Moreira, Caroline dos S. Santos, Thais B. Ferreira, Vitor F. Rocha, David R. da Pereira, Miriam C. S. |
| author_role |
author |
| author2 |
Lechuga, Guilherme C. Moreira, Caroline dos S. Santos, Thais B. Ferreira, Vitor F. Rocha, David R. da Pereira, Miriam C. S. |
| author2_role |
author author author author author author |
| dc.contributor.author.fl_str_mv |
Lara, Leonardo S. Lechuga, Guilherme C. Moreira, Caroline dos S. Santos, Thais B. Ferreira, Vitor F. Rocha, David R. da Pereira, Miriam C. S. |
| dc.subject.other.pt_BR.fl_str_mv |
Trypanosoma cruzi Atividade tripanocida Naftoquinonas Quimioterapia Otimização composta |
| topic |
Trypanosoma cruzi Atividade tripanocida Naftoquinonas Quimioterapia Otimização composta Trypanosoma cruzi Naphthoquinones Trypanocidal activity Chemotherapy Compound optimization |
| dc.subject.en.pt_BR.fl_str_mv |
Trypanosoma cruzi Naphthoquinones Trypanocidal activity Chemotherapy Compound optimization |
| description |
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Ultraestrutura Celular. Rio de Janeiro, RJ, Brasil. |
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2021 |
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2021-05-25T19:50:13Z |
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2021-05-25T19:50:13Z |
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2021 |
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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 |
| dc.identifier.citation.fl_str_mv |
LARA, Leonardo S. et al. Optimization of 1,4-Naphthoquinone Hit Compound: A Computational, Phenotypic, and In Vivo Screening against Trypanosoma cruzi. Molecules, v. 26, n. 2, 21p, 2021. |
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https://www.arca.fiocruz.br/handle/icict/47369 |
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1420-3049 |
| dc.identifier.doi.none.fl_str_mv |
10.3390/molecules26020423 |
| identifier_str_mv |
LARA, Leonardo S. et al. Optimization of 1,4-Naphthoquinone Hit Compound: A Computational, Phenotypic, and In Vivo Screening against Trypanosoma cruzi. Molecules, v. 26, n. 2, 21p, 2021. 1420-3049 10.3390/molecules26020423 |
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