Synthesis, Biological Evaluation, and Molecular Modeling Studies of New Thiadiazole Derivatives as Potent P2X7 Receptor Inhibitors

Detalhes bibliográficos
Autor(a) principal: Gonzaga, Daniel T. G.
Data de Publicação: 2019
Outros Autores: Oliveira, Felipe H., von Ranke, N. L., Pinho, G. Q., Salles, Juliana P., Bello, Murilo L., Rodrigues, Carlos R., Castro, Helena C., de Souza, Hellen V. C. M., Reis, Caroline R. C., Leme, Rennan P. P., Mafra, João C. M., Pinheiro, Luiz C. S., Hoelz, Lucas V. B., Boechat, Nubia, Faria, Robson X.
Tipo de documento: Artigo
Idioma: eng
Título da fonte: Repositório Institucional da FIOCRUZ (ARCA)
Texto Completo: https://www.arca.fiocruz.br/handle/icict/40408
Resumo: Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Departamento de Síntese de Fármacos Manguinhos. Instituto de Tecnologia em Fármacos, Farmanguinhos. Rio de Janeiro, RJ, Brasil / Centro Universitário Estadual da Zona Oeste. Rio de Janeiro, RJ, Brasil.
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spelling Gonzaga, Daniel T. G.Oliveira, Felipe H.von Ranke, N. L.Pinho, G. Q.Salles, Juliana P.Bello, Murilo L.Rodrigues, Carlos R.Castro, Helena C.de Souza, Hellen V. C. M.Reis, Caroline R. C.Leme, Rennan P. P.Mafra, João C. M.Pinheiro, Luiz C. S.Hoelz, Lucas V. B.Boechat, NubiaFaria, Robson X.2020-03-19T14:29:43Z2020-03-19T14:29:43Z2019GONZAGA, Daniel T. G. et al. Synthesis, Biological Evaluation, and Molecular Modeling Studies of new Thiadiazole Derivatives as potent P2XT Receptot Inhibiyors. Frontiers in Chemistry, v. 7, Article 261, 15p, Apr. 2019.2296-2646https://www.arca.fiocruz.br/handle/icict/4040810.3389/fchem.2019.00261engFrontiers MediaReceptores Purinérgicos P2X7TiadiazolPirazolCaptação de coranteEdema da pataDocking molecularP2X7 receptorThiadiazolePyrazoleDye uptakeIL-1β releasePaw edemaMolecular dockingSynthesis, Biological Evaluation, and Molecular Modeling Studies of New Thiadiazole Derivatives as Potent P2X7 Receptor Inhibitorsinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleFundação Oswaldo Cruz. Instituto Oswaldo Cruz. Departamento de Síntese de Fármacos Manguinhos. Instituto de Tecnologia em Fármacos, Farmanguinhos. Rio de Janeiro, RJ, Brasil / Centro Universitário Estadual da Zona Oeste. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Toxoplasmose e Outras Protozooses. Rio de Janeiro, RJ, Brasil.Universidade Federal do Rio de Janeiro. Faculdade de Farmácia. Departamento de Fármacos e Medicamentos. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Toxoplasmose e Outras Protozooses. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Toxoplasmose e Outras Protozooses. Rio de Janeiro, RJ, Brasil.Universidade Federal do Rio de Janeiro. Faculdade de Farmácia. Departamento de Fármacos e Medicamentos. Rio de Janeiro, RJ, Brasil.Universidade Federal do Rio de Janeiro. Faculdade de Farmácia. Departamento de Fármacos e Medicamentos. Rio de Janeiro, RJ, Brasil.Universidade Federal Fluminense. Laboratório de Antibióticos, Bioquímica, Ensino e Modelagem Molecular–LABiEMol. Niterói, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Departamento de Síntese de Fármacos Manguinhos. Instituto de Tecnologia em Fármacos, Farmanguinhos. Rio de Janeiro, RJ, BrasilFundação Oswaldo Cruz. Instituto Oswaldo Cruz. Departamento de Síntese de Fármacos Manguinhos. Instituto de Tecnologia em Fármacos, Farmanguinhos. Rio de Janeiro, RJ, BrasilFundação Oswaldo Cruz. Instituto Oswaldo Cruz. Departamento de Síntese de Fármacos Manguinhos. Instituto de Tecnologia em Fármacos, Farmanguinhos. Rio de Janeiro, RJ, BrasilFundação Oswaldo Cruz. Instituto Oswaldo Cruz. Departamento de Síntese de Fármacos Manguinhos. Instituto de Tecnologia em Fármacos, Farmanguinhos. Rio de Janeiro, RJ, BrasilFundação Oswaldo Cruz. Instituto Oswaldo Cruz. Departamento de Síntese de Fármacos Manguinhos. Instituto de Tecnologia em Fármacos, Farmanguinhos. Rio de Janeiro, RJ, BrasilFundação Oswaldo Cruz. Instituto Oswaldo Cruz. Departamento de Síntese de Fármacos Manguinhos. Instituto de Tecnologia em Fármacos, Farmanguinhos. Rio de Janeiro, RJ, BrasilFundação Oswaldo Cruz. Instituto Oswaldo Cruz. Departamento de Síntese de Fármacos Manguinhos. Instituto de Tecnologia em Fármacos, Farmanguinhos. Rio de Janeiro, RJ, BrasilCentro Universitário Estadual da Zona Oeste. Rio de Janeiro, RJ, Brasil.Twenty new 2-(1H-pyrazol-1-yl)-1,3,4-thiadiazole analogs were synthetized to develop P2X7 receptor (P2X7R) inhibitors. P2X7R inhibition in vitro was evaluated in mouse peritoneal macrophages, HEK-293 cells transfected with hP2X7R (dye uptake assay), and THP-1 cells (IL-1β release assay). The 1-(5-phenyl-1,3,4-thiadiazol-2-yl)-1H-pyrazol-5-amine derivatives 9b, 9c, and 9f, and 2-(3,5-dimethyl-1H-pyrazol-1-yl)-5-(4-fluorophenyl)-1,3,4-thiadiazole (11c) showed inhibitory effects with IC50 values ranging from 16 to 122 nM for reduced P2X7R-mediated dye uptake and 20 to 300 nM for IL-1β release. In addition, the in vitro ADMET profile of the four most potent derivatives was determined to be in acceptable ranges concerning metabolic stability and cytotoxicity. Molecular docking and molecular dynamics simulation studies of the molecular complexes human P2X7R/9f and murine P2X7R/9f indicated the putative intermolecular interactions. Compound 9f showed affinity mainly for the Arg268, Lys377, and Asn266 residues. These results suggest that 2-(1H-pyrazol-1-yl)-1,3,4-thiadiazole analogs may be promising novel P2X7R inhibitors with therapeutic potential.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/40408/1/license.txt5a560609d32a3863062d77ff32785d58MD51ORIGINALJulianaSales_GQPInho_etal_IOC_2019.pdfJulianaSales_GQPInho_etal_IOC_2019.pdfapplication/pdf5923086https://www.arca.fiocruz.br/bitstream/icict/40408/2/JulianaSales_GQPInho_etal_IOC_2019.pdf48e9b9f121c2875afa74f259ad2fe14aMD52TEXTJulianaSales_GQPInho_etal_IOC_2019.pdf.txtJulianaSales_GQPInho_etal_IOC_2019.pdf.txtExtracted texttext/plain78087https://www.arca.fiocruz.br/bitstream/icict/40408/3/JulianaSales_GQPInho_etal_IOC_2019.pdf.txt4426443cc10711a480cbb6c30258ad63MD53icict/404082020-03-20 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dc.title.pt_BR.fl_str_mv Synthesis, Biological Evaluation, and Molecular Modeling Studies of New Thiadiazole Derivatives as Potent P2X7 Receptor Inhibitors
title Synthesis, Biological Evaluation, and Molecular Modeling Studies of New Thiadiazole Derivatives as Potent P2X7 Receptor Inhibitors
spellingShingle Synthesis, Biological Evaluation, and Molecular Modeling Studies of New Thiadiazole Derivatives as Potent P2X7 Receptor Inhibitors
Gonzaga, Daniel T. G.
Receptores Purinérgicos P2X7
Tiadiazol
Pirazol
Captação de corante
Edema da pata
Docking molecular
P2X7 receptor
Thiadiazole
Pyrazole
Dye uptake
IL-1β release
Paw edema
Molecular docking
title_short Synthesis, Biological Evaluation, and Molecular Modeling Studies of New Thiadiazole Derivatives as Potent P2X7 Receptor Inhibitors
title_full Synthesis, Biological Evaluation, and Molecular Modeling Studies of New Thiadiazole Derivatives as Potent P2X7 Receptor Inhibitors
title_fullStr Synthesis, Biological Evaluation, and Molecular Modeling Studies of New Thiadiazole Derivatives as Potent P2X7 Receptor Inhibitors
title_full_unstemmed Synthesis, Biological Evaluation, and Molecular Modeling Studies of New Thiadiazole Derivatives as Potent P2X7 Receptor Inhibitors
title_sort Synthesis, Biological Evaluation, and Molecular Modeling Studies of New Thiadiazole Derivatives as Potent P2X7 Receptor Inhibitors
author Gonzaga, Daniel T. G.
author_facet Gonzaga, Daniel T. G.
Oliveira, Felipe H.
von Ranke, N. L.
Pinho, G. Q.
Salles, Juliana P.
Bello, Murilo L.
Rodrigues, Carlos R.
Castro, Helena C.
de Souza, Hellen V. C. M.
Reis, Caroline R. C.
Leme, Rennan P. P.
Mafra, João C. M.
Pinheiro, Luiz C. S.
Hoelz, Lucas V. B.
Boechat, Nubia
Faria, Robson X.
author_role author
author2 Oliveira, Felipe H.
von Ranke, N. L.
Pinho, G. Q.
Salles, Juliana P.
Bello, Murilo L.
Rodrigues, Carlos R.
Castro, Helena C.
de Souza, Hellen V. C. M.
Reis, Caroline R. C.
Leme, Rennan P. P.
Mafra, João C. M.
Pinheiro, Luiz C. S.
Hoelz, Lucas V. B.
Boechat, Nubia
Faria, Robson X.
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.contributor.author.fl_str_mv Gonzaga, Daniel T. G.
Oliveira, Felipe H.
von Ranke, N. L.
Pinho, G. Q.
Salles, Juliana P.
Bello, Murilo L.
Rodrigues, Carlos R.
Castro, Helena C.
de Souza, Hellen V. C. M.
Reis, Caroline R. C.
Leme, Rennan P. P.
Mafra, João C. M.
Pinheiro, Luiz C. S.
Hoelz, Lucas V. B.
Boechat, Nubia
Faria, Robson X.
dc.subject.other.pt_BR.fl_str_mv Receptores Purinérgicos P2X7
Tiadiazol
Pirazol
Captação de corante
Edema da pata
Docking molecular
topic Receptores Purinérgicos P2X7
Tiadiazol
Pirazol
Captação de corante
Edema da pata
Docking molecular
P2X7 receptor
Thiadiazole
Pyrazole
Dye uptake
IL-1β release
Paw edema
Molecular docking
dc.subject.en.pt_BR.fl_str_mv P2X7 receptor
Thiadiazole
Pyrazole
Dye uptake
IL-1β release
Paw edema
Molecular docking
description Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Departamento de Síntese de Fármacos Manguinhos. Instituto de Tecnologia em Fármacos, Farmanguinhos. Rio de Janeiro, RJ, Brasil / Centro Universitário Estadual da Zona Oeste. Rio de Janeiro, RJ, Brasil.
publishDate 2019
dc.date.issued.fl_str_mv 2019
dc.date.accessioned.fl_str_mv 2020-03-19T14:29:43Z
dc.date.available.fl_str_mv 2020-03-19T14:29:43Z
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 GONZAGA, Daniel T. G. et al. Synthesis, Biological Evaluation, and Molecular Modeling Studies of new Thiadiazole Derivatives as potent P2XT Receptot Inhibiyors. Frontiers in Chemistry, v. 7, Article 261, 15p, Apr. 2019.
dc.identifier.uri.fl_str_mv https://www.arca.fiocruz.br/handle/icict/40408
dc.identifier.issn.pt_BR.fl_str_mv 2296-2646
dc.identifier.doi.none.fl_str_mv 10.3389/fchem.2019.00261
identifier_str_mv GONZAGA, Daniel T. G. et al. Synthesis, Biological Evaluation, and Molecular Modeling Studies of new Thiadiazole Derivatives as potent P2XT Receptot Inhibiyors. Frontiers in Chemistry, v. 7, Article 261, 15p, Apr. 2019.
2296-2646
10.3389/fchem.2019.00261
url https://www.arca.fiocruz.br/handle/icict/40408
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 Frontiers Media
publisher.none.fl_str_mv Frontiers Media
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/40408/1/license.txt
https://www.arca.fiocruz.br/bitstream/icict/40408/2/JulianaSales_GQPInho_etal_IOC_2019.pdf
https://www.arca.fiocruz.br/bitstream/icict/40408/3/JulianaSales_GQPInho_etal_IOC_2019.pdf.txt
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