Furoxan derivatives demonstrated in vivo efficacy by reducing Mycobacterium tuberculosis to undetectable levels in a mouse model of infection
Objectives: The most recent survey conducted by the World Health Organization described Tuberculosis (TB) as one of the top 10 causes of death and the leading cause of death from a single infectious agent. The increasing number of TB-resistant cases has contributed to this scenario. In light of this...
| Autores: | , , , , , , , , , , , , , , , |
|---|---|
| Formato: | artículo |
| Estado: | Versión publicada |
| Fecha de publicación: | 2020 |
| País: | Brasil |
| Recursos: | Universidade Estadual Paulista (UNESP) |
| Repositorio: | Repositório Institucional da UNESP |
| Idioma: | inglés |
| OAI Identifier: | oai:repositorio.unesp.br:11449/200843 |
| Acesso em linha: | http://dx.doi.org/10.1016/j.biopha.2020.110592 http://hdl.handle.net/11449/200843 |
| Access Level: | acceso abierto |
| Palavra-chave: | Drug Discovery Furoxan Heterocyclic N-oxides Tuberculosis |
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Furoxan derivatives demonstrated in vivo efficacy by reducing Mycobacterium tuberculosis to undetectable levels in a mouse model of infectionDrug DiscoveryFuroxanHeterocyclic N-oxidesTuberculosisObjectives: The most recent survey conducted by the World Health Organization described Tuberculosis (TB) as one of the top 10 causes of death and the leading cause of death from a single infectious agent. The increasing number of TB-resistant cases has contributed to this scenario. In light of this, new strategies to control and treat the disease are necessary. Our research group has previously described furoxan derivatives as promising scaffolds to be explored as new antitubercular drugs. Results: Two of these furoxan derivatives, (14b) and (14c), demonstrated a high selectivity against Mycobacterium tuberculosis. The compounds (14b) and (14c) were also active against a latent M. tuberculosis strain, with MIC90 values of 6.67 μM and 9.84 μM, respectively; they were also active against monoresistant strains (MIC90 values ranging from 0.61 to 20.42 μM) and clinical MDR strains (MIC90 values ranging from 3.09 to 42.95 μM). Time-kill experiments with compound (14c) showed early bactericidal effects that were superior to those of the first- and second-line anti-tuberculosis drugs currently used in therapy. The safety of compounds (14b) and (14c) was demonstrated by the Ames test because these molecules were not mutagenic under the tested conditions. Finally, we confirmed the safety, and high efficacy of compounds (14b) and (14c), which reduced M. tuberculosis to undetectable levels in a mouse aerosol model of infection. Conclusion: Altogether, we have identified two advanced lead compounds, (14b) and (14c), as novel promising candidates for the treatment of TB infection.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)São Paulo State University (UNESP) School of Pharmaceutical Sciences Tuberculosis Research LaboratorySão Paulo State University (UNESP) School of Pharmaceutical Sciences Department of Drugs and MedicinesDepartment of Biological Sciences and Health UNIARA - University of AraraquaraSão Paulo State University (UNESP) School of Odontology Department of Physiology and PathologyInstitute of Tuberculosis Research UIC - University of Illinois at ChicagoSão Paulo State University (UNESP) School of Pharmaceutical Sciences Tuberculosis Research LaboratorySão Paulo State University (UNESP) School of Pharmaceutical Sciences Department of Drugs and MedicinesSão Paulo State University (UNESP) School of Odontology Department of Physiology and PathologyFAPESP: 2013/14957-5FAPESP: 2014/02240-1FAPESP: 2014/03920-6FAPESP: 2014/11586-9FAPESP: 2014/24811-0FAPESP: 2015/19531-1FAPESP: 2016/02860-5FAPESP: 2016/09502-7FAPESP: 2016/22429-7FAPESP: 2016/24633-0FAPESP: 2017/12419-7FAPESP: 2018/00163-0FAPESP: 2018/11079-0FAPESP: 2018/17739-2Universidade Estadual Paulista (Unesp)UNIARA - University of AraraquaraUIC - University of Illinois at Chicago2020-12-12T02:17:31Z2020-12-12T02:17:31Z2020-10-01info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articlehttp://dx.doi.org/10.1016/j.biopha.2020.110592Biomedicine and Pharmacotherapy, v. 130.1950-60070753-3322http://hdl.handle.net/11449/20084310.1016/j.biopha.2020.1105922-s2.0-85088938843Scopusreponame:Repositório Institucional da UNESPinstname:Universidade Estadual Paulista (UNESP)instacron:UNESPengBiomedicine and Pharmacotherapyinfo:eu-repo/semantics/openAccessde Souza, P. C. [UNESP]Fernandes, G. F.S. [UNESP]Marino, L. B. [UNESP]Ribeiro, C. M. [UNESP]Silva, P.B. da [UNESP]Chorilli, M. [UNESP]Silva, C. S.P. [UNESP]Resende, F. A.Solcia, M. C. [UNESP]de Grandis, R. A. [UNESP]Costa, C. A.S. [UNESP]Cho, S. H.Wang, Y.Franzblau, S. G.dos Santos, J. L. [UNESP]Pavan, F. R. [UNESP]2025-03-29T05:18:58Zoai:repositorio.unesp.br:11449/200843Repositório InstitucionalPUBhttp://repositorio.unesp.br/oai/requestrepositoriounesp@unesp.bropendoar:29462025-03-29T05:18:58Repositório Institucional da UNESP - Universidade Estadual Paulista (UNESP)false |
| dc.title.none.fl_str_mv |
Furoxan derivatives demonstrated in vivo efficacy by reducing Mycobacterium tuberculosis to undetectable levels in a mouse model of infection |
| title |
Furoxan derivatives demonstrated in vivo efficacy by reducing Mycobacterium tuberculosis to undetectable levels in a mouse model of infection |
| spellingShingle |
Furoxan derivatives demonstrated in vivo efficacy by reducing Mycobacterium tuberculosis to undetectable levels in a mouse model of infection de Souza, P. C. [UNESP] Drug Discovery Furoxan Heterocyclic N-oxides Tuberculosis |
| title_short |
Furoxan derivatives demonstrated in vivo efficacy by reducing Mycobacterium tuberculosis to undetectable levels in a mouse model of infection |
| title_full |
Furoxan derivatives demonstrated in vivo efficacy by reducing Mycobacterium tuberculosis to undetectable levels in a mouse model of infection |
| title_fullStr |
Furoxan derivatives demonstrated in vivo efficacy by reducing Mycobacterium tuberculosis to undetectable levels in a mouse model of infection |
| title_full_unstemmed |
Furoxan derivatives demonstrated in vivo efficacy by reducing Mycobacterium tuberculosis to undetectable levels in a mouse model of infection |
| title_sort |
Furoxan derivatives demonstrated in vivo efficacy by reducing Mycobacterium tuberculosis to undetectable levels in a mouse model of infection |
| dc.creator.none.fl_str_mv |
de Souza, P. C. [UNESP] Fernandes, G. F.S. [UNESP] Marino, L. B. [UNESP] Ribeiro, C. M. [UNESP] Silva, P.B. da [UNESP] Chorilli, M. [UNESP] Silva, C. S.P. [UNESP] Resende, F. A. Solcia, M. C. [UNESP] de Grandis, R. A. [UNESP] Costa, C. A.S. [UNESP] Cho, S. H. Wang, Y. Franzblau, S. G. dos Santos, J. L. [UNESP] Pavan, F. R. [UNESP] |
| author |
de Souza, P. C. [UNESP] |
| author_facet |
de Souza, P. C. [UNESP] Fernandes, G. F.S. [UNESP] Marino, L. B. [UNESP] Ribeiro, C. M. [UNESP] Silva, P.B. da [UNESP] Chorilli, M. [UNESP] Silva, C. S.P. [UNESP] Resende, F. A. Solcia, M. C. [UNESP] de Grandis, R. A. [UNESP] Costa, C. A.S. [UNESP] Cho, S. H. Wang, Y. Franzblau, S. G. dos Santos, J. L. [UNESP] Pavan, F. R. [UNESP] |
| author_role |
author |
| author2 |
Fernandes, G. F.S. [UNESP] Marino, L. B. [UNESP] Ribeiro, C. M. [UNESP] Silva, P.B. da [UNESP] Chorilli, M. [UNESP] Silva, C. S.P. [UNESP] Resende, F. A. Solcia, M. C. [UNESP] de Grandis, R. A. [UNESP] Costa, C. A.S. [UNESP] Cho, S. H. Wang, Y. Franzblau, S. G. dos Santos, J. L. [UNESP] Pavan, F. R. [UNESP] |
| author2_role |
author author author author author author author author author author author author author author author |
| dc.contributor.none.fl_str_mv |
Universidade Estadual Paulista (Unesp) UNIARA - University of Araraquara UIC - University of Illinois at Chicago |
| dc.subject.por.fl_str_mv |
Drug Discovery Furoxan Heterocyclic N-oxides Tuberculosis |
| topic |
Drug Discovery Furoxan Heterocyclic N-oxides Tuberculosis |
| description |
Objectives: The most recent survey conducted by the World Health Organization described Tuberculosis (TB) as one of the top 10 causes of death and the leading cause of death from a single infectious agent. The increasing number of TB-resistant cases has contributed to this scenario. In light of this, new strategies to control and treat the disease are necessary. Our research group has previously described furoxan derivatives as promising scaffolds to be explored as new antitubercular drugs. Results: Two of these furoxan derivatives, (14b) and (14c), demonstrated a high selectivity against Mycobacterium tuberculosis. The compounds (14b) and (14c) were also active against a latent M. tuberculosis strain, with MIC90 values of 6.67 μM and 9.84 μM, respectively; they were also active against monoresistant strains (MIC90 values ranging from 0.61 to 20.42 μM) and clinical MDR strains (MIC90 values ranging from 3.09 to 42.95 μM). Time-kill experiments with compound (14c) showed early bactericidal effects that were superior to those of the first- and second-line anti-tuberculosis drugs currently used in therapy. The safety of compounds (14b) and (14c) was demonstrated by the Ames test because these molecules were not mutagenic under the tested conditions. Finally, we confirmed the safety, and high efficacy of compounds (14b) and (14c), which reduced M. tuberculosis to undetectable levels in a mouse aerosol model of infection. Conclusion: Altogether, we have identified two advanced lead compounds, (14b) and (14c), as novel promising candidates for the treatment of TB infection. |
| publishDate |
2020 |
| dc.date.none.fl_str_mv |
2020-12-12T02:17:31Z 2020-12-12T02:17:31Z 2020-10-01 |
| dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
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info:eu-repo/semantics/article |
| format |
article |
| status_str |
publishedVersion |
| dc.identifier.uri.fl_str_mv |
http://dx.doi.org/10.1016/j.biopha.2020.110592 Biomedicine and Pharmacotherapy, v. 130. 1950-6007 0753-3322 http://hdl.handle.net/11449/200843 10.1016/j.biopha.2020.110592 2-s2.0-85088938843 |
| url |
http://dx.doi.org/10.1016/j.biopha.2020.110592 http://hdl.handle.net/11449/200843 |
| identifier_str_mv |
Biomedicine and Pharmacotherapy, v. 130. 1950-6007 0753-3322 10.1016/j.biopha.2020.110592 2-s2.0-85088938843 |
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eng |
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eng |
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Biomedicine and Pharmacotherapy |
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openAccess |
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