Furoxan derivatives demonstrated in vivo efficacy by reducing Mycobacterium tuberculosis to undetectable levels in a mouse model of infection

Detalhes bibliográficos
Autor(a) principal: de Souza, P. C. [UNESP]
Data de Publicação: 2020
Outros Autores: 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]
Tipo de documento: Artigo
Idioma: eng
Título da fonte: Repositório Institucional da UNESP
Texto Completo: http://dx.doi.org/10.1016/j.biopha.2020.110592
http://hdl.handle.net/11449/200843
Resumo: 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.
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spelling 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 Chicagode 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]2020-12-12T02:17:31Z2020-12-12T02:17:31Z2020-10-01info: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/openAccess2024-06-24T13:46:32Zoai:repositorio.unesp.br:11449/200843Repositório InstitucionalPUBhttp://repositorio.unesp.br/oai/requestopendoar:29462024-08-05T22:48:20.395938Repositório 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
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.contributor.author.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]
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
dc.type.driver.fl_str_mv 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
dc.language.iso.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv Biomedicine and Pharmacotherapy
dc.rights.driver.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.source.none.fl_str_mv Scopus
reponame:Repositório Institucional da UNESP
instname:Universidade Estadual Paulista (UNESP)
instacron:UNESP
instname_str Universidade Estadual Paulista (UNESP)
instacron_str UNESP
institution UNESP
reponame_str Repositório Institucional da UNESP
collection Repositório Institucional da UNESP
repository.name.fl_str_mv Repositório Institucional da UNESP - Universidade Estadual Paulista (UNESP)
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