Author(s):
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]
Date: 2020
Persistent ID: http://hdl.handle.net/11449/200843
Origin: Oasisbr
Subject(s): Drug Discovery; Furoxan; Heterocyclic N-oxides; Tuberculosis; Drug Discovery; Drug Discovery; Furoxan; Furoxan; Heterocyclic N-oxides; Heterocyclic N-oxides; Tuberculosis; Tuberculosis
Description
Made available in DSpace on 2020-12-12T02:17:31Z (GMT). No. of bitstreams: 0 Previous issue date: 2020-10-01
Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
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.
São Paulo State University (UNESP) School of Pharmaceutical Sciences Tuberculosis Research Laboratory
São Paulo State University (UNESP) School of Pharmaceutical Sciences Department of Drugs and Medicines
Department of Biological Sciences and Health UNIARA - University of Araraquara
São Paulo State University (UNESP) School of Odontology Department of Physiology and Pathology
Institute of Tuberculosis Research UIC - University of Illinois at Chicago
São Paulo State University (UNESP) School of Pharmaceutical Sciences Tuberculosis Research Laboratory
São Paulo State University (UNESP) School of Pharmaceutical Sciences Department of Drugs and Medicines
São Paulo State University (UNESP) School of Odontology Department of Physiology and Pathology
FAPESP: 2013/14957-5
FAPESP: 2014/02240-1
FAPESP: 2014/03920-6
FAPESP: 2014/11586-9
FAPESP: 2014/24811-0
FAPESP: 2015/19531-1
FAPESP: 2016/02860-5
FAPESP: 2016/09502-7
FAPESP: 2016/22429-7
FAPESP: 2016/24633-0
FAPESP: 2017/12419-7
FAPESP: 2018/00163-0
FAPESP: 2018/11079-0
FAPESP: 2018/17739-2
