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

Author(s):Show less -

de Souza, P. C. ^[1] ; Fernandes, G. F. S. ^[2] ; Marino, L. B. ^[1] ; Ribeiro, C. M. ^[1] ; da Silva, P. B. ^[2] ; Chorilli, M. ^[2] ; Silva, C. S. P. ^[1] ; Resende, F. A. ^[3] ; Solcia, M. C. ^[1] ; de Grandis, R. A. ^{[1, 3]} ; Costa, C. A. S. ^[4] ; Cho, S. H. ^[5] ; Wang, Y. ^[5] ; Franzblau, S. G. ^[5] ; dos Santos, J. L. ^[2] ; Pavan, F. R. ^[1]

Affiliation

^[1] Sao Paulo State Univ UNESP, Sch Pharmaceut Sci, TB Res Lab, BR-14800903 Araraquara, SP - Brazil

^[2] Sao Paulo State Univ UNESP, Sch Pharmaceut Sci, Dept Drugs & Med, BR-14800903 Araraquara, SP - Brazil

^[3] Univ Araraquara, Dept Biol Sci & Hlth, UNIARA, BR-14801340 Araraquara, SP - Brazil

^[4] Sao Paulo State Univ UNESP, Sch Odontol, Dept Physiol & Pathol, BR-14801903 Araraquara, SP - Brazil

^[5] UIC Univ Illinois Chicago, Inst TB Res, Chicago, IL 60612 - USA

• Document type: Journal article
• Source: BIOMEDICINE & PHARMACOTHERAPY; v. 130, OCT 2020.
• Web of Science Citations: 0

Abstract

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 mu M and 9.84 mu M, respectively; they were also active against monoresistant strains (MIC90 values ranging from 0.61 to 20.42 mu M) and clinical MDR strains (MICYY90 values ranging from 3.09 to 42.95 mu M). 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. (AU)

• FAPESP's process: 18/11079-0 - Synthesis and antitubercular activity of new N-oxide compounds designed to treat multiresistant-tuberculosis
• Grantee: Jean Leandro dos Santos
• Support type: Regular Research Grants
• FAPESP's process: 18/00163-0 - Development and search of new antimicrobials against Tuberculosis: from screening to pre-clinical studies in vivo
• Grantee: Fernando Rogério Pavan
• Support type: Regular Research Grants
• FAPESP's process: 14/03920-6 - Evaluation of pharmacological interaction and bactericidal kinetics of new furoxanic molecules in combination with rifampicin, isoniazid, amikacin, and moxifloxacin against Mycobacterium tuberculosis H37Rv
• Grantee: Camila Maríngolo Ribeiro
• Support type: Scholarships in Brazil - Scientific Initiation
• FAPESP's process: 17/12419-7 - Determination of the frequency of mutations of Mycobacterium tuberculosis against the compound tris-(1.10-phenanthroline)iron(II) and in vivo bioavailability studies
• Grantee: Caio Sander Paiva Silva
• Support type: Scholarships in Brazil - Scientific Initiation
• FAPESP's process: 16/09502-7 - Design, synthesis and antitubercular activity of new oxazolidinones useful for the treatment of multidrug-resistant tuberculosis
• Grantee: Guilherme Felipe dos Santos Fernandes
• Support type: Scholarships in Brazil - Doctorate
• FAPESP's process: 14/02240-1 - Design, Synthesis and anti Mycobacterium tuberculosis activity of new N-oxides derivatives
• Grantee: Guilherme Felipe dos Santos Fernandes
• Support type: Scholarships in Brazil - Master
• FAPESP's process: 13/14957-5 - Research potential against tuberculosis of a new class of furoxan compounds and nanostructured compounds of the ruthenium(II) and copper (II)
• Grantee: Fernando Rogério Pavan
• Support type: Research Grants - Young Investigators Grants
• FAPESP's process: 16/02860-5 - In vitro and in vivo studies of furoxan compounds: permeability, frequency of resistance, activity against resistance strains and in vivo efficacy
• Grantee: Paula Carolina de Souza
• Support type: Scholarships abroad - Research Internship - Doctorate
• FAPESP's process: 14/24811-0 - Design and synthesis of new 1,4-di-N-oxide quinoxaline as antitubercular compounds to treat multi drug-resistant (MDR) and latent tuberculosis
• Grantee: Guilherme Felipe dos Santos Fernandes
• Support type: Scholarships abroad - Research Internship - Master's degree
• FAPESP's process: 16/24633-0 - Study of the biological profile of tris-(1,10-phenanthroline) iron (II) complex and possible mechanisms of action against Mycobacterium tuberculosis
• Grantee: Mariana Cristina Solcia
• Support type: Scholarships in Brazil - Master
• FAPESP's process: 18/17739-2 - Synthesis of New Nitroimidazooxazine Derivatives Designed as Antitubercular Agents
• Grantee: Guilherme Felipe dos Santos Fernandes
• Support type: Scholarships abroad - Research Internship - Doctorate
• FAPESP's process: 15/19531-1 - Targeting histone deacetylase (HDAC-1 and HDAC-2) as mechanisms to induce fetal hemoglobin in sickle cell disease
• Grantee: Jean Leandro dos Santos
• Support type: Regular Research Grants
• FAPESP's process: 16/22429-7 - Toxicogenetics evaluation and study of antiproliferative response mechanisms of ruthenium-based metallodrugs containing naphthoquinones ligands in tumor cells growing in conventional and 3D systems
• Grantee: Rone Aparecido de Grandis
• Support type: Scholarships in Brazil - Doctorate
• FAPESP's process: 14/11586-9 - Studies in vitro and in vivo of furoxan compounds with potential application for the treatment of tuberculosis
• Grantee: Paula Carolina de Souza
• Support type: Scholarships in Brazil - Doctorate