Furoxan derivatives demonstrated in vivo efficacy by reducing Mycobacterium tuberculosis to undetectable levels in a mouse model of infection - 27/10/20
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Graphical abstract |
Highlights |
• | New furoxan compounds lead to undetectable M. tuberculosis in a mouse model of infection. |
• | High activity against MDR and XDR-TB. |
• | Early-bactericidal effect. |
• | No mutagenic results were detected by AMES. |
• | No damages in histological tissues. |
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 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.
Il testo completo di questo articolo è disponibile in PDF.Keywords : Furoxan, Heterocyclic N-oxides, Tuberculosis, Drug Discovery
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Vol 130
Articolo 110592- Ottobre 2020 Ritorno al numeroBenvenuto su EM|consulte, il riferimento dei professionisti della salute.
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