Abstract
ObjectivesThe 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.
Highlights
Mycobacterium tuberculosis is the primary causative agent of tuberculosis (TB) in humans
There is an alarming concern regarding the high incidence of TB-HIV coinfection, in which treatment with first-line drugs such as rifampicin presents a great challenge because of drug-drug interactions with anti
The minimum inhibitory concentration in latent M. tuberculosis of (14b) and (14c) compounds were determined in a microdilution technic after 10 days under anaerobic conditions and transferred to an ambient gaseous condition
Summary
Mycobacterium tuberculosis is the primary causative agent of tuberculosis (TB) in humans. In 2018, 10.0 million people developed TB worldwide. TB caused an estimated 1.2 million deaths among HIV-negative people and 251,000 deaths among HIV-positive people [1]. There is an alarming concern regarding the high incidence of TB-HIV coinfection, in which treatment with first-line drugs such as rifampicin presents a great challenge because of drug-drug interactions with anti-. As noted by the World Health Organization (WHO) new drugs that could simplify and/or shorten the treatment of TB would considerably improve TB control programs [6]. There is an urgent need to develop compounds that have good safety profiles and are active against drug-resistant strains of M. tuberculosis
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