In vitro and in vivo studies of furoxans, benzofuroxans and quinoxaline compounds with potential application for tuberculosis treatment

The search for new drugs is necessary under two main points: the cure / treatment of the patient for the improvement of quality of life and the importance of treating it in order to eliminate outbreaks of the spread of infecto-contagious diseases. Tuberculosis (TB) is part of this scenario, since TB is an infectious disease with Mycobacterium tuberculosis (Mtb) as its main pathogen. The TB mortality rate has dropped by 45% since 1990 and the world is on track to meet the global 50% reduction target by 2015. The latest survey conducted in 2015 showed 6.3 million TB cases notified by national disease programs, of which 55% correspond to cases of HIV-TB co-infection. A recent problem has repercussions: resistance. This is proven by the estimated 580,000 new cases of MDRTB in 2015 compared to 480,000 cases in 2014; actually 9.7% of these cases are TBXDR. Based on these epidemiological data, we observed the need to search for new drugs in order to improve therapy and consequently the quality of life and cure of patients. In this sense, this thesis sought to investigate the biological potential in vitro and in vivo of twenty-two new n-oxide compounds: furoxanic, benzofuroxanic and quinoxaline derivatives. We also investigated the safety and preliminary data on the mechanism of action of these compounds. The compounds showed activity (MIC90) in a ranging 0.40 to 62 µM. Among all the n-oxide studied, the benzofuroxan (8) was more promising (MIC90 values of 1.10 and 6.62 μM against the active and latent bacteria, respectively; and cytotoxicity against the MRC-5 cell line (IC50) was obtained at the concentration of 519.2 μM). This compound also showed activity against the monoresistant strains of important drugs of the therapy (isoniazid, rifampicin, moxifloxacin, bedaquiline, cycloserine and streptomycin) as well as demonstrated an intramacrophagic activity similar to the drug of rifampicin therapy - approximately 90% inhibition at all concentrations tested. For in vivo studies (oral bioavailability, tolerability and treatment) the compounds were incorporated into microemulsion due to instability at pH 1.0 and 9.0; being bioavailable and tolerable. Finally, we verified how much these classes are promising in vivo. Three compounds (two belonging to the group of furoxanic derivatives and a benzofuroxanic derivative) sterilize pulmonary infection with Mtb of BALB / c mice. Thus, we present three new compounds with potential for clinical studies and in future being chemical classes present in the therapy of the disease. (AU)