Safety assessment of benzofuroxan derivatives with potential use in antitubercular therapy by toxicological and toxigenomic approaches

Abstract

Tuberculosis is a contagious disease caused by Mycobacterium tuberculosis, which mainly attacks lungs and other parts of the body like kidneys, eyes and bones. It is a disease of global incidence, infecting one third of the entire world population. With this, tuberculosis is currently responsible for the deaths of 1.7 million people a year; indices greater than those observed for any other infectious disease in the world, overcoming AIDS.The disease has also become gradually more difficult to treat; it is estimated that in 2050, deaths from resistant bacterial infections will be the number one cause of death in the world.During the last 10 years, our group has been working on the study of different strategies for searching new antimicrobials against TB. More than 5.000 compounds from diferent sources were screened in our laboratory and less than 5% displayed promising activity. Among these, we have been able to find a benzofuroxane-derived lead compound showing an excellent activity in vitro and in vivo and also with a possible new mechanism of action. As a leading molecule, it's activity must to be improved. Thus, the present proposal aims to continue the work that has been done in our group, using molecules derived from the class of newly synthesized benzofuroxanes. For this, parameters related to the toxicological safety of such molecules will be investigated. Will be analyzed: the genotoxic and mutagenic potential; cell death profile (apoptosis / necrosis); gene regulation of toxicologically important cellular functions, permeability, transport and measurement of interindividual differences in the absorption of substances.