Molecular toxicology testing of benzofuraxanes

Abstract

Tuberculosis is a contagious disease caused by Mycobacterium tuberculosis, which mainly attacks lungs and other parts of the body such as 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 deaths of 1.7 million people per year; values higher 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. More than 5.000 compounds from different sources were screened in our laboratory during the las 10 years, less than 5% displayed promising activity. Among these, the benzofuroxane-derived (BFXs) lead compound displayed an excellent activity. Thus, the present proposal aims to perform a first characterization of the toxicological and pharmacological profile of BFXs in vitro. Tests will comprise cytotoxicity evaluation with characterization of apoptotic or necrotic mechanisms, investigating the potential regulation of toxicity related pathways by expression profiling in human cell lines with evaluation of potential adverse outcome pathways and further look into identified pathways with specific proteome profilers. HERG channel interaction studies would provide signals for potential cardiotoxic effects. This should enable to identify lead BFXs potentially connected with low cytotoxicity, cardiotoxicity and adverse effects in in vivo studies. The high relevance of interindividual differences of drug efficacy and toxicity due to genetic variability of individuals is mainly due to metabolism and drug transport. Intracellular drug concentrations not only affect toxicity but also efficacy. Potential differences within a patient population will be tested in a panel of LCL cell lines of different donors. (AU)