Parallel synthesis, in vitro screening and SAR studies of a nitroderivatives compounds library active against macrophage's pathogens: Mycobacterium tuberculosis NRP forms and Leishmania sp

Abstract

Leishmaniasis is one the diseases that presents great social and economic importance around the world, being one of the 7 major parasitic diseases caused by protozoa. Tuberculosis emerges as a major challenge to the health departments reaching about a third of the world population and becoming epidemiologically significant because of the frequent co-infection with HIV. What these two diseases have in common? Both are classified by the World Health Organization as Neglected Diseases, since their pharmacological therapies are far from satisfactory, presents recognized toxicity, high cost and modest efficacy. Still, these diseases share another common characteristic: their etiological agents have, as host cell, the human macrophages. This proposal comes to reach the needs for developing new therapies for these diseases while gives continuity to the research carried out, since 2005, by the main researcher of this project. It is intended to enlarge, through parallel synthesis, a library of nitroderivatives which have already demonstrated significant in vitro activity against Leishmania donovani and Mycobacterium tuberculosis NRP forms, exploring molecular modifications in their chemical structures that generate greater diversity for studies of the structure-activity relationships. Finally, it is also expected to understand some of the toxicological behavior of these compounds comparing the effects over infected macrophages as well as on healthy cells. The most general objective of this project is to obtain relevant chemical and biological information for optimizing nitroderivatives with potential leishmanicidal and antimycobacterial NRP activities, which have also a suitable therapeutic profile for reaching the following stages of drug development: studies of chronic toxicity and pharmacology in vivo. (AU)