In vitro and in vivo studies of furoxan compounds: permeability, frequency of resistance, activity against resistance strains and in vivo efficacy

Abstract

This project is associated to FAPESP doctoral fellowship process number 2014/11586-9, entitled: "Studies in vitro and in vivo of furoxan compounds with potential application for the treatment of tuberculosis". The work will be performed under supervisor of the Prof. Scott Gary Franzblau (Professor and Director) at the University of Illinois at Chicago (Institute for Tuberculosis Research) in Chicago, Illinois, United States of America. The University of Illinois at Chicago is a vital part of the educational and technological and cultural in the region. As Chicago's only public research University with 29,000 students, 15 colleges, a hospital and a health sciences system. Prof. Scott Gary Franzblau has a great experience in medicinal chemistry, natural chemical products, microbiology, drug metabolism and pharmacokinetics; the result of this experience is 242 articles published to date. This project aims to explore even more in vivo and in vitro efficacy related to the antibacterial activity of furoxan compounds. Once we found that these compounds have a high selective toxicity against MTB with extremely high activity with MIC values lower than 1 µg/mL along with low cytotoxicity against two different cell lines (MRC-5 and J774A.1) providing a select index. These furoxans have also demonstrated activity against at least 5 of the 9 MDR clinical isolates. We have assessed the mutagenic profile in the presence and absence of metabolism; only one proved to be mutagenic and only in the absence of metabolic activation. For the six-month period in Chicago, we propose to infect and take care of animals to determine the effectiveness of these compounds, and in vitro assays: bidirectional permeability in Caco-2 cells; MICs against MTB H37Rv isogenic monoresistant strains; and frequency of resistance development. In conclusion, this work will lead to knowledge acquisition to explore new approaches of furoxans with anti- TB properties. (AU)