Principal Investigator (PI)
University of Georgia + Bioaster
The Foundation is providing £159,226 in support.
Charlotte Fleau
Chemistry labs for synthesis, purification, structure analysis. Full Profiling of Development pre-Candidate (ADMET2 and early toxicology).
T. cruzi is a protozoan parasite that causes Chagas disease, the highest impact infectious disease in Latin America. Although the host immune response is highly effective at controlling T. cruzi, the infection persists in most infected hosts. Previous work between our groups at The University of Georgia (UGA), Sanofi and BIOASTER has identified several Acyl-AminoBenzothiazol (AAB) hits with potent in vitro and in vivo toxicity for T. cruzi. These related hits came from an initial in vitro screen of a ~300,000 small molecule library by the Broad Institute (Pubchem AID: 1885); 171 of the ~3500 in hits with in vitro activity were selected for in vivo screening based upon druglikeness, potential for oral delivery and ease of synthesis and novelty. In a rapid in vivo efficacy assay, 5 of the 171 compounds showed strong activity – 3 of those 5 were in this AAB group. Subsequent in vitro SAR of 240 analogues revealed 3 AAB compounds with IC50 of < 80 nM and identified the steps needed to optimize this compound class. Herein we describe the med chem plan for this optimization as well as for identification of the mechanism of action of these compounds. Paired with our unparalleled combination of in vitro and in vivo screening assays, and the prior evidence of in vivo efficacy of this compound class, we have an excellent opportunity to identify one or more compounds capable of providing parasitological cure.