Drug Discovery for Chagas Disease

Project Summary
The long-term objective of the proposed research is to develop a new drug for Chagas disease,
an infectious disease caused by the parasite Trypanosoma cruzi. Chagas disease is estimated to
effect 6-8 million people, mainly in Latin America. The work is motivated by the inadequacy of
current therapies with respect to their poor efficacy and tolerability. In the previous grant period,
we made excellent progress advancing an early lead series (benzothiazoles) to the late
preclinical-candidate stage while defining the mechanism of action of mitosis inhibition in the
trypanosome. This novel mechanism of action is uniquely associated with parasite clearance in
both in vitro (washout) assays and in the chronic mouse model of T. cruzi infection. In this
proposal, we will focus on three new compounds scaffolds discovered in high-throughput
phenotypic screening assays against T. cruzi (EC50 values ~1 µM). The compounds were
selected because of follow up experiments showing that they work by the same mechanism of
action as the aforementioned benzothiazoles. The goal of the project will be to bring forward
these compounds as backup series in lieu of the benzothiazole compounds which were
associated with unexpected genotoxicity in Ames testing. The new compounds series (oxazoles,
thienopyrimidinones, and diazines) will go into medicinal chemistry lead optimization campaigns
for Chagas disease, an area in which we have over two decades of experience. With over 100
analogs of each scaffold already synthesized, we are developing a detailed understanding of
structure activity relationships. Compound testing will include in vitro assays for anti-
trypanosomal activity, mammalian cell cytotoxicity, solubility, mouse pharmacokinetics, and
murine efficacy models following a screening cascade with defined go/no-go criteria. At the end
of this three-year project, one to two drug candidates will be selected for late-stage preclinical
development for Chagas disease.

Grant Number: 5R01AI147504-06
NIH Institute/Center: NIH
Principal Investigator: Frederick Buckner