The overall goal of this project is to identify new pre-clinical drug candidates to treat human African trypanosomiasis (HAT, sleeping sickness), including stage 2 of the disease when the parasites have entered the central nervous system. HAT remains one of the most neglected diseases on the globe. New drugs are needed since existing drugs are highly toxic or require very high dosing. We have identified five structural scaffolds that show sub-micromolar potency to kill the parasite that causes HAT (Trypanosoma brucei) and that have the potential to cross into the central nervous system. In preliminary results, we show that a compound of one of the scaffolds cures mice with acute T. brucei infection. We will carry out hit-to-lead medicinal chemistry on these five scaffolds. The compounds will be tested for their ability to kill trypanosomes preferentially over mammalian cells, and ultimately for efficacy in rodent models of HAT. In vitro experiments will be done to assess aqueous solubility, the stability of compounds to metabolism by liver microsomes, and membrane permeability. Pharmacokinetic and brain penetration experiments will be done to assess their suitability for treating stage 2 infection. Preliminary toxicology studies will also b carried out on our top performing compounds. The hope is to identify 1-2 new compounds that can be transitioned into clinical trials for treating HAT, including stage 2 of the disease.

Public Health Relevance

Approximately 60 million people in sub-Saharan Africa are at risk for human African trypanosomiasis (HAT, sleeping sickness). Existing drugs are inadequate because of severe side effects, arduous treatment regimens, and poor efficacy. The proposed research is aimed at developing new drugs for treating HAT, including the late stage of disease when parasites have entered the central nervous system.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI106850-01
Application #
8557888
Study Section
Drug Discovery and Mechanisms of Antimicrobial Resistance Study Section (DDR)
Program Officer
Rogers, Martin J
Project Start
2013-06-04
Project End
2018-05-31
Budget Start
2013-06-04
Budget End
2014-05-31
Support Year
1
Fiscal Year
2013
Total Cost
$689,303
Indirect Cost
$178,508
Name
University of Washington
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Tatipaka, Hari Babu; Gillespie, J Robert; Chatterjee, Arnab K et al. (2014) Substituted 2-phenylimidazopyridines: a new class of drug leads for human African trypanosomiasis. J Med Chem 57:828-35