In the current age of drug resistance, antimalarial choices are inadequate. In order to support the recent eradication agenda, new generations of both chemoprophylactic and chemotherapeutic antimalarials need to meet the following target product profiles: 1) efficacy against multidrug-resistant malaria; 2) activity against pre- erythrocytic parasites to prevent infection; 3) efficacy against gametocytes for transmission blocking; 4) ability to prevent relapse by targeting the hypnozoite forms of the parasites. We have discovered a novel antimalarial acridone chemotype with broad- spectrum activity against both liver stage and blood stage malaria, with potential to be effective against gametocytes and hypnozoites as well. Our proposed work in this application seeks to develop novel, potent, safe, and inexpensive antimalarial drugs for both prevention and treatment of malaria, thus supporting world-wide elimination of the disease. The specific goal of this project is to conduct lead optimization studies to produce candidates for full preclinical testing that retain the broad-spectrum features and demonstrate enhanced efficacy, safety and pharmacokinetic profiles that warrant further development; to investigate the propensity for drug resistance to selected acridone candidates and identify the molecular target(s) through whole genome sequencing and analysis; and to explore mode of action(s) for these broad-spectrum antimalarial acridones using functional assays and bioanalytical approaches.

Public Health Relevance

Malaria remains one of the deadliest diseases in the world today, and the situation is worsening due to the emergence and spread of multidrug-resistant strains of Plasmodium parasites. Each year, malaria causes 200-300 million clinical cases and claims 1-3 millions lives, mostly children under the age of five and pregnant women. There is a dire need for new and effective drugs in the prophylaxis and treatment of malaria.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
7R01AI093784-05
Application #
9121243
Study Section
Special Emphasis Panel (ZRG1-IDM-P (02))
Program Officer
Mcgugan, Glen C
Project Start
2012-04-01
Project End
2017-03-31
Budget Start
2015-04-02
Budget End
2016-03-31
Support Year
5
Fiscal Year
2015
Total Cost
$707,637
Indirect Cost
$142,467
Name
Portland State University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
052226800
City
Portland
State
OR
Country
United States
Zip Code
97207
Rasmussen, Stephanie A; Ceja, Frida G; Conrad, Melissa D et al. (2017) Changing Antimalarial Drug Sensitivities in Uganda. Antimicrob Agents Chemother 61: