The current global situation with respect to malaria indicates that about two billion people are exposed to the disease. Each year between 100 million to 200 million new cases of infection are reported and approximately 1 million to 2 million people die due to malaria. U.S. ground troops suffered a high percentage of casualties from malaria infection during the Vietnam War as did, more recently, British and U.S. soldiers deployed in Somalia, Africa. The situation is rapidly worsening, mainly due to non-availability of effective drugs and development of drug resistance to the existing first-line drugs, such as chloroquine and pyrimethamine. In addition to the drug resistance of the first-line antimalarial drugs, the usefulness of many, newer, antimalarial drugs has been impaired by their side effects. A lethal hemolysis side effect was observed in glucose-6-phosphate dehydrogenase (G6PD)-deficient recipients of 8-aminoquinoline drugs (primaquine and tafenoquine) and central nervous system toxicity was a problematic side effect in patients treated with mefloquine. Therefore, the need is imminent for new and safe antimalarial drugs to combat malarial parasites and protect U.S. forces deployed in the epidemic areas of the world.

The goal of this discovery project is to optimize novel, potent 2-guanidinoimidazolidinediones that possess radical curative and causal prophylactic activity, especially against exoerythrocytic stages of Plasmodium vivax. The current lead compounds are efficacious and nontoxic, but only via parenteral administration. This class is one of the few non-8-aminoquinoline drugs proven to be effective against hypnozoites. Hit expansion and lead optimization studies should lead to a safe, orally active, radical curative drug that is safe for use in persons with G6PD deficiency.

Since malarial infectious disease is mainly observed in poor underdeveloping countries, there is very limited commercial incentive to the pharmaceutical companies to invest in malarial drug discovery. This makes the U.S. Army one of the largest funding sources of malaria research in the world. This proposed research is part of the "PDP-A4 - New Drug to Prevent Malaria Program" funded by the U.S. Army Military Infectious Diseases Research Program (MIDRP). The high-efficacy, low-toxicity, and no-cross-resistance with existing antimalarial drugs properties have made imidazolidinedione derivatives the top priority for development by the Walter Reed Army Institute of Research drug discovery program. The current funding level from MIDRP for this project is insufficient to cover the total costs of development. With proper funding, an Investigational New Drug application package should be ready for submission to the U.S. Food and Drug Administration within 4 to 5 years. A patent application on the preparation and use of the compounds under this proposal was filed [Lin et al., US Utility 10/992,363, the PCT PCT/US04/38909 (2004)].

The success of this project will lead to the discovery of a new, safe, and effective antimalarial drug to protect U.S. Armed Forces deployed in the malarial epidemic areas of the world.