The most severe, often fatal, form of malaria is caused by the protozoan parasite Plasmodium falciparum. With regard to the annual toll of people killed, malaria remains one of the deadliest diseases in the world today, as it has been so for thousands of years. For each of the 1 million people killed each year there are hundreds that are severely sickened by malaria parasites. Indeed, malaria is one of the most frequent causes of sickness and death in the world today but especially in sub-Saharan Africa where its victims are primarily young children and pregnant women. And the situation is worsening due to the emergence and spread of strains of P. falciparum that harbor resistance to multiple drugs, including chloroquine. We have discovered a novel class of compounds, structurally similar to chloroquine, that are active against multidrug resistant parasites and they are highly effective in treating malaria infected mice. Although efficacious in the animal model of malaria we believe that we can improve the potency and the efficacy of our lead candidates, PH-128 and PH-203, by incorporating chemical features to enhance stability against liver metabolism and breakdown and other features designed to diminish the likelihood of resistance emerging to this new class of antimalarial agents. The primary objective for this project is to design novel therapeutics for drug resistant malaria. To achieve our objective we will employ modern chemical methods for the design and synthesis of structural variants of PH-128 and PH-203 and we will evaluate each new drug against malaria parasites in tissue culture vessels against drug resistant parasites as well as host cells. Drugs that are highly selective for the parasite are then tested in malaria-infected mice alongside of chloroquine which serves as a positive control. We hypothesize that by the planned iterative cycle of drug design, synthesis, and testing we will identify and fully characterize two pharmachin compounds for development as late lead candidates by large pharmaceutical firms or nonprofit public-private partnerships such as the Medicines for Malaria Venture. Due to the widespread nature of multidrug resistant malaria there is an urgent need for safe and effective replacement drugs. The pharmachins have the potential to fulfill this need and to have a major impact on global health. The resultant advantages of avoiding drug toxicity, febrile illness and complex medical management during deployment are also self-evident, as are the benefits to both short and long-term health of the US soldier.