Among infectious agents malaria is the number two killer, causing 2.1 million deaths annually with an estimated 500 million new cases each year. Drug resistant malaria has become one of the most important problems in malaria control in recent years, and there is a clear need for new antimalarial drugs for both treatment and prophylaxis. Tetracyclines are primarily known as an important class of antibacterials. However, in addition to their antibacterial properties, they are known to be clinically useful in other applications including the treatment of malaria. To our knowledge, no work has been done to try and improve the tetracyclines as antimalarial agents. Paratek Pharmaceuticals, a company specializing in tetracycline chemistry, has a large library of proprietary tetracycline derivatives. To date in collaboration with Dr. Philip Rosenthal's group at UCSF we have screened over 700 compounds for activity against P. falciparum and identified several with improved activity in a rodent model of malaria. Our Phase II efforts will be highly focused on the goal of discovering compounds suitable for clinical development. There will be four critical components to this effort, medicinal chemistry, in vitro screening, pharmacology, and in vivo efficacy. Medicinal chemistry efforts will utilize the existing structure activity relationship (SAR) established in Phase I. This SAR will be further refined as new data is generated. Compounds that demonstrate improved potency in vitro against the target organism P. falciparum will have their serum binding and oral bioavailability properties evaluated. Those compounds that successfully pass these tests will be chemically synthesized (1-2 gram scale) and evaluated for improved efficacy in a rodent model of malaria. We will place particular emphasis on the synthesis and discovery of compounds with improved potency in a rodent model of malaria by oral route of administration. Compounds demonstrating improved efficacy in the rodent model of malaria will be further evaluated. We anticipate that at the end of the Phase II period we will have identified several candidate molecules that are suitable for pre-clinical development.