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.  Paratek Pharmaceuticals, a company specializing in tetracycline chemistry, has a large library of proprietary tetracycline derivatives. A portion of the Paratek compound library has been screened for activity against Plasmodium falciparum in vitro. This work has resulted in the identification of several new tetracycline deritivates with antimalarial activity. We propose to continue the screening process and establish a defined structure activity relationship for the compounds. Using this information we will synthesize new derivatives and test these for improved activity. Finally, in preparation for efficacy studies the toxicity and Pharmacokinetics of compounds demonstrating good activity in vitro will be determined in mice.