Project Summary / Abstract The Medicines for Malaria Venture (MMV) recently published a “roadmap” for the types of medicines that are needed to support the long-term goal of malaria elimination and eradication. The roadmap consists of a wish list of target candidate profiles (TCP) and medicines (target product profiles, i.e., TPP). With the most recent revision to the anti-malarial target candidates and product profiles the MMV highlighted the need for identifying new rapid acting medicines for active case management while other drugs are needed for chemo-protection and chemo- prevention with long-acting molecules, and/or parenteral formulations (i.e., TCP-2) (Burrows, JN et al., 2017, Malaria Journal, 16:26). According to their updated roadmap new drugs are needed to protect populations entering areas of high endemicity during the final stages of malaria elimination. And drugs with causal liver- stage activity are needed for chemoprevention to prevent infection or outbreak of resistance during malarial seasons. This TCP has been modeled on the combination drug atovaquone + proguanil. As a potent and selective inhibitor of the parasite’s cytochrome bc1 complex ELQ-300 selectively targets Plasmodium falciparum in the blood and liver stages and even kills parasites developing in the midgut of the mosquito vector. Unlike atovaquone, ELQ-300 is a selective inhibitor of the Qi site of the target enzyme complex. With support from the NIH and US DOD we have been successful in developing an oral formulation of prodrug ELQ-331 for use in humans for weekly prophylaxis against malaria. In the present application we seek NIH support for work to develop ELQ derivatives that more effectively and comprehensively inhibit the parasite cytochrome bc1 complex. Advanced designs for improved ELQ constructs are supported by preliminary data provided with the application as well as our extensive knowledge of Endochin-Like Quinolone derivatives as inhibitors of the Plasmodium falciparum cytochrome bc1 Qo or Qi sites. Superior molecules will advance through a down-selection test cascade for assessment of selective potency and lack of mammalian cytotoxicity, metabolic stability, solubility in simulated intestinal fluids, resistance propensity and mode of action as well as efficacy against blood and liver stage malaria in mice. Prodrugs of superior molecules will be explored to assess for enhancement of oral bioavailability and antimalarial performance over parent molecules.