We seek to develop a potent Pharmachin derivative with activity against blood forms of P. falciparum and P. vivax. It is our ultimate goal to develop an inexpensive anti-malarial that is safe for use in G6PD deficient individuals, and in the most vulnerable populations, i.e., pregnant women and children, and can be administered by oral and parenteral routes for weekly chemo-prevention as well as treatment of malaria, including severe malaria. Our 4-year goal for this VA Merit Review Award is to identify two lead molecules and to carry both molecules through the preclinical tests outlined here to provide sufficient information on each to warrant efficacy trials in preclinical species (beyond the budget and scope of the work proposed here) infected with P. falciparum or P. cynomolgi (a surrogate model for vivax malaria). More specifically, we hope to advance a Pharmachin, possibly late lead candidate PH-284, with a projection from the 3-position of the quinoline ring, for more advanced studies. We will also explore the amodiaquine scaffold to create a new series that we refer to as “Amodiachins” where we have moved this key structural feature to the 4-position for reasons described below. It is also our goal to advance one of these Amodiachin constructs for advanced preclinical testing as well. We believe that the combination of a relatively low developmental safety risk together with a high likelihood for therapeutic success in this endeavor (i.e., given the structural similarities to CQ and amodiaquine and the long history of their clinical use worldwide for treatment of malaria) will attract the attention of Big Pharma, the US DOD and the MMV for advancement of a fast-acting 3-substituted-pharmachin and/or an 4-position-modified amodiachin for use in humans. We hypothesize that members of these two series will serve as lead candidates for consideration as 4-aminoquinoline replacement drugs for worldwide use. Our strategic plan is to optimize these two scaffolds for: 1) anti-plasmodial activity, 2) antimalarial efficacy (in vivo mouse model), 3) low mammalian cell cytotoxicity, 4) enhanced metabolic stability (in vitro), 4) improved oral pharmacokinetics (extended T1/2 and increased AUC/exposure), and 5) improved safety/cardiotoxicity risk (diminished inhibition of herg channel, >30µM), and overall suitability to MMV’s Target Product Profiles TPP1 (treatment of uncomplicated as well as severe malaria) and TPP2 (use in chemoprevention). Our experience of working with the MMV towards the preclinical development of prodrug ELQ-331 for treatment and prophylaxis against malaria should accelerate the transformation of optimized Pharmachins and Amodiachins from concept/design to frontrunners to late leads and preclinical candidates that gain acceptance into their developmental pipeline for clinical use.