Structures of compounds.

<div> The human pathogens <i>Plasmodium</i> and <i>Schistosoma</i> are each responsible for over 200 million infections annually, especially in low- and middle-income countries. There is a pressing need for new drug targets for these diseases, driven by emergence of drug-resistance in <i>Plasmodium</i> and an overall dearth of drug targets against <i>Schistosoma</i>. Here, we explored the opportunity for pathogen-hopping by evaluating a series of quinoxaline-based anti-schistosomal compounds for their activity against <i>P. falciparum</i>. We identified compounds with low nanomolar potency against 3D7 and multidrug-resistant strains. <i>In vitro</i> resistance selections using wildtype and mutator <i>P. falciparum</i> lines revealed a low propensity for resistance. Only one of the series, compound <b>22</b>, yielded resistance mutations, including point mutations in a non-essential putative hydrolase <i>pfqrp1,</i> as well as copy number amplification of a phospholipid-translocating ATPase, <i>pfatp2</i>, a potential target. Notably, independently generated CRISPR-edited mutants in <i>pfqrp1</i> also showed resistance to compound <b>22</b> and a related analogue. Moreover, previous lines with <i>pfatp2</i> copy number variations were similarly less susceptible to challenge with the new compounds. Finally, we examined whether the predicted hydrolase activity of PfQRP1 underlies its mechanism of resistance, showing that both mutation of the putative catalytic triad and a more severe loss of function mutation elicited resistance. Collectively, we describe a compound series with potent activity against two important pathogens and their potential target in <i>P. falciparum</i>. </div>