Optimization and Characterization of the Antimalarial Activity of <i>N</i>-Aryl Acetamides that are Susceptible to Mutations in ROM8 and CSC1

New antimalarials are needed due to the threat of emerging resistance against existing antimalarial therapies. A phenotypic screen uncovered the <i>N</i>-aryl acetamide class that inhibits the development of <i>P. falciparum</i> asexual ring-stage parasites. The structure-activity relationship of this class was investigated, and key modifications were introduced that produced WEHI-326 with potent antimalarial activity. Enhancing the metabolic stability of this class will be a future challenge to achieve efficacy in a malaria mouse model. WEHI-326 was found to have a moderate barrier to resistance and a moderate rate of asexual kill, potently inhibited gametocyte and gamete development, and in turn, blocked the transmission of parasites to the mosquito. Forward genetics and cross-resistance profiling determined that parasites resistant to <i>N</i>-aryl acetamides had mutations in rhomboid protease 8 (ROM8) and the putative cation channel, CSC1. WEHI-326 will be an important tool in unraveling the role of ROM8 and CSC1 in <i>P. falciparum</i> development.