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

A phenotypic screen uncovered the N-aryl acetamide class that inhibits the development of P. falciparum 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 N-aryl acetamides had mutations in rhomboid protease 8 (ROM8) and the putative cation channel, CSC1.