Journal of medicinal chemistry · 2025
Optimization and Characterization of the Antimalarial Activity of N-Aryl Acetamides that are Susceptible to Mutations in ROM8 and CSC1.
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Nguyen William, Boulet Coralie, Dans Madeline G, Loi Katie, Jarman Kate E, Barnes Claudia B G, Yeo Tomas, Sheth Tanaya, Mukherjee Partha, Chakraborty Arnish, Famodimu Mufuliat T, Delves Michael J, Pollard Harry, Sutherland Colin J, Coyle Rachael, Sevilleno Nicole, Boonyalai Nonlawat, Lee Marcus C S, Rabie Tayla, Birkholtz Lyn-Marié, Baud Delphine, Brand Stephen, Chowdury Mrittika, de Koning-Ward Tania F, Fidock David A, Gilson Paul R, Sleebs Brad E
Аннотация
New antimalarials are needed due to the threat of emerging resistance against existing antimalarial therapies. 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. WEHI-326 will be an important tool in unraveling the role of ROM8 and CSC1 in P. falciparum development.