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

Nguyen, W; Boulet, C; Dans, MG; Loi, K; Jarman, KE; Barnes, CBG; Yeo, T; Sheth, T; Mukherjee, P; Chakraborty, A; Famodimu, MT; Delves, MJ; Pollard, H; Sutherland, CJ; Coyle, R; Sevilleno, N; Boonyalai, N; Lee, MCS; Rabie, T; Birkholtz, LM; Baud, D; Brand, S; Chowdury, M; de Koning-Ward, TF; Fidock, DA; Gilson, PR; Sleebs, BE

Author(s): Nguyen, W; Boulet, C; Dans, MG; Loi, K; Jarman, KE; Barnes, CBG; Yeo, T; Sheth, T; Mukherjee, P; Chakraborty, A; Famodimu, MT; Delves, MJ; Pollard, H; Sutherland, CJ; Coyle, R; Sevilleno, N; Boonyalai, N; Lee, MCS; Rabie, T; Birkholtz, LM; Baud, D; Brand, S; Chowdury, M; de Koning-Ward, TF; Fidock, DA; Gilson, PR; Sleebs, BE;
Details: Publication Year 2025-08-14,Volume 68,Issue #15,Page 16613-16644
Journal Title: Journal of Medicinal Chemistry
Abstract: 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.
Publisher: ACS
Research Division(s): New Medicines and Diagnostics
PubMed ID: 40680058
Publisher's Version: https://doi.org/10.1021/acs.jmedchem.5c01471
Open Access at Publisher's Site: https://doi.org/10.1021/acs.jmedchem.5c01471
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2025-07-28 03:09:57

Last Modified: 2025-08-29 08:42:33