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

TY - JOUR

T1 - Optimization and Characterization of the Antimalarial Activity of N-Aryl Acetamides that are Susceptible to Mutations in ROM8 and CSC1

AU - Nguyen, William

AU - Boulet, Coralie

AU - Dans, Madeline G

AU - Loi, Katie

AU - Jarman, Kate E

AU - Barnes, Claudia B G

AU - Yeo, Tomas

AU - Sheth, Tanaya

AU - Mukherjee, Partha

AU - Chakraborty, Arnish

AU - Famodimu, Mufuliat T

AU - Delves, Michael J

AU - Pollard, Harry

AU - Sutherland, Colin J

AU - Coyle, Rachael

AU - Sevilleno, Nicole

AU - Boonyalai, Nonlawat

AU - Lee, Marcus C S

AU - Rabie, Tayla

AU - Birkholtz, Lyn-Marié

AU - Baud, Delphine

AU - Brand, Stephen

AU - Chowdury, Mrittika

AU - de Koning-Ward, Tania F

AU - Fidock, David A

AU - Gilson, Paul R

AU - Sleebs, Brad E

N1 - ©2025 The Authors

PY - 2025/7/18

Y1 - 2025/7/18

N2 - 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.

AB - 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.

KW - Antimalarials/pharmacology

KW - Plasmodium falciparum/drug effects

KW - Animals

KW - Structure-Activity Relationship

KW - Mutation

KW - Acetamides/pharmacology

KW - Mice

KW - Protozoan Proteins/genetics

KW - Humans

KW - Membrane Proteins/genetics

KW - Drug Resistance/genetics

U2 - 10.1021/acs.jmedchem.5c01471

DO - 10.1021/acs.jmedchem.5c01471

M3 - Article

C2 - 40680058

SN - 0022-2623

VL - 68

SP - 16613

EP - 16644

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 15

ER -