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. 2025 Aug 14;68(15):16613-16644.
doi: 10.1021/acs.jmedchem.5c01471. Epub 2025 Jul 18.

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

William Nguyen  1   2 , Coralie Boulet  3 , Madeline G Dans  1   2 , Katie Loi  1 , Kate E Jarman  1   2 , Claudia B G Barnes  3 , Tomas Yeo  4   5 , Tanaya Sheth  4   5 , Partha Mukherjee  6 , Arnish Chakraborty  6 , Mufuliat T Famodimu  7 , Michael J Delves  7 , Harry Pollard  7 , Colin J Sutherland  7 , Rachael Coyle  8   9 , Nicole Sevilleno  8 , Nonlawat Boonyalai  9 , Marcus C S Lee  8   9 , Tayla Rabie  10 , Lyn-Marié Birkholtz  10 , Delphine Baud  11 , Stephen Brand  11 , Mrittika Chowdury  12   13 , Tania F de Koning-Ward  12   13 , David A Fidock  4   5   14 , Paul R Gilson  3 , Brad E Sleebs  1   2
Affiliations

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

William Nguyen et al. J Med Chem. .

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.

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Figures

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1
Structure of MMV020512 (1).
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1. Synthetic Route to Access N-Aryl Acetamide Derivatives
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2. Synthetic Route to Access N-Substituted Amino Acetamide Analogs
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3. Synthesis of N-Substituted Biaryl Derivatives
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4. Synthesis of N-Substituted Pyridyl Acetamide Derivatives
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5. Synthesis of Fluoro Substituted N-Aryl Acetamide Derivatives
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Homology models of P. falciparum ROM8 and CSC1 showing the mutations found in MIR, AReBar and MMV020512-resistance studies. A. A homology model of P. falciparum ROM8 catalytic transmembrane domain showing the location of T622K and L562R mutations (purple) from MMV020512-resistant 3D7-Pop A and D parasites respectively, and the P534S mutation (blue) from WEHI-326-resistant Dd2-Pop A6 parasites from the MIR study. The homology model of P. falciparum ROM8 was created from the X-ray structure of Escherichia coli GlpG (PDB: 6XRP). Amino acids 1–506 and 696–738 are excluded for clarity. B. A homology model of P. falciparum CSC1 showing the location of the L945F mutation from (purple) from MMV020512-resistant 3D7-Pop D parasites, the L800P mutation (cyan) from the resistant parasite strain from the AReBar study, and the R823S and F957L mutations (blue) from WEHI-326-resistant Dd2-A3 and -C2 parasites respectively from the MIR study. The homology model of P. falciparum CSC1 transmembrane domain was created from the X-ray structure of Arabidopsis thaliana OSCA (PDB: 8GRN). Amino acids 181–686 and 966–1039 were excluded for clarity. The dotted line in both ROM8 and CSC1 models indicates the approximate transmembrane regions and predicted orientation relative to the parasitophorous vacuole (PV) and parasite cytosol.
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Activity of WEHI-326 (33) was benchmarked against antimalarial drugs in a parasite reduction ratio assay. Data represent the means and SDs of 3 replicate experiments using P. falciparum 3D7 parasites using an LDH assay.
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Activity of WEHI-326 (33) in a standard membrane feeding assay. Oocyst counts from midguts dissected from Anopheles stephensi mosquitoes 7 days post a blood meal infected with P. falciparum NF54 stage V gametocytes treated with compound at the indicated concentration. Numbers indicate the total number of mosquito midguts dissected per treatment group. Red bars indicate average oocyst intensity and error bars represent SEM. WEHI-326 (33) at both 100 and 500 nM compared to the vehicle: Wilcoxon P < 0.0001. The repeat experiment is shown in .
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