2. Academic Validation
  3. Optimization and Characterization of the Antimalarial Activity of N-Aryl Acetamides that are Susceptible to Mutations in ROM8 and CSC1

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

  • J Med Chem. 2025 Aug 14;68(15):16613-16644. doi: 10.1021/acs.jmedchem.5c01471.
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

Affiliations

  • 1 The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia.
  • 2 Department of Medical Biology, The University of Melbourne, Parkville 3010, Australia.
  • 3 Burnet Institute, Melbourne, Victoria 3004, Australia.
  • 4 Department of Microbiology & Immunology, Columbia University Irving Medical Center, New York, New York 10032, United States.
  • 5 Center for Malaria Therapeutics and Antimicrobial Resistance, Columbia University Irving Medical Center, New York, New York 10032, United States.
  • 6 TCG Lifesciences, Kolkata, West Bengal 700091, India.
  • 7 Department of Infection Biology, London School of Hygiene and Tropical Medicine, London WC1E 7HT, United Kingdom.
  • 8 Wellcome Genome Campus, Wellcome Sanger Institute, Hinxton CB10 1SA, United Kingdom.
  • 9 Biological Chemistry and Drug Discovery, Wellcome Centre for Anti-Infectives Research, University of Dundee, Dundee DD1 4HN, United Kingdom.
  • 10 Department of Biochemistry, Genetics and Microbiology, Institute for Sustainable Malaria Control, University of Pretoria, Pretoria 0028, South Africa.
  • 11 Medicines for Malaria Venture, Geneva 1215, Switzerland.
  • 12 School of Medicine, Deakin University, Waurn Ponds 3216, Australia.
  • 13 Institute for Mental and Physical Health and Clinical Translation, Deakin University, Geelong 3216, Australia.
  • 14 Division of Infectious Diseases, Department of Medicine, Columbia University Irving Medical Center, New York, New York 10032, United States.
PMID: 40680058 DOI: 10.1021/acs.jmedchem.5c01471
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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