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2025

J Med Chem. 2025 Apr 24;68(8):8933-8966. doi: 10.1021/acs.jmedchem.5c00614. Epub 2025 Apr 14.

Optimization and Characterization of N-Acetamide Indoles as Antimalarials That Target PfATP4

Jon Kyle Awalt, Zi Kang Ooi, Trent D Ashton, Mahta Mansouri, Petar P S Calic, Qingmiao Zhou, Santhya Vasanthan, Serena Lee, Katie Loi, Kate E Jarman, Jocelyn S Penington, Deyun Qiu, Xinxin Zhang, Adele M Lehane, Emma Y Mao, Maria R Gancheva, Danny W Wilson 4 , Carlo Giannangelo 5 , Christopher A MacRaild 5 , Darren J Creek 5 , Tomas Yeo 6 7 , Tanaya Sheth 6 7 , David A Fidock, Alisje Churchyard, Jake Baum, Mufuliat T Famodimu, Michael J Delves, Mojca Kristan, Lindsay Stewart, Colin J Sutherland, Rachael Coyle, Hannah Jagoe, Marcus C S Lee, Mrittika Chowdury, Tania F de Koning-Ward, Delphine Baud, Stephen Brand, Paul F Jackson, Alan F Cowman, Madeline G Dans, Brad E Sleebs

The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia. Department of Medical Biology, The University of Melbourne, Parkville 3010, Australia. Research School of Biology, Australian National University, Canberra 2601, Australia. Research Centre for Infectious Diseases, School of Biological Sciences, University of Adelaide, Adelaide 5005, Australia. Monash Institute of Pharmaceutical Sciences, Monash University, Parkville 3052, Australia. Department of Microbiology & Immunology, Columbia University Irving Medical Center, New York, New York 10032, United States. Center for Malaria Therapeutics and Antimicrobial Resistance, Columbia University Irving Medical Center, New York, NY 10032, USA. Division of Infectious Diseases, Department of Medicine, Columbia University Irving Medical Center, New York, New York 10032, United States. Department of Life Sciences, Imperial College London, South Kensington SW7 2AZ, U.K. School of Biomedical Sciences, University of New South Wales, Sydney 2031, Australia. London School of Hygiene and Tropical Medicine, London WC1E 7HT, U.K. Wellcome Sanger Institute, Wellcome Genome Campus Hinxton CB10 1SA, U.K. Wellcome Centre for Anti-Infectives Research, Biological Chemistry and Drug Discovery, University of Dundee, Dundee DD1 5EH, U.K. School of Medicine, Deakin University, Waurn Ponds 3216, Australia. Institute for Mental and Physical Health and Clinical Translation, Deakin University, Geelong 3216, Australia. Medicines for Malaria Venture, Geneva 1215, Switzerland. Emerging Science & Innovation, Discovery Sciences, Janssen R&D LLC, La Jolla 92121, United States.

Service type: Stock strains

Abstract

To discover new antimalarials, a screen of the Janssen Jumpstarter library against Plasmodium falciparum uncovered the N-acetamide indole hit class. The structure-activity relationship of this chemotype was defined and culminated in the optimized frontrunner analog WJM664, which exhibited potent asexual stage activity and high metabolic stability. Resistant selection and whole-genome sequencing revealed mutations in PfATP4, which was validated as the target by showing that analogs exhibited reduced potency against parasites with resistance-conferring mutations in PfATP4, a metabolomic signature similar to that of the PfATP4 inhibitor KAE609, and inhibition of Na+-dependent ATPase activity consistent with on-target inhibition of PfATP4. WJM664 inhibited gamete development and blocked parasite transmission to mosquitoes but exhibited low efficacy in aPlasmodium berghei mouse model, which was attributed to ATP4 species differentiation and its moderate systemic exposure. Optimization of these attributes is required for N-acetamide indoles to be pursued for development as a curative and transmission-blocking therapy.

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