Optimization and Characterization of N-Acetamide Indoles as Antimalarials That Target PfATP4
To discover new antimalarials, a screen of the Janssen Jumpstarter library against <i>Plasmodium falciparum</i> 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<sup>+</sup>-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 a<i>Plasmodium berghei</i> 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.
Authors
- Carlo Giannangelo (ORCID: https://orcid.org/0000-0002-6654-7266)
- Stephen Brand (ORCID: https://orcid.org/0000-0002-7010-5348)
- Tania F. de Koning‐Ward (ORCID: https://orcid.org/0000-0001-5810-8063)
- Lindsay B. Stewart (ORCID: https://orcid.org/0000-0002-9003-0160)
- Mufuliat T. Famodimu (ORCID: https://orcid.org/0000-0002-8852-1040)
- Mrittika Chowdury
- Hannah Jagoe
- Darren J. Creek (ORCID: https://orcid.org/0000-0001-7497-7082)
- Maria R. Gancheva (ORCID: https://orcid.org/0000-0001-7428-6791)
- Jon Kyle Awalt (ORCID: https://orcid.org/0000-0003-4840-2757)
- S. S. Lee (ORCID: https://orcid.org/0000-0001-7568-6746)
- Jake Baum (ORCID: https://orcid.org/0000-0002-0275-352X)
- Delphine Baud (ORCID: https://orcid.org/0009-0005-6745-233X)
- Mojca Kristan (ORCID: https://orcid.org/0000-0002-0363-8558)
- Paul Jackson
- Trent D. Ashton (ORCID: https://orcid.org/0000-0002-6707-6064)
- Danny W. Wilson (ORCID: https://orcid.org/0000-0002-5073-1405)
- Adele M. Lehane (ORCID: https://orcid.org/0000-0002-0050-9101)
- Alan F. Cowman (ORCID: https://orcid.org/0000-0001-5145-9004)
- Tomas Yeo (ORCID: https://orcid.org/0000-0003-2923-6060)
- Alisje Churchyard (ORCID: https://orcid.org/0000-0002-4726-6397)
- Mahta Mansouri (ORCID: https://orcid.org/0000-0001-8428-5370)
- Kate E. Jarman (ORCID: https://orcid.org/0009-0000-5561-6636)
- Rachael Coyle (ORCID: https://orcid.org/0000-0001-5838-1086)
- Petar P. S. Calic (ORCID: https://orcid.org/0000-0001-6538-2394)
- Brad E. Sleebs (ORCID: https://orcid.org/0000-0001-9117-1048)
- David A. Fidock (ORCID: https://orcid.org/0000-0001-6753-8938)
- Jocelyn Sietsma Penington (ORCID: https://orcid.org/0000-0003-1561-0074)
- Michael J. Delves (ORCID: https://orcid.org/0000-0001-8526-4782)
- Madeline G. Dans (ORCID: https://orcid.org/0000-0001-9386-0648)
- Colin J. Sutherland
- Christopher A. MacRaild (ORCID: https://orcid.org/0000-0002-3694-3989)
- Katie Loi (ORCID: https://orcid.org/0009-0002-8460-8920)
- Tanaya Sheth
- Xinxin Zhang (ORCID: https://orcid.org/0000-0003-1730-8573)
- Lee M (ORCID: https://orcid.org/0000-0002-4973-0915)
- Deyun Qiu (ORCID: https://orcid.org/0000-0002-7297-8660)
- Emma Y. Mao (ORCID: https://orcid.org/0000-0001-8709-1897)
- Zi Kang Ooi
- S. Vasanthan
- Qingmiao Zhou
Institutions
- Australian National University (AU)
- Deakin University (AU)
- The University of Melbourne (AU)
- University of Dundee (GB)
- Walter and Eliza Hall Institute of Medical Research (AU)
- Columbia University Irving Medical Center (US)
- Australian Regenerative Medicine Institute (AU)
- Wellcome Sanger Institute (GB)
- UNSW Sydney (AU)
- London School of Hygiene & Tropical Medicine (GB)
- Office of Infectious Diseases (US)
- Janssen (Switzerland) (CH)
- Wellcome Centre for Anti-Infectives Research (GB)
- CNR de la Résistance aux Antibiotiques (FR)
- National Centre for Infectious Diseases (SG)
- National Student Clearinghouse Research Center (US)
- Indiana University School of Medicine
- Imperial College London (GB)
- Medicines for Malaria Venture (CH)
- Monash University (AU)
- The University of Adelaide (AU)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-04-14
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c00614
- Citations
- 5
- Primary Topic
- Malaria Research and Control
- Type
- article
- Field-Weighted Citation Impact
- 9.39