Identification of α-Azacyclic Acetamide-Based Inhibitors of <i>P. falciparum</i> Na <sup>+</sup> Pump ( <i>Pf</i> ATP4) with Fast-Killing Asexual Blood-Stage Antimalarial Activity by Phenotypic Screening
Malaria treatments are compromised by drug resistance, creating an urgent need to discover new drugs. We used a phenotypic high-throughput screening (HTS) platform to identify new antimalarials, uncovering three related pyrrole-, indole-, and indoline-based series with a shared α-azacyclic acetamide core. These compounds showed fast-killing activity on asexual blood-stage <i>Plasmodium falciparum</i> parasites, were not cytotoxic, and disrupted parasite intracellular pH and Na<sup>+</sup> regulation similarly to cipargamin (KAE609), a clinically advanced inhibitor of the <i>P. falciparum</i> Na<sup>+</sup> pump (<i>Pf</i>ATP4). <i>Pf</i>ATP4 is localized to the parasite plasma membrane and is essential for maintaining a low cytosolic Na<sup>+</sup> concentration. Resistance selections on <i>P. falciparum</i> parasites with two α-azacyclic acetamide analogs identified mutations in <i>Pf</i>ATP4, and cross-resistance was observed across the α-azacyclic acetamides and KAE609, confirming <i>Pf</i>ATP4 as the target. <i>Pf</i>ATP4 is a well-established antimalarial target, and identification of additional <i>Pf</i>ATP4 inhibitors provides alternative avenues to disrupt its function.
Authors
- Benoı̂t Laleu (ORCID: https://orcid.org/0000-0002-7530-2113)
- Margaret A. Phillips (ORCID: https://orcid.org/0000-0001-5250-5578)
- Kate J. Fairhurst
- A. Casas
- Aloysus K. Lawong (ORCID: https://orcid.org/0000-0002-3367-4883)
- Hanspeter Niederstrasser
- Adele M. Lehane (ORCID: https://orcid.org/0000-0002-0050-9101)
- Vandana Thathy (ORCID: https://orcid.org/0000-0001-7797-8638)
- Ashwani Kumar (ORCID: https://orcid.org/0000-0002-2449-9331)
- Josefine Striepen (ORCID: https://orcid.org/0000-0003-4673-3114)
- Bruce A. Posner (ORCID: https://orcid.org/0000-0002-7033-4933)
- Leah S. Imlay (ORCID: https://orcid.org/0000-0001-6048-4615)
- Susan A. Charman (ORCID: https://orcid.org/0000-0003-1753-8213)
- David A. Fidock (ORCID: https://orcid.org/0000-0001-6753-8938)
- Joseph M. Ready (ORCID: https://orcid.org/0000-0003-1305-9581)
- Ioanna Deni (ORCID: https://orcid.org/0000-0002-5266-8243)
- Chao Xing (ORCID: https://orcid.org/0000-0002-1838-0502)
- Seungheon Lee (ORCID: https://orcid.org/0000-0001-9631-4853)
Institutions
- Australian National University (AU)
- Columbia University Irving Medical Center (US)
- Donnelly College (US)
- Office of Infectious Diseases (US)
- McDermott International (United States) (US)
- CNR de la Résistance aux Antibiotiques (FR)
- National Student Clearinghouse Research Center (US)
- Southwestern Medical Center (US)
- Medicines for Malaria Venture (CH)
- Monash University (AU)
- The University of Texas Southwestern Medical Center (US)
Publication Details
- Journal
- ACS Infectious Diseases
- Published
- 2025-09-08
- DOI
- https://doi.org/10.1021/acsinfecdis.5c00436
- Primary Topic
- Malaria Research and Control
- Type
- article
- Field-Weighted Citation Impact
- 0.00