Identification of α-Azacyclic Acetamide-Based Inhibitors of P. falciparum Na + Pump ( Pf ATP4) with Fast-Killing Asexual Blood-Stage Antimalarial Activity by Phenotypic Screening

作者：Arturo Casas Jr, Leah S. Imlay, Vandana Thathy, Kate J. Fairhurst, Adele M. Lehane, Aloysus K. Lawong, Ioanna Deni, Josefine Striepen, Seungheon Lee, Ashwani Kumar, Chao Xing, Hanspeter Niederstrasser, Bruce A. Posner, Benoı̂t Laleu, Susan A. Charman, David A. Fidock, Joseph M. Ready, Margaret A. Phillips · 发表于：ACS Infectious Diseases · 年份：2025 · DOI：10.1021/acsinfecdis.5c00436 · 被引用次数：3 · 研究领域：Malaria Research and Control、Traditional and Medicinal Uses of Annonaceae、Computational Drug Discovery Methods

High Resolution Image Download MS PowerPoint Slide 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 Plasmodium falciparum parasites, were not cytotoxic, and disrupted parasite intracellular pH and Na + regulation similarly to cipargamin (KAE609), a clinically advanced inhibitor of the P. falciparum Na + pump ( Pf ATP4). Pf ATP4 is localized to the parasite plasma membrane and is essential for maintaining a low cytosolic Na + concentration. Resistance selections on P. falciparum parasites with two α-azacyclic acetamide analogs identified mutations in Pf ATP4, and cross-resistance was observed across the α-azacyclic acetamides and KAE609, confirming Pf ATP4 as the target. Pf ATP4 is a well-established antimalarial target, and identification of additional Pf ATP4 inhibitors provides alternative avenues to disrupt its function.