{"doi":"10.1101/2025.05.20.655166","title":"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","abstract":"ABSTRACT 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.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":566483,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9451,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":706684,"name":"Leah S. Imlay","orcid":"0000-0001-6048-4615","position":1,"is_corresponding":false},{"id":477193,"name":"Vandana Thathy","orcid":"0000-0001-7797-8638","position":2,"is_corresponding":false},{"id":859656,"name":"Kate J. Fairhurst","orcid":null,"position":3,"is_corresponding":false},{"id":858861,"name":"Adele M. Lehane","orcid":"0000-0002-0050-9101","position":4,"is_corresponding":false},{"id":679740,"name":"Aloysus K. Lawong","orcid":"0000-0002-3367-4883","position":5,"is_corresponding":false},{"id":679739,"name":"Ioanna Deni","orcid":"0000-0002-5266-8243","position":6,"is_corresponding":false},{"id":644315,"name":"Josefine Striepen","orcid":"0000-0003-4673-3114","position":7,"is_corresponding":false},{"id":1402914,"name":"Seungheon Lee","orcid":"0000-0001-9631-4853","position":8,"is_corresponding":false},{"id":813317,"name":"Ashwani Kumar","orcid":"0000-0002-2449-9331","position":9,"is_corresponding":false},{"id":240348,"name":"Chao Xing","orcid":"0000-0002-1838-0502","position":10,"is_corresponding":false},{"id":370527,"name":"Hanspeter Niederstrasser","orcid":null,"position":11,"is_corresponding":false},{"id":350017,"name":"Bruce A. Posner","orcid":"0000-0002-7033-4933","position":12,"is_corresponding":false},{"id":679744,"name":"Benoı̂t Laleu","orcid":"0000-0002-7530-2113","position":13,"is_corresponding":false},{"id":471524,"name":"Susan A. Charman","orcid":"0000-0003-1753-8213","position":14,"is_corresponding":false},{"id":107758,"name":"David A. Fidock","orcid":"0000-0001-6753-8938","position":15,"is_corresponding":false},{"id":369682,"name":"Joseph M. Ready","orcid":"0000-0003-1305-9581","position":16,"is_corresponding":false},{"id":421934,"name":"Margaret A. Phillips","orcid":"0000-0001-5250-5578","position":17,"is_corresponding":false},{"id":1237421,"name":"Arturo Casas","orcid":null,"position":0,"is_corresponding":true}],"reference_count":54,"raw_metadata":null,"created_at":"2026-07-19T02:56:36.440192Z","pmid":"40475615","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}