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

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dc.contributor.authorAwalt, J.K.
dc.contributor.authorOoi, Z.K.
dc.contributor.authorAshton, T.D.
dc.contributor.authorMansouri, M.
dc.contributor.authorCalic, P.P.S.
dc.contributor.authorZhou, Q.
dc.contributor.authorVasanthan, S.
dc.contributor.authorLee, S.
dc.contributor.authorLoi, K.
dc.contributor.authorJarman, K.E.
dc.contributor.authorPenington, J.S.
dc.contributor.authorQiu, D.
dc.contributor.authorZhang, X.
dc.contributor.authorLehane, A.M.
dc.contributor.authorMao, E.Y.
dc.contributor.authorGancheva, M.R.
dc.contributor.authorWilson, D.W.
dc.contributor.authorGiannangelo, C.
dc.contributor.authorMacRaild, C.A.
dc.contributor.authorCreek, D.J.
dc.contributor.authoret al.
dc.date.issued2025
dc.description.abstractTo 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 resistanceconferring 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.
dc.description.statementofresponsibilityJon 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, Carlo Giannangelo, Christopher A. MacRaild, Darren J. Creek, Tomas Yeo, Tanaya Sheth, 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, and Brad E. Sleebs
dc.identifier.citationJournal of Medicinal Chemistry, 2025; 68(8):8933-8966
dc.identifier.doi10.1021/acs.jmedchem.5c00614
dc.identifier.issn0022-2623
dc.identifier.issn1520-4804
dc.identifier.orcidMao, E.Y. [0000-0001-8709-1897] [0000-0002-4040-1381]
dc.identifier.orcidGancheva, M.R. [0000-0001-7428-6791]
dc.identifier.orcidWilson, D.W. [0000-0002-5073-1405]
dc.identifier.urihttps://hdl.handle.net/2440/147203
dc.language.isoen
dc.publisherAmerican Chemical Society
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/20414427
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/2031542
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1185354
dc.rights© 2025 The Authors. Published by American Chemical Society. This article is licensed under CC-BY-NC-ND 4.0
dc.source.urihttps://doi.org/10.1021/acs.jmedchem.5c00614
dc.subjectAlkyls; Antimicrobial agents; Assays; Indoles; Parasites
dc.subject.meshAnimals
dc.subject.meshHumans
dc.subject.meshMice
dc.subject.meshPlasmodium berghei
dc.subject.meshPlasmodium falciparum
dc.subject.meshAcetamides
dc.subject.meshIndoles
dc.subject.meshAntimalarials
dc.subject.meshStructure-Activity Relationship
dc.titleOptimization and Characterization of N-Acetamide Indoles as Antimalarials That Target PfATP4
dc.typeJournal article
pubs.publication-statusPublished

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