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

Jon Kyle Awalt ORCID logo ; Zi Kang Ooi ORCID logo ; Trent D Ashton ORCID logo ; Mahta Mansouri ORCID logo ; Petar PS Calic ORCID logo ; Qingmiao Zhou ; Santhya Vasanthan ; Serena Lee ; Katie Loi ; Kate E Jarman ; +31 more... Jocelyn S Penington ORCID logo ; Deyun Qiu ; Xinxin Zhang ; Adele M Lehane ORCID logo ; Emma Y Mao ; Maria R Gancheva ; Danny W Wilson ; Carlo Giannangelo ORCID logo ; Christopher A MacRaild ORCID logo ; Darren J Creek ORCID logo ; Tomas Yeo ; Tanaya Sheth ; David A Fidock ; Alisje Churchyard ; Jake Baum ; Mufuliat T Famodimu ORCID logo ; Michael J Delves ORCID logo ; Mojca Kristan ORCID logo ; Lindsay Stewart ; Colin J Sutherland ORCID logo ; Rachael Coyle ; Hannah Jagoe ; Marcus CS Lee ; Mrittika Chowdury ; Tania F de Koning-Ward ; Delphine Baud ORCID logo ; Stephen Brand ; Paul F Jackson ; Alan F Cowman ; Madeline G Dans ; Brad E Sleebs ORCID logo ; (2025) Optimization and Characterization of N-Acetamide Indoles as Antimalarials That Target PfATP4. Journal of medicinal chemistry, 68 (8). pp. 8933-8966. ISSN 0022-2623 DOI: 10.1021/acs.jmedchem.5c00614
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To 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 resistance-conferring 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.


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