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Toward this goal, we recently optimised the antimalarial activity of the dihydroquinazolinone scaffold and showed it targeted PfATP4. Here, we deconstruct the lactam moiety of the tricyclic dihydroquinazolinone scaffold and investigate the structure\u2010activity relationship of the truncated scaffold. It was shown that SAR between scaffolds was largely transferrable and generated analogues with potent asexual stage activity. Evaluation of the truncated analogues against PfATP4 mutant drug\u2010resistant parasite strains and in assays measuring PfATP4\u2010associated ATPase activity demonstrated retention of PfATP4 as the molecular target. Analogues exhibited activity against both male and female gametes and multidrug resistant parasites. Limited efficacy of analogues in a <jats:italic>P. berghei<\/jats:italic> asexual stage mouse model was attributed to their moderate metabolic stability and low aqueous stability. Further development is required to address these attributes toward the potential use of the dihydroquinazolinone class in a curative and transmission blocking combination antimalarial therapy.<\/jats:p>","DOI":"10.1002\/cmdc.202400549","type":"journal-article","created":{"date-parts":[[2024,8,30]],"date-time":"2024-08-30T03:40:07Z","timestamp":1724989207000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Lactam Truncation Yields a Dihydroquinazolinone Scaffold with Potent Antimalarial Activity that Targets PfATP4"],"prefix":"10.1002","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6707-6064","authenticated-orcid":false,"given":"Trent D.","family":"Ashton","sequence":"first","affiliation":[{"name":"Walter and Eliza Hall Institute of Medical Research  Parkville 3052 Victoria Australia"},{"name":"Department of Medical Biology University of Melbourne  Parkville 3010 Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6538-2394","authenticated-orcid":false,"given":"Petar P. 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