Lactam Truncation Yields a Dihydroquinazolinone Scaffold with Potent Antimalarial Activity that Targets PfATP4
The emergence of resistance against current antimalarial treatments has necessitated the need for the development of novel antimalarial chemotypes. 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-activity 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-resistant parasite strains and in assays measuring PfATP4-associated 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 P. berghei 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.
Authors
- Stephen Brand (ORCID: https://orcid.org/0000-0002-7010-5348)
- Tania F. de Koning‐Ward (ORCID: https://orcid.org/0000-0001-5810-8063)
- Mufuliat T. Famodimu (ORCID: https://orcid.org/0000-0002-8852-1040)
- Mrittika Chowdury
- Maria R. Gancheva (ORCID: https://orcid.org/0000-0001-7428-6791)
- Delphine Baud (ORCID: https://orcid.org/0009-0005-6745-233X)
- Paul Jackson
- Trent D. Ashton (ORCID: https://orcid.org/0000-0002-6707-6064)
- Danny W. Wilson (ORCID: https://orcid.org/0000-0002-5073-1405)
- Josephine Palandri
- Adele M. Lehane (ORCID: https://orcid.org/0000-0002-0050-9101)
- Alan F. Cowman (ORCID: https://orcid.org/0000-0001-5145-9004)
- Kate E. Jarman (ORCID: https://orcid.org/0009-0000-5561-6636)
- Petar P. S. Calic (ORCID: https://orcid.org/0000-0001-6538-2394)
- Brad E. Sleebs (ORCID: https://orcid.org/0000-0001-9117-1048)
- Nirupam De (ORCID: https://orcid.org/0000-0002-6328-2610)
- Michael J. Delves (ORCID: https://orcid.org/0000-0001-8526-4782)
- Madeline G. Dans (ORCID: https://orcid.org/0000-0001-9386-0648)
- Katie Loi (ORCID: https://orcid.org/0009-0002-8460-8920)
- Deyun Qiu (ORCID: https://orcid.org/0000-0002-7297-8660)
- Bikash C. Maity
- Emma Y. Mao (ORCID: https://orcid.org/0000-0001-8709-1897)
- Zi Kang Ooi
- Qingmiao Zhou
Institutions
- Australian National University (AU)
- University of London (GB)
- Janssen (Belgium) (BE)
- Deakin University (AU)
- The University of Melbourne (AU)
- Walter and Eliza Hall Institute of Medical Research (AU)
- London School of Hygiene & Tropical Medicine (GB)
- TCG Lifesciences (India) (IN)
- Medicines for Malaria Venture (CH)
- The University of Adelaide (AU)
Publication Details
- Journal
- ChemMedChem
- Published
- 2024-08-30
- DOI
- https://doi.org/10.1002/cmdc.202400549
- Citations
- 3
- Primary Topic
- Quinazolinone synthesis and applications
- Type
- article
- Field-Weighted Citation Impact
- 0.75
Funders
- Australian Government
- University of Melbourne
- Medicines for Malaria Venture
- China Scholarship Council
- Medical Research Council
- National Health and Medical Research Council