Property and Activity Refinement of Dihydroquinazolinone-3-carboxamides as Orally Efficacious Antimalarials that Target PfATP4
To contribute to the global effort to develop new antimalarial therapies, we previously disclosed initial findings on the optimization of the dihydroquinazolinone-3-carboxamide class that targets PfATP4. Here we report on refining the aqueous solubility and metabolic stability to improve the pharmacokinetic profile and consequently in vivo efficacy. We show that the incorporation of heterocycle systems in the 8-position of the scaffold was found to provide the greatest attainable balance between parasite activity, aqueous solubility, and metabolic stability. Optimized analogs, including the frontrunner compound <i>S</i>-WJM992, were shown to inhibit PfATP4-associated Na<sup>+</sup>-ATPase activity, gave rise to a metabolic signature consistent with PfATP4 inhibition, and displayed altered activities against parasites with mutations in PfATP4. Finally, <i>S</i>-WJM992 showed appreciable efficacy in a malaria mouse model and blocked gamete development preventing transmission to mosquitoes. Importantly, further optimization of the dihydroquinazolinone class is required to deliver a candidate with improved pharmacokinetic and risk of resistance profiles.
Authors
- Carlo Giannangelo (ORCID: https://orcid.org/0000-0002-6654-7266)
- 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
- Darren J. Creek (ORCID: https://orcid.org/0000-0001-7497-7082)
- 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)
- Colin J. Sutherland
- Christopher A. MacRaild (ORCID: https://orcid.org/0000-0002-3694-3989)
- 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
- Harry Pollard
- Qingmiao Zhou
Institutions
- Australian National University (AU)
- University of London (GB)
- 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)
- Janssen (United States) (US)
- Medicines for Malaria Venture (CH)
- Monash University (AU)
- The University of Adelaide (AU)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2024-08-12
- DOI
- https://doi.org/10.1021/acs.jmedchem.4c01241
- Citations
- 6
- Primary Topic
- Malaria Research and Control
- Type
- article
- Field-Weighted Citation Impact
- 3.26
Funders
- Wellcome Trust
- Australian Government
- Medicines for Malaria Venture
- China Scholarship Council
- Medical Research Council
- Australian Research Council
- National Health and Medical Research Council
- Medical Research Foundation