Development of Next-Generation Antimalarial Acridones with Radical Cure Potential
Building from our previous lead compound T111 (<b>1</b>) possessing activity against both <i>Plasmodium falciparum</i> asexual blood-stage (ABS) and <i>Plasmodium berghei</i> liver-stage (LS) parasites, next-generation antimalarial acridones were systematically designed and synthesized. A large number of newly generated acridones displayed excellent antimalarial activities against both ABS and LS parasites, with feasible safety and metabolic profiles. In a high-throughput hypnozoitocidal assay using <i>Plasmodium cynomolgi</i>, a number of these acridones significantly inhibited schizont and hypnozoite formation in both prophylactic and radical cure-dosing modes. Notably, newer generation acridones substantially mitigated cross-resistance with atovaquone. Representative compound <b>28</b> (T229) provided full LS protection and a sustained blood-stage cure for murine <i>P. berghei</i> infection dosed at both 10 and 40 mg/kg/day orally. Furthermore, compound <b>28</b> demonstrated a low risk of both genotoxicity and cardiotoxicity and was highly effective against ART-resistant parasites. This study demonstrated the first and robust antirelapse LS activity from a novel acridone family.
Authors
- Roland A. Cooper (ORCID: https://orcid.org/0000-0002-8437-9382)
- Amrendra Kumar (ORCID: https://orcid.org/0000-0002-3599-7520)
- Liwang Cui (ORCID: https://orcid.org/0000-0002-8338-1974)
- Diana Caridha (ORCID: https://orcid.org/0000-0002-9857-0719)
- Brandon Pybus (ORCID: https://orcid.org/0000-0002-0392-225X)
- Michael K. Riscoe (ORCID: https://orcid.org/0000-0002-1343-5279)
- Jennifer Legac
- Jane X. Kelly (ORCID: https://orcid.org/0000-0001-8871-0207)
- Xiannu Jin (ORCID: https://orcid.org/0009-0000-9200-062X)
- Stephen Orena
- Aaron Nilsen (ORCID: https://orcid.org/0000-0002-3827-8222)
- Susan E. Leed
- Jesse DeLuca
- Katherine M. Liebman
- Yuexin Li (ORCID: https://orcid.org/0000-0001-8525-2853)
- Rachel Williams (ORCID: https://orcid.org/0000-0002-1497-1567)
- Cameron Blount
- Michael S. Madejczyk (ORCID: https://orcid.org/0000-0002-6000-2599)
- Patricia Lee (ORCID: https://orcid.org/0000-0002-8593-2733)
- Papireddy Kancharla (ORCID: https://orcid.org/0000-0002-6381-1236)
- Sovitj Pou
- Karl Kudyba (ORCID: https://orcid.org/0000-0001-5681-321X)
- Xiaowei Zhang (ORCID: https://orcid.org/0000-0002-0419-0679)
- Rozalia A. Dodean (ORCID: https://orcid.org/0000-0001-5002-4607)
- Anongruk Chim-Ong
- Alison Roth (ORCID: https://orcid.org/0000-0001-6917-3485)
- Hieu Dinh (ORCID: https://orcid.org/0009-0000-4759-2064)
- Philip J. Rosenthal (ORCID: https://orcid.org/0000-0002-7953-7622)
- Chau Vuong (ORCID: https://orcid.org/0000-0002-7441-4295)
- Oriana Kreutzfeld (ORCID: https://orcid.org/0000-0003-2026-345X)
- Monica L. Martin
- Oswald Byaruhanga
- Ravi Chetree
- William E. Dennis
- Rolf W. Winter
- Kristina Pannone
- Sharon McEnearney
- Kennedy Mdaki
- Jackson Assimwe
- Innocent Tibagambirwa
- Patrick Angutoko
Institutions
- Portland State University (US)
- Oregon Health & Science University (US)
- Dominican University of California (US)
- University of California, San Francisco (US)
- University of South Florida (US)
- Infectious Diseases Research Collaboration (UG)
- Bipar (FR)
- Walter Reed Army Institute of Research (US)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-04-03
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c00419
- Citations
- 5
- Primary Topic
- Synthesis and biological activity
- Type
- article
- Field-Weighted Citation Impact
- 4.68
Funders
- U.S. Department of Veterans Affairs
- National Institute of Allergy and Infectious Diseases
- Congressionally Directed Medical Research Programs