Optimization of B-Ring-Functionalized Antimalarial Tambjamines and Prodiginines
Malaria has been a deadly enemy of mankind throughout history, affecting over 200 million people annually, along with approximately half a million deaths. Resistance to current therapies is of great concern, and there is a dire need for novel and well-tolerated antimalarials that operate by clinically unexploited mechanisms. We have previously reported that both tambjamines and prodiginines are highly potent novel antiplasmodial agents, but they required rigor optimizations to enhance the oral efficacy, safety, and physicochemical properties. Here, we launched a comprehensive structure-activity relationship study for B-ring-functionalized tambjamines and prodiginines with 54 novel analogues systematically designed and synthesized. A number of compounds exhibited remarkable antiplasmodial activities against asexual erythrocytic <i>Plasmodium</i> parasites, with improved safety and metabolic profiles. Notably, several prodiginines cured erythrocytic <i>Plasmodium yoelii</i> infections after oral 25 mg/kg × 4 days in a murine model and provided partial protection against liver stage <i>Plasmodium berghei</i> sporozoite-induced infection in mice.
Authors
- Amrendra Kumar (ORCID: https://orcid.org/0000-0002-3599-7520)
- Diana Caridha (ORCID: https://orcid.org/0000-0002-9857-0719)
- Jane X. Kelly (ORCID: https://orcid.org/0000-0001-8871-0207)
- Xiannu Jin (ORCID: https://orcid.org/0009-0000-9200-062X)
- Susan E. Leed
- Jesse DeLuca
- Yuexin Li (ORCID: https://orcid.org/0000-0001-8525-2853)
- Sivanna Chithanna
- Cameron Blount
- Michael S. Madejczyk (ORCID: https://orcid.org/0000-0002-6000-2599)
- Patricia Lee (ORCID: https://orcid.org/0000-0002-8593-2733)
- Kevin A. Reynolds (ORCID: https://orcid.org/0000-0003-0270-9809)
- Papireddy Kancharla (ORCID: https://orcid.org/0000-0002-6381-1236)
- Xiaowei Zhang (ORCID: https://orcid.org/0000-0002-0419-0679)
- Rozalia A. Dodean (ORCID: https://orcid.org/0000-0001-5002-4607)
- Alison Roth (ORCID: https://orcid.org/0000-0001-6917-3485)
- Hieu Dinh (ORCID: https://orcid.org/0009-0000-4759-2064)
- Chau Vuong (ORCID: https://orcid.org/0000-0002-7441-4295)
- Ravi Chetree
- William E. Dennis
- Kristina Pannone
Institutions
- Portland State University (US)
- Portland VA Medical Center (US)
- Walter Reed Army Institute of Research (US)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2024-10-19
- DOI
- https://doi.org/10.1021/acs.jmedchem.4c02093
- Citations
- 8
- Primary Topic
- Microbial Metabolism and Applications
- Type
- article
- Field-Weighted Citation Impact
- 3.09
Funders
- National Institutes of Health
- National Institute of Allergy and Infectious Diseases