Tambjamines as Fast-Acting Multistage Antimalarials
Well-tolerated and novel antimalarials that can combat multiple stages of the parasite life cycle are desirable but challenging to discover and develop. Herein, we report results for natural product-inspired novel tambjamine antimalarials. We show that they are potent against liver, asexual erythrocytic, and sexual erythrocytic parasite life cycle stages. Notably, our lead candidate <b>1</b> (KAR425) displays excellent oral efficacy with complete clearance of parasites within 72 h of treatment in the humanized <i>Plasmodium falciparum</i> (NOD-scid) mouse model at 50 mg/kg × 4 days. Profiling of compound <b>1</b> demonstrated a fast <i>in vitro</i> killing profile. In addition, several other tambjamine analogues cured erythrocytic <i>Plasmodium yoelii</i> infections after oral doses of 30 and 50 mg/kg × 4 days in a murine model while exhibiting good safety and metabolic profiles. This study presents the first account of multiple-stage antiplasmodial activities with rapid killing profile in the tambjamine family.
Authors
- Roland A. Cooper (ORCID: https://orcid.org/0000-0002-8437-9382)
- Amrendra Kumar (ORCID: https://orcid.org/0000-0002-3599-7520)
- Pamela Orjuela-Sánchez (ORCID: https://orcid.org/0000-0002-1093-9105)
- Diana Caridha (ORCID: https://orcid.org/0000-0002-9857-0719)
- Chad Black (ORCID: https://orcid.org/0000-0002-6033-6660)
- Brandon Pybus (ORCID: https://orcid.org/0000-0002-0392-225X)
- Jane X. Kelly (ORCID: https://orcid.org/0000-0001-8871-0207)
- Xiannu Jin (ORCID: https://orcid.org/0009-0000-9200-062X)
- R. Lee Kirby (ORCID: https://orcid.org/0000-0002-0005-1209)
- Jake Baum (ORCID: https://orcid.org/0000-0002-0275-352X)
- Susan E. Leed
- Jesse DeLuca
- Yuexin Li (ORCID: https://orcid.org/0000-0001-8525-2853)
- Jason Sousa
- Frida G. Ceja
- Matthias Rottmann (ORCID: https://orcid.org/0000-0002-2207-7899)
- Cameron Blount
- Martin Evans (ORCID: https://orcid.org/0000-0001-8455-0023)
- Michael S. Madejczyk (ORCID: https://orcid.org/0000-0002-6000-2599)
- Patricia Lee (ORCID: https://orcid.org/0000-0002-8593-2733)
- Holly Matthews (ORCID: https://orcid.org/0000-0002-3890-9098)
- Stephanie A. Rasmussen
- Kevin A. Reynolds (ORCID: https://orcid.org/0000-0003-0270-9809)
- Papireddy Kancharla (ORCID: https://orcid.org/0000-0002-6381-1236)
- Robert J. Nadeau
- Christina K. Nolan
- Stephan Meister (ORCID: https://orcid.org/0000-0003-2436-7037)
- 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)
- Michael J. Delves (ORCID: https://orcid.org/0000-0001-8526-4782)
- James Duffy (ORCID: https://orcid.org/0000-0002-9447-8982)
- Philip J. Rosenthal (ORCID: https://orcid.org/0000-0002-7953-7622)
- Patrick K. Tumwebaze (ORCID: https://orcid.org/0000-0002-5933-1432)
- Elizabeth A. Winzeler (ORCID: https://orcid.org/0000-0002-4049-2113)
- Chau Vuong (ORCID: https://orcid.org/0000-0002-7441-4295)
- Jeremy N. Burrows (ORCID: https://orcid.org/0000-0001-8448-6068)
- David H. Peyton (ORCID: https://orcid.org/0000-0001-5828-055X)
- Ravi Chetree
- Monica Martin
- William E. Dennis
- Kristina Pannone
Institutions
- University of London (GB)
- Portland State University (US)
- Swiss Tropical and Public Health Institute (CH)
- Dominican University of California (US)
- University of California, San Francisco (US)
- University of Basel (CH)
- Portland VA Medical Center (US)
- UNSW Sydney (AU)
- University of California San Diego (US)
- London School of Hygiene & Tropical Medicine (GB)
- Infectious Diseases Research Collaboration (UG)
- Imperial College London (GB)
- Medicines for Malaria Venture (CH)
- Walter Reed Army Institute of Research (US)
Publication Details
- Journal
- ACS Infectious Diseases
- Published
- 2024-11-11
- DOI
- https://doi.org/10.1021/acsinfecdis.4c00659
- Citations
- 5
- Primary Topic
- Malaria Research and Control
- Type
- article
- Field-Weighted Citation Impact
- 2.71
Funders
- Wellcome Trust
- Medicines for Malaria Venture
- National Institutes of Health
- Medical Research Council
- National Institute of Allergy and Infectious Diseases