Identifying a next-generation antimalarial trioxolane in a landscape of artemisinin partial resistance
- Matthew T. Klope
- Poulami Talukder
- Brian R. Blank
- Sevil Chelebieva
- Jun Chen
- Shaun D. Fontaine
- Ryan L. Gonciarz
- Priyadarshini Jaishankar
- Grace J. Lee
- Jennifer Legac
- Vineet Mathur
- Avani Narayan
- Martin Okitwi
- Stephen Orena
- Nicholas S. Settineri
- Juan A. Tapia
- Yoweri Taremwa
- Patrick K. Tumwebaze
- Aswathy Vinod
- Jeremy N. Burrows
- Philip J. Rosenthal
- Roland A. Cooper
- Adam R. Renslo
2025-08-08
For over two decades, artemisinin-based combination therapy (ACT) has been the standard of care for the treatment of uncomplicated falciparum malaria. However, artemisinin partial resistance (ART-R) is now prevalent in Southeast Asia and has emerged in eastern Africa, threatening ACT efficacy. Artefenomel, a synthetic 1,2,4-trioxolane, exhibits an extended pharmacokinetic exposure profile that predicts for efficacy against ART-R parasites. Unfortunately, the development of artefenomel was halted recently after almost a decade in the clinic. Here, we describe studies of an artefenomel-adjacent chemotype that combines potent in vitro activity against clinical ART-R parasites, an extended pharmacokinetic profile with single-exposure efficacy in a murine malaria model, and enhanced stability in human microsomes and hepatocytes. Overall, our studies reveal a heretofore underexplored trioxolane chemotype with the potential to address ART-R in a next-generation trioxolane development candidate.