Acridone Prodrugs with Enhanced Dual-Stage Antimalarial Efficacy
Rozalia A. Dodean, Yuexin Li, Xiaowei Zhang, Amrendra Kumar, Sovitj Pou, Rolf Walter Winter, Katherine M. Liebman, Lev N. Zakharov, Diana Caridha, Michael S. Madejczyk, Chau V. Vuong, Jesse P. DeLuca, Geoffrey Chin, Karl A. Kudyba, Sharon McEnearney, Xiannu Jin, William E. Dennis, Ravi Chetree, Cameron Blount, Kristina Pannone · ACS Medicinal Chemistry Letters · 2025
In this study, we present a prodrug strategy that successfully led to the development of highly potent dual-stage antimalarial acridone analogs with radical cure potential. Notably, the prodrug T235, featuring a carbamate promoiety on the middle ring of the acridone core, demonstrated greater oral efficacy than its parent compound, T226 . T235 provided a complete cure in Plasmodium yoelii -infected mice up to 28 days at doses of 3 and 10 mg/kg administered over 4 days and was also curative with a single oral dose of 20 mg/kg. Furthermore, T235 offered full liver-stage protection and a sustained blood-stage cure in murine Plasmodium berghei infection when administered orally at 10 mg/kg/day, exhibiting superior prophylactic efficacy compared to T226 . This study paves the way for the development of highly effective acridone-based prodrugs for both malaria prevention and treatment.