Acridone Prodrugs with Enhanced Dual-Stage Antimalarial Efficacy

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.