Acridone Prodrugs with Enhanced Dual-Stage Antimalarial Efficacy

Area of Science:

• Medicinal Chemistry
• Parasitology
• Drug Development

Background:

• Malaria remains a significant global health challenge, necessitating the development of new antimalarial drugs.
• Existing treatments face challenges such as drug resistance and incomplete parasite clearance, highlighting the need for radical cure strategies.

Purpose of the Study:

• To develop and evaluate novel acridone-based prodrugs with dual-stage antimalarial activity and radical cure potential.
• To assess the oral efficacy and prophylactic capabilities of a lead prodrug, T235, in preclinical malaria models.

Main Methods:

• Synthesis of acridone analogs incorporating a carbamate prodrug moiety.
• Evaluation of antimalarial activity in *Plasmodium yoelii* and *Plasmodium berghei* infection models in mice.
• Assessment of oral efficacy, radical cure potential, and prophylactic efficacy through varying dosing regimens.

Main Results:

• The prodrug T235 demonstrated significantly enhanced oral efficacy compared to its parent compound T226.
• T235 achieved complete cure in *P. yoelii*-infected mice with multi-day and single-dose oral administration.
• T235 provided complete liver-stage protection and sustained blood-stage cure in *P. berghei*-infected mice, outperforming T226 in prophylactic efficacy.

Conclusions:

• Acridone-based prodrugs, exemplified by T235, represent a promising strategy for developing highly potent dual-stage antimalarials.
• T235 exhibits significant potential for both malaria treatment and prevention, offering radical cure and prophylactic benefits.
• This research paves the way for the clinical development of advanced acridone derivatives for malaria control.