Optimization of Prodiginines as Single-Dose Curative Antimalarials

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Abstract The emergence of drug-resistant malaria underscores the urgent need for novel, well-tolerated antimalarials with multistage activity and distinct mechanisms of action. Here, we report the design and synthesis of 54 new prodiginine (PG) analogs through systematic modification of the B and C rings of the core scaffold. This effort led to the identification of lead compound PG102 (6), which demonstrated curative oral efficacy in the erythrocytic Plasmodium yoelii murine model at both 25 mg/kg × 4 days and 80 mg/kg × 1 day dosing regimens. PG102 also provided protection against liver-stage Plasmodium berghei sporozoite-induced infection at 20 mg/kg × 3 days and retained high potency against artemisinin-resistant Plasmodium falciparum strains. Profiling of PG102 demonstrated a medium parasite-killing profile. Notably, PG102 exhibited low potential for genotoxicity and cardiotoxicity. This study provides the first demonstration of robust single-dose antimalarial efficacy within the prodiginine class, paving the way for the development of next-generation antimalarial agents.

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