Development of Next-Generation Antimalarial Acridones with Radical Cure Potential

Abstract

Building from our previous lead compound T111 (1) possessing activity against both Plasmodium falciparum asexual blood-stage (ABS) and Plasmodium berghei liver-stage (LS) parasites, next-generation antimalarial acridones were systematically designed and synthesized. A large number of newly generated acridones displayed excellent antimalarial activities against both ABS and LS parasites, with feasible safety and metabolic profiles. In a high-throughput hypnozoitocidal assay using Plasmodium cynomolgi, a number of these acridones significantly inhibited schizont and hypnozoite formation in both prophylactic and radical cure-dosing modes. Notably, newer generation acridones substantially mitigated cross-resistance with atovaquone. Representative compound 28 (T229) provided full LS protection and a sustained blood-stage cure for murine P. berghei infection dosed at both 10 and 40 mg/kg/day orally. Furthermore, compound 28 demonstrated a low risk of both genotoxicity and cardiotoxicity and was highly effective against ART-resistant parasites. This study demonstrated the first and robust antirelapse LS activity from a novel acridone family.