Malaria bites and quinoline delights: the discovery and development of novel 4-aminoquinolines for use against multidrug-resistant Plasmodium falciparum

This study optimized amodiaquine analogs to combat drug-resistant Plasmodium falciparum. Structural modifications yielded compound 43 (ADC-028), which showed nanomolar activity, low cytotoxicity, and a single-dose murine cure at 50 mg/kg. Further development of the 4-anilinoquinoline core produced analog 69, which demonstrated superior intrinsic metabolic stability and complete curative protection at lower doses, despite lower bioavailability than compound 43. Both compounds represent promising candidates to overcome modern malaria resistance mechanisms.