Designing novel bisquinoline antimalarials from historical 4-aminoquinolines to combat drug-resistant malaria.

Plasmodium falciparum, the deadliest causative agent of malaria, continues to evade eradication efforts through widespread drug resistance. The recent development of ADC-028, a 4-aminoquinoline antimalarial with excellent activity and pharmacokinetic properties, prompted the investigation of bisquinoline analogs featuring similar structural motifs. Here, we describe a structure-activity relationship study that guided the optimization of compounds with key features, including the 4-anilinoquinoline core and diverse bridging linkers. Several analogs exhibited potent in vitro activity (IC50 < 20 nM) against both drug-sensitive and multidrug-resistant P. falciparum strains, while maintaining favorable cytotoxicity profiles. Among them, 25 demonstrated improved intrinsic metabolic stability (t1/2 = 121 min) and potent in vivo efficacy (ED50 = 0.32 mg/kg/day), achieving complete curative protection at a reduced dose compared to ADC-028. While 25 showed moderately reduced oral bioavailability (F = 43%) and a shorter half-life (T1/2 = 27.2 h) relative to ADC-028, its enhanced in vivo efficacy underscores its therapeutic potential. This work highlights a promising path forward in developing antimalarials that retain the efficacy of legacy compounds while overcoming modern resistance mechanisms.