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

<i>Plasmodium falciparum,</i> the deadliest causative agent of malaria, continues to evade eradication efforts through widespread drug resistance. The recent development of <b>ADC-028</b>, 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 <i>in vitro</i> activity (IC₅₀ < 20 nM) against both drug-sensitive and multidrug-resistant <i>P. falciparum</i> strains, while maintaining favorable cytotoxicity profiles. Among them, <b>25</b> demonstrated improved intrinsic metabolic stability (t_1/2 = 121 min) and potent <i>in vivo</i> efficacy (ED₅₀ = 0.32 mg/kg/day), achieving complete curative protection at a reduced dose compared to ADC-028. While <b>25</b> showed moderately reduced oral bioavailability (F = 43%) and a shorter half-life (T_1/2 = 27.2 h) relative to ADC-028, its enhanced <i>in vivo</i> 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.