Discovery of Amodiachins, a Novel Class of 4-Aminoquinoline Antimalarials Active against Multidrug-Resistant <i>Plasmodium falciparum</i>

A structure activity relationship study was conducted to optimize metabolic stability and in vivo activity of amodiaquine analog antimalarials. Antiplasmodial activity of synthesized amodiachins (ADCs) were evaluated against drug-sensitive and drug-resistant strains of <i>Plasmodium falciparum</i>. Select compounds were tested in <i>Plasmodium yoelli</i> murine models. Structural modifications, including introduction of a piperidine ring and varied <i>N</i>-alkyl substitutions enhanced antiparasitic activity, metabolic stability, and in vivo efficacy. Compound <b>43</b> (ADC-028) emerged as a standout candidate, exhibiting nanomolar activity against drug-sensitive and multidrug-resistant <i>P. falciparum</i>, minimal cytotoxicity, and favorable murine microsomal stability (<i>t</i>_1/2 = 48.2 min). In vivo, <b>43</b> achieved a nonrecrudescence dose at 16 mg/kg/d and a single dose cure at 50 mg/kg. Pharmacokinetic analysis of <b>43</b> showed excellent metabolic stability (<i>T</i>_1/2 = 84 h) and oral bioavailability (<i>F</i> = 76%). This study identifies <b>43</b> as a potential candidate for further evaluation as a novel compound to overcome drug-resistant malaria.