Discovery of Amodiachins, a Novel Class of 4‑Aminoquinoline Antimalarials Active against Multidrug-Resistant Plasmodium falciparum

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 Plasmodium falciparum. Select compounds were tested
in Plasmodium yoelli murine models.
Structural modifications, including introduction of a piperidine ring
and varied N-alkyl substitutions enhanced antiparasitic
activity, metabolic stability, and in vivo efficacy. Compound 43 (ADC-028) emerged as a standout candidate, exhibiting nanomolar
activity against drug-sensitive and multidrug-resistant P. falciparum, minimal cytotoxicity, and favorable
murine microsomal stability (t1/2 = 48.2
min). In vivo, 43 achieved a nonrecrudescence dose at
16 mg/kg/d and a single dose cure at 50 mg/kg. Pharmacokinetic analysis
of 43 showed excellent metabolic stability (T1/2 = 84 h) and oral bioavailability (F = 76%). This study identifies 43 as a potential candidate
for further evaluation as a novel compound to overcome drug-resistant
malaria.