3‑Hydroxy-propanamidines, a New Class of Orally Active Antimalarials Targeting Plasmodium falciparum

3-Hydroxypropanamidines are a new
promising class of highly active
antiplasmodial agents. The most active compound 22 exhibited
excellent antiplasmodial in vitro activity with nanomolar
inhibition of chloroquine-sensitive and multidrug-resistant parasite
strains ofPlasmodium falciparum (with
IC50 values of 5 and 12 nM against 3D7 and Dd2 strains,
respectively) as well as low cytotoxicity in human cells. In addition, 22 showed strong in vivo activity in thePlasmodium berghei mouse model with a cure rate of
66% at 50 mg/kg and a cure rate of 33% at 30 mg/kg in the Peters test
after once daily oral administration for 4 consecutive days. A quick
onset of action was indicated by the fast drug absorption shown in
mice. The new lead compound was also characterized by a high barrier
to resistance and inhibited the heme detoxification machinery in P. falciparum.