Structure–Activity Relationships of 3-Hydroxypropanamidines (HPAs) with Potent In Vivo Antimalarial Activity

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Abstract New treatment strategies are required to combat the spread of drug-resistant Plasmodium falciparum malaria. The synthesis and preclinical evaluation of novel 3-hydroxy-propanamidines (HPAs), with modifications of the phenanthrene and the 4-fluorobenzamidine moieties, has yielded several analogs exhibiting excellent in vitro growth inhibition of drug-sensitive or resistant P. falciparum fresh clinical isolates and culture-adapted strains. No cytotoxicity in the human HepG2 cell line was observed, demonstrating notable parasite selectivity. The most active HPA 7d, which features a 4-bromobenzamidine moiety, inhibited the formation of synthetic hemozoin (β-hematin) with IC50 values lower than chloroquine and the lead compound TKK130. Additionally, 7d showed a killing rate comparable to chloroquine. In initial in vivo pharmacokinetics, 7d displayed a favorable pharmacokinetic profile, with a fast onset and slow elimination phase. In vivo, 7d demonstrated dose-dependent curative activity after oral administration in the Plasmodium berghei mouse model, without apparent signs of toxicity.

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