2. Academic Validation
  3. Structure-Activity Relationships of 3-Hydroxypropanamidines (HPAs) with Potent In Vivo Antimalarial Activity

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

  • J Med Chem. 2025 Sep 25;68(18):19229-19248. doi: 10.1021/acs.jmedchem.5c01337.
Saskia Klein 1,  Alena Moritz 2,  Lais Pessanha de Carvalho 3 4,  Tanja C Knaab 5,  Beate Lungerich 2,  Lukas Meyer 1,  Jona Sandström 1,  Jessica L Thibaud 6,  Katherine A de Villiers 6,  David A Fidock 4,  Sergio Wittlin 7 8,  Matthias Rottmann 7 8,  Jana Held 3 9 10,  Bjoern B Burckhardt 2,  Thomas Kurz 1
Affiliations

Affiliations

  • 1 Faculty of Mathematics and Natural Sciences, Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany.
  • 2 Individualized Pharmacotherapy, Institute of Pharmaceutical and Medicinal Chemistry, University of Muenster, 48149 Muenster, Germany.
  • 3 Institute of Tropical Medicine, Eberhard Karls University Tuebingen, 72074 Tuebingen, Germany.
  • 4 Department of Microbiology and Immunology and Center for Malaria Therapeutics and Antimalarial Resistance, Division of Infectious Diseases, Department of Medicine, Columbia University Irving Medical Center, New York, New York 10032, United States.
  • 5 Department of Pharmacy, Ludwig Maximilians University München, 81377 München, Germany.
  • 6 Department of Chemistry and Polymer Science, Stellenbosch University, Matieland 7602, South Africa.
  • 7 Swiss Tropical and Public Health Institute, Allschwil CH-4123, Switzerland.
  • 8 University of Basel, Basel CH-4003, Switzerland.
  • 9 German Center for Infection Research, Partner Site Tübingen, 72074 Tübingen, Germany.
  • 10 Centre de Recherches Médicales de Lambaréné, B.P. 242 Lambaréné, Gabon.
PMID: 40921080 DOI: 10.1021/acs.jmedchem.5c01337
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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