2. Academic Validation
  3. 3-Hydroxy-propanamidines, a New Class of Orally Active Antimalarials Targeting Plasmodium falciparum

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

  • J Med Chem. 2021 Mar 25;64(6):3035-3047. doi: 10.1021/acs.jmedchem.0c01744.
Tanja C Knaab 1,  Jana Held 2 3,  Bjoern B Burckhardt 4,  Kelly Rubiano 5,  John Okombo 5,  Tomas Yeo 5,  Sachel Mok 5,  Anne-Catrin Uhlemann 6,  Beate Lungerich 1,  Christoph Fischli 7 8,  Lais Pessanha de Carvalho 2,  Benjamin Mordmüller 2 3,  Sergio Wittlin 7 8,  David A Fidock 5 6,  Thomas Kurz 1
Affiliations

Affiliations

  • 1 Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Universitaetsstraße 1, Düsseldorf 40225, Germany.
  • 2 Institute of Tropical Medicine, Eberhard Karls University Tübingen, Wilhelmstraße 27, Tübingen 72074, Germany.
  • 3 Centre de Recherches Médicales de Lambaréné, Lambaréné B.P.: 242, Gabon.
  • 4 Institute of Clinical Pharmacy and Pharmacotherapy, Heinrich Heine University Düsseldorf, Universitaetsstraße 1, Düsseldorf 40225, Germany.
  • 5 Department of Microbiology & Immunology, Columbia University Irving Medical Center, New York 10032, New York, United States.
  • 6 Division of Infectious Diseases, Department of Medicine, Columbia University Irving Medical Center, New York 10032, New York, United States.
  • 7 Swiss Tropical and Public Health Institute, Socinstraße 57, Basel 4002, Switzerland.
  • 8 University of Basel, Basel CH-4003, Switzerland.
PMID: 33666415 DOI: 10.1021/acs.jmedchem.0c01744
Abstract

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.

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