2. Academic Validation
  3. A Novel Antimalarial Agent that Inhibits Protein Synthesis in Plasmodium falciparum

A Novel Antimalarial Agent that Inhibits Protein Synthesis in Plasmodium falciparum

  • Angew Chem Int Ed Engl. 2025 Oct 20:e202514085. doi: 10.1002/anie.202514085.
Patricia Bravo # 1 2,  Eleonora Diamanti # 3,  Mostafa M Hamed 3,  Lorenzo Bizzarri 4,  Natalie Wiedemar 1 2,  Armin Passecker 1 2,  Nicolas M B Brancucci 1 2,  Anna Albisetti 1 2,  Christin Gumpp 1 2,  Boris Illarionov 5,  Markus Fischer 5,  Matthias Witschel 6,  Tobias Schehl 6,  Hannes Hahne 4,  Pascal Mäser 1 2,  Matthias Rottmann # 1 2,  Anna K H Hirsch # 3 7 8
Affiliations

Affiliations

  • 1 Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, Kreuzstrasse 2, Allschwil, 4123, Switzerland.
  • 2 Universität Basel, Petersplatz 1, Basel, 4003, Switzerland.
  • 3 Helmholtz Institute for Pharmaceutical Research Saarland (HIPS)─Helmholtz Centre for Infection Research (HZI), PharmaScienceHub, Campus Building E8.1, 66123, Saarbrücken, Germany.
  • 4 OmicScouts GmbH, Lise-Meitner-Straße 30, D-85354, Freising, Germany.
  • 5 Hamburg School of Food Science, Institute of Food Chemistry, Grindelallee 117, 20146, Hamburg, Germany.
  • 6 BASF-SE Carl-Bosch-Strasse 38, 67056, Ludwigshafen, Germany.
  • 7 Department of Pharmacy, Helmholtz Institute for Pharmaceutical Research Saarland (HIPS)─Helmholtz Centre for Infection Research (HZI), Saarland University, PharmaScienceHub, Campus Building E8.1, 66123, Saarbrücken, Germany.
  • 8 PharmaScienceHub, Campus A 2.3, 66123, Saarbrücken, Germany.
  • # Contributed equally.
PMID: 41116297 DOI: 10.1002/anie.202514085
Abstract

The emergence of drug resistance to nearly all antimalarials following their rollout underscores the need for novel chemotypes with novel modes of action to replenish the antimalarial drug-development pipeline. We identified a novel class of compounds in the antimalarial armory. Compound 31, characterized by a 2-hydroxyphenyl benzamide scaffold, displays potent activity against blood-stage and mature sexual stages of Plasmodium falciparum and no toxicity in human cells. Resistance Selection studies with 31 identified a previously unknown point mutation in the P. falciparum multidrug-resistance protein 1 (pfmdr1) gene, for which we confirmed causality by CRISPR/Cas9-based gene editing as the primary mediator of resistance. No cross-resistance toward first-line antimalarials was identified in compound 31-resistant parasites. Proteomics studies indicated that the primary mode of action of 31 is through direct binding to cytosolic ribosomal subunits, thereby inhibiting protein synthesis in the Parasite. Taken together, compound 31 is a promising starting point for the development of a next-generation antimalarial.

Keywords

2‐hydroxyphenyl benzamides; Antimalarial; Cytosolic ribosomes; Drug discovery; Drug resistance.

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