iScience (Feb 2023)

Hemisynthetic alkaloids derived from trilobine are antimalarials with sustained activity in multidrug-resistant Plasmodium falciparum

  • Flore Nardella,
  • Irina Dobrescu,
  • Haitham Hassan,
  • Fabien Rodrigues,
  • Sabine Thiberge,
  • Liliana Mancio-Silva,
  • Ambre Tafit,
  • Corinne Jallet,
  • Véronique Cadet-Daniel,
  • Stéphane Goussin,
  • Audrey Lorthiois,
  • Yoann Menon,
  • Nicolas Molinier,
  • Dany Pechalrieu,
  • Christophe Long,
  • François Sautel,
  • Mariette Matondo,
  • Magalie Duchateau,
  • Guillaume Médard,
  • Benoit Witkowski,
  • Artur Scherf,
  • Ludovic Halby,
  • Paola B. Arimondo

Journal volume & issue
Vol. 26, no. 2
p. 105940

Abstract

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Summary: Malaria eradication requires the development of new drugs to combat drug-resistant parasites. We identified bisbenzylisoquinoline alkaloids isolated from Cocculus hirsutus that are active against Plasmodium falciparum blood stages. Synthesis of a library of 94 hemi-synthetic derivatives allowed to identify compound 84 that kills multi-drug resistant clinical isolates in the nanomolar range (median IC50 ranging from 35 to 88 nM). Chemical optimization led to compound 125 with significantly improved preclinical properties. 125 delays the onset of parasitemia in Plasmodium berghei infected mice and inhibits P. falciparum transmission stages in vitro (culture assays), and in vivo using membrane feeding assay in the Anopheles stephensi vector. Compound 125 also impairs P. falciparum development in sporozoite-infected hepatocytes, in the low micromolar range. Finally, by chemical pull-down strategy, we characterized the parasite interactome with trilobine derivatives, identifying protein partners belonging to metabolic pathways that are not targeted by the actual antimalarial drugs or implicated in drug-resistance mechanisms.

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