The Redox Cycler Plasmodione Is a Fast-Acting Antimalarial Lead Compound with Pronounced Activity against Sexual and Early Asexual Blood-Stage Parasites.
Previously, we presented the chemical design of a promising series of antimalarial agents, 3-[substituted-benzyl]-menadiones, with potent in vitro and in vivo activities. Ongoing studies on the mode of action of antimalarial 3-[substituted-benzyl]-menadiones revealed that these agents disturb the redox balance of the parasitized erythrocyte by acting as redox cyclers-a strategy that is broadly recognized for the development of new antimalarial agents. Here we report a detailed parasitological characterization of the in vitro activity profile of the lead compound 3-[4-(trifluoromethyl)benzyl]-menadione 1c (henceforth called plasmodione) against intraerythrocytic stages of the human malaria parasite Plasmodium falciparum We show that plasmodione acts rapidly against asexual blood stages, thereby disrupting the clinically relevant intraerythrocytic life cycle of the parasite, and furthermore has potent activity against early gametocytes. The lead's antiplasmodial activity was unaffected by the most common mechanisms of resistance to clinically used antimalarials. Moreover, plasmodione has a low potential to induce drug resistance and a high killing speed, as observed by culturing parasites under continuous drug pressure. Drug interactions with licensed antimalarial drugs were also established using the fixed-ratio isobologram method. Initial toxicological profiling suggests that plasmodione is a safe agent for possible human use. Our studies identify plasmodione as a promising antimalarial lead compound and strongly support the future development of redox-active benzylmenadiones as antimalarial agents.
UMR 7509 CNRS and University of Strasbourg, European School of Chemistry, Polymers and Materials (ECPM), Strasbourg, France Center of Infectious Diseases, Parasitology, Heidelberg University, Heidelberg, Germany.
Katharina
K
Ehrhardt
Museum National d'Histoire Naturelle, UMR 7245 CNRS, Paris Cedex 05, France.
Christiane
C
Deregnaucourt
INSERM, U963, Strasbourg, France CNRS, UPR9022, Institut de Biologie Moléculaire et Cellulaire, Strasbourg, France Université de Strasbourg, Strasbourg, France.
Alice-Anne
AA
Goetz
SRSMC Laboratory, UMR CNRS 7565, University of Lorraine, Metz, France.
Tzvetomira
T
Tzanova
Department of Oncology, University of Torino Medical School, Turin, Italy.
Valentina
V
Gallo
Department of Oncology, University of Torino Medical School, Turin, Italy.
Paolo
P
Arese
Institut de Recherche Biomédicale des Armées, Département des Maladies Infectieuses, Unité de Parasitologie et d'Entomologie, Brétigny sur Orge, France Aix Marseille Université, Unité de Recherche sur les Maladies Infectieuses et Tropicales Emergentes, UM 63, CNRS 7278, IRD 198, INSERM 1095, Marseille, France Centre National de Référence du Paludisme, Marseille, France.
Bruno
B
Pradines
Genome Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany.
Sophie H
SH
Adjalley
SRSMC Laboratory, UMR CNRS 7565, University of Lorraine, Metz, France.
Denyse
D
Bagrel
INSERM, U963, Strasbourg, France CNRS, UPR9022, Institut de Biologie Moléculaire et Cellulaire, Strasbourg, France Université de Strasbourg, Strasbourg, France.
Stephanie
S
Blandin
Center of Infectious Diseases, Parasitology, Heidelberg University, Heidelberg, Germany.
Michael
M
Lanzer
UMR 7509 CNRS and University of Strasbourg, European School of Chemistry, Polymers and Materials (ECPM), Strasbourg, France elisabeth.davioud@unistra.fr.
Elisabeth
0000-0001-7026-4034
E
Davioud-Charvet
D000962:Antimalarials / Q000138:chemical synthesis / Q000494:pharmacology*; D037621:Artemisinins / Q000494:pharmacology; D053626:Atovaquone / Q000494:pharmacology; D004347:Drug Interactions; D004351:Drug Resistance / Q000187:drug effects; D004912:Erythrocytes / Q000187:drug effects / Q000469:parasitology; D005718:Gametogenesis / Q000187:drug effects*; D006801:Humans; D020128:Inhibitory Concentration 50; D008018:Life Cycle Stages / Q000187:drug effects*; D008751:Methylene Blue / Q000494:pharmacology; D009285:Naphthoquinones / Q000138:chemical synthesis / Q000494:pharmacology*; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000254:growth & development
D000962:Antimalarials; D037621:Artemisinins; D009285:Naphthoquinones; C039060:artenimol; D008751:Methylene Blue; D053626:Atovaquone