Rédigé le 1 septembre 2016 à 12:00 par , publié dans Non classé.

Katharina Ehrhardt, Christiane Deregnaucourt, Alice-Anne Goetz, Tzvetomira Tzanova, Valentina Gallo, Paolo Arese, Bruno Pradines, Sophie H. Adjalley, Denyse Bagrel, Stephanie A. Blandin, Michael Lanzer, Elisabeth Davioud-Charvet: The redox-cycler plasmodione is a fast acting antimalarial lead compound with pronounced activity against sexual and early asexual blood-stage parasites. Dans: Antimicrob. Agents Chemother., 60 (9), p. 5146-5158 , 2016, ISSN: 1098-6596.

Résumé

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 intra-erythrocytic stages of the human malaria parasite Plasmodium falciparum We show that plasmodione acts rapidly against asexual blood stages, thereby disrupting the clinically relevant intra-erythrocytic life cycle of the parasite, and furthermore has potent activity against early gametocytes. The lead's antiplasmodial activity was unaffected by the most common resistance mechanisms to clinically used antimalarials. Moreover, plasmodione has a low potential to induce drug resistance and a fast 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 it 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.

BibTeX (Download)

@article{ehrhardt_redox-cycler_2016,
title = {The redox-cycler plasmodione is a fast acting antimalarial lead compound with pronounced activity against sexual and early asexual blood-stage parasites},
author = { Katharina Ehrhardt and Christiane Deregnaucourt and Alice-Anne Goetz and Tzvetomira Tzanova and Valentina Gallo and Paolo Arese and Bruno Pradines and Sophie H. Adjalley and Denyse Bagrel and Stephanie A. Blandin and Michael Lanzer and Elisabeth Davioud-Charvet},
url = {http://aac.asm.org/content/60/9/5146},
doi = {10.1128/AAC.02975-15},
issn = {1098-6596},
year  = {2016},
date = {2016-09-01},
journal = {Antimicrob. Agents Chemother.},
volume = {60},
number = {9},
pages = { 5146-5158 },
abstract = {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 intra-erythrocytic stages of the human malaria parasite Plasmodium falciparum We show that plasmodione acts rapidly against asexual blood stages, thereby disrupting the clinically relevant intra-erythrocytic life cycle of the parasite, and furthermore has potent activity against early gametocytes. The lead's antiplasmodial activity was unaffected by the most common resistance mechanisms to clinically used antimalarials. Moreover, plasmodione has a low potential to induce drug resistance and a fast 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 it 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.},
keywords = {antimalarial, parasites, Plasmodium, redox-cycler},
pubstate = {published},
tppubtype = {article}
}