3‑Benzylmenadiones and their Heteroaromatic Analogues Target the Apicoplast of Apicomplexa Parasites: Synthesis and Bioimaging Studies

The apicoplast is an essential organelle for the viability of apicomplexan parasites Plasmodium falciparum or Toxoplasma gondii, which has been proposed as a suitable drug target for the development of new antiplasmodial drug-candidates. Plasmodione, an antimalarial redox-active lead drug is active...

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Published inACS infectious diseases Vol. 10; no. 10; pp. 3553 - 3576
Main Authors Dupouy, Baptiste, Donzel, Maxime, Roignant, Matthieu, Charital, Sarah, Keumoe, Rodrigue, Yamaryo-Botté, Yoshiki, Feckler, Alexander, Bundschuh, Mirco, Bordat, Yann, Rottmann, Matthias, Mäser, Pascal, Botté, Cyrille Y., Blandin, Stéphanie A., Besteiro, Sébastien, Davioud-Charvet, Elisabeth
Format Journal Article
LanguageEnglish
Published United States American Chemical Society 11.10.2024
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Summary:The apicoplast is an essential organelle for the viability of apicomplexan parasites Plasmodium falciparum or Toxoplasma gondii, which has been proposed as a suitable drug target for the development of new antiplasmodial drug-candidates. Plasmodione, an antimalarial redox-active lead drug is active at low nM concentrations on several blood stages of Plasmodiumsuch as early rings and gametocytes. Nevertheless, its precise biological targets remain unknown. Here, we described the synthesis and the evaluation of new heteroaromatic analogues of plasmodione, active on asexual blood P. falciparum stages and T. gondii tachyzoites. Using a bioimaging-based analysis, we followed the morphological alterations of T. gondii tachyzoites and revealed a specific loss of the apicoplast upon drug treatment. Lipidomic and fluxomic analyses determined that drug treatment severely impacts apicoplast-hosted FASII activity in T. gondii tachyzoites, further supporting that the apicoplast is a primary target of plasmodione analogues. To follow the drug localization, “clickable” analogues of plasmodione were designed as tools for fluorescence imaging through a Cu­(I)-catalyzed azide–alkyne cycloaddition reaction. Short-time incubation of two probes with P. falciparum trophozoites and T. gondii tachyzoites showed that the clicked products localize within, or in the vicinity of, the apicoplast of both Apicomplexa parasites. In P. falciparum, the fluorescence signal was also associated with the mitochondrion, suggesting that bioactivation and activity of plasmodione and related analogues are potentially associated with these two organelles in malaria parasites.
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ISSN:2373-8227
2373-8227
DOI:10.1021/acsinfecdis.4c00304