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DNA Methylation Bisubstrate Inhibitors Are Fast-Acting Drugs Active against Artemisinin-Resistant Plasmodium falciparum Parasites

Abstract : Malaria is the deadliest parasitic disease affecting over 200 million people worldwide. The increasing number of treatment failures due to multi-drug-resistant parasites in SouthEast Asia hinders the efforts for elimination. It is thus urgent to develop new antimalarials to contain these resistant parasites. Based on a previous report showing the presence of DNA methylation in Plasmodium, we generated new types of DNA methylation inhibitors against malaria parasites. The quinoline−quinazoline-based inhibitors kill parasites, including artemisinin-resistant field isolates adapted to culture, in the low nanomolar range. The compounds target all stages of the asexual cycle, including early rings, during a 6 h treatment period; they reduce DNA methylation in the parasite and show in vivo activity at 10 mg/kg. These potent inhibitors are a new starting point to develop fast-acting antimalarials that could be used in combination with artemisinins.
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https://hal.univ-angers.fr/hal-02571983
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Soumis le : mercredi 13 mai 2020 - 12:33:17
Dernière modification le : mardi 20 octobre 2020 - 10:21:17

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Flore Nardella, Ludovic Halby, Elie Hammam, Diane Erdmann, Véronique Cadet-Daniel, et al.. DNA Methylation Bisubstrate Inhibitors Are Fast-Acting Drugs Active against Artemisinin-Resistant Plasmodium falciparum Parasites. ACS Central Science, ACS Publications, 2020, 6 (1), pp.16-21. ⟨10.1021/acscentsci.9b00874⟩. ⟨hal-02571983⟩

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