Synthesis and Biological Evaluation of Acridine Derivatives as Antimalarial Agents

Authors

  • Dr. Xiao-Min Yu,

    1. Université Paris-Sud 11, Institut de Chimie Moléculaire et des Matériaux d'Orsay, Equipe de Chimie Bioorganique et Bioinorganique, Orsay 91405 CEDEX (France)
    2. CNRS, UMR 8182, Orsay 91405 CEDEX (France)
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  • Dr. Florence Ramiandrasoa,

    1. Université Paris-Sud 11, Institut de Chimie Moléculaire et des Matériaux d'Orsay, Equipe de Chimie Bioorganique et Bioinorganique, Orsay 91405 CEDEX (France)
    2. CNRS, UMR 8182, Orsay 91405 CEDEX (France)
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  • Dr. Lucie Guetzoyan,

    1. Université Paris-Sud 11, Institut de Chimie Moléculaire et des Matériaux d'Orsay, Equipe de Chimie Bioorganique et Bioinorganique, Orsay 91405 CEDEX (France)
    2. CNRS, UMR 8182, Orsay 91405 CEDEX (France)
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  • Dr. Bruno Pradines,

    1. Institut de Recherche Biomédicale des Armées, Unité de Parasitologie, Unité Mixte de Recherche 6236, Allée du Médecin Colonel Jamot, Parc du Pharo, BP 60109, Marseille 13262 CEDEX 07 (France)
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  • Edgar Quintino,

    1. Université Paris-Sud 11, Institut de Génétique et Microbiologie, Orsay 91405 CEDEX (France)
    2. CNRS, UMR 8621, Orsay 91405 CEDEX (France)
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  • Dr. Daniele Gadelle,

    1. Université Paris-Sud 11, Institut de Génétique et Microbiologie, Orsay 91405 CEDEX (France)
    2. CNRS, UMR 8621, Orsay 91405 CEDEX (France)
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  • Dr. Patrick Forterre,

    1. Université Paris-Sud 11, Institut de Génétique et Microbiologie, Orsay 91405 CEDEX (France)
    2. CNRS, UMR 8621, Orsay 91405 CEDEX (France)
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  • Dr. Thierry Cresteil,

    1. Ciblothèque cellulaire, Institut de Chimie des Substances Naturelles, CNRS, UPR 2301, Gif-sur-Yvette, 91198 CEDEX (France)
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  • Prof. Jean-Pierre Mahy,

    1. Université Paris-Sud 11, Institut de Chimie Moléculaire et des Matériaux d'Orsay, Equipe de Chimie Bioorganique et Bioinorganique, Orsay 91405 CEDEX (France)
    2. CNRS, UMR 8182, Orsay 91405 CEDEX (France)
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  • Dr. Stéphanie Pethe

    Corresponding author
    1. Université Paris-Sud 11, Institut de Chimie Moléculaire et des Matériaux d'Orsay, Equipe de Chimie Bioorganique et Bioinorganique, Orsay 91405 CEDEX (France)
    2. CNRS, UMR 8182, Orsay 91405 CEDEX (France)
    • Université Paris-Sud 11, Institut de Chimie Moléculaire et des Matériaux d'Orsay, Equipe de Chimie Bioorganique et Bioinorganique, Orsay 91405 CEDEX (France)
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Abstract

New N-alkylaminoacridine derivatives attached to nitrogen heterocycles were synthesized, and their antimalarial potency was examined. They were tested in vitro against the growth of Plasmodium falciparum, including chloroquine (CQ)-susceptible and CQ-resistant strains. This biological evaluation has shown that the presence of a heterocyclic ring significantly increases the activity against P. falciparum. The best compound shows a nanomolar IC50 value toward parasite proliferation on both CQ-susceptible and CQ-resistant strains. The antimalarial activity of these new acridine derivatives can be explained by the two mechanisms studied in this work. First, we showed the capacity of these compounds to inhibit heme biocrystallization, a detoxification process specific to the parasite and essential for its survival. Second, in our search for alternative targets, we evaluated the in vitro inhibitory activity of these compounds toward Sulfolobus shibatae topoisomerase VI-mediated DNA relaxation. The preliminary results obtained reveal that all tested compounds are potent DNA intercalators, and significantly inhibit the activity of S. shibatae topoisomerase VI at concentrations ranging between 2.0 and 2.5 μM.

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