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Antagonistic antimalarial properties of a methoxyamino chalcone derivative and 3-hydroxypyridinones in combination with dihydroartemisinin against Plasmodium falciparum

Tanyaluck Kampoun, Pimpisid Koonyosying, Jetsada Ruangsuriya, Parichat Prommana, Philip J. Shaw, Sumalee Kamchonwongpaisan, Hery Suwito, Ni Nyoman Tri Puspaningsih, Chairat Uthaipibull, View ORCID ProfileSomdet Srichairatanakool
doi: https://doi.org/10.1101/2022.11.19.517177
Tanyaluck Kampoun
1Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
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Pimpisid Koonyosying
1Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
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Jetsada Ruangsuriya
1Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
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Parichat Prommana
2Medical Molecular Biotechnology Research Group, National Center for Genetic Engineering and Biotechnology (BIOTEC), Thailand Science Park, Pathum Thani, Thailand
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Philip J. Shaw
2Medical Molecular Biotechnology Research Group, National Center for Genetic Engineering and Biotechnology (BIOTEC), Thailand Science Park, Pathum Thani, Thailand
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Sumalee Kamchonwongpaisan
2Medical Molecular Biotechnology Research Group, National Center for Genetic Engineering and Biotechnology (BIOTEC), Thailand Science Park, Pathum Thani, Thailand
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Hery Suwito
3Department of Chemistry, Faculty of Science and Technology, Airlangga University, Surabaya, Indonesia
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Ni Nyoman Tri Puspaningsih
4Laboratory of Proteomics, University-CoE Research Center for Bio-Molecule Engineering, Universitas Airlangga, Kampus C-UNAIR, Surabaya, East Java, Indonesia
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Chairat Uthaipibull
2Medical Molecular Biotechnology Research Group, National Center for Genetic Engineering and Biotechnology (BIOTEC), Thailand Science Park, Pathum Thani, Thailand
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Somdet Srichairatanakool
1Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
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  • ORCID record for Somdet Srichairatanakool
  • For correspondence: somdet.s@cmu.ac.th
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Abstract

The spread of artemisinin (ART)-resistant Plasmodium falciparum threatens the control of malaria and mutations in the propeller domains of P. falciparum Kelch13 (k13) are strongly associated with the resistance. Ferredoxin (Fd) in the ferredoxin/NADP+ reductase (Fd/FNR) redox system is essential for isoprenoid precursor synthesis in the plasmodial apicoplast; nonetheless, mutations of Fd gene (fd) may modulate ART resistance and Fd would be an important target for antimalarial drugs. We investigated the inhibitory effects of dihydroartemisinin (DHA), methoxyamino chalcone (C3), and iron chelators including deferiprone (DFP), 1-(N-acety1-6-aminohexyl)-3-hydroxy-2-methylpyridin-4-one (CM1) and deferiprone-resveratrol hybrid (DFP-RVT) against the growth of wild-type (WT) P. falciparum parasites and those with k13 and fd mutations. C3 showed antimalarial potency similar to the iron chelators. Surprisingly, combined treatments of DHA with the C3 or iron chelators showed moderately antagonistic effects against P. falciparum growth. No differences were observed among the mutant parasites with respect to their sensitivity to C3 and the chelators, or the interactions of these compounds with DHA. The data suggest that inhibitors of the Fd/FNR redox system should be avoided as ART partner drugs in ART combination therapy for treating malaria.

Competing Interest Statement

The authors have declared no competing interest.

  • Abbreviations

    ANOVA
    analysis of variance
    arps10
    apicoplast ribosomal protein S10 gene
    ART
    artemisinin
    CI
    confidential interval
    CM1
    1-(A-acetyl-6-aminohexyl)-3-hydroxy-2-methylpyridin-4-one
    crt
    chloroquine-resistant transporter gene
    C3
    Fd-FNR inhibitor compound 3
    DFO
    desferrioxiamine
    DFP
    deferiprone
    DFP-RVT
    deferiprone-resveratrol hybrid
    DFX
    deferasorix
    DHA
    dihydroartemisinin
    DI
    deionized water
    DMSO
    dimethyl sulfoxide
    Fd
    ferredoxin
    fd
    ferredoxin gene
    fd-D193Y
    fd mutation
    Fe-S
    iron-sulfur
    FI
    fluorescence intensity
    FIC
    fractional inhibition concentration
    FIC
    fractional inhibition concentration index
    FNR
    ferredoxin NADP+ reductase
    HEPES
    hydroxyethylpiperazine ethanosulfonic acid
    IC50
    inhibitory concentration 50%
    K13
    Kelch 13
    k13
    Kelch 13 gene
    k13C580Y mutant and k13MTfdMT mutant
    k13 gene mutant
    mdr2
    multidrug resistance protein 2
    P. falciparum
    Plasmodium falciparum
    MSF
    malaria SYBR Green I-based fluorescence
    ROS
    reactive oxygen species.
  • Copyright 
    The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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    Antagonistic antimalarial properties of a methoxyamino chalcone derivative and 3-hydroxypyridinones in combination with dihydroartemisinin against Plasmodium falciparum
    Tanyaluck Kampoun, Pimpisid Koonyosying, Jetsada Ruangsuriya, Parichat Prommana, Philip J. Shaw, Sumalee Kamchonwongpaisan, Hery Suwito, Ni Nyoman Tri Puspaningsih, Chairat Uthaipibull, Somdet Srichairatanakool
    bioRxiv 2022.11.19.517177; doi: https://doi.org/10.1101/2022.11.19.517177
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    Antagonistic antimalarial properties of a methoxyamino chalcone derivative and 3-hydroxypyridinones in combination with dihydroartemisinin against Plasmodium falciparum
    Tanyaluck Kampoun, Pimpisid Koonyosying, Jetsada Ruangsuriya, Parichat Prommana, Philip J. Shaw, Sumalee Kamchonwongpaisan, Hery Suwito, Ni Nyoman Tri Puspaningsih, Chairat Uthaipibull, Somdet Srichairatanakool
    bioRxiv 2022.11.19.517177; doi: https://doi.org/10.1101/2022.11.19.517177

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