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

PeerJ

article

Tanyaluck Kampoun¹  Pimpisid Koonyosying¹  Jetsada Ruangsuriya¹  Parichat Prommana²  Philip J. Shaw²  Sumalee Kamchonwongpaisan²  Hery Suwito³  Ni Nyoman Tri Puspaningsih⁴  Chairat Uthaipibull²  Somdet Srichairatanakool¹ 

[1] Department of Biochemistry, Faculty of Medicine, Chiang Mai University;Medical Molecular Biotechnology Research Group, National Center for Genetic Engineering and Biotechnology ,(BIOTEC), National Science and Technology Development Agency;Department of Chemistry, Faculty of Science and Technology, Airlangga University;Laboratory of Proteomics, University-CoE Research Center for Bio-Molecule Engineering, Universitas Airlangga;Thailand Center of Excellence for Life Sciences

关键词: Plasmodium;    Antimalarial;    Artemisinin;    Chalcone;    Hydroxypyridinone;    Drug resistance;    Ferredoxin;   

DOI  :  10.7717/peerj.15187

学科分类：社会科学、人文和艺术（综合）

来源: Inra

【 摘 要 】

Background The spread of artemisinin (ART)-resistant Plasmodium falciparum threatens the control of malaria. Mutations in the propeller domains of P. falciparum Kelch13 (k13) are strongly associated with ART resistance. Ferredoxin (Fd), a component of the ferredoxin/NADP+ reductase (Fd/FNR) redox system, is essential for isoprenoid precursor synthesis in the plasmodial apicoplast, which is important for K13-dependent hemoglobin trafficking and ART activation. Therefore, Fd is an antimalarial drug target and fd mutations may modulate ART sensitivity. We hypothesized that loss of Fd/FNR function enhances the effect of k13 mutation on ART resistance. Methods In this study, methoxyamino chalcone (C3), an antimalarial compound that has been reported to inhibit the interaction of recombinant Fd and FNR proteins, was used as a chemical inhibitor of the Fd/FNR redox system. We investigated the inhibitory effects of dihydroartemisinin (DHA), C3, and iron chelators including deferiprone (DFP), 1-(N-acetyl-6-aminohexyl)-3-hydroxy-2-methylpyridin-4-one (CM1) and deferiprone-resveratrol hybrid (DFP-RVT) against wild-type (WT), k13 mutant, fd mutant, and k13 fd double mutant P. falciparum parasites. Furthermore, we investigated the pharmacological interaction of C3 with DHA, in which the iron chelators were used as reference ART antagonists. Results C3 showed antimalarial potency similar to that of the iron chelators. As expected, combining DHA with C3 or iron chelators exhibited a moderately antagonistic effect. No differences were observed among the mutant parasites with respect to their sensitivity to C3, iron chelators, or the interactions of these compounds with DHA. Discussion 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.

【 授权许可】

CC BY