TY - JOUR
T1 - Antagonistic antimalarial properties of a methoxyamino chalcone derivative and 3-hydroxypyridinones in combination with dihydroartemisinin against Plasmodium falciparum
AU - Kampoun, Tanyaluck
AU - Koonyosying, Pimpisid
AU - Ruangsuriya, Jetsada
AU - Prommana, Parichat
AU - Shaw, Philip J.
AU - Kamchonwongpaisan, Sumalee
AU - Suwito, Hery
AU - Puspaningsih, Ni Nyoman Tri
AU - Uthaipibull, Chairat
AU - Srichairatanakool, Somdet
N1 - Funding Information:
This work was funded by the Royal Golden Jubilee PhD Program (NSTDA), the Thailand Research Fund (PHD0234/2558) and the Faculty of Medicine Endowment Fund, Chiang Mai University (Grant number 113-2561). The APC was funded by the Royal Golden Jubilee PhD Program (NSTDA), Thailand Research Fund (PHD0234/2558). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Publisher Copyright:
Copyright 2023 Kampoun et al.
PY - 2023
Y1 - 2023
N2 - 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.
AB - 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.
KW - Antimalarial
KW - Artemisinin
KW - Chalcone
KW - Drug resistance
KW - Ferredoxin
KW - Hydroxypyridinone
KW - Plasmodium
UR - http://www.scopus.com/inward/record.url?scp=85159191203&partnerID=8YFLogxK
U2 - 10.7717/peerj.15187
DO - 10.7717/peerj.15187
M3 - Article
AN - SCOPUS:85159191203
SN - 2167-8359
VL - 11
JO - PeerJ
JF - PeerJ
M1 - e15187
ER -