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

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.