Identifying a Deferiprone–Resveratrol Hybrid as an Effective Lipophilic Anti-Plasmodial Agent

Abstract

Malaria i a serious health problem caused by Plasmodium spp. that can be treated by an anti-folate pyrimethamine (PYR) drug. Deferiprone (DFP) is an oral iron chelator used for the treatment of iron overload and has been recognized for its potential anti-malarial activity. Deferiprone–resveratrol hybrids (DFP-RVT) have been synthesized to present therapeutic efficacy at a level which is superior to DFP. We have focused on determining the lipophilicity, toxicity and inhibitory effects on P. falciparum growth and the iron-chelating activity of labile iron pools (LIPs) by DFP-RVT. According to our findings, DFP-RVT was more lipophilic than DFP (p < 0.05) and nontoxic to blood mononuclear cells. Potency for the inhibition of P. falciparum was PYR > DFP-RVT > DFP in the 3D7 strain (IC50 = 0.05, 16.82 and 47.67 µM, respectively) and DFP-RVT > DFP > PYR in the K1 strain (IC50 = 13.38, 42.02 and 105.61 µM, respectively). The combined treatment of DFP-RVT with PYR additionally enhanced the PYR activity in both strains. DFP-RVT dose-dependently lowered LIP levels in PRBCs and was observed to be more effective than DFP at equal concentrations. Thus, the DFP-RVT hybrid should be considered a candidate as an adjuvant anti-malarial drug through the deprivation of cellular iron.

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

“…Licochalcone A inhibits P. falciparum mitochondrial complexes II and III, and possibly the erythrocyte membrane [33,34]. In this study, the tested iron chelators showed modest antimalarial activity, similar to previous reports [15,16,18,35]. No differences in sensitivity to DHA were observed among the parasites tested, although it should be noted that the ART resistance phenotype manifested in k13 mutants is not detectable by the growth inhibition assay employed in this study [5].…”

“…In addition to Fd, iron is a cofactor for enzymes such as aconitase, oxidoreductases, and ribonucleotide reductase. Moreover, hemoglobin, myoglobin, and cytochromes contain an iron- [15][16][17][18][19][20]. Some antimalarial drugs, such as quinine, mefloquine, and artesunate are antagonized by DFP [21].…”

Anti-Malarial and Anti-Lipid Peroxidation Activities of Deferiprone-Resveratrol Hybrid in Plasmodium berghei-Infected Mice

“…In addition, the ability of drugs to withhold iron from malarial parasites is a critical point for this suggested treatment [ 35 ]. We have previously reported that DFP-RVT exhibited greater lipophilicity and higher efficiency in the protection of β1-42 peptide aggregation in lipid-rich neuronal cells and the inhibition of cultured P. falciparum growth than DFP [ 16 , 23 ]. In addition, the iron-chelating activity (pFe) of DFP-RVT was found to be stronger than DFP (pFe(III) = 19.6 and 20.6, respectively) [ 23 ].…”

“…Inversely, iron chelators withhold available iron from malarial parasites and subsequently inhibit parasite growth; therefore, they could potentially be candidates for adjuctive anti-malarial drugs in the treatment of malaria infections. Importantly, many iron chelators, such as deferoxamine (DFO), deferiprone (DFP), deferasirox (DFX), alkylthiocarbamates, 8-hydroxyquinoline, synthetic ferrichromes, FR160 catechol, 1-(N-acetyl-6-aminohexyl)-3-hydroxy-2-methylpyridin-4-one (CM1) and deferiprone-resveratrol (DFP-RVT) hybrid, have been administered in the treatment of P. falciparum -infected RBC (PRBC), while P. bergheir - and P. vinckei -infected mice have exhibited effective anti-plasmodium agents [ 10 , 13 , 14 , 15 , 16 , 17 , 18 , 19 ].…”

“…However, it did exhibit stronger metal-chelating activity than DFP [ 23 ]. Currently, we have demonstrated that the DFP-RVT hybrid was more efficient in decreasing LIP content in PRBC than DFP and was more effective in inhibiting parasitic growth than DFP and PYR in both mono- and combined-treatments [ 16 ]. This study focused on investigating the inhibitory effects of the DFP-RVT hybrid on parasitic growth and oxidative stress levels in P. berghei -infected mice.…”