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Identifying a Deferiprone-Resveratrol Hybrid as an Effective Lipophilic Anti-Plasmodial Agent
Supawadee Maneekesorn1, Hataichanok Chuljerm2, Pimpisid Koonyosying1
1Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand.
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.
Insights
New deferiprone-resveratrol hybrids (DFP-RVT) show potent anti-malarial activity by inhibiting Plasmodium falciparum growth and depleting iron. DFP-RVT enhances pyrimethamine efficacy, suggesting its potential as an adjuvant therapy.
Area of Science:
- Medicinal Chemistry
- Parasitology
- Pharmacology
Background:
- Malaria, caused by Plasmodium parasites, remains a significant global health threat.
- Pyrimethamine (PYR) is an anti-folate drug used for malaria treatment.
- Deferiprone (DFP), an iron chelator, exhibits potential anti-malarial properties.
Purpose of the Study:
- To synthesize and evaluate novel deferiprone-resveratrol hybrids (DFP-RVT) for anti-malarial activity.
- To assess DFP-RVT's lipophilicity, toxicity, and inhibitory effects on Plasmodium falciparum.
- To investigate DFP-RVT's iron-chelating capacity and its impact on labile iron pools (LIPs).
Main Methods:
- Synthesis of DFP-RVT compounds.
- Lipophilicity and cytotoxicity assessments using blood mononuclear cells.
- In vitro anti-malarial activity testing against P. falciparum strains (3D7 and K1).
- Measurement of LIP levels in parasite-infected red blood cells (PRBCs).
Main Results:
- DFP-RVT demonstrated increased lipophilicity compared to DFP and was non-toxic to mononuclear cells.
- DFP-RVT exhibited significant P. falciparum growth inhibition, with varying potency across strains: PYR > DFP-RVT > DFP (3D7) and DFP-RVT > DFP > PYR (K1).
- Combined DFP-RVT and PYR treatment synergistically enhanced anti-malarial efficacy.
- DFP-RVT effectively reduced LIP levels in PRBCs, outperforming DFP at equivalent concentrations.
Conclusions:
- DFP-RVT represents a promising anti-malarial agent with enhanced efficacy and reduced toxicity.
- The hybrid's ability to chelate iron and disrupt LIPs is a key mechanism of action.
- DFP-RVT warrants further investigation as a potential adjuvant therapy to combat malaria, particularly in combination with existing drugs like PYR.
