Abstract
Dunnione, a natural product isolated from the leaves of Streptocarpus dunnii (Gesneriaceae), acts as a substrate for quinone-reductases that may be associated with its antimalarial properties. Following our exploration of reactive oxygen species-producing compounds such as indolones, as possible new approaches for the research of new ways to treat this parasitosis, we explored derivatives of this natural product and their possible antiplasmodial and antimalarial properties, in vitro and in vivo, respectively. Apart from one compound, all the products tested had weak to moderate antiplasmodial activities, the best IC50 value being equal to 0.58 µM. In vivo activities in the murine model were moderate (at a dose of 50 mg/kg/mice, five times higher than the dose of chloroquine). These results encourage further pharmacomodulation steps to improve the targeting of the parasitized red blood cells and antimalarial activities.
Highlights
The control of malaria, a parasitic disease, is a great challenge for countries in tropical and sub-tropical areas
Four dunnione derivatives and three tricyclic compounds were tested for their antiplasmodial properties
The two-electron reduction of these compounds by NQO2 generates the reduced form hydroquinone, which is unstable and rapidly undergoes auto-oxidation to give back the parent compound
Summary
The control of malaria, a parasitic disease, is a great challenge for countries in tropical and sub-tropical areas. Several strategies have been implemented to break the parasite/mosquito/host cycle, but none of them have been able to overcome this disease. Therapeutic strategies adopted in humans have mainly targeted the asexual blood stage of the parasite with artemisinin-based combination therapies recommended by the WHO over the past decades [1]. We have shown that indolone-N-oxides (INODs), which generate radical intermediates, exhibited strong in vivo activities against P. falciparum in a humanized mouse model [4,5,6,7]. This work made it possible to study their targets within the parasitized red blood cells by demonstrating that INODs are substrates for type 2 quinone-reductase (NQO2) [8]. The work we have carried out to identify new NQO2 substrates showed that ortho-quinones were suitable to produce a futile cycle
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