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Flavone derivatives: a promising tool in the fight against malaria
14 December 2016 (online)
P. falciparum malaria is the deadliest parasitic disease with 438.000 deaths every year . The increasing resistance of Plasmodium to antimalarials, notably to the first line treatment, artemisinins , is a major threat and fast acting drugs with new mechanisms of action are needed. We isolated an active biflavonoid from Campnosperma panamense (Anacardiaceae, IC50= 480 nM in vitro on P. falciparum K1 multi-resistant strain) , and developed novel simplified synthetic analogs (MR series) with improved pharmacological and pharmacokinetic profiles. One of these analogs, MR70 is parasiticidal on early blood stages of P. falciparum in less than 6 hours. Moreover, MR70 and its analog MR87 exhibit a partial in vivo antimalarial activity, reducing parasitemia by 35% to 70%, respectively, on day 4 in a murine model (P. berghei ANKA, 100 mg/kg for 4 days). But these compounds showed no significant improvement in terms of survival. A structure-activity relationship study is still ongoing to further improve these results. MR70 is a fast acting drug. To our knowledge, it is the only compound targeting specifically these stages, suggesting a potential new mechanism of action. Interestingly, this stage is specifically the one that is resistant to artemisinins  and we are currently assessing MR70 efficacy on resistant isolates. Further investigation is needed to optimize MR70 activity and to understand its underlying mechanism(s) of action.
Acknowledgements: Fondation Groupe Pasteur Mutualité, Fondation Pierre Ledoux Jeunesse Internationale, Réseau International des Instituts Pasteur.
Keywords: Plasmodium, flavone, in vivo, artemisinin, resistance, fast acting drug.
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