P. falciparum malaria is the deadliest parasitic disease with 438.000 deaths in 2015. The increasing proportion of P. falciparum parasites resistant to artemisinin, the most potent antimalarial, is a major concern in Southeast Asia. Fast acting drugs with unaltered activity versus the current multi-drug resistant strains are urgently needed to replace artemisinin. We are developing new antimalarials based on the structure of an active natural product: a biflavonoid from Campnosperma panamense (IC50 = 480 nM in vitro on P. falciparum). One of the simplified synthetic analogs, MR70, is acting faster than artemisinin in vitro at 10 times the IC50. MR70 exhibit a partial in vivo antimalarial activity, reducing parasitemia by 35% at day 4 using Peter's model (P. berghei ANKA, 100 mg/kg for 4 days). As MR70 acts on early ring stage, which has been associated to artemisinin resistance, we assessed the in vitro susceptibility of artemisinin-resistant isolates to MR70 and found no cross-resistance between MR70 and artemisinins. These findings make flavone derivatives a promising new class of antimalarials. To optimize MR70 activity, we synthesized new derivatives and managed to increase its in vitro antiplasmodial activity and selectivity. We now have to assess if the activity is conserved in vivo.