Malaria is one of the most devastating infectious diseases in the developing 
world. Until now, only one candidate malaria vaccine RTS,S/AS01 has shown modest 
protection in phase 3 trial in African infants. Hence the treatment of malaria 
still depends on the current chemotherapeutic drugs. Considering the resistance 
of malaria parasites to almost all used antimalarial drugs, aiming at 
multi-targets rather than a single target will be a more promising strategy. 
Previous studies have shown that myricetin and fisetin exhibited in vitro 
antimalarial activity against Plasmodium falciparum, but very little research 
focused on the molecular mechanism for their parasiticidal activity. The 
cysteine protease falcipain-2 and aspartic protease plasmepsin II have long been 
considered as important antimalarial drug targets, especially combined 
inhibition of these two proteases. In this study, we determined that myricetin 
and fisetin are dual inhibitors of falcipain-2 and plasmepsin II, which might 
account for their antimalarial properties. Overall, the dual inhibition of 
falcipain-2 and plasmepsin II by myricetin and fisetin has shed light on a 
possible mechanism for their antimalarial activity and provided a rationale for 
further development as antimalarial drugs.