Girolline is a 2-aminoimidazole derivative extracted from Cymbastela cantharella (a New-Caledonian sponge) that has shown antitumor activity. In this study, we investigated its antimalarial activity and the point of action within the erythrocytic cycle of Plasmodium falciparum. Initially, we tested girolline and some synthetic analogues in vitro against four P. falciparum strains. The IC (50) values of girolline ranged from 77 to 215 nM, and as with artemisinin or chloroquine, girolline inhibited parasitic growth by 100 %. Girolline was found to be active at a dose of 1 mg/kg/d (orally and intraperitoneally) in vivo. Moreover, there was a significant synergistic effect between girolline and chloroquine in vitro. The investigation of the mechanism of action of girolline during the erythrocytic life cycle of the parasite showed that its action targets the synthesis of proteins by the parasite. With such a biological profile, girolline could be considered as a model chemical structure for new candidates in the arsenal of new drugs and in particular of drugs able to fight malaria.