A novel class of antimalarial compounds, based on an indol-3-yl linked to the 2-position of a 4-aminoquine moiety, shows promising activity against the malaria parasite, Plasmodium falciparum. Compounds with a quaternary nitrogen on the quinoline show improved activity against the chloroquine-resistant K1 strain. Non-quaternerized 4-aminoquinolines retain significant potency but are relatively less active against the K1 strain. Alkylation of the 4-amino group preferentially improves the activity against the chloroquine-sensitive 3D7 strain. The quinoline-indoles show only weak activity as inhibitors of β-hematin formation and their activities are only weakly antagonized by a hemoglobinase inhibitor. The compounds appear to dissipate mitochondrial potential as an early event in their antimalarial action, and therefore may exert their activity by compromising Plasmodium mitochondrial function. Interestingly, we observed a structural relationship between our compounds and the anti-cancer and anthelmintic compound, pyrvinium pamoate, which has also been proposed to exert its action via compromising mitochondrial function.