In an attempt to augment the efficacy of 7-chloro 4-aminoquinoline analogs and also to overcome resistance to antimalarial agents, we synthesized three cyclen (1,4,7,10-tetraazacyclododecane) analogs of chloroquine [a bisquinoline derivative, 7-chloro-4-(1,4,7,10-tetraaza-cyclododec-1-yl)-quinoline HBr, and a 7-chloro-4-(1,4,7,10-tetraaza-cyclododec-1-yl)-quinoline-Zn(2+) complex]. The bisquinoline displays the most potent in vitro and in vivo antimalarial activities. It displays 50% inhibitory concentrations (IC(50)s) of 7.5 nM against the D6 (chloroquine-sensitive) clone of Plasmodium falciparum and 19.2 nM against the W2 (chloroquine-resistant) clone, which are comparable to those of artemisinin (10.6 and 5.0 nM, respectively) and lower than those of chloroquine (10.7 and 87.2 nM, respectively), without any evidence of cytotoxicity to mammalian cells, indicating a high selectivity index (>1,333 against D6 clone and >521 against W2 clone). Potent antimalarial activities of the bisquinoline against chloroquine- and mefloquine-resistant strains of P. falciparum were also confirmed by in vitro [(3)H]hypoxanthine incorporation assay. The in vivo antimalarial activity of the bisquinoline, as determined in P. berghei-infected mice, is comparable to that of chloroquine (50% effective dose, <or=1.1 mg/kg when given orally); no apparent toxicity has been observed up to the highest dose tested (3 x 30 mg/kg). The bisquinoline inhibits in vitro hemozoin (beta-hematin) formation with an IC(50) of 1.1 microM, which is about 10-fold more potent than chloroquine (IC(50) 9.5 microM). Overall, this article describes the discovery of a new class of cyclen 4-aminoquinoline analogs as potent antimalarial drugs.