Development of Mitochondria Targeting AIE‐Active Cyclometalated Iridium Complexes as Potent Antimalarial Agents

The emergence of resistance to conventional antimalarial treatments remains a major cause for concern. New drugs that target the distinct development stages of Plasmodium parasites are required to address this risk. Herein, water‐soluble aggregation‐induced emission active cyclometalated iridium(III) polypyridyl complexes (Ir1–Ir12) are developed for the elimination of malaria parasites. Remarkably, these complexes show potent antimalarial activity in low nanomolar range against 3D7 (chloroquine and artemisinin sensitive strain), RKL9 (chloroquine resistant strain), and R539T (artemisinin resistant strains) strains of Plasmodium falciparum with faster killing rate of malaria parasites. Concomitantly, these complexes exhibit efficient in vivo antimalarial activity against both the asexual and gametocyte stages of Plasmodium berghei malaria parasite, suggesting promising transmission‐blocking potential. The complexes tend to localize into mitochondria of P. falciparum determined by image and cell‐based assay. The mechanistic studies reveal that these complexes exert their antimalarial activity by increasing reactive oxygen species levels and disrupting its mitochondrial membrane potential. Furthermore, the mitochondrial‐dependent antimalarial activity of these complexes is confirmed in yeast model. Thus, this study for the first time highlights the potential role of targeting P. falciparum mitochondria by iridium complexes in discovering and developing the next‐generation antimalarial agents for treating multidrug resistant malaria parasites. Aggregation‐induced‐emission active cyclometalated iridium(III) complexes are reported to target Plasmodium falciparum mitochondria for the elimination of malaria parasites. The complexes demonstrate potent in vitro antimalarial activity against various sensitive and resistant strains at all the intraerythrocytic stages of Plasmodium falciparum. These complexes inhibit both the asexual and gametocyte stage of Plasmodium berghei malaria parasite, suggesting promising transmission‐blocking efficiency.