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Antimalarial Pyrido[1,2-a]benzimidazoles Exert Strong Parasiticidal Effects by Achieving High Cellular Uptake and Suppressing Heme Detoxification.

Pyrido[1,2-a]benzimidazoles (PBIs) are synthetic antiplasmodium agents with potent activity and are structurally differentiated from benchmark antimalarials. To study the cellular uptake of PBIs and understand the underlying phenotype of their antiplasmodium activity, their antiparasitic activities were examined in chloroquine (CQ)-susceptible and CQ-resistant Plasmodium falciparum in vitro. Moreover, drug uptake and heme detoxification suppression were examined in Plasmodium berghei-infected mice. The in vitro potency of PBIs is comparable to most 4-aminoquinolines. They have a speed of action in vitro that is superior to that of atovaquone and an ability to kill rings and trophozoites. The antiparasitic effects observed for the PBIs in cell culture and in infected mice are similar in terms of potency and efficacy and are comparable to CQ but with the added advantage of demonstrating equipotency against both CQ susceptible and resistant parasite strains. PBIs have a high rate of uptake by parasite cells and, conversely, a limited rate of uptake by host cells. The mechanism of cellular uptake of the PBIs differs from the ion-trap mechanism typically observed for 4-aminoquinolines, although they share key structural features. The high cellular uptake, attractive parasiticidal profile, and susceptibility of resistant strains to PBIs are desirable characteristics for new antimalarial agents.