A rational approach in the search for new antiparasitic drugs is the exploitation of biochemical differences between the parasite and its mammalian host. One specific example in the case of Leishmania relates to the biosynthesis of heme, a critical prosthetic group for proteins involved in metabolism and electron transport. Like all Trypanosomatids, Leishmania parasites require heme or pre-formed porphyrins for survival because they lack several key enzymes in the heme biosynthetic pathway. Considering their specific nutritional requirements, we speculated that they would be particularly sensitive to the effects of heme-complexing xanthones. In this report, we document the antileishmanial activity of selected nitrogenated xanthones and correlate drug potency with heme affinity. In vitro tests demonstrated that 3,6-bis-omega-diethylaminoamyloxyxanthone, C5, was at least 100 times more active than pentamidine against intracellular amastigotes of Leishmania mexicana. Our findings provide practical guidance for optimizing the antileishmanial activity of the xanthone pharmacophore to better exploit parasite heme salvage processes.