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A total of 44 bis-aryl-monocyclic polyamines, monoaryl-monocyclic polyamines and their transition metal complexes were prepared, chemically characterized, and screened in vitro against the Leishmania donovani promastigotes, axenic amastigotes and intracellular amastigotes in THP1 cells. The IC(50) and/or IC(90) values showed that 10 compounds were similarly active at about 2-fold less potent than known drug pentamidine against promastigotes. The most potent compound had an IC(50) of 2.82 μM (compared to 2.93 μM for pentamidine). Nine compounds were 1.1–13.6-fold more potent than pentamidine against axenic amastigotes, the most potent one being about 2-fold less potent than amphotericin B. Fourteen compounds were about 2–10 fold more potent than pentamidine, the most potent one is about 2-fold less potent than amphotericin B against intracellular amastigotes in THP1 cells. The 2 most promising compounds (FeL7Cl(2) and MnL7Cl(2)), with strong activity against both promastigotes and amastigotes and no observable toxicity against the THP1 cells are the Fe(2+)- and Mn(2+)- complexes of a dibenzyl cyclen derivative. Only 2 of the 44 compounds showed observable cytotoxicity against THP1 cells. Tetraazamacrocyclic monocyclic polyamines represent a new class of antileishmanial lead structures that warrant follow up studies.