5-Nitro-furan nitrones (<b>1</b>) and 5-nitro-thiophene nitrones (<b>2</b>) were synthesized in one step. Compounds <b>1a</b>-<b>c</b> had the most potent leishmanicidal activity against intracellular amastigote forms of <i>Leishmania amazonensis</i> and <i>L. infantum</i> (from 0.019 to 2.76 μM), with excellent selectivity (from 39 to 5673). The comparison of the leishmanicidal activity in promastigotes of wild type <i>L. donovani</i> with those overexpressing nitroreductases NRT1 or NRT2 shows that <b>1a</b>,<b>b</b> are activated by both, which could slow the development of resistance. Their redox potential (<i>E</i> <sub>redox</sub>) obtained by cyclic voltammetry (-0.67 and -0.62 V) shows that the reduction of the nitro group is modulated by the nitrone group. Oral administration of <b>1b</b> to mice infected by <i>L. infantum</i> reduced the parasite load on the spleen by 76.6 and 95.0% with doses of 50 and 100 mg/kg, respectively, administered twice a day, for 5 days. In the liver, the parasite load suppression was above 75% with either treatment.