Monocyclic Nitro-heteroaryl Nitrones with Dual Mechanism of Activation: Synthesis and Antileishmanial Activity.

5-Nitro-furan nitrones () and 5-nitro-thiophene nitrones () were synthesized in one step. Compounds - had the most potent leishmanicidal activity against intracellular amastigote forms of and (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 with those overexpressing nitroreductases NRT1 or NRT2 shows that , are activated by both, which could slow the development of resistance. Their redox potential ( ) 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 to mice infected by 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.