Antileishmanial Activities of ()-2-(Nitroimidazolylmethylene)-3()-Benzofuranones: Synthesis, Assessment, and Bioactivation by NTR 1 and 2.

The antileishmanial activity of a series of ()-2-(heteroarylmethylene)-3(2)-benzofuranone derivatives, possessing 5-nitroimidazole or 4-nitroimidazole moieties, was investigated against Leishmania major promastigotes and some analogues exhibited prominent activities. Compounds with IC values lower than 20 μM were further examined against L. donovani axenic amastigotes. Evaluated analogues in 5-nitroimidazole subgroup demonstrated significantly superior activity (~17-88-folds) against L. donovani in comparison to L. major. ()-7-Methoxy-2-(1-methyl-5-nitroimidazole-2-ylmethylene)-3(2)-benzofuranone (5n) showed the highest L. donovani anti-axenic amastigote activity with IC of 0.016 μM. The cytotoxicity of these analogues was determined using PMM peritoneal mouse macrophage and THP-1 human leukemia monocytic cell lines and high selectivity indices of 26 to 431 were obtained for their anti-axenic amastigote effect over the cytotoxicity on PMM cells. Further studies on their mode of action showed that 5-nitroimidazole compounds were bioactivated predominantly by nitroreductase 1 (NTR1) and 4-nitroimidazole analogues by both NTR1 and 2. It is likely that this bioactivation results in the production of nitroso and hydroxylamine metabolites that are cytotoxic for the parasite.