New imidazoles cause cellular toxicity by impairing redox balance, mitochondrial membrane potential, and modulation of HIF-1α expression

Abstract

BackgroundOur previous reports demonstrated the prospects of a new series of imidazoles as a source of alternative anti-parasite treatments, thus warranting further studies that include toxicity profiling. ObjectiveIn this study, we evaluated three imidazoles: bis-imidazole (compound 1), phenyl-substituted 1H-imidazole (compound 2), and thiopene-imidazole (compound 3) for cellular toxicity and possible mechanisms. MethodsThe three (3) compounds were assessed for in vitro cytotoxic action. Additionally, we probed likely mechanistic actions of these imidazoles. Findings showed dose-dependent cellular toxicity by these imidazoles. ResultsIn the presence of antioxidant (Trolox), cytotoxicity was improved for compounds 2 and 3 but not for compound 1. Meantime, compound 7 promoted reactive oxygen species (ROS) production, which was abated in the presence of a standard antioxidant (Trolox). Additionally, the three (3) imidazoles impaired mitochondrial membrane potential (MMP). While MMP was not restored after treatment removal, the addition of antioxidant (Trolox) improved MMP for compounds 2 and 3 treatment. Additionally, compound 1 elevated expression of hypoxia-inducing factor 1-alpha (HIF-1α). This may not be unconnected with the capacity of compound 1 to cause oxidative stress. ConclusionWe show evidence that supports the cytotoxic action of imidazoles involves likely impairment to redox balance and mitochondrial membrane potential. The findings help our understanding of the mechanistic action of these imidazoles in living cells, and altogether may boost their prospects as new and alternative anti-protozoans.