New benzimidazole-aldehyde hybrids as neuroprotectors with hypochlorite and superoxide radical-scavenging activity.

Abstract

Many neurodegenerative disorders include oxidative stress-mediated pathology. Melatonin and its metabolites act as endogenous reactive oxygen species (ROS) scavengers and antioxidants. N,N'-Disubstituted benzimidazole-2-thiones with extended side chains could exert antioxidant and neuroprotective properties due to structural similarities to melatonin. The toxicological potential of the compounds was evaluated by monitoring the synaptosomal viability and the levels of reduced glutathione (GSH) in isolated rat brain synaptosomes. The neuroprotective effects were assessed in vitro in a model of 6-hydroxydopamine (6-OHDA)-induced neurotoxicity. The capability to decrease superoxide anion radical and hypochlorite was evaluated by luminol-dependent chemiluminescent assays. Compounds 5-7 containing residues of veratraldehyde, vanillin, and syringaldehyde at concentration 250μM, preserved at the highest degree the synaptosomal viability and GSH levels. Further screening of compounds 5-7 at lower concentrations of 100μM, 10μM, and 1μM, respectively, demonstrated that 6 and 7 do not show any toxicity within this concentration range. In the model of 6-OHDA-induced oxidative stress, 6 revealed concentration-dependent, neuroprotective, and antioxidant activities similar to melatonin. All the three compounds demonstrated ability to decrease the chemiluminescent scavenging index (CL-SI) in the hypochlorite containing system. In the superoxide system, the hydrazones exhibited different effects on the signal. Our studies suggest that the benzimidazole-aldehyde hybrids act as direct ROS scavengers and membranes' stabilizers against free radicals. Thus, they play a role in the antioxidative defense system and have a promising potential as therapeutic neuroprotective agents for the treatment of neurodegenerative disorders.