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

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Abstract

Background

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.

Methods

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.

Results

Compounds 5–7 containing residues of veratraldehyde, vanillin, and syringaldehyde at concentration 250 μM, preserved at the highest degree the synaptosomal viability and GSH levels. Further screening of compounds 5–7 at lower concentrations of 100 μM, 10 μM, and 1 μM, 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.

Conclusions

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.

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Acknowledgements

The financial support by the National Science Fund of Bulgaria (contract KP-06-М29/4) is gratefully acknowledged.

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Authors and Affiliations

  1. Institute of Organic Chemistry With Center of Phytochemistry, Bulgarian Academy of Sciences, Acad. G. Bonchev Str., Building 9, 1113, Sofia, Bulgaria

    Neda Anastassova & Denitsa Yancheva

  2. Department of Medical Physics and Biophysics, Faculty of Medicine, Medical University of Sofia, 2 Zdrave Str., 1431, Sofia, Bulgaria

    Nadya Hristova-Avakumova, Vera Hadjimitova & Trayko Traykov

  3. Laboratory of Drug Metabolism and Drug Toxicity, Department of Pharmacology, Pharmacotherapy and Toxicology, Faculty of Pharmacy, Medical University-Sofia, 2 Dunav Str., 1000, Sofia, Bulgaria

    Denitsa Aluani, Virginia Tzankova & Magdalena Kondeva-Burdina

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  1. Neda Anastassova
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Anastassova, N., Yancheva, D., Hristova-Avakumova, N. et al. New benzimidazole-aldehyde hybrids as neuroprotectors with hypochlorite and superoxide radical-scavenging activity. Pharmacol. Rep 72, 846–856 (2020). https://doi.org/10.1007/s43440-020-00077-3

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  • DOI: https://doi.org/10.1007/s43440-020-00077-3

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