Radical Scavenging Mechanisms of 1-Arylhydrazone Benzimidazole Hybrids with Neuroprotective Activity

Benzimidazole-arylhydrazone hybrids showed promising potential as multifunctional drugs for the treatment of neurodegenerative disorders. The neuroprotection studies conducted using an in vitro model of H2O2-induced oxidative stress on the SH-SY5Y cell line revealed a remarkable activity of the compound possessing a vanilloid structural fragment. The cell viability was preserved up to 84% and this effect was significantly higher than the one exerted by the reference compounds melatonin and rasagiline. Another compound with a catecholic moiety demonstrated the second-best neuroprotective activity. Computational studies were further conducted to characterize in depth the antioxidant properties of both compounds. The possible radical scavenging mechanisms were estimated as well as the most reactive sites through which the compounds may deactivate a variety of free radicals. Both of the compounds are able to deactivate not only the highly reactive hydroxyl radicals but also alkoxyl and hydroperoxyl radicals, following hydrogen atom transfer or radical adduct formation mechanism. In nonpolar medium, 3e is predicted to react slightly faster than 3a with alkoxyl radicals and around two orders of magnitude faster than 3a with hydroperoxyl radicals. The most reactive sites for formal hydrogen atom transfer in 3a are the meta-hydroxy group in the phenyl ring in water and the amide N–H group in benzene; in 3e, the amide N–H group is more reactive in both solvents. The radical adduct formation can occur at several positions in 3a and 3e, the most active being C4, C6, and C14. The stability of the formed radicals was estimated by NBO calculations. The NBO calculations indicated that the spin density in the radicals formed by the abstraction of a hydrogen atom from the amide groups of both compounds is delocalized over the phenyl ring and the hydrazone chain. The obtained theoretical data for the better radical scavenging ability of the vanilloid hybrid corroborate its experimentally established better neuroprotective activity.