Design, synthesis, antioxidant properties and mechanism of action of new N,N′-disubstituted benzimidazole-2-thione hydrazone derivatives

Abstract New series of N,N′-disubstituted benzimidazole-2-thione were synthesized by introduction of hydrazone moiety in the side chains. The toxicological potential of studied compounds was evaluated by monitoring the cell viability and levels of lactate dehydrogenase, glutathione and malonaldehyde in isolated rat hepatocytes. The antioxidant properties of the compounds with the lowest toxicity were evaluated using oxidative stress induced by tert -butylhydroperoxide ( tert -BOOH) on rat hepatocytes. The unsubstituted benzimidazole-2-thiones containing methoxyphenyl moieties, which revealed the lowest cytotoxic effects on isolated rat hepatocytes, exhibited statistically significant cytoprotective and antioxidant effects similar to those of quercetin. The elucidation of the antioxidant activity of the tested hydrazones was complimented by evaluation of their protective effect against iron induced oxidative damage in classic model systems containing basic biologically relevant molecules – lecithin and deoxyribose. It was demonstrated that all the tested compounds have protective effect on Fe (II) oxidative stress cellular damage of cellular lipids. DFT calculations were applied in order to calculate the reaction enthalpies of hydrogen atom abstraction and single-electron transfer in nonpolar and polar medium and to estimate the most probable mechanisms of free-radicals scavenging in comparison with those suggested for melatonin. The membrane permeability of the studied compounds was characterized based on calculated physico-chemical properties such as polar surface area, molecular weight, number of rotatable bonds and number of hydrogen-bond acceptors and donors.