Hepatotoxicity and antioxidant activity of some new N,N′-disubstituted benzimidazole-2-thiones, radical scavenging mechanism and structure-activity relationship

Abstract

A new method for the synthesis of 1,3-disubstituted benzimidazole derivatives was developed using aza-Michael addition. The target compounds were synthesized in good yields and purity and tested on isolated hepatocytes for their toxicity and antioxidant activity. The antioxidant properties of the substances with lowest toxicity were evaluated using oxidative stress induced by tert-butyl hydroperoxide (tert-BOOH). Some of them as methyl 3-[3-(3-methoxy-3-oxopropyl)-5-benzoyl-2-thioxo-2,3-dihydro-1H-benzimidazol-1-yl]propanoate 10 and 1,3-bis[3-(hydrazinooxy)-3-oxopropyl]-5-benzoyl-1,3-dihydro-2H-benzimidazole-2-thione 15 exhibited statistically significant cytoprotective and antioxidant effects which were similar to those of quercetin. In order to estimate the influence of the structure on the biological properties, structural characterization of the studied compounds was performed by X-ray diffraction analysis and DFT methods. On the basis of the calculated reaction enthalpies of hydrogen atom abstraction (HAT mechanism) and single-electron transfer (SET mechanism) the mechanisms of the antioxidant action of the tested compounds were studied. Subsequently it was established that the HAT mechanism governs the radical scavenging of 10 and 15 in the lipid phase, while the SET mechanism is preferred in water medium for 10 and competitive to HAT for 15.

Keywords

• 1,3-Disubstituted benzimidazole-2-thiones
• Michael addition
• Hepatotoxicity
• Oxidative stress
• Radical scavenging
• DFT calculations