Spectroscopic and in silico study on the conversion of N,N'-disubstituted hydrazone derivatives of 5-nitrobenzimidazole-2-thione into anion and radical anion products: Implications in hepatotoxicity.

Abstract

The conversion of N,N'-disubstituted hydrazone derivatives of 5-nitrobenzimidazole-2-thione into radical anion and dianion products was studied through infrared (IR) spectroscopy and computational methods. The electrochemical reduction of 3,3'-(5-nitro-2-thioxo-1H-benzo[d]imidazole-1,3(2H)-diyl)bis(N'-(2-methoxybenzylidene))propane-hydrazide was performed directly in the IR cell and the spectral changes were monitored over time in order to identify the spectral bands originating from the reduction product. In order to clarify whether the reduction leads to the generation of radical anion or deprotonated radical dianion, a second spectroscopic experiment was carried out where deprotonation was achieved by treatment with sodium methoxide. Both experiments resulted in distinctly different spectral features, giving evidence that the reduction to radical anion is not accompanied by deprotonation. In order to explain the experimentally observed differences in the hepatotoxicity within the series of N,N'-disubstituted derivatives of 5-nitrobenzimidazole-2-thione, several molecular electronic parameters such as frontier molecular orbitals, spin and charge distribution over fragments, and electron affinities of the studied hydrazone derivatives were compared to those of a previously studied ester derivative. Based on the estimated electronic parameters, it was shown that the type of the side chains (ester, hydrazone etc.) attached to the N-atoms in the nitrobenzimidazole derivatives do not change significantly the propensity of the compounds towards nitro reduction, but however the generated radical anions are characterized by different reactivity accounting for the different hepatotoxicity.