Protection of Endogenous Thiols against Methylmercury with Benzimidazole‐Based Thione by Unusual Ligand‐Exchange Reactions

Abstract

Abstract Organomercurials, such as methylmercury (MeHg + ), are among the most toxic materials to humans. Apart from inhibiting proteins, MeHg + exerts its cytotoxicity through strong binding with endogenous thiols cysteine (CysH) and glutathione (GSH) to form MeHgCys and MeHgSG complexes. Herein, it is reported that the N,N‐disubstituted benzimidazole‐based thione 1 containing a N−CH 2 CH 2 OH substituent converts MeHgCys and MeHgSG complexes to less toxic water‐soluble HgS nanoparticles (NPs) and releases the corresponding free thiols CysH and GSH from MeHgCys and MeHgSG, respectively, in solution by unusual ligand‐exchange reactions in phosphate buffer at 37 °C. However, the corresponding N‐substituted benzimidazole‐based thione 7 and N,N‐disubstituted imidazole‐based thione 3 , in spite of containing a N−CH 2 CH 2 OH substituent, failed to convert MeHgX (X=Cys, and SG) to HgS NPs under identical reaction conditions, which suggests that not only the N−CH 2 CH 2 OH moiety but the benzimidazole ring and N,N‐disubstitution in 1 , which leads to the generation of a partial positive charge at the C2 atom of the benzimidazole ring in 1:1 MeHg‐conjugated complex of 1 , are crucial to convert MeHgX to HgS NPs under physiologically relevant conditions.