Inhibition of Lactoperoxidase‐Catalyzed Oxidation by Imidazole‐Based Thiones and Selones: A Mechanistic Study

Abstract Herein, we describe the synthesis and biomimetic activity of a series of N,N‐disubstituted thiones and selones that contain an imidazole pharmacophore. The N,N‐disubstituted thiones do not show any inhibitory activity towards LPO‐catalyzed oxidation reactions, but their corresponding N,N‐disubstituted selones exhibit inhibitory activity towards LPO‐catalyzed oxidation reactions. Substituents on the N atom of the imidazole ring appear to have a significant effect on the inhibition of LPO‐catalyzed oxidation and iodination reactions. Selones 16 , 17 , and 19 , which contain methyl, ethyl, and benzyl substituents, exhibit similar inhibition activities towards LPO‐catalyzed oxidation reactions with IC 50 values of 24.4, 22.5, and 22.5 μ M , respectively. However, their activities are almost three‐fold lower than that of the commonly used anti‐thyroid drug methimazole (MMI). In contrast, selone 21 , which contains a NCH 2 CH 2 OH substituent, exhibits high inhibitory activity, with an IC 50 value of 7.2 μ M , which is similar to that of MMI. The inhibitory activity of these selones towards LPO‐catalyzed oxidation/iodination reactions is due to their ability to decrease the concentrations of the co‐substrates (H 2 O 2 and I 2 ), either by catalytically reducing H 2 O 2 (anti‐oxidant activity) or by forming stable charge‐transfer complexes with oxidized iodide species. The inhibition of LPO‐catalyzed oxidation/iodination reactions by N,N‐disubstituted selones can be reversed by increasing the concentration of H 2 O 2 . Interestingly, all of the N,N‐disubstituted selones exhibit high anti‐oxidant activities and their glutathione peroxidase (GPx)‐like activity is 4–12‐fold higher than that of the well‐known GPx‐mimic ebselen. These experimental and theoretical studies suggest that the selones exist as zwitterions, in which the imidazole ring contains a positive charge and the selenium atom carries a large negative charge. Therefore, the selenium moieties of these selones possess highly nucleophilic character. The 77 Se NMR chemical shifts for the selones show large upfield shift, thus confirming the zwitterionic structure in solution.