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

• Published in: Chemistry, an Asian journal Vol. 8; no. 8; pp. 1910 - 1921
• Main Authors: Roy, Gouriprasanna, Jayaram, P. N., Mugesh, Govindasamy
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY-VCH Verlag 01.08.2013; WILEY‐VCH Verlag; Wiley Subscription Services, Inc
• Subjects: Antioxidants - chemistry; Antithyroid Agents; Azoles - chemistry; Azoles - metabolism; Biocatalysis; bioorganic chemistry; chalcogens; Chemistry; Crystallography, X-Ray; Glutathione Peroxidase - chemistry; Glutathione Peroxidase - metabolism; heterocycles; Hydrogen Bonding; Imidazoles - chemical synthesis; Imidazoles - chemistry; inhibitors; Lactoperoxidase - antagonists & inhibitors; Lactoperoxidase - metabolism; Molecular Conformation; Organoselenium Compounds - chemical synthesis; Organoselenium Compounds - chemistry; Organoselenium Compounds - metabolism; Oxidation-Reduction; Quantum Theory; scavengers; Thiones - chemical synthesis; Thiones - chemistry; scavengers; inhibitors; chalcogens; heterocycles; bioorganic chemistry
• ISSN: 1861-4728; 1861-471X
• DOI: 10.1002/asia.201300274

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 IC50 values of 24.4, 22.5, and 22.5 μM, 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CH2CH2OH substituent, exhibits high inhibitory activity, with an IC50 value of 7.2 μM, 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 (H2O2 and I2), either by catalytically reducing H2O2 (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 H2O2. 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 77Se NMR chemical shifts for the selones show large upfield shift, thus confirming the zwitterionic structure in solution. Stop, in the name of love: The inhibition of lactoperoxidase (LPO)‐catalyzed reactions by a series of N,N‐disubstituted thiones and selones that contain an imidazole pharmacophore is described. The inhibitory activity not only depends on the substituent that is attached to the nitrogen atom, but also on the nature of the chalcogen atom. The inhibition of LPO activity by selones is due to their ability to scavenge the substrate, hydrogen peroxide.