Bioinorganic chemistry aspects of the inhibition of thyroid hormone biosynthesis by anti-hyperthyroid drugs

Abstract

In this paper, the synthesis and characterization of thiones and selones having N,N-disubstituted imidazole are described. Experimental and theoretical studies were performed on a number of selones, which suggest that these compounds exist as zwitterions in which the selenium atom carries a large negative charge. The structures of selones were studied in solution by ⁷⁷Se NMR spectroscopy and the ⁷⁷Se NMR chemical shifts for the selones show large upfield shifts in the signals, confirming the zwitterionic structure of the selones in solution. The thermal isomerization of some S- and Se-substituted methyl and benzyl imidazole derivatives to produce the thermodynamically more stable N-substituted derivatives are described. A structure-activity correlation was attempted on the inhibition of LPO-catalyzed oxidation and iodination reactions by several thiouracil compounds, which indicate that the presence of an n-propyl group in PTU is important for an efficient inhibition. In contrast to the S- and Se-substituted derivatives, the selones produced by thermal isomerization exhibited efficient inhibition, indicating the importance of reactive selone (zwitterionic) moiety in the inhibition. The inhibition data on carbimazole (CBZ) support the assumption that CBZ acts as a prodrug, requiring a conversion to methimazole (MMI) for its inhibitory action on thyroid peroxidase. Graphical abstract: Experimental and theoretical studies on a number of selones suggest that these compounds exist as zwitterions in which the selenium atom carries a large negative charge. The S- and Se-substituted methyl and benzyl imidazole derivatives undergo thermal isomerization to produce the thermodynamically more stable N-substituted derivatives. In contrast to the S- and Se-substituted derivatives, the selones produced by thermal isomerization show efficient inhibition on lactoperoxidase activity, indicating the importance of reactive selone (zwitterionic) moiety in the inhibition. This study also supports the assumption that carbimazole (CBZ) acts as a prodrug that must be metabolized in vivo to methimazole (MMI) to exert its anti-thyroidal action.