Selenium Analogues of Anti-Thyroid Drugs

Abstract

The inhibition of lactoperoxidase (LPO)-catalyzed oxidation of ABTS by anti-thyroid drugs and related derivatives is described. The commonly used anti-thyroid agent methimazole (MMI) inhibits the LPO with an IC ₅₀ value of 7.0 ± 1.1 μ M which is much lower than that of the other two anti-thyroid drugs, PTU and MTU. The selenium analogue of methimazole (MSeI) also inhibits LPO with an IC ₅₀ value of 16.4 ± 1.5 μ M, which is about 4–5 times lower than that of PTU and MTU. In contrast to thiones and selones, the S- and Se-protected compounds do not show any noticeable inhibition under identical experimental conditions. While the inhibition of LPO by MMI cannot be reversed by increasing the hydrogen peroxide concentration, the inhibition by MSeI can be completely reversed by increasing the peroxide concentration. Experimental and theoretical studies were performed on a number of selones, which suggest that these compounds exist as selenolates or zwitterions in which the selenium atom carries a large negative charge. The structures of selones were studied in solution by NMR spectroscopy and the ⁷⁷ Se 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 is described.

Keywords:

• Anti-thyroid drugs
• bioinorganic chemistry
• iodine
• methimazole
• selenium

Acknowledgments

This study was supported by the Department of Science and Technology (DST), New Delhi, India.

Notes

^a Concentration of the compound causing 50% inhibition. Each IC₅₀ value was calculated from at least three independent experiments.

^a The chemical shifts (δ) are cited with respect to dimethyl selenide. The calculated chemical shift for dimethyl selenide in B3LYP/6-311+G(d,p)//B3LYP/6-311++G(2d,p) level is 1637.6348. ^b77Se NMR for all compounds were taken in CDCl₃ except compound 73, which is not soluble in CDCl₃ taken in D₂O.

^a Raper et al.; ⁵⁶

^b Ansell et al.; ⁵⁴

^c Tomlin et al. ⁵⁵