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A number of compounds of pharmaceutical importance from a variety of chemical families, including thiocyanates, isothiocyanates, thiourea and derivatives, imidazoles, and various amines, were found to form charge transfer complexes with iodine. Parallel studies were carried out to investigate the actions of these drugs on lactoperoxidase and thyroid activity in vivo in the rat (assays of T3 and T4 and histology of the thyroid gland). The results showed that there was a good correlation between the value of Kc (the formation constant of the iodinated complex) and antithyroid activity in vivo. The higher the electron donor power of the compound, the higher the Kc value and the stronger the action on the thyroid. The results indicated that a number of drugs could have secondary antithyroid activity. Some compounds, such as levamisole, tetramethylthiourea, tetrahydrozoline, phenothiazines, and imipramines, with no action on peroxidase had high Kc values (tetramethylthiourea, 13,825 liters/M) and had strong antithyroid activity in the rat. These results suggest that synthetic antithyroid agents may act either on peroxidase and/or the molecular iodine which may be produced by oxidation of iodides (2I(-)----I2----2I+). It has been shown that oxidation of I- can occur in the absence of thyroglobulin. In the absence of a suitable receptor, significant amounts of I2 may, thus, accumulate. The action of such drugs on molecular iodine may have considerable pharmacological significance.

Inspection of the chemical structures of tricyclic antidepressant drugs indicates that they might interfere with the synthesis of thyroid hormones. This iatrogenic potential was demonstrated in vitro by the spectrophotometric detection in both the visible and UV regions of the formation of a complex between antidepressants and iodine. The values of Kc, the formation constant of the drug-iodine complex, were calculated. The concentration of antidepressant which led to a 50% inhibition (IC50) of horseradish peroxidase was also determined. The anti-thyroid activity of drugs can be evaluated from these two parameters, Kc and IC50. The results were compared to those obtained with methimazole, a reference anti-thyroid agent. Antidepressants derived from imipramine appeared to have anti-thyroid activity. This result is now awaiting confirmation in animal experiments.

A series of compounds was synthesized by linking various derivatives of pyridine, pyrimidine or pyrazine to thiazole-2-thiol or to its partially hydrogenated derivative 2-thiazoline-2-thiol. The reactions of the compounds with molecular iodine and lactoperoxidase were examined in vitro. Their antithyroid activity was also examined in vivo in the rat. T4 and TSH levels were determined, and the thyroid gland was examined histologically. 2-(3-Hydroxy-2-pyridyl)-2-thiothiazoline had the highest antithyroid activity of the compounds tested (Kc = 14931.mol(-1),IC(50)0.65 x 10(-4) M, activity of thyroid gland).

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