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.

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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).

The anti-inflammatory activity of 1-methylimidazole-2-thiol (methimazole), the most widely used antithyroid drug, was investigated. Methimazole had a marked inhibitory action on prostaglandin H synthase (IC₅₀ = 10 µmol/l), inhibiting the peroxidase (IC₅₀ = 330 µmol/l), although the cyclo-oxygenase was slightly activated. Methimazole was less potent than indometacin (IC₅₀ = 1.7 µmol/l) on prostaglandin H synthase, but was more potent than acetylsalicylic acid (IC₅₀ =160 µmol/l). Methimazole has been found to trap superoxide (O^·₂) radicals and to decrease the level of blood prostaglandin E₂.

Inspection of the chemical structure of ketoconazole indicates that it may have antithyroid activity. The antithyroid action of this drug was demonstrated in-vitro and in-vivo. In-vitro, it was found to form a complex with iodine (formation constant Kc 141 L mol-1), and to inhibit lactoperoxidase (IC50 2 x 10(-4) M). Its effects in-vivo in the rat were assessed by assay of circulating-thyroxine, and from the histological appearance of the thyroid gland. Thyroid gland weight was increased in rats treated with ketoconazole.