Thyroxine, the main secretory hormone of thyroid gland, is produced from thyroglobulin by thyroid peroxidase/hydrogen peroxide/iodide system. The prohormone T4 is then converted to its potent form T3 by a selenocysteine- containing enzyme iodothyronine deiodinase. Autoantibodies which activate thyroid-stimulating hormone receptor are not under the pituitary feedback control system, and therefore, the uncontrolled production of thyroid hormones leads to a condition called "hyperthyroidism." The overproduction of T4 and T3 can be controlled by specific inhibitors, which either block the synthesis of thyroid hormone or reduce the conversion of T4-T3. Unique classes of such inhibitors are thiourea drugs, methimazole (MMI), 6-n-propyl-2- thiouracil, and carbimazole suggesting that thione moiety exhibit excellent antithyroid activity. We have carried out biomimetic studies by HPLC assay, which suggested that isochromene-1-thiones exhibit significant antithyroid activity by inhibiting the lactoperoxidase (LPO)-catalyzed iodination, comparable with MMI, and that the inhibitory effects of some of them were found to be much superior to those of MMI. Kinetic studies demonstrate that isochromene-1-thiones inhibit LPO irreversibly. Our inhibition studies suggest that isochromene-1-thiones might be another promising candidate with potential for developing therapeutics for hyperthyroidism. The quantitative structure-activity relationship (QSAR) was developed between the LPO-inhibitory activities of isochromene-1-thiones and their physiochemical properties. The statistical measures, such as r2 (0.81), r2adj (0.79), q2 (0.73), and F-ratio (39.05), were found to be within the acceptable range. © 2013 Springer Science+Business Media New York.