Antithyroid agents and QSAR studies: inhibition of lactoperoxidase-catalyzed iodination reaction by isochromene-1-thione
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Med Chem Res DOI 10.1007/s00044-013-0475-x
ORIGINAL RESEARCH
Antithyroid agents and QSAR studies: inhibition of lactoperoxidase-catalyzed iodination reaction by isochromene-1-thiones M. V. Kirthana • F. Nawaz Khan • Ponnurengam Malliappan Sivakumar Mukesh Doble • P. Manivel • K. Prabakaran • V. Krishnakumar
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Received: 8 October 2012 / Accepted: 6 January 2013 Springer Science+Business Media New York 2013
Abstract 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
M. V. Kirthana F. Nawaz Khan (&) P. Manivel K. Prabakaran V. Krishnakumar Organic Chemistry Division, School of Advance Sciences, VIT University, Vellore 632 014, Tamil Nadu, India e-mail: [email protected] P. M. Sivakumar M. Doble Department of Biotechnology, Indian Institute of Technology Madras, Adyar, Chennai 600 036, India
structure–activity relationship (QSAR) was developed between the LPO-inhibitory activities of isochromene-1thiones 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. Keywords Lactoperoxidase inhibition Isochromene-1-thiones Antithyroid activity Iodination Methimazole QSAR
Introduction Thyroxine (T4), the main secretory hormone of the thyroid gland, is produced from thyroglobulin by thyroid peroxidase (TPO)/hydrogen peroxide/iodide system. Thyroid hormone biosynthesis involves two steps: the first step being the TPO-catalyzed iodination of tyrosine residue of thyroglobulin (Tg) and coupling of two tyrosyl residues, resulting in the formation of T4. The second step involves the deiodination of T4 by the enzyme type-1 iodothyronine deiodinase (ID
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