Skip to main content
SpringerLink
Log in

Antithyroid agents and QSAR studies: inhibition of lactoperoxidase-catalyzed iodination reaction by isochromene-1-thiones

  • Original Research
  • Published:
Medicinal Chemistry Research Aims and scope Submit manuscript

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 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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Scheme 1
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  • Baruah AK, Prajapati D, Sandhu J (1988) Some novel aspects of regioselectivity in 1,3 dipolar cycloadditions of 4 h–1-benzopyran-4-thione. Tetrahedron 44(19):6137–6142

    Article  CAS  Google Scholar 

  • Batolkina O, Kabankin A, Landau M, Libinzon R (1991) Search for cyclo-AMP phosphodiesterase inhibitors by means of substructural and topological descriptors. Pharm Chem J 25(2):74–78

    Google Scholar 

  • Berry MJ, Banu L, Larsen PR (1991) Type I iodothyronine deiodinase is a selenocysteine-containing enzyme. Nature 349(6308):438–440

    Article  PubMed  CAS  Google Scholar 

  • Bianco AC, Salvatore D, Gereben B, Berry MJ, Larsen PR (2002) Biochemistry, cellular and molecular biology, and physiological roles of the iodothyronine selenodeiodinases. Endocr Rev 23(1):38–89

    Article  PubMed  CAS  Google Scholar 

  • Björkman U, Ekholm R (1992) Hydrogen peroxide generation and its regulation in FRTL-5 and porcine thyroid cells. Endocrinology 130(1):393–399

    Article  PubMed  Google Scholar 

  • Cañedo LM, Fernández Puentes JL, Baz JP, Acebal C, De La Calle F, Grávalos DG, De Quesada TG (1997) PM-94128, a new isocoumarin antitumor agent produced by a marine bacterium. J Antibiot 50(2):175–176

    Article  PubMed  Google Scholar 

  • Carvalho DP, Dupuy C, Gorin Y, Legue O, Pommier J, Haye B, Virion A (1996) The Ca2+- and reduced nicotinamide adenine dinucleotide phosphate-dependent hydrogen peroxide generating system is induced by thyrotropin in porcine thyroid cells. Endocrinology 137(3):1007–1012

    Article  PubMed  CAS  Google Scholar 

  • Chinworrungsee M, Kittakoop P, Isaka M, Chanphen R, Tanticharoen M, Thebtaranonth Y (2002) Halorosellins A and B, unique isocoumarin glucosides from the marine fungus Halorosellinia oceanica. J Chem Soc Perkin Trans 1(22):2473–2476

    Article  Google Scholar 

  • Davidson B, Neary JT, Strout HV (1978) Evidence for a thyroid peroxidase associated ‘active iodine’ species. Biochim Biophys Acta 522(2):318–326

    Article  PubMed  CAS  Google Scholar 

  • Devienne KF, Raddi MSG, Varanda EA, Vilegas W (2002) In vitro cytotoxicity of some natural and semi-synthetic isocoumarins from Paepalanthus bromelioides. Zeitschrift fur Naturforschung Section C J Biosci 57(1–2):85–88

    CAS  Google Scholar 

  • Doerge D, Divi R (1995) Porphyrin π-cation and protein radicals in peroxidase catalysis and inhibition by anti-thyroid chemicals. Xenobiotica 25(7):761–767

    Article  PubMed  CAS  Google Scholar 

  • Duddeck H, Kaiser M (1985) NMR-spektroskopische untersuchung von isocumarin-und isocarbostyril-derivaten. Spectrochim Acta Part A 41(7):913–924

    Article  Google Scholar 

  • Dudley KH, Miller HW, Corley RC, Wall ME (1967) Flavonoids. v. thiation of isoflavones. J Med Chem 10(5):985–986. doi:10.1021/jm00317a073

    Article  PubMed  CAS  Google Scholar 

  • Gonsalves IS, Shaikh AR (2012) 2D QSAR Analysis of 3’,4’,5’-trimethoxychalcone analogues as inhibitors of nitric oxide production and tumor cell proliferation. J Comput Methods Mol Des 2(1):24–38

    CAS  Google Scholar 

  • Hathwar VR, Manivel P, Nawaz Khan F, Row TNG (2007a) 3-Butyl-1H-isochromen-1-one. Acta Crystallogr Sect E 63(9):o3707–o3707

    Article  CAS  Google Scholar 

  • Hathwar VR, Manivel P, Nawaz Khan F, Row TNG (2007b) 3-Butyl-1H-isochromene-1-thione. Acta Crystallogr Sect E 63(9):o3708–o3708

    Article  CAS  Google Scholar 

  • Hathwar VR, Manivel P, Nawaz Khan F, Row TNG (2008) Evaluation of intermolecular interactions in thioisocoumarin derivatives: the role of the sulfur atom in generating packing motifs. Cryst Eng Commun 11(2):284–291

    Article  Google Scholar 

  • Hathwar VR, Roopan SM, Subashini R, Nawaz Khan F, Row TNG (2010) Analysis of Cl… Cl and CH… Cl intermolecular interactions involving chlorine in substituted 2-chloroquinoline derivatives. J Chem Sci 122(5):677–685

    Article  CAS  Google Scholar 

  • Hussain MT, Rama NH, Malik A (2001) Synthesis of some new 3-(bromophenyl)isocoumarins and their conversion to (dl)-3,4-dihydroisocoumarins. Indian J Chem Sect B Org Med Chem 40(5):372–376

    Google Scholar 

  • Kang SY, Lee KY, Sung SH, Park MJ, Kim YC (2001) Coumarins isolated from angelica g igas inhibit acetylcholinesterase: structure-activity relationships. J Nat Prod 64(5):683–685

    Article  PubMed  CAS  Google Scholar 

  • Karelson M (2000) Molecular descriptors in QSAR/QSPR. John Wiley & Sons, New York

  • Kier LB, Hall LH (1976) Molecular connectivity in chemistry and drug research, vol 2. Academic Press, New York

    Google Scholar 

  • Kohler H, Taurog A, Dunford HB (1988) Spectral studies with lactoperoxidase and thyroid peroxidase: interconversions between native enzyme, compound II, and compound III. Arch Biochem Biophys 264(2):438–449

    Google Scholar 

  • Kumar S, Singh BK, Kalra N, Kumar V, Kumar A, Prasad AK, Raj HG, Parmar VS, Ghosh B (2005) Novel thiocoumarins as inhibitors of TNF-α induced ICAM-1 expression on human umbilical vein endothelial cells (HUVECs) and microsomal lipid peroxidation. Bioorg Med Chem 13(5):1605–1613

    Article  PubMed  CAS  Google Scholar 

  • Lü JX, Shen Q, Jiang JH, Shen GL, Yu RQ (2004) QSAR analysis of cyclooxygenase inhibitor using particle swarm optimization and multiple linear regression. J Pharm Biomed Anal 35(4):679–687

    Article  PubMed  Google Scholar 

  • Maiyalagan T, Hathwar VR, Manivel P, Arslan NB, Khan FN (2008) 3-(4-Methoxyphenyl)-1H-isochromen-1-one. Acta Crystallogr Sect E 65(1):o128–o128

    Article  CAS  Google Scholar 

  • Manivel P, Roopan SM, Kumar DP, Khan FN (2009) Isocoumarin thioanalogues as potential antibacterial agents. Phosphorus Sulfur Silicon Relat Elem 184(10):2576–2582

    Article  CAS  Google Scholar 

  • Manivel P, Sharma A, Maiyalagan T, Rajeswari MR, Khan FN (2010) Synthesis and antiproliferative activity of some 1H-isochromen-1-ones and their thio analogues. Phosphorus Sulfur Silicon Relat Elem 185(2):387–393

    Article  CAS  Google Scholar 

  • Matsuda H, Shimoda H, Yoshikawa M (1999) Structure-requirements of isocoumarins, phthalides, and stilbenes from hydrangeae dulcis folium for inhibitory activity on histamine release from rat peritoneal mast cells. Bioorg Med Chem 7(7):1445–1450

    Article  PubMed  CAS  Google Scholar 

  • Napolitano E (1997) The synthesis of isocoumarins over the last decade. A review. Org Prep Proced Int 29(6):631–664

    Article  CAS  Google Scholar 

  • Nozawa K, Yamada M, Tsuda Y, Kawai K, Nakajima S (1981) Syntheses of antifungal isocoumarins. II. Synthesis and antifungal activity of 3-substituted isocoumarins. Chem Pharm Bull 29(9):2491

    Article  PubMed  CAS  Google Scholar 

  • Ohtaki S, Nakagawa H, Kimura S, Yamazaki I (1981) Analyses of catalytic intermediates of hog thyroid peroxidase during its iodinating reaction. J Biol Chem 256(2):805–810

    PubMed  CAS  Google Scholar 

  • Pommier J, Sokoloff L, Nunez J (1973) Enzymatic iodination of protein. Eur J Biochem 38(3):497–506

    Article  PubMed  CAS  Google Scholar 

  • QSARpro (2011) VLife Sciences Technologies, Pvt. Ltd., Pune, India. http://www.vlifesciences.com. Accessed 22 Jan 2013

  • Raparti V, Chitre T, Bothara K, Kumar V, Dangre S, Khachanea C, Gore S, Deshmane B (2009) Novel 4-(morpholin-4-yl)-N9-(arylidene) benzohydrazides: synthesis, antimycobacterial activity and QSAR investigations. Eur J Med Chem 44:3954

    Article  PubMed  CAS  Google Scholar 

  • Roy G, Nethaji M, Mugesh G (2004) Biomimetic studies on anti-thyroid drugs and thyroid hormone synthesis. J Am Chem Soc 126(9):2712–2713

    Article  PubMed  CAS  Google Scholar 

  • Saeed A (2003) Stereoselective synthesis of (3R)-3,4-dihydro-6,8-dimethoxy-3-undecyl- 1H-[2] benzopyran-1-one and derivatives, metabolites from Ononis natrix. Helv Chim Acta 86(2):377–383. doi:10.1002/hlca.200390038

    Article  CAS  Google Scholar 

  • Saeed A (2004) Synthesis of 6,8-dihydroxy-3-(2′-Acetyl-3′, 5′-dihydroxyphenyl)methylisocoumarin related to feralolide. Nat Prod Res 18(4):373–378. doi:10.1080/14786410310001630555

    Article  PubMed  CAS  Google Scholar 

  • Saeed A (2006) Synthesis of 6-O-methyl ether of scorzocreticin and scorzocreticoside I, metabolites from Sorzonera cretica. J Asian Nat Prod Res 8(5):417–423. doi:10.1080/10286020500172632

    Article  PubMed  CAS  Google Scholar 

  • Shen Q, Jiang JH, Tao J, Shen G, Yu RQ (2005) Modified ant colony optimization algorithm for variable selection in QSAR modeling: QSAR studies of cyclooxygenase inhibitors. J Chem Inf Model 45(4):1024–1029

    Article  PubMed  CAS  Google Scholar 

  • Singh J, Singh S, Thakur S, Lakhwani M, Khadikar PV, Agrawal VK, Supuranf CT (2006) QSAR study on murine recombinant isozyme mCAXIII: topological vs structural descriptors. Arkivoc 14:103–118

    Article  Google Scholar 

  • Sivakumar P, Seenivasan SP, Kumar V, Doble M (2007) Synthesis, antimycobacterial activity evaluation, and QSAR studies of chalcone derivatives. Bioorg Med Chem Lett 17(6):1695–1700

    Article  PubMed  CAS  Google Scholar 

  • Sivakumar PM, Priya S, Doble M (2009) Synthesis, biological evaluation, mechanism of action and quantitative structure–activity relationship studies of chalcones as antibacterial agents. Chem Biol Drug Des 73(4):403–415

    Article  PubMed  CAS  Google Scholar 

  • Stanton DT, Jurs PC (1990) Development and use of charged partial surface area structural descriptors in computer-assisted quantitative structure-property relationship studies. Anal Chem 62(21):2323–2329

    Article  CAS  Google Scholar 

  • Tajudeen SS, Nawaz Khan F (2007) Synthesis of some 3-substituted isochromen-1-ones. Synth Commun 37(20):3649–3656

    Article  CAS  Google Scholar 

  • Taurog A, Dorris ML, Guziec LJ, Guziec FS (1994) The selenium analog of methimazole measurement of its inhibitory effect on type I 5′-deiodinase and of its antithyroid activity. Biochem Pharmacol 48(7):1447–1453

    Article  PubMed  CAS  Google Scholar 

  • Thrash TP, Welton TD, Behar V (2000) Synthesis of an elaborated heliquinomycin isocoumarin moiety. Tetrahedron Lett 41(1):29–31

    Article  CAS  Google Scholar 

  • Todeschini R, Consonni V (2008) Handbook of molecular descriptors, vol 79. Wiley-vch, New York

    Google Scholar 

  • Virion A, Michot J, Deme D, Kaniewski J, Pommier J (1984) NADPH-dependent H2O2 generation and peroxidase activity in thyroid particular fraction. Mol Cell Endocrinol 36(1–2):95–105

    Article  PubMed  CAS  Google Scholar 

  • Whyte AC, Gloer JB, Scott JA, Malloch D (1996) Cercophorins AC: novel antifungal and cytotoxic metabolites from the coprophilous fungus Cercophora areolata. J Nat Prod 59(8):765–769

    Article  PubMed  CAS  Google Scholar 

  • Wildman SA, Crippen GM (1999) Prediction of physicochemical parameters by atomic contributions. J Chem Inf Comput Sci 39:868–873

    Article  CAS  Google Scholar 

Download references

Acknowledgments

The authors wish to express their gratitude to Prof G. Mughesh, IISc, Bangalore for the research facilities and the support offered to MVK.

Author information

Authors and Affiliations

  1. Organic Chemistry Division, School of Advance Sciences, VIT University, Vellore, 632 014, Tamil Nadu, India

    M. V. Kirthana, F. Nawaz Khan, P. Manivel, K. Prabakaran & V. Krishnakumar

  2. Department of Biotechnology, Indian Institute of Technology Madras, Adyar, Chennai, 600 036, India

    Ponnurengam Malliappan Sivakumar & Mukesh Doble

Authors
  1. M. V. Kirthana
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. F. Nawaz Khan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ponnurengam Malliappan Sivakumar
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mukesh Doble
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. P. Manivel
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. K. Prabakaran
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. V. Krishnakumar
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to F. Nawaz Khan.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kirthana, M.V., Nawaz Khan, F., Sivakumar, P.M. et al. Antithyroid agents and QSAR studies: inhibition of lactoperoxidase-catalyzed iodination reaction by isochromene-1-thiones. Med Chem Res 22, 4810–4817 (2013). https://doi.org/10.1007/s00044-013-0475-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00044-013-0475-x

Keywords

Search

Navigation