Structure and molecular interactions of anti-thyroid drugs. Part 3.1 Methimazole: a diiodine sponge

Laurence, Christian; Ghomari, Mohamed J. El; Questel, Jean‐Yves Le; Berthelot, M.; Mokhlisse, R.

doi:10.1039/a803002b

Cited by 87 publications

(75 citation statements)

References 45 publications

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“…The difference can reach 0.9 pK units and has been explained [82,83] by the formation of an intermolecular hydrogen bond (Scheme 2, structure 1) NH···I, which assists the I···S halogen bond. In structure 1, the iodine atom behaves as an amphoteric Lewis site, being both an acidic site towards sulfur and a basic site towards the amino group.…”

Section: Hydrogen-bond-assisted Iodine Bondsmentioning

confidence: 98%

The Diiodine Basicity Scale: Toward a General Halogen‐Bond Basicity Scale

Laurence

Graton

Berthelot

et al. 2011

Chemistry A European J

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The new diiodine basicity scale pK(BI2) is quasi-orthogonal to most known Lewis basicity scales (hydrogen-bond, dative-bond and cation basicity scales). The diiodine basicity falls in the sequence N>P≈Se>S>I≈O>Br>Cl>F for the iodine-bond acceptor atomic site and SbO≈NO≈AsO>SeO>PO>SO>C=O>-O->SO(2) or PS≫-S->C=S≫N=C=S for the functionality of oxygen or sulfur bases. Substituent effects are quantified through linear free energy relationships, which allow the calculation of individual complexation constants for each site of polybases and thus the classification of aromatic ethers as carbon π bases and of aromatic amines, thioethers and selenoethers as N, S and Se bases, respectively. The pK(BI2) values of nBu(3)N(+)-N(-)C≡N, 2-aminopyridine and 1,10-phenanthroline reveal a superbasic nitrile, a hydrogen-bond-assisted iodine bond and a two-centre iodine bond, respectively. The diiodine basicity scale is a general inorganic but family-dependent organic halogen-bond basicity scale because organic halogen-bond donors such as IC≡N and ICF(3) have a stronger electrostatic character than I(2). The family independence can be restored by the addition of an electrostatic parameter, either the experimental pK(BHX) hydrogen-bond basicity scale or the computed minimum electrostatic potential.

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Section: Hydrogen-bond-assisted Iodine Bondsmentioning

confidence: 98%

The Diiodine Basicity Scale: Toward a General Halogen‐Bond Basicity Scale

Laurence

Graton

Berthelot

et al. 2011

Chemistry A European J

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128

130

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“…In addition, to what extent maternal MMI reaching the embryo/foetus is present in the reduced or oxidised form has hardly been investigated. While oxidised MMI metabolites are no longer active as anti-thyroid drugs, they have been associated with cytotoxic effects (Kedderis & Rickert 1985, Laurence et al 1998, Heidari et al 2012) and as such they may still disturb normal development.…”

Section: Introductionmentioning

confidence: 99%

Maternal transfer of methimazole and effects on thyroid hormone availability in embryonic tissues

Herck

Geysens²,

Bald³

et al. 2013

Journal of Endocrinology

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Methimazole (MMI) is an anti-thyroid drug used in the treatment of chronic hyperthyroidism. There is, however, some debate about its use during pregnancy as MMI is known to cross the mammalian placenta and reach the developing foetus. A similar problem occurs in birds, where MMI is deposited in the egg and taken up by the developing embryo. To investigate whether maternally derived MMI can have detrimental effects on embryonic development, we treated laying hens with MMI (0.03% in drinking water) and measured total and reduced MMI contents in the tissues of hens and embryos at different stages of development. In hens, MMI was selectively increased in the thyroid gland, while its levels in the liver and especially brain remained relatively low. Long-term MMI treatment induced a pronounced goitre with a decrease in thyroxine (T 4 ) content but an increase in thyroidal 3,5,3 0 -triiodothyronine (T 3 ) content. This resulted in normal T 3 levels in tissues except in the brain. In chicken embryos, MMI levels were similar in the liver and brain. They gradually decreased during development but always remained above those in the corresponding maternal tissues. Contrary to the situation in hens, T 4 availability was only moderately affected in embryos. Peripheral T 3 levels were reduced in 14-day-old embryos but normal in 18-day-old embryos, while brain T 3 content was decreased at all embryonic stages tested. We conclude that all embryonic tissues are exposed to relatively high doses of MMI and its oxidised metabolites. The effect of maternal MMI treatment on embryonic thyroid hormone availability is most pronounced for brain T 3 content, which is reduced throughout the embryonic development period.

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“…Most of the antithyroid drugs (S-containing drugs, 1, 3, 4, and 6) mainly exist as the thione tautomers in solid state [47], and the stability of the thione tautomer may prevent these compounds from being oxidized spontaneously to their corresponding disulfides, which may account for their high antithyroidal activity. Laurence et al have shown that the thione tautomer of MMI is responsible for its complexation with diiodine, and the iodine complex of the thione tautomer 1a is favored by 13.2 kJ mol À 1 compared to that of the thiol tautomer 1b [25]. Theoretical calculations show that, in case of MMI, the thione tautomer 1a is more stable than the thiol tautomer 1b by ca.…”

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confidence: 97%

“…3). Although there is no definitive evidence for the coordination of the thione moiety of the antithyroid drugs to the Fecenter, this model is given based on the fact that FeÀS coordination is very common in metalloenzymes, and H-bonding of heme ligands with a distal histidine appears to be common in peroxidases [25] [26]. In another mechanism, it has been proposed that the thiourea drugs may be oxidized by the TPO/H 2 O 2 system to produce the corresponding electrophilic sulfenic acid intermediates, which may bind irreversibly to the electronrich prosthetic heme of the TPO [27] [28].…”

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confidence: 99%

Selenium Analogues of Antithyroid Drugs – Recent Developments

Roy

Mugesh

2008

Chemistry & Biodiversity

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Thyroxine (T4), the main secretory hormone of the thyroid gland, is produced on thyroglobulin by thyroid peroxidase (TPO)/H(2)O(2)/iodide system and deiodinated to its active form (T3) by a selenocysteine-containing enzyme, iodothyronine deiodinase (ID). The activation of thyroid-stimulating hormone (TSH) receptor by auto-antibodies leads to 'hyperthyroidism', a life-threatening disease which is treated by antithyroid drugs such as 6-propyl-2-thiouracil (PTU) and methimazole (MMI). The present review describes the biological activities of a number of S/Se derivatives bearing the methimazole pharmacophore. It is shown that the isosteric substitutions in the existing drugs lead to compounds that can effectively and reversibly inhibit the heme-containing lactoperoxidase (LPO). In contrast to methimazole, the selenium analogue, MSeI, does not interfere with the enzyme directly, but it inhibits LPO by reducing the H(2)O(2) that is required for the oxidation of the Fe-center in LPO. These studies reveal that the degradation of the intracellular H(2)O(2) by the Se analogues of antithyroid drugs may be beneficial to the thyroid gland, as these compounds may act as antioxidants and protect thyroid cells from oxidative damage. Because the drugs with an action essentially on H(2)O(2) can reversibly inhibit the thyroid peroxidase, such drugs could be of great importance in the treatment of hyperthyroidism.

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Structure and molecular interactions of anti-thyroid drugs. Part 3.1 Methimazole: a diiodine sponge

Cited by 87 publications

References 45 publications

The Diiodine Basicity Scale: Toward a General Halogen‐Bond Basicity Scale

The Diiodine Basicity Scale: Toward a General Halogen‐Bond Basicity Scale

Maternal transfer of methimazole and effects on thyroid hormone availability in embryonic tissues

Selenium Analogues of Antithyroid Drugs – Recent Developments

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