Antithyroid activity

Although the antithyroid activity of compounds incorporating an enolizable thioamide function was discussed earlier, this activity was in fact first found in the pyrimidine series. The simplest compound to show this activity, methylthiouracil (80) (shown in both enol and keto forms), is prepared quite simply by condensation of ethyl acetoacetate with thiourea.Further work in this series shows that better activity was obtained by incorporation of a lipophilic side chain. Preparation of the required dicarbonyl compound starts with acylation of the magnesium enolate of the unsyrametrically esterified malonate, 81, with butyryl chlo-... 

Inclusion of iodine in the thiouracyl molecule similarly proves compatible with antithyroid activity. Alkylation of thiouracyl proper (85) with benzyl chloride affords the thioether,... 

Since thyroid de-iodinase contains selenocysteine [16], the seleno-analog of PTU (PSeU) is expected to exhibit a higher antithyroid activity than PTU, because of the easier formation of the Enzyme-Se-Se-PSeU species, than Enzyme-Se-S-PTU due to the higher nucleophilicity of Se. To examine this possibility we have extended our studies to the interaction of with selenoamides. 

Among the dihydro analogues of thiouracil, 2-mercapto-6-methyl-5,6-dihydro-uracil (LXXX) retains some of the antithyroid activity exhibited by 2-thiouracils [642] (see Part 1 of this review. Volume 6). This compound can be obtained either by the condensation of thiourea with ethyl crotonate or by the hydrogenation of 2-mercapto-6-methyluracil. 

Oral gavage of rat pups with 14mg/kg/day ftom posmatal day 5 through 20 caused reductions in serum thyroxine levels that correlated with depressed behavioral parameters. Further studies using the same protocol reported decreased cell proliferation in the cerebellum and forebrain on postnatal days 11 and 21, respectively. In yet another study, 14mg/day of chlorine dioxide on posmatal days 1-20 was associated with some neurotoxicity (decreased forebrain weight and reduced synapse formation on day 35), but the neurotoxicity was not correlated with any antithyroid activity of this chemical. ... 

Some substituted 3-thiomethyltriazole derivatives show antithyroid activity <92EJM359> and some 7V-l-methylcarboxylates mimic the action of penicillins <92EJM193>. An Aja adenosine receptor antagonist containing a triazole ring has been described <94BMC2539>. 

The available agents with antithyroid activity are the thioamides propylthiouracil, carbimazole and methimazole also known as thiamazole. Their thio-carbamide group is indispensable for antithyroid activity. The mechanism of action is complex. The most important action is the prevention of hormone synthesis by an inhibition of the thyroid peroxidase-catalyzed reactions involved in iodine organification. These agents also block the coupling of the iodoty-rosines. 

Diets rich in millet have been associated with endemic goiter in parts of West Africa where millet is a staple. The damage has been attributed to vitexin, a C-glycosyl flavone, that in rats has antithyroid activity and that in vitro inhibits thyroid peroxidase and the free radical iodination step in thyroid hormone biosynthesis. Isoflavones have produced similar antithyroid effects in rats, but clinical studies in adults have not. " However, this remains a possible concern in infants fed soya-based milk-replacers, especially if iodine supply is compromised. 

Diamino-l,2,4-thiadiazole is devoid of antithyroid activity, as measured by the effect of a single dose on the uptake of radioactive iodine by rat thyroid gland over a 4 hour period.210... 

Co-trimoxazole has been suggested to have some antithyroid activity. However, whether this effect is due to trimethoprim alone is still unclear (1142,1143). Co-trimoxazole 27-31 mg/kg bd orally substantially altered serum total T4 and TSH concentrations and neutrophil counts in dogs within as short a time as a few weeks (1144), and 14—16 mg/kg orally every 12 hours for 3 weeks reduced total and free T4 concentrations and increased the TSH concentration, conditions that would be compatible with hypothyroidism (1145). 

The chemical structures of these compounds are shown in Figure 38-5. The thiocarbamide group is essential for antithyroid activity. 

Hyperthyroidism (excessive production of thyroid hormones) asually requires surgery, but before. surgery the patient mu.st be prepared by preliminary abolition of the hyper-thyroidi.sm through the use of antithyroid drugs. Thiourea and related eompounds. show an antithyroid activity, but they arc too toxic for clinical use. The more useful drugs are 2-thiouracil derivatives and a closely related 2-thioimidazolc derivative. All of these appear to have a similar mechanism of action (i.c.. prevention of the iodination of the precursors of thyroxine and triiodothyronine). The main difference in the compounds lies in their relative toxieities. 

Some 300 related structures have been evaluated for antithyroid activity, but of these, only the 6-alkyl-2-thiouracil and closely related structures possess useful clinical activity. The most serious adverse effect of thiouracil therapy is agranulocytosi.s. 

Chronic exposure to ANTU led to the investigation of two cases of bladder cancer in two rodent operators. Therefore, the use of ANTU was restricted to professional operators. Available data were inadequate to evaluate carcinogenicity in humans. Chronic sublethal exposure may result in antithyroid activity and hyperglycemia. 

Thiouracil. 2,3-Dihydro-2-ihioxo-4(IH)-pyri-midinone 2-mercapto-4-hydroxypyrimidine 4-hydroxy -2( I ft) -pyrimidinethione 2 -mercapto -4( 1H) -py rimidinone 6 -hydroxy -2 -mercaptopyrimidine 2-mercapto-4. pyrimi -done Deracil. C4H4N,OS mol wt 128.15. C 37.49%, H 3.15%, O 12.48%, N 21.86%, S 25 02%. Occurs in seeds of Brassica, Cruciferae Purves, Brit. J. Exp. Pathol 22, 241 (1941). Prepd by condensing ethyl formylacetate with thiourea Wheeler. Liddle, 3m. Chem. J. 40, 550(1908). Antithyroid activity results from its interference with the iodina-tion of thyroxine precursors see Maloof, Soodak, Pharmacol. Rev. 15, 72-79 (1963). Inhibition of nucleic acid metabolism Cardeilhac, Proc, Soc. Exp. Biot Med. 125, 692 (1967). Toxicology K. K. Carroll, R. L, Noble, J. Pharmacol. Exp. Ther. 97, 478 (1949). 

E) More sustained antithyroid activity when used continuously for several months... 

Thiourea was initially found to exhibit an antithyroid activity but had to be abandoned due to their high toxicity. Later on, it was revealed that similar activity was shown by 2-thiouracil derivatives and 4-keto-2-thiopyrimidines more precisely 6-alkyl-2-2 thiouracils and their congeners display meaningful clinical characteristics. 

The drug fails to cause interference with the release or usage of accumulated thyroid hormone and the time-gap that essentially elapses between the very initial stage of medication together with the manifestations of its antithyroid activity entirely depends upon the quantum of thyroid hormone present in the gland (thyroid). The resulting marked and pronormced hyperplasia of the thyroid gland which follows soonafter its administration, in fact, is a consequence of a compensatory enhancement of thyroprotein release as a result in the thyroid hormone titer value of the blood. 

The study of 6-alkylthiouracil showed maximal antithyroid activity with 6-propylthiouracil. 6-Methylthiouracil has less than one-tenth the activity of PTU. 

In vitro and in vivo data indicate that the antithyroidal activity of resorcinol is caused by inhibition of thyroid peroxidase enzymes, resulting in decreased thyroid hormone production and increased proliferation due to an increase in the secretion of TSH (see section 8.8). The iodination process is catalysed by a haemcontaining enzyme. Resorcinol is known to form covalent bonds with haem (Sessler et al., 1988). 

It is doubtful if the goitrogenic activity of all these foods is due to the same chemical compound or compounds or to the same mechanism within the animal body. Astwood and his associates have wholly or predominantly accounted for the antithyroid activity of Brassica seeds by the presence in these seeds, in a combined inactive form, of a compound which they have isolated and characterized as L-5-vinyl-2-thiooxazolidone (Fig. 6) the antithyroid compound of the cabbage family. 

Isothiocyanates react with N -terminal amino groups of pep-tides to form thiourea, which spontaneously cyclises to imidazo-lidine derivatives under acidic conditions and the reaction product is the original peptide without N-terminal amino acids (Figure 2.68). Reactions of isothiocyanates with the N-terminal amino groups of proteins and other nucleophilic centres containing thiol, disulfide, e-amino and hydroxyl groups can cause changes in protein conformations. These proteins are poorly hydrolysable in the protein conformation, which is related to the antimicrobial and antithyroid activity of isothiocyanates. 

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