The mechanism of action of synthetic antithyroid drugs: iodine complexation during oxidation of iodide.

A number of compounds of pharmaceutical importance from a variety of chemical families, including thiocyanates, isothiocyanates, thiourea and derivatives, imidazoles, and various amines, were found to form charge transfer complexes with iodine. Parallel studies were carried out to investigate the actions of these drugs on lactoperoxidase and thyroid activity in vivo in the rat (assays of T3 and T4 and histology of the thyroid gland). The results showed that there was a good correlation between the value of Kc (the formation constant of the iodinated complex) and antithyroid activity in vivo. The higher the electron donor power of the compound, the higher the Kc value and the stronger the action on the thyroid. The results indicated that a number of drugs could have secondary antithyroid activity. Some compounds, such as levamisole, tetramethylthiourea, tetrahydrozoline, phenothiazines, and imipramines, with no action on peroxidase had high Kc values (tetramethylthiourea, 13,825 liters/M) and had strong antithyroid activity in the rat. These results suggest that synthetic antithyroid agents may act either on peroxidase and/or the molecular iodine which may be produced by oxidation of iodides (2I(-)----I2----2I+). It has been shown that oxidation of I- can occur in the absence of thyroglobulin. In the absence of a suitable receptor, significant amounts of I2 may, thus, accumulate. The action of such drugs on molecular iodine may have considerable pharmacological significance.

Formation of molecular iodine during oxidation of iodide by the peroxidase/H2O2 system. Implications for antithyroid therapy.

The first step in the biogenesis of thyroid hormones is the oxidation of iodides taken up by the thyroid gland. Oxidation of I- by the H2O2/peroxidase system leads to the formation of iodinium ions I+ which bond to thyroglobulin by electrophilic substitution. However, it is not clear whether I- is transformed directly to I+ or whether it passes through a molecular iodine intermediate. This latter possibility is indicated by the oxidation potentials of the reactions. I2 can be detected in vitro from the formation of I3- ions, although this has yet to be confirmed in vivo. The present study was designed to determine, albeit indirectly, whether this reaction occurs in vivo. If I2 is produced, it may form charge transfer complexes with numerous drugs. We also investigated the action of various drugs on lactoperoxidase and assessed their antithyroid activity in the rat by assay of plasma levels of T3, T4, and TSH. We found a good correlation between the value of Kc, the formation constant of the complex of the drug with molecular iodine, and the antithyroid activity in vivo. This correlation was observed in four different classes of compound. The possibility that molecular iodine is produced in the thyroid gland has implications for antithyroid therapy.

Biological evaluation of compounds with -NCS- group or derived from thiazole and imidazole. Activity on prostaglandin synthetase complex.

The effects of compounds with activity against thyroid peroxidase were tested on the activity of hydroperoxidase and cyclo-oxygenase of the prostaglandin synthetase complex in-vitro. Active compounds were found to inhibit the peroxidase, and the cyclo-oxygenase function. These compounds were also found to have anti-inflammatory activity as demonstrated by the reduction of carrageenan-induced oedema of the hind paw of the rat. Indomethacin and non-steroidal anti-inflammatory drugs tested under the same conditions were shown to have activity towards the cyclo-oxygenase rather than the peroxidase function of the prostaglandin synthetase complex. A common feature of the active compounds was the presence of an -NCS- linkage or free -SH group.

Influence of dietary iodine on drug-induced hypothyrodism in the rat.

Several compounds of pharmaceutical importance from a variety of chemical families, for example chlorpromazine and clomipramine, have been found to form charge-transfer complexes with iodine. We have investigated the influence of dietary iodine on thyroid-gland dysfunction induced by clomipramine, chlorpromazine or 2-thiazoline-2-thiol. We suggest that iodine is partly diverted from its metabolic pathway by complexation with drugs, and so the urinary concentration of iodide is increased. Both chlorpromazine and clomipramine, at doses which do not inhibit thyroperoxidase, enhanced urinary iodine excretion when dietary iodine was restricted (3.944+/-0.96 microg/day for chlorpromazine-tested rats, 3.43+/-1.33 microg/day for clomipramine-tested rats, compared with 2.34+/-0.11 microg/day in control rats). Concurrently, these pharmaceutical compounds increased the level of free thyroid-stimulating hormone (TSH) in comparison with controls and induced histological modifications in, and enlargement of, the thyroid gland. We have demonstrated that drug-induced loss of iodine in the urine was associated with antithyroid action when iodine intake was limited.

Antithyroid action of ketoconazole: in-vitro studies and rat in-vivo studies.

Inspection of the chemical structure of ketoconazole indicates that it may have antithyroid activity. The antithyroid action of this drug was demonstrated in-vitro and in-vivo. In-vitro, it was found to form a complex with iodine (formation constant Kc 141 L mol-1), and to inhibit lactoperoxidase (IC50 2 x 10(-4) M). Its effects in-vivo in the rat were assessed by assay of circulating-thyroxine, and from the histological appearance of the thyroid gland. Thyroid gland weight was increased in rats treated with ketoconazole.

Synthesis and anti-inflammatory activity of 2-pyridyl-2-thiobenzothiazole derivatives.

A series of novel 2-pyridyl-2-thiobenzothiazole compounds was prepared and investigated by a number of in vitro methods in order to determine their anti-inflammatory properties. Results are discussed with reference to well known NSAIDs. (3-carboxy-2-pyridyl)-2-thiobenzothiazole had the most potent anti-inflammatory activity, being 1.34 times more active than indomethacin used as reference compound.

Synthesis and antithyroid activity of 1,4,5-trialkyl 2-thioimidazole derivatives.

A series of compounds based on the structure of MTI (1-methyl-2-thioimidazole) were synthesized by condensation of alpha-hydroxyketones and alkylthioureas. The alpha-hydroxyketones were obtained by a radical reaction in the presence of sodium and the alkyl ester, while the alkylthioureas were prepared by nucleophilic addition of ammonia on an alkylisothiocyanate. The antithyroid activity of the 13 compounds prepared was evaluated in vitro by determination of the concentrations which led to a 50% inhibition (IC50) of the activity of thyroid peroxidase, and in vivo by assay of thyroid hormones levels and histological examination of the thyroid gland in rats treated chronically with the compounds. 1-methyl-4,5-dipropyl 2-thioimidazole (compound 10) was found to have the highest antithyroid activity of the 13 compounds synthesized.

[Analgesic and anti-inflammatory activity of saponins of Argania spinoza]. / Activité analgésique et anti-inflammatoire des saponines d'Argania spinosa.

We studied analgesic and antiinflammatory actions of saponins of Argania spinosa cakes in mice and rats. With oral doses of 50 to 300 mg/kg, we found peripheric analgesic actions equivalent to the acetyl salicylic acid ones. The maximum protection was obtained with 500 mg/kg per os. There is no morphine-like central analgesic effect. Antiinflammatory studies were done in vivo using oedema due to carrageenine or experimental trauma in rats. There was a decrease in the paw swelling at doses of 10 mg/kg per os. At doses of 50 to 100 mg/kg per os, the antiinflammatory effect was similar to the one of indomethacin at doses of 10 to 20 mg/kg per os. In vitro, there was an inhibition of beef synovial fluid degradation by OH. radicals. The inhibition action is evaluated with an IC20 > or = 6 microM. Argania spinosa saponins have also an antiradical action against DPPH (IC25 = 85 mM) and against OH. radicals (IC25 = 0.56 M). Since they do not have any inhibition effect on PGE2 synthesis, their antiinflammatory activity can be explained by their action on leucotriens in the metabolic pathway of arachidonic acid.

Synthesis and inhibitory effects of 1,4,5-trialkyl-2-thioimidazole derivatives on platelet aggregation.

New 1,4,5-trialkyl-2-thioimidazole have been synthesized by the condensation of alpha-hydroxyketones and alkylthioureas. The in vitro platelet aggregation inhibiting effect of prepared compounds on human platelets was studied in the presence of ADP and collagen as inducers. The formation of thromboxane B2(TXB2) was inhibited. 1-isopropyl-4,5-dimethyl-2-thioimidazole has the greatest aggregation inhibiting effect, about 4 times that of aspirin. It highly inhibits the production of TXB2 (68.5% for a final concentration of 0.04 M).

Synthesis and inhibitory effects of 1,2,4-triazole derivatives on platelet aggregation.

Various derivatives of triazole substituted in the 2-position were prepared, and their activity on platelet aggregation tested. Compounds 4 and 14 had the most powerful action. These agents were thought to inhibit platelet aggregation via an inhibition of the cyclo-oxygenase-peroxidase complex (PGS complex), preventing synthesis of prostaglandins.

Anti-inflammatory action of methimazole.

The anti-inflammatory activity of 1-methylimidazole-2-thiol (methimazole), the most widely used antithyroid drug, was investigated. Methimazole had a marked inhibitory action on prostaglandin H synthase (IC50 = 10 mumol/l), inhibiting the peroxidase (IC50 = 330 mumol/l), although the cyclo-oxygenase was slightly activated. Methimazole was less potent than indometacin (IC50 = 1.7 mumol/l) on prostaglandin H synthase, but was more potent than acetylsalicylic acid (IC50 = 160 mumol/l). Methimazole has been found to trap superoxide (O2.-) radicals and to decrease the level of blood prostaglandin E2.

Synthesis and antithyroid activity of pyridine, pyrimidine and pyrazine derivatives of thiazole-2-thiol and 2-thiazoline-2-thiol.

A series of compounds was synthesized by linking various derivatives of pyridine, pyrimidine or pyrazine to thiazole-2-thiol or to its partially hydrogenated derivative 2-thiazoline-2-thiol. The reactions of the compounds with molecular iodine and lactoperoxidase were examined in vitro. Their antithyroid activity was also examined in vivo in the rat. T4 and TSH levels were determined, and the thyroid gland was examined histologically. 2-(3-Hydroxy-2-pyridyl)-2-thiothiazoline had the highest antithyroid activity of the compounds tested (Kc = 14931.mol(-1),IC(50)0.65 x 10(-4) M, activity of thyroid gland).

Methimazole inhibits peripheral lymphocyte proliferation by inducing S-quiescent phase arrest.

The influence of methimazole (MTI) on the mitogenic proliferation of human blood lymphocytes was studied in vitro to evaluate the potential immunomodulatory activity of this antithyroid drug. The effects of the drug on the lymphocyte cell cycle were assessed by multiparametric flow cytometry. Although MTI induced an increase in the number of lymphocytes in the synthesis and G2M compartments, it failed to stimulate proliferation as the cells tended to accumulate in the quiescent S compartment. The effect was dose-dependent over a range from 0.1 to 100 mM. These in vitro results indicate that MTI possesses immunosuppressive activity.

Sites of action of 2-thiazoline-2-thiol on biogenesis of thyroid hormones.

2-Thiazoline-2-thiol is an antithyroid agent that strongly reduces thyroid hormone levels. Synthesis of these hormones is catalyzed in vivo by thyroid peroxidase. The interaction of this drug with molecular iodine and its effect on peroxidase activity were investigated. Iodine and 2-thiazoline-2-thiol form a complex of the charge transfer type of 1:1 stoichiometry characterized by a formation constant of 2,527 l.mole-1 at 20 degrees C. This drug was found to inhibit both horseradish peroxidase and lactoperoxidase (used as a model of thyroid peroxidase) in a competitive manner, giving inhibition constants of 5.7 mM and 0.13 mM, respectively. T3 and T4 levels were reduced significantly after a three-week administration of this drug to a group of 10 rats. Histological examination of the thyroid gland showed the presence of a cylindrical epithelium, which is indicative of hyperactivity of the gland. The results indicated that 2-thiazoline-2-thiol acts on both molecular iodine and thyroid peroxidase.

Lymphoproliferative activity of methimazole: free SH group dependency.

1. The comparative effects of methimazole (MTI), an antithyroid drug, and its S-methyl derivate (MMTI), were studied in vitro on the lymphoproliferative response to lectin in order to point out the free SH group importance. The cell cycle analysis was performed by flow cytometry after cellular DNA staining by propidium iodide. 2. We showed that MTI enhanced the PHA-induced DNA synthesis phase (P < 0.05 from 1 to 100 microns) whereas MMTI had no significant activity. The free SH group seems to be necessary to the MTI immunomodulatory activity.

[Antibacterial sulfonamides, antiparasitic and antifungal derivatives of imidazole: evaluation of their antithyroid effects in the rat]. / Sulfamides antibactériens, antiparasitaires et antifongiques dérivés de l'imidazole: évaluation des effets antithyroïdiens sur le rat.

Antithyroid action of some antibacterial, antiparasitic or antifungal agents, was studied by 2 in vitro and 3 in vivo experimentations in the rat. These drugs can upset thyroid hormone synthesis by forming a molecular complex with iodine, and/or by inhibiting thyroid peroxidase activity. Rats treated with these drugs showed an hypothyroidism, demonstrated both by a decrease in T4 concentration and an hyperactivity of thyroid gland by positive feed-back, whose consequence was the presence of cylindrical cells. We noticed this iatrogenic hypothyroidism with all the drugs experimented, by an increase in thyroid gland weight. But the increase of rats body weight, which should have appeared, was not shown. The use of anabolic steroid is now forbidden, therefore, such drugs could be used for breeding animals, in order to gain body weight. Detection of use of these drugs in breeding, to obtain this side effect, should be advised.

Synthesis and inhibitory effects of 2-pyridyl-2-thiobenzoxazole and 2-pyridyl-2-thiobenzimidazole derivatives on arachidonic acid metabolism.

A series of new 2-pyridyl-2-thiobenzoxazole and 2-pyridyl-2-thiobenzimidazole compounds was prepared and investigated by a number of in vitro methods in order to determine their prostaglandin synthesis inhibitory activity. The most active compound decreases prostaglandin production and carrageenin edema, but has a less platelet antiaggregatory activity.

Spectroscopic analysis of charge transfer complexes between morpholine and iodine.

It has been demonstrated spectroscopically that many nitrogen-containing heterocyclic compounds can form charge transfer complexes with iodine. The complexes of morpholine with iodine were shown to be of the n-sigma type with a 1:1 stoichiometry. A strong donor-acceptor interaction was found (Kc = 1261 +/- 12 mol-1 at 20 degrees C in CCl4), considerably higher than those of complexes of aromatic compounds with iodine. The high value of the formation constant for this complex indicated that morpholine could serve as a starting point for the synthesis of novel anti-thyroid drugs.

1,4,5-trialkyl imidazole system anti-inflammatory properties of new substituted derivatives.

In an investigation of the anti-inflammatory properties of five-membered ring nitrogen-containing heterocyclic compounds, two series of derivatives of imidazole were prepared by altering the sites of substitution and by joining aliphatic chains to the nitrogen atom in the 1 position of the imidazole ring. Some of them were more potent inhibitors of carrageenan-induced edema than indomethacin. An electron spin resonance study indicated that these compounds possess anti-radical activity.

Thyroid accumulation and adverse effects of imipramine and desipramine in rats after long-term administration.

The respective adverse effects of imipramine and desipramine on serum thyroid hormone levels and their accumulation in thyroid were investigated in male Wistar rats. Two groups of 30 rats were gavaged for 4 weeks with 30 mg/kg/day imipramine hydrochloride (IMI) or desipramine hydrochloride (DESI), while the control group (12 rats) received the arabic gum vehicle only. In the IMI-treated group, the serum thyroxine (T4) level significantly decreased (by 13%) and IMI and its metabolite DESI were accumulated in the thyroid, as pointed out by mean thyroid-to-serum concentration ratios close to 12 and 8, respectively. In the DESI-treated group, the mean thyroid-to-serum concentration ratio of the drug was close to 14, and significant decreases in both serum T4 (-20%) and triiodothyronine serum levels (-14%) were found. The accumulation of antidepressant drugs in the thyroid was more pronounced and the thyroid serum levels were even lower after DESI administration than after IMI administration. These results are in favour of an antithyroid action of IMI and DESI due to the formation of a complex in the thyroid between molecular iodine and the drugs or metabolites.