Thiouracil antithyroid agents

Thiouracil antithyroid agents have been found to inhibit NOS with modest selectivity for nNOS inhibition (56). These compounds are essentially thiocitrulline analogs and are competitive inhibitors with respect to arginine and tetrahydrobiopterin. 6-Propylthiouracil, 6-methyl-2-thiouracil, and S-methylthiouracil were found to be NOS inhibitors with K- values of 15, 14, and 60 /llM, respectively. Dithiouracil, thiobarbituric acid, 5-carbo-ethoxythiouracil, 2-mercaptopyridine, 2-mer-captothiazoline, 2-mercaptoimidazole,and er-gothioneine were found to be poor NOS... 

In addition to chlorpromazine, phenylbutazone (an analgesic and antiinflammatory agent), sulfonamides (chemotherapeutic agents), chlorothiazide (a diuretic), thiouracil and methima-zole (antithyroid drugs), phenytoin (an anticonvulsant), pyribenzamine (an antihistaminic), and chloramphenicol... 

Thionamides are the most important class of antithyroid compounds in clinical practice used in nondestructive therapy of hyperthyroidism. These agents are potent inhibitors of TPO, which is responsible for the iodination of tyrosine residues of thyroglobulin and the coupling of iodotyrosine residues to form iodothyronines. These drugs have no effect on the iodide pump or on thyroid hormone release. The most clinically useful thionamides are thioureylenes, which are five- or six-membered heterocyclic derivatives of thiourea and include the thiouracil 6-n-propyl-2-thiouracil (PTU) and the thioimidazole 1-methyl-2-mercaptoimidazole (methimazole, Tapazole, MMI). The uptake of these drugs into the thyroid gland is stimulated by TSH and inhibited by iodide. 

Our motivation for investigating thioamide derivatives, which potentially can form N-H... S interactions, arises from the presence of the -N(H)-C(=S)- residue, and derivatives thereof, in several dmgs [20], see Scheme 6.2 for chemical structures of these species. Thus, the antithyroid drugs 6-n-propyl-thiouracil (I) and l-methyl-3//-imidazole-2-thione (II, Methimazole , also marketed as Tapazole ) feature the -N(H)-C(=S)- functional group [21]. Hyperthyroidism may be treated with 3-methyl-2-thioxo-4-imidazoline-l-carboxylate (III, Carbimazole ) which is metabolised in vivo to the active form, known as Methimazole [22]. Anti-tubercular agents containing the thioamide residue and which inhibit mycolic acid synthesis include 2-ethyl-thioisonicotinamide (IV, Ethionamide ) and its -propyl derivative (Prothionamide ) [23-25]. 

While it complicates matters even further in terms of screening and assessing risk, it is clear from structure-activity considerations that some toxic agents can have multiple modes of action. For instance, the thiouracils not only act as antithyroids but also can serve as a source of electrophilic sulfur during oxidative desulfurization and presumably have antiuracil effects. 

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