Thiamin antagonists

In brain, as in most mammalian cells, thiamine occurs predominantly in the form of TDP, the remainder being made up of thiamine monophosphate (10%), thiamine triphosphate (5-10%) and trace amounts of free thiamine. Thiamine is transported into brain and phosphory-lated by the action of thiamine pyrophosphokinase, and inhibition of this enzyme by thiamine antagonists such as pyrithiamine results in decrease synthesis of TDP. Treatment of experimental animals with pyrithiamine results in a generalized reduction of TDP concentrations and an early selective loss in activity of a-KGDH in regions... 

Thomas, A.A., Le Huerou, Y., De Meese, J., et al. (2008) Synthesis, in vitro and in vivo activity of thiamine antagonist transketolase inhibitors. Bioorg. Med. Chem. Lett. 18, 2206-2210. 

A model for some rifamycin conversions has been proposed (Scheme 8), based on experimental results with Nocardia mediterranei mutants, conversions of rifamycin n vivo, and the incorporation of different precursors the conversion of rifamycin S (107) into rifamycin B (108) and rifamycin L (109) was completely inhibited by a thiamine antagonist. It was concluded... 

Pyrithjamine. I-[(4-Amino-2-methyl-S-pyrimidi-tyl)methyl]-3 (2-hydroxyethyl)-2-methyipyridinium bromide eonokydrobromide I -(2-methyl-4-amino-5-pyrimidy[)-methyl-2-methyl-3-hydroxyethy]pyridinium bromide hy-drqbromide neopyrithiamine. C14HltBr,N40 mol wt 20,16. C 40,02%, H 4.80%, Br 38.04%, N 13,34%., O 3.81%, Thiamine antagonist prepd by condensation of 2-methyl-3-(S-hydroxyethyl)pyridine with the pyrimidine moiety of vitamin B( Tracy, Elderfield, J. Org. Chem. 6, 54 (1941) improved procedure Wilson, Harris. J. Am. Chem. Soc. 71, 2231 (1949) U.S. pat. 2,587,262 (1952 to Merck Co.). Cf. Woolley, J. Am. Chem. Soc. 72, 5763 (1950). 

C6H9N3O2, Mr 155.16, crystals (from methanol), mp. 175 °C. Thiamine antagonist isolated from culture filtrates of Bacillus megaterium and Streptomyces albus. B. is assumed to inhibit phosphorylation of the pyrimidine part in thiamine biosynthesis. 

Holowach, J., Kaufmann, F., Ikossi, M.G., Thomas, C. and McDougal, D.B. (1968). The effects of a thiamine antagonist, pyrithiamine, on levels of selected metabolic intermediates and activities of thiamine dependent enzymes in brain and liver. J. Neurochem. 15 621-631. 

Amprolium Hydrochloride, C14H19CINH4HCI is of low molecular weight, 315.25 daltons. It is a white, odourless substance, readily soluble in water. It is a thiamine antagonist and is used in poultry feeds to prevent coccidioidomycosis. 

Amprolium (Figure 9.7) is a thiamine antagonist. Its oral use as a veterinary drug is permitted for control of coccidiosis in poultry.However, its use as a feed additive is no longer permitted. Authorisation as a coccidiostatic feed additive was withdrawn in 1992 when data requested by SCAN for evaluation of amprolium-containing products (Pancoxin and Pancoxin Plus) were not provided. 

Antagonistic metabolite analogues have been found for almost every known vitamin. For example, when the thiazole portion of thiamine (2.1) is replaced by a similarly substituted pyridine ring, the product ( pyrithia-mine ) produces characteristic symptoms of thiamine-deficiency in mice (Woolley, 1950) [see Section 9.4 for a commercially successful thiamine antagonist (9.24)]. 

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