Production of Thiamine Deficiency Disease by the Feeding of a Pyridine Analogue of Thiamixe

The product,ion of bacterial growth inhibitors derived from acidic vitamins by the substitution of a sulfonic acid group for the carboxyl group of the vitamin is now well known. Thus sulfanilamide, the sulfur analogue of p-aminobenzoic acid (I), pyridine-3-sulfonic acid, the analogue of nicotinic acid (2), and thiopanic acid, the analogue of pantothenic acid (3-5), have been shown to prevent growth of certain microorganisms. Since addition of the analogous vitamin to cultures inhibited by one of these compounds restored growth, it seemed that the sulfonic acids caused failure of growth by producing deficiencies of the growth factors structurally related to them. However, these three sulfur analogues did not cause deficiency diseases when fed to animals (6, 7). The only deficiency diseases thus far produced in animals by the feeding of structurally similar compounds have been the hypoprothrombinemia caused by administration of 3,3’-methylenebis[4-hydroxycoumarin] (related to vitamin K) (8), and the scurvy-like disease caused by glucoascorbic acid.1 Since a study of the action of these inhibitors related to the vitamins may provide a key to the study of the mode of action of the vitamins,’ an attempt has been made to discover such inhibitors derived from some of the other vitamins. The work of Erlenmeyer (9) suggested that physiological activity was partially retained in compounds in which sulfur in a ring system was interchanged with -CH:CH-. Others (10,ll) have endeavored to show that such an alteration in nicotinic acid (to yield thiazole-5-carboxylic acid) and in thiamine (to yield 2-methyl-4-amino-5-pyrimidylmethyl(2-methyl-3-hydroxyethyl)pyridinium bromide) would result in compounds with vitamin action. However, Robbins (12) has shown recently that the latter substance, the pyridine analogue of thiamine, had no growth factor action, and actually inhibited growth of certain fungi. It has now been observed that the feeding of 2-methyl-4-amino-5pyrimidylmethyl-(2-methyl-3-hydroxyethyl)pyridinium bromide to mice maintained on an adequate diet caused a fatal disease, with many of the characteristic symptoms of thiamine deficiency as seen in other species. For the sake of brevity, the pyridine analogue of thiamine has been named