2-Amino-4-hydroxy-6-methyl-5, 6-dihydropteridine

Bacteria use/ -aminobenzoic acid only for conversion to 7.8-dihydrofolic acid (Griffin and Brown, 1964). Thus, E, coli condenses j -aminobenzoic acid (and, alternatively, -aminobenzoylglutamic acid) with 2-amino-4-oxo-6-hydroxy-methyl-7,8-dihydropteridine 9.21) (as the 6-pyrophosphate) to give dihydro-pteroic acid (and alternatively, dihydrofolic acid) (Jaenicke and Chan, 1960). The sulfonamides competitively inhibit the isolated enzyme dihydrofolate the-tase which catalyses these steps (G. Brown, 1962). From Lactobacillus plantamm two enzymes responsible for this synthesis have been isolated in a pure state (Shiota et al., 1969a). The first of these catalyses the esterification of the pteridine 9.21) to its pyrophosphoryl derivative. The second is Brown s dihydrofolate synthetase. This second enzyme has also been isolated from several strains of Pneumococcus, found to have a mol. wt. of 90000, and to need ATP and Mg " as coenzymes (Ortiz, 1970). 

The antagonism of bactericidal sulfanilamides by p-aminobenzoic acid (PABA), a precursor of the vitamin folic acid, has been well documented in the pharmacological literature. More recently, it was shown that the phytotoxic activity of asulam, a herbicidal sulfanilamide derivative, also results from an inhibition of the biosynthesis of the vitamin folic acid. " In particular, asulam inhibits competitively the enzyme 7,8-dihydropteroate synthase, which catalyzes the conversion of 2-amino-4-hydroxy-6-hydroxy-methyl-7,8-dihydropteridine and PABA to dihydropteroic acid, leading to folate depletion. A consequence of the depletion of folic acid derivatives is the buildup of intermediates of the de novo synthesis of purine nucleo-tides. ° Such intermediates include 5 -phosphoribosyl glycineamide (GAR) or 5 -phosphoribosyl-5-amino-4-imidazole (AICAR). The accumulation of GAR and AICAR in asulam-treated pea seedlings has been reported. 

Equilibria in aqueous solutions of pteridine have been investigated. When pteridine was added to acid, the cation of 4-hydroxy-3,4-dihydropteridine was rapidly formed and this slowly underwent ring fission to the cation of 2-amino-methyleneamino-3-formylpyrazine. Both 2- and 7-methylpteridine behaved similarly 4-methylpteridine gave 3-acetyl-2-aminomethyleneaminopyrazine, but production of 44iydroxy-4-methyl-3,4-dihydropteridine could not be demonstrated (1167). 

Various bicyclic heterocycles have been prepared from carbamoylpyrazine V-oxides 2-amino-5-chloro-3-7V-methyIcarbamoylpyrazine 1-oxide refluxed with triethyl orthoformate and acetic anhydride gave 6-chloro-3-methyl-4-oxo-3,4-dihydropteridine 8-oxide (1222) 2-amino-3-carbamoyl-5-methyl(or phenyl)pyrazine 1-oxide with triethyl orthoformate, or with ethyl chloroformate followed by cyclization of the intermediate urethane, gave 6-methyl(or phenyl)-4-hydroxy-pteridine 8-oxide (537). 

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