Antibacterial agents pyrimidines

A search for antimetabolites, i.e. analogues of essential metabolites that might displace the latter in vital processes, was proposed as a rational approach to the discovery of antibacterial agents, but it has had little success other than the achievements in the folic acid field (Section 1.06.6). Substances that resemble the components of nucleic acids have, however, had considerable success in the chemotherapy of cancer and of some virus diseases and in the suppression of the immune response. They may act by becoming incorporated in false nucleic acids or by blocking the synthesis of nucleic acids, nucleotides, nucleosides or of the pyrimidine and purine bases cytosine (88), thymine (89 R = Me), adenine (90) and guanine (91 X = CH). The simplest antimetabolites are analogues of these bases. 

The two nitrogens in the pyrimidine structure are also likely candidates for enzymatic oxygenation. Indeed, the antibacterial agent 2,4-diamino-5-(3,4,5-trimethoxybenzyl)... 

Minami S, Shono T, Matsumoto J. Pyrido[2,3-d]pyrimidine antibacterial agents. II. Piromidic acid and related compounds. Chem. Pharm. Bull., 1971, 19, 1426. 

Matsumoto J, Minami S. Pyrido(2,3-d)pyrimidine antibacterial agents. 3. 8-Alkyl- and 8-vinyl-5,8-dihydro-5-oxo-2-(l-piperazinyl) pyrido(2,3-d)pyrimidine-6-carboxylic acids and their derivatives./. Med. Chem., 1975, 18, 74-79. 

Diamino-5-benzylpyrimidines and analogues antibacterial agents. II. C-AIkylation of pyrimidines with Mannich bases and application to the synthesis of trimetoprim and analogues, J. Med. Chem.. 23,379. 1980 see also J. Med. Chem.. 23, 384 and 5.35. 1980. 

Besides its application in mechanistic studies, the Friedel-Crafts alkylation has also been used to prepare synthetically useful compounds. Roth and Aig attempted the Friedel-Crafts ethylation of p-ethyl-acetophenone (equation 12) under carefully optimized conditions to obtain the 3,4,S-triethyl derivatives (7) in reasonable yield. They also noted that when less ethyl bromide was employed, the product, surprisingly, was hexaethylbenzene. Compound (7) is a key intermediate in the synthesis of 2,4-diamino-5-(3,4,5-triethylbenzyl)pyrimidine (8), an antibacterial agent. 

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