Benzylpyrimidines

DHFR - Dihydrofolate Reductase inhibitors - triazines, benzylpyrimidines, etc. 

DHFR —> chicken DHFR) (benzylpyrimidines -> chicken DHFR) (inhibitors -> benzylpyrimidines) (3,4,5 OMe -> benzylpyrimidines) (equation -> benzylpyrimidines) (4-C1 4-Br)... 

Hopfinger, A. J. (1981) Inhibition of dihydrofolate reductase structure-activity correlations of 2,4-diamino-5-benzylpyrimidines based upon molecular shape analysis. J. Med. Chem. 24, 818-822. 

O -Benzylfolates, such as 230, have been investigated as inhibitors of DNA allyltransferase with some promise <2004JME3887> they can readily be prepared from 2,5,6-triamino-4-0-benzylpyrimidine by standard ring-forming condensation via the pteridine 6-aldehyde and reductive amination to insert the 4-aminobenzoyl glutamate. 

Trimethoprim, a trimethoxybenzylpyrimidine, selectively inhibits bacterial dihydrofolic acid reductase, which converts dihydrofolic acid to tetrahydrofolic acid, a step leading to the synthesis of purines and ultimately to DNA (Figure 46-2). Trimethoprim is about 50,000 times less efficient in inhibition of mammalian dihydrofolic acid reductase. Pyrimethamine, another benzylpyrimidine, selectively inhibits dihydrofolic acid reductase of protozoa compared with that of mammalian cells. As noted above, trimethoprim or pyrimethamine in combination with a sulfonamide blocks sequential steps in folate synthesis, resulting in marked enhancement (synergism) of the activity of both drugs. The combination often is bactericidal, compared with the bacteriostatic activity of a sulfonamide alone. 

Tab. 4.31 Code, structure, /50-values against various E. coli mutants, and physicochemical properties of the tested 2,4-diamino-5-benzylpyrimidines. (Reprinted from Tab. 2 of ref. 106)... 

The final equation for the inhibition of resistant cell cultures by the benzylpyrimidines was ... 

Tab. 5.5 Inhibitory activity (/C50, uM) of 3-OCH3, 4-alkoxy-benzylpyrimidines (x= 1-6) in cell-free and whole cell systems of coli ATCC 11 775 (TMP sensitive) and . coli RT 500 (TMP resistant) and the lipophilicity descriptor log /7r. (Reprinted from Tab. 2 ref. 39)...

The observed variation in the ICS0 for the sensitive E. coli culture can be described by a parabolic relationship to the lipophilicity (log k ) of the benzylpyrimidines ... 

In conclusion, in the case of resistant E. coli cultures, the increase in antibacterial activity of the more lipophilic benzylpyrimidines is due not to a favorable influence on the transport through the cell membrane but to their interaction with membrane components leading to membrane destruction and cell death. 

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. 

In this reaction, benzene methyl ketone (BMK) is reacted with formamide, followed by reaction of the products with hydrogen peroxide and HCl in methanol, to form amphetamine. There are a number of variations on the basic route. The impurities which arise include, as examples, methylphenylpyrimidines (4-methyl-5-phenylpyrimidine) (8), benzylpyrimidines (4-benzylpyrimidine) (9), iV-formylamphetamine (10), Al,Al-di(j6-phenylisopropyl)amines (Al,Al-di(/i-phenylisopropyl)amine) (11) and dimethyldiphenylpyrimidines (2,4-dimethyl-3,5-diphenylpyridine) (12) (see structures in Figure 2.8). 

Hopfinger, A.J. (1981). Inhibition of Dihydrofolate Reductase Structure-Activity Correlations of 2,4-Diamino-5-benzylpyrimidines Based upon Molecular Shape Analysis. J.Med.Chem., 24, 818-822. 

Mabilia, M., Pearlstein, R.A. and Hopfinger, A.J. (1985). Molecular Shape Analysis and Energetics-Based Intermolecular Modelling of Benzylpyrimidine Dihydropholate Reductase Inhibitors. Eur.J.Med.Chem.,20,163-174. 

Hopfinger, A.J. (1983) Theory and application of molecular potential energy fields in molecular shape analysis a quantitative structure-activity relationship study of 2,4-diamino-5-benzylpyrimidines as dihydrofolate reductase inhibitors. J. Med. Chem., 26,... 

C. D. Selassie, Z. Fang, R. Li, C. Hansch, G. Debnath, T. E. Klein, R. Langridge, and B. T. Kaufman. On the structure selectivity problem in drug design. A comperative study of benzylpyrimidine inhibition of vertebrate and bacterial dihydrofolate reductase via molecular graphics and quantitative structure-activity relationships. Journal of Medicinal Chemistry, 32 1895-1905, 1989. 

Acid hydrolysis of 2,4,6-tris(aminoalkenyl)-l,3,5-triazines (48) has now been shown to give 1-amino-5-aryl-2-benzylpyrimidines via the trisenol tautomer (51) (Scheme 23) (see Section 6.12.4.5) <92LA411>. 

Hopfinger s method is illustrated by his treatment of a series of 2,4-diamino-5-benzylpyrimidines 16.1), of which the most outstanding member is the antibacterial drug, trimethoprim (9.32), discussed on p. 352. The test, inhibition of bovine liver DHFR (dihydrofolate reductase), furnished the following equation ... 

B. Sulfonamides Including Benzylpyrimidine Sulfonamides L Physicochemical and Pharmacologic Properties... 

Benzylpyrimidine sulfonamides are based on the combination of a sulfonamide with trimethoprim or tetroxoprim. Chemically, trimethoprim is a 2,4-diamino-5-(3,4,5-trimethoxybenzyl)pyrimidine and has the following structural formula. 

Recently, mainly benzylpyrimidine sulfonamides have been applied in 5.9% of cases allergic reactions are described on the skin which are probably chiefly due to sulfonamide (Clark et al. 1980 Bernstein 1975). 

A. J. Hopfinger, /. Med. Chem., 26, 990 (1983). Theory and Application of Molecular Potential Energy Fields in Molecular Shape Analysis A Quantitative Structure—Activity Relationship Study of 2,4-Diamino-5-benzylpyrimidines as Dihydrofolate Reductase Inhibitors. 

Benzylideneacetylacetone followed by ammonium acetate added to 4-nitro-benzaldehyde dissolved at 60-70° in glacial acetic acid, allowed to cool after 30 min., and the product isolated after 24 hrs. 4,6-dimethyl-2- (4-nitrophenyl) -5-benzylpyrimidine. Y 94%.—Many pyrimidines hitherto difficult to obtain can be easily prepared under mild conditions by this and two other methods. F. e. and methods s. F. Krohnke, E. Schmidt, and W. Zecher, B. 97, 1163 (1964). 

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