Certain benzylpyrimidines, such as trimethoprim 1 are potent and selective inhibitors of bacterial dihydrofolate reductase, the enzyme responsible for the NADPH-dependent reduction of 7,8-dihydrofolate to 5,6,7,8,-tetrahydrofolate. The latter is essential for various biosynthetic reactions e.g. biosynthesis of nucleic acids and certain amino acids. Trimethoprim is used solely or in combination with sulphonamides (synergic effect) to treat a wide range of bacterial infections in humans [1].

The adamantyl moiety present in numerous agents and drugs improves their lipophilicity due to aliphatic cage-like structure. Such compounds could be much better taken up by cells, and have enhanced blood-brain barrier penetration and increased accumulation in lipids [2].

Our previous investigation revealed that the combination of an adamantyl moiety with pyrimidine ring leads to compounds of significant antimicrobial properties [3]. It has inspired us to synthetize a new adamantane analog of trimethoptim 2.

The known 1-formyladamantane 3 was prepared here from 1-hydroxymethyladamantane by a Swern oxidation (yield > 95%). The conversion [4] of the aldehyde 3 into β-methoxypropionitrile 4 was followed by condensation with guanidine base in methanol [5] affording 5-adamantan-1-ylmethyl-pirimidine-2,4-diamine 2.

Compound 2 was tested against selected Gram-negative and Gram-positive strains.

Literatura:

1. P.S. Manchand, P. Rosen, P.S. Belica, G.V. Oliva, A.V. Perrota, J. Org. Chem. 57 (1992) 3531
2. K. Gerzon, D. Kau, J. Med. Chem. 10 (1967) 189
3. B. Orzeszko, Z. Kazimierczuk, J.K. Maurin, A.E. Laudy, B.J. Starościak, J. Vilpo, L. Vilpo, J. Balzarini, A. Orzeszko, Farmaco 59 (2004) 929
4. C.D. Selassie, W-X. Gan, L.S. Kallander, T.E. Klein., J. Med. Chem. 41 (1998) 4261
5. R-L. Lee, S.W. Dietrich, C. Hansch, J. Med. Chem. 24 (1981) 538

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