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SYNTHESIS AND ANTIBACTERIAL ACTIVITY OF NEW TRIMETHOPRIM ANALOGUE

Barbara Orzeszko 1Michał Fedoryński 1Agnieszka E. Laudy 2Bohdan J. Starościak 2

1. Warsaw University of Technology, Faculty of Chemistry, Koszykowa 75, Warszawa 00-662, Poland
2. Medical University, Department of Pharmaceutical Microbiology, Oczki 3, Warszawa 00-007, Poland

Abstract

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].

dwojka_1_1.GIF

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].

schematto_1.GIF

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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Related papers

Presentation: Poster at V Multidyscyplinarna Konferencja Nauki o Leku, by Barbara Orzeszko
See On-line Journal of V Multidyscyplinarna Konferencja Nauki o Leku

Submitted: 2006-01-23 17:42
Revised:   2009-06-07 00:44