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Microwave-assisted preparation of the quorum-sensing molecule 2-heptyl-3-hydroxy-4(1H)-quinolone and structurally related analogs


An optimized procedure for the efficient preparation of 2-heptyl-3-hydroxy-4(1H)-quinolone (Pseudomonas quinolone signal or PQS) and a diverse range of structurally related 2-alkyl-4-quinolones with biological activity is presented. The two-step synthesis begins with the formation of α-chloro ketones by the coupling of a Weinreb amide (2-chloro-N-methoxy-N-methylacetamide) and an appropriate Grignard reagent. The resulting α-chloro ketones can be reacted with commercially available anthranilic acids under microwave irradiation conditions to furnish the desired 2-alkyl-4-quinolone products. As a typical example, the synthesis of PQS, a molecule involved in quorum sensing in the pathogenic bacterium Pseudomonas aeruginosa, is described in detail. The first step of this process (α-chloro ketone formation) takes 10 h in total to complete from commercially available bromoheptane and 2-chloro-N-methoxy-N-methylacetamide. The second step (microwave-assisted reaction with anthranilic acid) takes 14 h in total to complete (the reaction typically proceeds in 30 min, with work-up and purification requiring 13 h).

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Figure 1
Figure 2: Outline of the synthetic route to PQS developed by Pesci et al.9.
Figure 3
Figure 4: Synthesis of PQS.
Figure 5: PQS analogs successfully generated using this protocol2,3.
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Figure 7
Figure 8


  1. 1

    Galloway, W.R.J.D., Hodgkinson, J.T., Bowden, S.D., Welch, M. & Spring, D.R. Quorum sensing in Gram-negative bacteria: small-molecule modulation of AHL and AI-2 quorum sensing pathways. Chem. Rev. 111, 28–67 (2011).

    CAS  Article  Google Scholar 

  2. 2

    Hodgkinson, J., Bowden, S.D., Galloway, W.R.J.D., Spring, D.R. & Welch, M. Structure-activity analysis of the Pseudomonas quinolone signal molecule. J. Bacteriol. 192, 3833–3837 (2010).

    CAS  Article  Google Scholar 

  3. 3

    Hodgkinson, J.T. et al. Microwave and flow syntheses of Pseudomonas quinolone signal (PQS) and analogues. Org. Biomol. Chem. 9, 57–61 (2011).

    CAS  Article  Google Scholar 

  4. 4

    Popat, R., Crusz, S.A. & Diggle, S.P. The social behaviours of bacterial pathogens. Br. Med. Bull. 87, 63–75 (2008).

    Article  Google Scholar 

  5. 5

    Diggle, S.P. et al. The Pseudomonas aeruginosa quinolone signal molecule overcomes the cell density-dependency of the quorum sensing hierarchy, regulates rhl-dependent genes at the onset of stationary phase and can be produced in the absence of LasR. Mol. Microbiol. 50, 29–43 (2003).

    CAS  Article  Google Scholar 

  6. 6

    Deziel, E. et al. The contribution of MvfR to Pseudomonas aeruginosa pathogenesis and quorum sensing circuitry regulation: multiple quorum sensing-regulated genes are modulated without affecting lasRI, rhlRI or the production of N-acyl-L-homoserine lactones. Mol. Microbiol. 55, 998–1014 (2005).

    CAS  Article  Google Scholar 

  7. 7

    Collier, D.N. et al. A bacterial cell to cell signal in the lungs of cystic fibrosis patients. FEMS Microbiol. Lett. 215, 41–46 (2002).

    CAS  Article  Google Scholar 

  8. 8

    Pitt, T.L., Sparrow, M., Warner, M. & Stefanidou, M. Survey of resistance of Pseudomonas aeruginosa from UK patients with cystic fibrosis to six commonly prescribed antimicrobial agents. Thorax 58, 794–796 (2003).

    CAS  Article  Google Scholar 

  9. 9

    Pesci, E.C. et al. Quinolone signaling in the cell-to-cell communication system of Pseudomonas aeruginosa. Proc. Natl. Acad. Sci. USA 96, 11229–11234 (1999).

    CAS  Article  Google Scholar 

  10. 10

    Pritchard, D.I., Bycroft, B.W., Chhabra, S.R. & Hooi, D. Substituted 4-quinolones. PCT international patent WO/2002/047686 (2002).

  11. 11

    Hradil, P., Hlavac, J. & Lemr, K. Preparation of 1,2-disubstituted-3-hydroxy-4(1H)-quinolinines and the influence of substitution on the course of cyclization. J. Heterocycl. Chem. 36, 141–144 (1999).

    CAS  Article  Google Scholar 

  12. 12

    Galloway, W.R.J.D., Isidro-Llobet, A. & Spring, D.R. Diversity-oriented synthesis as a tool for the discovery of novel biologically active small molecules. Nat. Commun. 1, 1–13 (2010).

    Article  Google Scholar 

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We gratefully acknowledge financial support from the Engineering and Physical Sciences Research Council, the Biotechnology and Biological Sciences Research Council, the Medical Research Council and the Newman Trust.

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J.T.H., M.W. and D.R.S. conceived the experiments. M.W. and D.R.S. supervised the work. J.T.H. performed the experiments and analyzed the data. W.R.J.D.G. assisted with data analysis and wrote the paper.

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Correspondence to David R Spring.

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The authors declare no competing financial interests.

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Hodgkinson, J., Galloway, W., Welch, M. et al. Microwave-assisted preparation of the quorum-sensing molecule 2-heptyl-3-hydroxy-4(1H)-quinolone and structurally related analogs. Nat Protoc 7, 1184–1192 (2012).

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