Rational design and synthesis of new quorum-sensing inhibitors derived from acylated homoserine lactones and natural products from garlic.

T. Persson, Thomas Bovbjerg Rasmussen, M. Skindersoe, Michael Christian Givskov, J. Nielsen

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    Parallel solution-phase synthesis of sulfide AHL analogues (10a s) by one-pot or a sequential approach is reported. The corresponding sulfoxides 13a-e and sulfones 14a-e were prepared to expand the diversity of the 19-member array of sulfides 10a-s. Likewise, dithianes 12a-c were prepared with similarity both to sulfides 10a-s and to bioactive structures from garlic. Design and biological screening of all compounds presented in this work targeted inhibition of quorum-sensing comprising competitive inhibition of transcriptional regulators LuxR and LasR. The design was based on critical interactions within the binding-site and structural motifs in molecular components isolated from garlic, 7 and 8, shown to be quorum-sensing inhibitors but not antibiotics. A potent quorum-sensing inhibitor N-(heptylsulfanylacetyl)-L-homoserine lactone (10c) was identified. Together with data collected for the other analogues, the resulting structure activity relationship led to a hypothesis in which competitive binding was assumed.
    Original languageEnglish
    JournalOrganic & Biomolecular Chemistry
    Issue number2
    Pages (from-to)253-262
    Publication statusPublished - 2005

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