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

Organic & Biomolecular Chemistry Pub Date: 2004-12-01 DOI: 10.1039/B415761C

Abstract

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.

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