Rational design and synthesis of new quorum-sensing inhibitors derived from acylated homoserine lactones and natural products from garlic (original) (raw)
* Corresponding authors
a Department of Natural Sciences, Bioorganic Chemistry Section, Royal Veterinary and Agricultural University, Frederiksberg C, Denmark
E-mail: jn@kvl.dk
Fax: +45 3528 2398
Tel: +45 3528 2428
b Department of Chemistry, Technical University of Denmark, Kgs. Lyngby, Denmark
c Centre for Biomedical Microbiology, BioCentrum, Technical University of Denmark, Kgs. Lyngby, Denmark
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.
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Article information
DOI
https://doi.org/10.1039/B415761C
Article type
Paper
Submitted
12 Oct 2004
Accepted
29 Oct 2004
First published
01 Dec 2004
Download Citation
Org. Biomol. Chem., 2005,3, 253-262
Permissions
Rational design and synthesis of new quorum-sensing inhibitors derived from acylated homoserine lactones and natural products from garlic
T. Persson, T. H. Hansen, T. B. Rasmussen, M. E. Skindersø, M. Givskov and J. Nielsen,Org. Biomol. Chem., 2005, 3, 253DOI: 10.1039/B415761C
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