title: Rational design and synthesis of new quorum-sensing inhibitors derived from acylated homoserine lactones and natural products from garlic.
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 . 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.
authors.affiliation: Department of Natural Sciences, Bioorganic Chemistry Section, Royal Veterinary and Agricultural University, Frederiksberg C, DK-1871, Denmark.
authors.forename: Tobias
authors.initials: T
authors.lastname: Persson
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Hansen
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Rasmussen
authors.forename: Mette E
authors.initials: ME
authors.lastname: Skindersø
authors.forename: Michael
authors.initials: M
authors.lastname: Givskov
authors.forename: John
authors.initials: J
authors.lastname: Nielsen
mesh_terms: D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001688:Biological Products / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015195:Drug Design; D005737:Garlic / Q000737:chemistry*; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D011550:Pseudomonas aeruginosa / Q000187:drug effects*; D013329:Structure-Activity Relationship
chemical_list: D001688:Biological Products; C088386:homoserine lactone; D015107:4-Butyrolactone