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

TY - JOUR

T1 - Rational design and synthesis of new quorum-sensing inhibitors derived from acylated homoserine lactones and natural products from garlic

AU - Persson, Tobias

AU - Hansen, Thomas H

AU - Rasmussen, Thomas B

AU - Skindersø, Mette E

AU - Givskov, Michael

AU - Nielsen, John

N1 - Keywords: 4-Butyrolactone; Biological Products; Drug Design; Garlic; Microbial Sensitivity Tests; Molecular Structure; Pseudomonas aeruginosa; Structure-Activity Relationship

PY - 2004

Y1 - 2004

N2 - 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.

AB - 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.

U2 - 10.1039/b415761c

DO - 10.1039/b415761c

M3 - Journal article

C2 - 15632967

SN - 1477-0520

VL - 3

SP - 253

EP - 262

JO - Organic & Biomolecular Chemistry

JF - Organic & Biomolecular Chemistry

IS - 2

ER -