Antagonism of Quorum Sensing Phenotypes by Analogs of the Marine Bacterial Secondary Metabolite 3-Methyl- N -(2'-Phenylethyl)-Butyramide

Quorum sensing (QS) antagonists have been proposed as novel therapeutic agents to combat bacterial infections. We previously reported that the secondary metabolite 3-methyl- -(2'-phenylethyl)-butyramide, produced by a marine bacterium identified as , inhibits QS controlled phenotypes in multiple Gram-negative reporter strains. Here we report that -phenethyl hexanamide, a structurally-related compound produced by the marine bacterium , similarly demonstrates QS inhibitory properties. To more fully explore structure-activity relationships within this new class of QS inhibitors, a panel of twenty analogs was synthesized and biologically evaluated. Several compounds were identified with increased attenuation of QS-regulated phenotypes, most notably -(4-fluorophenyl)-3-phenylpropanamide against the marine pathogen (IC = 1.1 µM). These findings support the opportunity to further develop substituted phenethylamides as QS inhibitors.