Structure–activity relationship of brominated 3-alkyl-5-methylene-2(5H)-furanones and alkylmaleic anhydrides as inhibitors of Salmonella biofilm formation and quorum sensing regulated bioluminescence in Vibrio harveyi Original Research Article

Structure–activity relationship of brominated 3-alkyl-5-methylene-2(5H)-furanones and alkylmaleic anhydrides as inhibitors of Salmonella biofilm formation and quorum sensing regulated bioluminescence in Vibrio harveyi Original Research Article Pages 5224-5233 Hans P. Steenackers, Jeremy Levin, Joost C. Janssens, Ami De Weerdt, Jan Balzarini, Jos Vanderleyden, Dirk E. De Vos, Sigrid C. De Keersmaecker Close preview | | Supplementary content Related articles | Related reference work articles Abstract | Figures/Tables | References Abstract A library of 25 1′-unsubstituted and 1′-bromo or 1′-acetoxy 3-alkyl-5-methylene-2(5H)-furanones and two 3-alkylmaleic anhydrides was synthesized using existing and new methods. This library was tested for the antagonistic effect against the biofilm formation by Salmonella Typhimurium and the quorum sensing regulated bioluminescence of Vibrio harveyi. The length of the 3-alkyl chain and the bromination pattern of the ring structure were found to have a major effect on the biological activity of the 1′-unsubstituted furanones. Remarkably, the introduction of a bromine atom on the 1′ position of the 3-alkyl chain did drastically enhance the activity of the furanones in both biological test systems. The introduction of an acetoxy function in this position did in general not improve the activity. Finally, the potential of the (bromo)alkylmaleic anhydrides as a new and chemically easily accessible class of biofilm and quorum sensing inhibitors was demonstrated. Article Outline 1. Introduction 2. 3-Alkyl-5-methylene-2(5H)-furanones 2.1. Chemistry 2.2. Biological results 3. 1′-Substituted 3-alkyl-5-methylene-2(5H)-furanones 3.1. Chemistry 3.2. Biological results 4. Experimental section 4.1. Chemistry 4.1.1. General procedure for 5-methylene-2(5H)-furanones without 3-alkyl side (Scheme 1) 4.1.2. General procedure for 3-alkyl-5-methylene-2(5H)-furanones via protocol of Manny et al. (1999) (Scheme 2 (pathway A)) 4.1.3. General procedure for alkylmaleic anhydrides (8b–d) (Scheme 2 (pathway B)) 4.1.3.1. Oxidative carbonylation procedure 4.1.4. General procedure for 3-alkyl-4-bromo-5-(bromomethylene)-2(5H)-furanones and 3-alkyl-5-bromomethylene-2(5H)-furanones starting from alkylmaleic anhydrides (Scheme 2 (pathway B)) 4.1.4.1. Wittig coupling procedure 4.1.4.2. Deprotection procedure 4.1.4.3. Bromination/debromocarboxylation and bromination/dehydrobromination procedure 4.1.4.4. (E/Z)-2-(4-Hexyl-5-oxofuran-2(5H)-ylidene)acetic acid (10c) 4.1.4.5. (E/Z)-2-(4-Octyl-5-oxo-furan-2(5H)-ylidene)acetic acid (10d) 4.1.4.6. 3-Hexyl-5-bromomethylene-2(5H)-furanone (11c) 4.1.5. General procedure for 3-alkyl-4-bromo-5-methylene-2(5H)-furanones starting from alkylmaleic anhydrides (Scheme 2 (pathway C)) 4.1.5.1. Grignard methylation procedure 4.1.5.2. Bromo/dehydrobromination procedure 4.1.5.3. 3-Hexyl-5-hydroxy-5-methyl-2(5H)-furanone (12c) 4.1.5.4. 3-Hexyl-4-bromo-5-methylene-2(5H)-furanone (13c) 4.1.6. General procedure for bromoalkylmaleic anhydrides starting from alkylmaleic anhydrides (Scheme 2 (pathway D)) 4.1.6.1. Bromohexylmaleic anhydride (20c) 4.1.7. General procedure for 3-(1′-bromoalkyl)-5-methylene-2(5H)-furanones (Scheme 3) 4.1.8. General procedure for 3-(1′-acetoxalkyl)-5-methylene-2(5H)-furanones (Scheme 3) 4.2. Biological assays 4.2.1. Static peg assay for prevention of S. Typhimurium biofilm formation10 4.2.2. Bioscreen assay for measuring S. Typhimurium growth inhibition 4.2.3. Luminescence assay for inhibition of V. harveyi quorum sensing 4.2.4. Determination of cytostatic activity Acknowledgements . Supplementary data References and notes