title: Synthesis, quorum sensing inhibition and docking studies of 1,5-dihydropyrrol-2-ones.
abstract: Gram-negative bacteria such as Pseudomonas aeruginosa and Escherichia coli use N-acylated l-homoserine lactones (AHLs) as autoinducers (AIs) for quorum sensing (QS), a chief regulatory and cell-to-cell communication system. QS is responsible for social adaptation, virulence factor production, biofilm production and antibiotic resistance in bacteria. Fimbrolides, a class of halogenated furanones isolated from the red marine alga Delisea pulchra, have been shown to exhibit promising QS inhibitory activity against various Gram-negative and Gram-positive bacterial strains. In this work, various lactam analogues of fimbrolides viz., 1,5-dihydropyrrol-2-ones, were designed and synthesized via an efficient lactamization protocol. All the synthesized analogues were tested for QS inhibition against the E. coli AHL-monitor strain JB357 gfp (ASV). Compound 17a emerged as the most potent compound, followed by 9c, with AIC40 values (the ratio of synthetic inhibitor to natural AHL signaling molecule that is required to lower GFP expression to 40%) of 1.95 and 19.00, respectively. Finally, the potential binding interactions between the synthesized molecules and the LasR QS receptor were studied by molecular docking. Our results indicate that 1,5-dihydropyrrol-2-ones have the ability to serve as potential leads for the further development of novel QS inhibitors as antimicrobial therapeutics.
authors.affiliation: School of Chemistry, UNSW Australia, Sydney, NSW 2052, Australia.
authors.forename: Wai-Kean
authors.initials: WK
authors.lastname: Goh
authors.affiliation: School of Chemistry, UNSW Australia, Sydney, NSW 2052, Australia.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Gardner
authors.affiliation: Department of Chemistry, Birla Institute of Technology & Science, Pilani, Hyderabad Campus, Hyderabad, Telangana 500078, India.
authors.forename: Kondapalli V G
authors.initials: KV
authors.lastname: Chandra Sekhar
authors.affiliation: School of Chemistry, UNSW Australia, Sydney, NSW 2052, Australia.
authors.forename: Nripendra N
authors.initials: NN
authors.lastname: Biswas
authors.affiliation: School of Chemistry, UNSW Australia, Sydney, NSW 2052, Australia.
authors.forename: Shashidhar
authors.initials: S
authors.lastname: Nizalapur
authors.affiliation: Centre for Marine Bio-Innovation, School of Biological, Earth and Environmental Sciences, UNSW Australia, Sydney, NSW 2052, Australia; The Singapore Centre on Environmental Life Sciences Engineering and the School of Biological Sciences, Nanyang Technological University, Singapore.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Rice
authors.affiliation: School of Optometry and Vision Science, UNSW Australia, Sydney, NSW 2052, Australia.
authors.forename: Mark
authors.initials: M
authors.lastname: Willcox
authors.affiliation: School of Chemistry, UNSW Australia, Sydney, NSW 2052, Australia.
authors.forename: David StC
authors.initials: DS
authors.lastname: Black
authors.affiliation: School of Chemistry, UNSW Australia, Sydney, NSW 2052, Australia. Electronic address: n.kumar@unsw.edu.au.
authors.forename: Naresh
authors.initials: N
authors.lastname: Kumar
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000737:chemistry; D004926:Escherichia coli / Q000187:drug effects; D007769:Lactams / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D062105:Molecular Docking Simulation; D011760:Pyrrolidinones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D053038:Quorum Sensing / Q000187:drug effects*; D015534:Trans-Activators / Q000737:chemistry
chemical_list: C000610529:4-bromo-3-(1-bromobutyl)-5-(dibromomethylene)-1-phenyl-1H-pyrrol-2-one; D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D007769:Lactams; C080365:LasR protein, Pseudomonas aeruginosa; D011760:Pyrrolidinones; D015534:Trans-Activators
keywords: 1,5-Dihydropyrrol-2-ones; Antimicrobial; Gram-negative bacteria; N-Acylated l-homoserine lactones; Quorum sensing