Synthesis, quorum sensing inhibition and docking studies of 1,5-dihydropyrrol-2-ones.

Autor: Goh WK; School of Chemistry, UNSW Australia, Sydney, NSW 2052, Australia., Gardner CR; School of Chemistry, UNSW Australia, Sydney, NSW 2052, Australia., Chandra Sekhar KV; Department of Chemistry, Birla Institute of Technology & Science, Pilani, Hyderabad Campus, Hyderabad, Telangana 500078, India., Biswas NN; School of Chemistry, UNSW Australia, Sydney, NSW 2052, Australia., Nizalapur S; School of Chemistry, UNSW Australia, Sydney, NSW 2052, Australia., Rice SA; 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., Willcox M; School of Optometry and Vision Science, UNSW Australia, Sydney, NSW 2052, Australia., Black DS; School of Chemistry, UNSW Australia, Sydney, NSW 2052, Australia., Kumar N; School of Chemistry, UNSW Australia, Sydney, NSW 2052, Australia. Electronic address: n.kumar@unsw.edu.au.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry [Bioorg Med Chem] 2015 Dec 01; Vol. 23 (23), pp. 7366-77. Date of Electronic Publication: 2015 Oct 23.
DOI: 10.1016/j.bmc.2015.10.025
Abstrakt: 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.
(Copyright © 2015 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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