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Design, synthesis and evaluation of oxazolopyridinone derivatives as quorum sensing inhibitors
[Display omitted] •Benzoxazolone, oxazolopyridinone and 3-(2-hydroxyphenyl)hydantoin derivatives were designed and synthesized.•Their QS inhibitory activity was systematically evaluated.•Oxazolopyridinone derivatives exhibited potent QS inhibitory activity against P. aeruginosa.•In particular, B20 e...
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Published in: | Bioorganic chemistry 2023-01, Vol.130, p.106266-106266, Article 106266 |
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Main Authors: | , , , , , , , , |
Format: | Article |
Language: | English |
Subjects: | |
Citations: | Items that this one cites Items that cite this one |
Online Access: | Get full text |
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Summary: | [Display omitted]
•Benzoxazolone, oxazolopyridinone and 3-(2-hydroxyphenyl)hydantoin derivatives were designed and synthesized.•Their QS inhibitory activity was systematically evaluated.•Oxazolopyridinone derivatives exhibited potent QS inhibitory activity against P. aeruginosa.•In particular, B20 exhibited the best synergistic antibacterial effect against multiple drug-resistant P. aeruginosa.•Mechanistic studies indicated that B20 directly inhibited the QS pathway.
The antibiotic crisis is associated with the appearance of multidrug resistant (MDR) pathogens, which has caused severe bacterial infections and imposed a huge burden on modern society. Therefore, there is an urgent need to develop new antibacterial drugs with novel mechanism of action. Here we designed and synthesized three series of benzoxazolone, oxazolopyridinone and 3-(2-hydroxyphenyl)hydantoin derivatives and evaluated their activity as novel quorum sensing (QS) inhibitors. We found that benzoxazolone and oxazolopyridinone derivatives had promising QS inhibitory activity in the minimum inhibitory concentration, pyocyanin and rhamnolipid inhibition assays. In particular, A10 and B20 at 256 μg/mL not only suppressed pyocyanin production regulated by QS in P. aeruginosa PAO1 by 36.55% and 46.90%, respectively, but also showed the strongest rhamnolipid inhibitory activity with the IC50 values of 66.35 and 56.75 µg/mL, respectively. Further studies demonstrated that B20 at 64 μg/mL inhibited biofilm formation in P. aeruginosa PAO1 by 40%, and weakened its swarming motility. More importantly, the bacterial mortality of B20 combined with ciprofloxacin and clarithromycin against P. aeruginosa were 48.27% and 49.79%, respectively, while ciprofloxacin and clarithromycin had only 16.99% and 29.11% of bacterial mortality against P. aeruginosa when used alone. Mechanistic studies indicated that B20 directly inhibited the QS pathway based on the GFP reporter strain assay. Overall, this compound with oxazolopyridinone core could serve as an antibacterial lead of QS inhibitor for further evaluation of its drug-likeness. |
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ISSN: | 0045-2068 1090-2120 |
DOI: | 10.1016/j.bioorg.2022.106266 |