Design, synthesis and biological evaluation of 2-substituted 3-hydroxy-6-methyl-4H-pyran-4-one derivatives as Pseudomonas aeruginosa biofilm inhibitors

• Published in: European journal of medicinal chemistry 2018-10, Vol.158, p.753-766
• Main Authors: Li, Yi-Bin, Liu, Jun, Huang, Zhi-Xing, Yu, Jia-Hui, Xu, Xiao-Fang, Sun, Ping-Hua, Lin, Jing, Chen, Wei-Min
• Format: Article
• Language: English
• Subjects: Animals; Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Biofilm inhibitor; Biofilms - drug effects; Humans; Methylation; Mice; PQS pathway; Pseudomonas aeruginosa; Pseudomonas aeruginosa - drug effects; Pseudomonas aeruginosa - physiology; Pseudomonas Infections - drug therapy; Pyrans - chemical synthesis; Pyrans - chemistry; Pyrans - pharmacology; Quorum sensing; Quorum Sensing - drug effects; RAW 264.7 Cells; Synthesis
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2018.09.041

Drug-resistant bacteria associated with biofilm formation are rapidly on the rise, requiring novel therapeutic options to combat biofilm induced drug-resistance. In this study, a class of 3-hydroxy-2-(phenylhydroxy-methyl)-6-methyl-4H-pyran-4-one derivatives (1a-1e) were found by screening of an in-house compound library to be potential Pseudomonas aeruginosa biofilm inhibitors. Thirty one novel 2-substituted 3-hydroxy-6-methyl-4H-pyran-4-one derivatives were synthesized and assayed for their biofilm inhibitory activity. A promising biofilm inhibitor 6a was identified, and showed an obvious biofilm inhibitory effect even at a concentration of 2.5 μM. Further mechanism studies revealed that 6a only shows inhibitory effects on the expression of pqsA-gfp in a fluorescent reporter strain, and the production of a PQS- regulated virulence factor, pyocyanin. This indicates that this type of compound exercises its anti-biofilm activity specifically through the PQS pathway. Novel chemical biofilm inhibitors are described here and guard against biofilm formation associated with Pseudomonas aeruginosa infections. [Display omitted] •Four series of 2-substituted 3-hydroxy-6-methyl-4H-pyran-4-one derivatives were synthesized.•Potent biofilm inhibitor 6a exhibited excellent Pseudomonas aeruginosa biofilm inhibitory effect were identified.•The PQS pathway specific anti-biofilm mechanism of this type of compound was uncovered.