New bicyclic brominated furanones as potent autoinducer-2 quorum-sensing inhibitors against bacterial biofilm formation

• Published in: European journal of medicinal chemistry Vol. 137; pp. 76 - 87
• Main Authors: Park, Ji Su, Ryu, Eun-Ju, Li, Linzi, Choi, Bong-Kyu, Kim, B. Moon
• Format: Journal Article
• Language: English
• Published: PARIS Elsevier Masson SAS 08.09.2017; Elsevier
• Subjects: AI-2 inhibitors; Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Bacterial biofilm; Biofilms - drug effects; Brominated furanones; Chemistry, Medicinal; Dose-Response Relationship, Drug; Furans - chemical synthesis; Furans - pharmacology; Fusobacterium nucleatum - drug effects; Homoserine - analogs & derivatives; Homoserine - antagonists & inhibitors; Lactones - antagonists & inhibitors; Life Sciences & Biomedicine; Microbial Sensitivity Tests; Molecular Structure; Pharmacology & Pharmacy; Porphyromonas gingivalis - drug effects; Quorum sensing; Quorum Sensing - drug effects; Science & Technology; Structure-Activity Relationship; Tannerella forsythia - drug effects; AI-2 inhibitors; Quorum sensing; Bacterial biofilm; Brominated furanones; SIGNAL; FUSOBACTERIUM-NUCLEATUM; INFECTIONS; MOLECULE; CHEMICAL COMMUNICATION; ANHYDRIDES; COAGGREGATION; FAMILY
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2017.05.037

Bacterial behaviors such as virulence factor secretion and biofilm formation are critical for survival, and are effectively regulated through quorum sensing, a mechanism of intra- and interspecies communication in response to changes in cell density and species complexity. Many bacterial species colonize host tissues and form a defensive structure called a biofilm, which can be the basis of inflammatory diseases. Periodontitis, a chronic inflammatory disease affecting the periodontium, is caused by subgingival biofilms related to periodontopathogens. In particular, Fusobacterium nucleatum is a major co-aggregation bridge organism in the formation and growth of subgingival biofilms, linking the early and late colonizers in periodontal biofilms. According to our previous study, the intergeneric quorum-sensing signal molecule autoinducer-2 (AI-2) of F. nucleatum plays a key role in intra- and interspecies interactions of periodontopathogens, and may be a good target for periodontal biofilm inhibition. Recently, brominated furanones produced by the macroalga Delisea pulchra were shown to inhibit biofilm formation via AI-2, and have been investigated toward the goal of increasing the inhibition effect. In this study, we describe the synthesis of new bromofuranone analogs, i.e., 3-(dibromomethylene)isobenzofuran-1(3H)-one derivatives, and demonstrate their inhibitory activities against biofilm formation by periodontopathogens, including F. nucleatum, Porphyromonas gingivalis, and Tannerella forsythia. [Display omitted] •New bicyclic brominated furanones were synthesized as potent QS inhibitors.•Inhibitors showed high inhibitory effects on the periodontopathogen biofilm formation.•Active compounds significantly inhibited the F. nucleatum AI-2 activity.•The inhibitors showed neither cytotoxicity nor induction of inflammatory response.