Synthesis of pyrrolidine-based hamamelitannin analogues as quorum sensing inhibitors in Staphylococcus aureus

• Published in: Beilstein journal of organic chemistry Vol. 14; no. 1; pp. 2822 - 2828
• Main Authors: Bouton, Jakob, Van Hecke, Kristof, Rasooly, Reuven, Van Calenbergh, Serge
• Format: Journal Article
• Language: English
• Published: Germany Beilstein-Institut zur Föerderung der Chemischen Wissenschaften 12.11.2018; Beilstein-Institut
• Subjects: Alcohol; Antibiotics; Antimicrobial agents; Antimicrobial resistance; Bacteria; Bacterial infections; Biofilms; Cell interactions; Chemical communication; Chemistry; Drug resistance; Full Research Paper; hamamelitannin; iminosugar; Lead; Natural products; Nitrogen; Pathogens; pyrrolidine; quorum sensing; Staphylococcus aureus; Staphylococcus infections; Belgium; United States > US; iminosugar; quorum sensing; hamamelitannin; pyrrolidine; Staphylococcus aureus
• ISSN: 1860-5397; 2195-951X; 1860-5397
• DOI: 10.3762/bjoc.14.260

Interfering with bacterial cell-to-cell communication is a promising strategy to combat antimicrobial resistance. The natural product hamamelitannin and several of its analogues have been identified as quorum sensing inhibitors. In this paper the synthesis of pyrrolidine-based analogues of a more lead-like hamamelitannin analogue is reported. A convergent synthetic route based on a key ring-closing metathesis reaction was developed and delivered the pyrrolidine analogue in 17 steps in high yield. Chemoselective derivatization of the pyrrolidine nitrogen atom resulted in 6 more compounds. The synthesized compounds were evaluated in a biofilm model, but were all inactive.