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

Jakob Bouton,Reuven Rasooly,Serge Van Calenbergh,Kristof Van Hecke

doi:10.3762/bjoc.14.260

Abstract

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.

Highlights

Antimicrobial resistance is rapidly becoming a global threat [1,2]
In this work we report the design, synthesis and biological evaluation of a number of pyrrolidine-based hamamelitannin analogues
The envisioned strategy for the synthesis of the target pyrrolidine-based hamamelitannin analogues is depicted in Scheme 1

Summary

Introduction

Antimicrobial resistance is rapidly becoming a global threat [1,2]. It is estimated that worldwide, at least 700 000 people die every year from drug-resistant strains of common bacterial infections. 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 natural product hamamelitannin (1) has been identified as a non-peptide analogue of RIP (RNAIII-inhibiting protein), an inhibitor of the RAP/TRAP (RNAIII-activating protein/target of RAP) quorum sensing system in S. aureus (Figure 1) [12,13,14].

Results

Conclusion