Enantioselectivity of Chiral Derivatives of Xanthones in Virulence Effects of Resistant Bacteria.

Fernando Durães,Paulo Martins-Da-Costa,Nikoletta Szemerédi,Madalena Pinto,Eugénia Pinto,Joana Freitas-Silva,Gabriella Spengler,Carla Fernandes,Maria Elizabeth Tiritan,Sara Cravo,Emília Sousa

doi:10.3390/ph14111141

Abstract

Antimicrobial peptides are one of the lines of defense produced by several hosts in response to bacterial infections. Inspired by them and recent discoveries of xanthones as bacterial efflux pump inhibitors, chiral amides with a xanthone scaffold were planned to be potential antimicrobial adjuvants. The chiral derivatives of xanthones were obtained by peptide coupling reactions between suitable xanthones with enantiomerically pure building blocks, yielding derivatives with high enantiomeric purity. Among 18 compounds investigated for their antimicrobial activity against reference strains of bacteria and fungi, antibacterial activity for the tested strains was not found. Selected compounds were also evaluated for their potential to inhibit bacterial efflux pumps. Compound (R,R)-8 inhibited efflux pumps in the Gram-positive model tested and three compounds, (S,S)-8, (R)-17 and (R,S)-18, displayed the same activity in the Gram-negative strain used. Studies were performed on the inhibition of biofilm formation and quorum-sensing, to which the enantiomeric pair 8 displayed activity for the latter. To gain a better understanding of how the active compounds bind to the efflux pumps, docking studies were performed. Hit compounds were proposed for each activity, and it was shown that enantioselectivity was noticeable and must be considered, as enantiomers displayed differences in activity.

Highlights

The synthesis of the methoxylated xanthone 1 has been previously described, through a benzophenone intermediate, which produced the main product 3-methoxy-4hydroxy-9H-xanthen-9-one (2), and the secondary products 3,4-dihydroxy-9H-xanthen9-one (3) and 3-hydroxy-4-methoxy-9H-xanthen-9-one (4), which were used for the synthesis of derivatives [41]
Amines and amino alcohols were chosen as chiral building blocks, to demonstrate the efficiency and applicability of this methodology, resulting in a peptide bond
In order to accomplish this coupling with chiral building blocks, a short spacer was introduced through a Williamson ether synthesis with methyl 2-bromoacetate affording compound 9

Summary

Introduction

Antimicrobial peptides are proteins produced by several hosts as a defense mechanism against bacteria. They are a response from the innate immune system, and to this day, still present effectiveness against a multiplicity of pathogenic microbes [1,2]. They are composed of amino acids and, present an amphipathic character, and their cationic charge is able to latch onto the negatively charged bacterial membrane, where they can insert and originate pores, which can lead to bacterial death [3]. Several other mechanisms have been brought to light, such as competition with magnesium

Methods

Results

Conclusion