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

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.

Antibacterial Potential of Symmetrical Twin-Drug 3,6-Diaminoxanthones

“…As such, it could be highlighted that compound 7 was effective at inhibiting efflux pumps in S. aureus 272123, while compounds 18 and 19 displayed the same effects on S. enterica Typhimurium SL1344, and compound 5 was effective against both strains. Compared with previously analyzed hydroxylated [12], aminated [12], and amidated [24] xanthones, we can conclude that this approach benefits EPI effects, with the most potent EPI xanthones being disclosed in this work. As in previous studies [12] and contrary to growth inhibitory studies, the stereochemistry of the substituents is determinant for EPI.…”

Synthesis and Anti-Inflammatory Evaluation of a Library of Chiral Derivatives of Xanthones Conjugated with Proteinogenic Amino Acids

“…The ester of leucine enantiomers (6 and 7) reacted from 30 min to 1 h, while the coupling reaction with isoleucine derivative (5) was only accomplished after 24 h. This is because of the space occupied by the ramification of the isoleucine side chain that increases the steric hindrance with the coupling reagent. All CDXs of amino esters were firstly prepared using the coupling reagent COMU, however, as the purification of CDXs of serine (20 and 21) and glutamic acid (25) enantiomers was difficult, an additional reaction with TBTU as coupling reagent was required. In these first attempts, the preparation of the CDXs with the amino esters of serine using COMU was accomplished in 2 h, yielding 42% of the enantiomer X1AELSer (20) and 64% of the enantiomer X1AEDSer (21).…”

“…Consequently, the research of new CDXs and their biological/pharmacological properties constitutes a promising field that has already shown relevant results [ 2 , 3 ]. Examples of synthesized CDXs with enantioselectivity that have been explored in our research group include CDXs as cell growth inhibitors [ 6 , 22 , 23 ], sciatic nerve blockers [ 24 ], antimicrobial resistance mechanism inhibitors [ 25 ], and cyclooxygenase inhibitors [ 10 ]. A great contribution in this field was also made by Professor Marona’s research team, describing a variety of CDXs with diverse activities, such as anticonvulsant [ 26 ], local anesthetic [ 26 ], cardiovascular [ 27 ], antifungal and antibacterial [ 28 ], antiarrhythmic [ 29 ], antiplatelet aggregation [ 30 ], antiadrenergic receptors [ 31 ], and more recently antioxidant [ 32 , 33 ] and anticancer potential [ 34 , 35 ].…”

Evaluation of Antitumor Activity of Xanthones Conjugated with Amino Acids

“…Nature is the main source of chiral bioactive compounds, which can be used as therapeutic agents, such as xanthone derivatives. Many naturally occurring xanthones, isolated from plants and marine sources, are chiral and exhibit interesting biological activities [8][9][10][11]. Nevertheless, one of the main biological activities reported within this class of compounds is their antitumor activity [12][13][14].…”

“…The xanthone nucleus is considered a privileged structure, given its ability to have diverse substituents and, consequently, bind to several biotargets [12], and its association with a chiral moiety can improve the potency and the selectivity of their derivatives in the biological activity [11,15,20,21]. The introduction of amino acids into natural products is expected to improve both pharmacodynamics and pharmacokinetics of these compounds and minimize their adverse effects [22].…”