Browse
Submit Data
Databases
API
Help

Dataset Information

9 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

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.

SUBMITTER: Duraes F

PROVIDER: S-EPMC8623869 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Chiral Derivatives of Xanthones: Investigation of the Effect of Enantioselectivity on Inhibition of Cyclooxygenases (COX-1 and COX-2) and Binding Interaction with Human Serum Albumin.

Project description:Searching of new enantiomerically pure chiral derivatives of xanthones (CDXs) with potential pharmacological properties, particularly those with anti-inflammatory activity, has remained an area of interest of our group. Herein, we describe in silico studies and in vitro inhibitory assays of cyclooxygenases (COX-1 and COX-2) for different enantiomeric pairs of CDXs. The evaluation of the inhibitory activities was performed by using the COX Inhibitor Screening Assay Kit. Docking simulations between the small molecules (CDXs; known ligands and decoys) and the enzyme targets were undertaken with AutoDock Vina embedded in PyRx-Virtual Screening Tool software. All the CDXs evaluated exhibited COX-1 and COX-2 inhibition potential as predicted. Considering that the (S)-(-)-enantiomer of the nonsteroidal anti-inflammatory drug ketoprofen preferentially binds to albumin, resulting in lower free plasma concentration than (R)-(+)-enantiomer, protein binding affinity for CDXs was also evaluated by spectrofluorimetry as well as in in silico. For some CDXs enantioselectivity was observed.

| S-EPMC5490407 | biostudies-literature

Xanthones Active against Multidrug Resistance and Virulence Mechanisms of Bacteria.

Project description:The emergence of multidrug and extensively drug-resistant pathogenic bacteria able to resist to the action of a wide range of antibiotics is becoming a growing problem for public health. The search for new compounds with the potential to help in the reversion of bacterial resistance plays an important role in current medicinal chemistry research. Under this scope, bacterial efflux pumps are responsible for the efflux of antimicrobials, and their inhibition could reverse resistance. In this study, the multidrug resistance reversing activity of a series of xanthones was investigated. Firstly, docking studies were performed in the AcrAB-TolC efflux pump and in a homology model of the NorA pump. Then, the effects of twenty xanthone derivatives on bacterial growth were evaluated in Staphylococcus aureus 272123 and in the acrA gene-inactivated mutant Salmonella enterica serovar Typhimurium SL1344 (SE03). Their efflux pump inhibitory properties were assessed using real-time fluorimetry. Assays concerning the activity of these compounds towards the inhibition of biofilm formation and quorum sensing have also been performed. Results showed that a halogenated phenylmethanamine xanthone derivative displayed an interesting profile, as far as efflux pump inhibition and biofilm formation were concerned. To the best of our knowledge, this is the first report of xanthones as potential efflux pump inhibitors.

| S-EPMC8158687 | biostudies-literature

Evaluation of the enantioselectivity of new chiral ligands based on imidazolidin-4-one derivatives.

Project description:The new chiral ligands I-III based on derivatives of imidazolidin-4-one were synthesised and characterised. The catalytic activity and enantioselectivity of their corresponding copper(II) complexes were studied in asymmetric Henry reactions. It was found that the enantioselectivity of these catalysts is overall very high and depends on the relative configuration of the ligand used; cis-configuration of ligand affords the nitroaldols with major enantiomer S- (up to 97% ee), whereas the application of ligands with trans-configuration led to nitroaldols with major R-enantiomer (up to 96% ee). The "proline-type" ligand IV was also tested in asymmetric aldol reactions. Under the optimised reaction conditions, aldol products with enantioselectivities of up to 91% ee were obtained.

| S-EPMC10999975 | biostudies-literature

Azide-Functionalized Derivatives of the Virulence-Associated Sugar Pseudaminic Acid: Chiral Pool Synthesis and Labeling of Bacteria.

Project description:Pseudaminic acid (Pse) is a significant prokaryotic monosaccharide found in important Gram-negative and Gram-positive bacteria. This unique sugar serves as a component of cell-surface-associated glycans or glycoproteins and is associated with their virulence. We report the synthesis of azidoacetamido-functionalized Pse derivatives as part of a search for Pse-derived metabolic labeling reagents. The synthesis was initiated with d-glucose (Glc), which served as a cost-effective chiral pool starting material. Key synthetic steps involve the conversion of C1 of Glc into the terminal methyl group of Pse, and inverting deoxyaminations at C3 and C5 of Glc followed by backbone elongation with a three-carbon unit using the Barbier reaction. Metabolic labeling experiments revealed that, of the four Pse derivatives, ester-protected C5 azidoacetamido-Pse successfully labeled cells of Pse-expressing Gram-positive and Gram-negative strains. No labeling was observed in cells of non-Pse-expressing strains. The ester-protected and C5 azidoacetamido-functionalized Pse is thus a useful reagent for the identification of bacteria expressing this unique virulence-associated nonulosonic acid.

| S-EPMC8360151 | biostudies-literature

Chiral Thioxanthones as Modulators of P-glycoprotein: Synthesis and Enantioselectivity Studies.

Project description:Recently, thioxanthone derivatives were found to protect cells against toxic P-glycoprotein (P-gp) substrates, acting as potent inducers/activators of this efflux pump. The study of new P-gp chiral modulators produced from thioxanthone derivatives could clarify the enantioselectivity of this ABC transporter towards this new class of modulators. The aim of this study was to evaluate the P-gp modulatory ability of four enantiomeric pairs of new synthesized chiral aminated thioxanthones (ATxs) 1-8, studying the influence of the stereochemistry on P-gp induction/ activation in cultured Caco-2 cells. The data displayed that all the tested compounds (at 20 ?M) significantly decreased the intracellular accumulation of a P-gp fluorescent substrate (rhodamine 123) when incubated simultaneously for 60 min, demonstrating an increased activity of the efflux, when compared to control cells. Additionally, all of them except ATx 3 (+), caused similar results when the accumulation of the P-gp fluorescent substrate was evaluated after pre-incubating cells with the test compounds for 24 h, significantly reducing the rhodamine 123 intracellular accumulation as a result of a significant increase in P-gp activity. However, ATx 2 (-) was the only derivative that, after 24 h of incubation, significantly increased P-gp expression. These results demonstrated a significantly increased P-gp activity, even without an increase in P-gp expression. Therefore, ATxs 1-8 were shown to behave as P-gp activators. Furthermore, no significant differences were detected in the activity of the protein when comparing the enantiomeric pairs. Nevertheless, ATx 2 (-) modulates P-gp expression differently from its enantiomer, ATx 1 (+). These results disclosed new activators and inducers of P-gp and highlight the existence of enantioselectivity in the induction mechanism.

| S-EPMC6017912 | biostudies-other

Asymmetric epoxidation of fluoroolefins by chiral dioxirane. Fluorine effect on enantioselectivity.

Project description:The asymmetric epoxidation of various fluoroolefins has been studied using chiral ketone catalyst, and up to 93% ee was achieved with fructose-derived ketone 1.

| S-EPMC2784290 | biostudies-literature

Conformational Control of Chiral Amido-Thiourea Catalysts Enables Improved Activity and Enantioselectivity.

Project description:While aryl pyrrolidinoamido-thioureas derived from ?-amino acids are effective catalysts in a number of asymmetric transformations, they exist as mixtures of slowly interconverting amide rotamers. Herein, the compromising role of amide bond isomerism is analyzed experimentally and computationally. A modified catalyst structure that exists almost exclusively as a single amide rotamer is introduced. This modification is shown to result in improved reactivity and enantioselectivity by minimizing competing reaction pathways.

| S-EPMC5096793 | biostudies-literature

Discovery of antipsychotic loxapine derivatives against intracellular multidrug-resistant bacteria.

Project description:The emergence and spread of multidrug-resistant bacteria highlight the need for new antibacterial interventions. A screening of 24 newly synthesized dibenzoxazepines identified a small molecule compound, SW14, with potent inhibitory activity against intracellular multidrug-resistant and fluoroquinolone-resistant strains of S. typhimurium in macrophages and epithelial cells. Moreover, intra-macrophagic Salmonella typhi, Yersinia enterocolitica, and Listeria monocytogenes and methicillin-resistant Staphylococcus aureus are also susceptible to SW14. Overall, our findings suggest that SW14 has a broad-spectrum activity against intracellular bacteria.

| S-EPMC9667769 | biostudies-literature

Chiral phosphine-mediated intramolecular [3 + 2] annulation: enhanced enantioselectivity by achiral Bronsted acid.

Project description:Enantioselective intramolecular [3 + 2] annulation of chalcones bearing an allene moiety has been successfully developed. The reaction was effectively promoted by amino acid-derived phosphines, in combination with achiral Brønsted acids. Dihydrocoumarin architectures were constructed in high yields and with excellent enantiomeric excesses. Theoretical studies via DFT calculations revealed that the hydrogen bonding network induced by achiral Brønsted acids/chiral phosphines could more efficiently distinguish between two enantioselective pathways, thus leading to enhanced enantioselectivity.

| S-EPMC5618691 | biostudies-other

Enantioselectivity of chiral dihydromyricetin in multicomponent solid solutions regulated by subtle structural mutation.

Project description:Multicomponent crystals of a chiral drug with non-chiral components have attracted increasing attention in the application of enantiomer purification and regulation of the physicochemical properties of crystalline materials. Crystalline solid solutions provide opportunities for fine-tuning material properties because of continuously adjustable component stoichiometry ratios. The synthesis, crystal structure, thermodynamics and solid-state enantioselectivity of a series of multicomponent crystals of chiral dihydromyricetin (DMY) with caffeine (CAF) or theophylline (THE) were investigated and the results reveal how the subtle change of molecular structure of the coformer dictates the enantiomer selectivity in multicomponent cocrystals. A series of multicomponent cocrystal solvates of chiral DMY with CAF and THE were synthesized by the slurry cocrystallization method in acetonitrile. Although most racemic mixtures crystallize as racemic compounds or conglomerates, both DMY-CAF and DMY-THE crystallize as chiral solid solutions, unveiled by pseudo-binary melt phase diagrams and pseudo-ternary solution phase diagrams. Crystal structures of Rac-DMY-CAF, R,R-DMY-CAF, Rac-DMY-THE and R,R-DMY-THE are reported for the first time via single-crystal X-ray diffraction, displaying two distinct types of solid solution differing in mixing scale of enantiomers spanning several orders of magnitude. Surprisingly, this remarkable impact on enantiomer discrimination was simply achieved by the reduction of a methyl group of CAF to the THE coformer, which was further rationalized from their crystal structures and intermolecular interactions. Collectively, this work has demonstrated that a subtle change in the molecular structure of a coformer can regulate enantioselectivity in crystalline materials, guiding the purification of chiral racemic compounds via the cocrystallization method and the design of solid-solution crystalline materials.

| S-EPMC9980384 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data