betadex and tedizolid

Molecular modeling (MM) results for tedizolid and radezolid with heptakis-(2,3-diacetyl-6-sulfo)-β-cyclodextrin (HDAS-β-CD) are presented and compared with the results previously obtained for linezolid and sutezolid. The mechanism of interaction of chiral oxazolidinone ligands belonging to a new class of antibacterial agents, such as linezolid, tedizolid, radezolid, and sutezolid, with HDAS-β-CD based on capillary electrokinetic chromatography (cEKC), nuclear magnetic resonance (NMR) spectroscopy, and MM methods was described. Principles of chiral separation of oxazolidinone analogues using charged single isomer derivatives of cyclodextrin by the cEKC method were presented, including the selection of the optimal chiral selector and separation conditions, complex stoichiometry, and binding constants, which provided a comprehensive basis for MM studies. In turn, NMR provided, where possible, direct information on the geometry of the inclusion complexes and also provided the necessary structural information to validate the MM calculations. Consequently, MM contributed to the understanding of the structure of diastereomeric complexes, the thermodynamics of complexation, and the visualization of their structures. The most probable mean geometries of the studied supramolecular complexes and their dynamics (geometry changes over time) were determined by molecular dynamics methods. Oxazolidinone ligands have been shown to complex mainly the inner part of cyclodextrin, while the external binding is less privileged, which is consistent with the conclusions of the NMR studies. Enthalpy values of binding of complexes were calculated using long-term molecular dynamics in explicit water as well as using molecular mechanics, the Poisson-Boltzmann or generalized Born, and surface area continuum solvation (MM/PBSA and MM/GBSA) methods. Computational methods predicted the effect of changes in pH and composition of the solution on the strength and complexation process, and it adapted the conditions selected as optimal during the cEKC study. By changing the dielectric constant in the MM/PBSA and MM/GBSA calculations, the effect of changing the solution to methanol/acetonitrile was investigated. A fairly successful attempt was made to predict the chiral separation of the oxazolidinones using the modified cyclodextrin by computational methods.

Topics: beta-Cyclodextrins; Cyclodextrins; Electrophoresis, Capillary; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Models, Molecular; Oxazolidinones; Stereoisomerism; Tetrazoles

Progressive increase in bacterial resistance has caused an urgent need to introduce new antibiotics, one of them being oxazolidinones with their representative tedizolid. Despite the broad spectrum of activity of the parent tedizolid, it is characterized by low water solubility, which limits its use. The combination of the active molecule with a multifunctional excipient, which is cyclodextrins, allows preservation of its pharmacological activity and modification of its physicochemical properties. Therefore, the aim of the study was to change the dissolution rate and permeability through the model membrane of tedizolid by formation of solid dispersions with a cyclodextrin. The research included identification of tedizolid-hydroxypropyl-β-cyclodextrin (tedizolid/HP-β-CD) inclusion complex by thermal method (Differential Scanning Colorimetry), spectroscopic methods (powder X-ray diffraction, Fourier-Transform Infrared spectroscopy), and molecular docking. The second part of the research concerned the physicochemical properties (dissolution and permeability) and the biological properties of the system in terms of its microbiological activity. An increase in the dissolution rate was observed in the presence of cyclodextrin, while maintaining a high permeation coefficient and high microbiological activity. The proposed approach is an opportunity to develop drug delivery systems used in the treatment of resistant bacterial infections, in which, in addition to modifying the physicochemical properties caused by cyclodextrin, we observe a favorable change in the pharmacological potential of the bioactives.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Anti-Bacterial Agents; beta-Cyclodextrins; Calorimetry, Differential Scanning; Cyclodextrins; Delayed-Action Preparations; Drug Delivery Systems; Drug Liberation; Drug Resistance, Bacterial; Hydrogen-Ion Concentration; Molecular Docking Simulation; Oxazolidinones; Oxidative Stress; Permeability; Powders; Solubility; Spectroscopy, Fourier Transform Infrared; Tetrazoles; X-Ray Diffraction

A method for the enantioseparation of sutezolid, the next analogue after linezolid and tedizolid, belonging to the truly new class of antibacterial agents, the oxazolidinones, was developed based on non-aqueous capillary electrophoresis (NACE), using a single isomer of cyclodextrins as a chiral pseudophase. During the experiment, the enantioseparation of sutezolid together with its predecessor, linezolid, both weak base antibacterial agents, was evaluated using anionic single-isomers of cyclodextrins from hydrophilic, up to hydrophobic: heptakis-(2,3-dihydroxy-6-sulfo)-β-cyclodextrin, heptakis-(2,3-diacetyl-6-sulfo)-β-cyclodextrin (HDAS-β-CD), as well as heptakis-(2,3-dimethyl-6-sulfo)-β-cyclodextrin (HDMS-β-CD), respectively. Based on the observed results, the cyclodextrins, HDAS-β-CD and HDMS-β-CD which carry the acetyl and methyl groups at the C2 and C3 positions, respectively, provided the baseline separation of sutezolid enantiomers. However, HDMS-β-CD led to a reversal of enantiomer migration order (EMO) in comparison to HDAS-β-CD. Instead, enantiomers of linezolid were separated only by HDMS-β-CD. During the experiments, different organic solvents and their mixtures in various ratios were tested. The selectivity and separation efficiency were critically affected by the nature of the buffer system, the type of organic solvent, and the concentrations of trifluoroacetic acid (TFA) in the NACE buffer system. Focusing on the desired EMO in which the eutomers (S)-sutezolid and (S)-linezolid migrated last, the highest enantioresolution using the NACE method was achieved at normal polarity mode with 45  mM HDMS-β-CD dissolved in MeOH/ACN (85:15, v/v) containing 200  mM TFA/20  mM ammonium formate. Moreover, infrared spectroscopy, NMR and molecular modelling were investigated to provide information about complex formation.

Topics: beta-Cyclodextrins; Cyclodextrins; Electrophoresis, Capillary; Linezolid; Magnetic Resonance Spectroscopy; Models, Molecular; Oxazolidinones; Spectrophotometry, Infrared; Stereoisomerism; Tetrazoles

NMR spectroscopy is used to investigate the host-guest complexation of (R)-tedizolid, such as tedizolid with the hydroxymethyl substituent at the C5 position of the oxazolidinone ring ((R)-TED) or tedizolid with 5-methyl dihydrogen phosphate ((R)-TED-PO

Topics: beta-Cyclodextrins; gamma-Cyclodextrins; Magnetic Resonance Spectroscopy; Oxazolidinones; Stereoisomerism; Tetrazoles