David G. Durham

Baicalin Synergy with β-Lactam Antibiotics Against Methicillin-resistant Staphylococcus aureus and Other β-Lactam-resistant Strains of S. aureus

Bacterial resistance to antibiotics is a serious global problem and includes strains of β‐lactam‐resistant Staphylococcus aureus and methicillin‐resistant S. aureus (MRSA). Novel antimicrobials and/or new approaches to combat the problem are urgently needed. The Chinese herb Xi‐nan Huangqin (Scutellaria amoena CM. Wright) has been used in traditional Chinese medicine to treat a wide range of infectious diseases. In this study we have examined the antibacterial action of baicalin, a flavone isolated from the herb.

Development of QSARs to investigate the bacterial toxicity and biotransformation potential of aromatic heterocylic compounds.

A series of aromatic heterocyclic and hydrocarbon compounds were tested for toxicity and biotransformation potential against two contrasting lux-marked whole-cell microbial biosensors. Toxicity was determined by inhibition of light output of a Pseudomonas fluorescens construct that expresses lux constitutively. Biotransformation was tested by increase in light output of P. fluorescens HK44 (pUTK21), which expresses lux when in the presence of a metabolic intermediate (salicylate). The data were then modelled against physical/chemical properties of the compounds tested to see if quantitative structure-activity relationships (QSARs) could be derived. Toxicity was found to be accurately predicted by log Kow (R2 = 0.95, Q2 = 0.88), with the basic (pyridine-ring containing) heterocycles modelled separately. The biotransformation data were best modelled using lowest unoccupied molecular orbital (LUMO) energies (R2 = 0.90, Q2 = 0.87).

Vancomycin resistance reversal in enterococci by flavonoids

The development of clinical vancomycin‐resistant strains of enterococci (VRE) is a major cause for concern. Here we show that a combination of galangin or 3,7‐dihydroxyflavone with vancomycin may be used to sensitize resistant strains of Enterococcus faecalis and Enterococcus faecium to the level of vancomycin‐sensitive strains.

A triterpene from Rubus pinfaensis.

A new pentacyclic triterpene, pinfaensin, was isolated from the roots of Rubus pinfaensis and the structure elucidated by 13C NMR methods. This triterpene, a glycoside of pinfaensic acid (glucosyl 23-formyl-2 alpha,3 beta,19 alpha-trihydroxyurs-12-en-28-oate), in order to achieve purification and characterization, was hydrolysed to previously unreported pinfaensic acid which on acetylation and methylation gave methyl diacetoxypinfaensate (methyl 2 alpha,3 beta-diacetoxy-23-formyl-19 alpha-hydroxyurs-12-en-28-oate).

Unsaturated E-ring triterpenes from rubus pinfaensis

Abstract Two new isomeric unsaturated E-ring pentacyclic triterpenoids have been isolated from the roots of Rubus pinfaensis . These triterpenes, glucosides of 2α,3β,23-trihydroxyurs- 12-en-28-oic acids with additional Δ 18 or Δ 19 unsaturation, were hydrolysed to the previously unreported pinfaenoic and isopinfaenoic acids, which, on acetylation and methylation, were converted into methyl triacetoxy-esters (methyl 2α,3β,23-triacetoxyursa- 12, 18-or -12,19-dien-28-oates), allowing purification and characterization by 13 C and 1 H NMR techniques. The possibility of these triterpenoids arising as artefacts of the isolation process has been addressed.

Application of force field calculations to the prediction of chirally discriminating chromatographic behaviour for ?-CDs

β-Cyclodextrin and its derivatives have been utilised to effect chiral separation in HPLC and CZE, both as stationary phases and mobile phase additives. The basis of the method is assumed to depend upon the formation of inclusion complexes of differing stabilities between enantiomeric analytes and the cyclodextrin, resulting in a differential dynamic distribution between chromatographic phases. In this study, force field calculations have been employed to model the inclusion complexes of enantiomeric brompheniramine, ephedrine, pseudoephedrine, ibuprofen, mandelic acid, methylphenobarbitone, and hexobarbitone with β-cyclodextrin. The resulting values for Δ(ΔH), the difference in enthalpy of complex formation between enantiomeric pairs has been compared with literature chromatographic data to explain the ability of the systems to achieve enantiomeric separations.

Investigating the specificity of regulators of degradation of hydrocarbons and hydrocarbon-based compounds using structure-activity relationships.

Microbial biosensors which have genes forbioluminescence coupled to genes that controlhydrocarbon degradation pathways can be used asreporters on the specificity of regulation of thosepathways. Structure-activity relationships can be usedto discover what governs that specificity, and canalso be used to separate compounds into differentgroups depending on mode of action. Published data forfour different bioluminescent biosensors, reporting ontoluene (two separate biosensors), isopropylbenzene,and octane, were analyzed to developstructure-activity relationships between biologicalresponse and physical/chemical properties.Good QSARs (quantitative structure-activityrelationships) were developed for three out of thefour biosensors, with between 88 and 100 per cent ofthe variance explained. Parameters found to beimportant in controlling regulator specificity werehydrophobicity, lowest unoccupied molecular orbitalenergies, and molar volume. For one of the biosensors,it was possible to show that the biological responseto chemicals tested fell into three separate classes(non-hydrocarbons, aliphatic hydrocarbons, andaromatic hydrocarbons). A statistically significantQSAR based on hydrophobicity was developed for thefourth biosensor, but was poor in comparison to theother three (44 per cent variance explained).

A new class of fluorescent chemosensors based on the β-aminobisphosphonate receptor

The photophysical properties of a range of fluorescent sensors with β-aminobisphosphonate receptors have been studied. The compounds were designed according to the fluorophore–spacer–receptor format of photoinduced electron transfer-based sensors. The sensors displayed unusual fluorescence intensity–pH profiles that were attributed to a receptor–fluorophore H-bonding interaction that resulted in a quenching of fluorescence. The number of receptors and the nature of the fluorophore were both shown to have an effect on the pH profiles of the sensors. In addition, compound 1 was also shown to be selective for Cu2+ ions, in water at pH 7.4 with sensitivity in the micromolar range.

Extraction of baicalin and characterization of its methylated derivatives. X-ray structure of 7-hydroxy-5,6-dimethoxyflavone 7-glucuronide methyl ester dihydrate

Baicalin has been isolated and four of its methyl derivatives have been characterised by IR, UV, mass, 1H and 13C NMR and one of these, 7-hydroxy-5,6-dimethoxyflavone 7-glucuronide methyl ester, was subjected to an X-ray crystallographic analysis.

Molecular structures of four triterpenoids. X-ray crystallographic analysis of methyl 2α,3β,23α-triacetoxy-19α-hydroxyurs-12-en-28β-oate

A triterpenoid glycoside has been isolated from the roots of a herb used in traditional Chinese medicine. The molecular structure of this compound and its derivatives have been determined by spectroscopic studies and an X-ray analysis of the 2α,3β,23α-triacetoxy-28β-methyl ester of the aglycone. This aglycone belongs to the ursene structure series. The hydroxy group on ring E of these triterpenoids is α orientated and the side chains at C(2), C(3), C(4) and C(17) are α.,β, α andβ orientated, respectively. The C ring, which has a double bond at C(12)=C(13), adopts a sofa conformation.