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2,4‐Thiazolidinedione (TZD) is a privileged and highly utilised scaffold for the development of pharmaceutically active compounds. This sulfur‐containing heterocycle is a versatile pharmacophore that confers a diverse range of pharmacological activities. TZD has been shown to exhibit biological action towards a vast range of targets interesting to medicinal chemists. In this review, we attempt to provide insight into both the historical conventional and the use of novel methodologies to synthesise the TZD core framework. Further to this, synthetic procedures utilised to substitute the TZD molecule at the activated methylene C5 and N3 position are reviewed. Finally, research into developing clinical agents, which act as modulators of peroxisome proliferator‐activated receptors gamma (PPARγ), protein tyrosine phosphatase 1B (PTP1B) and aldose reductase 2 (ALR2), are discussed. These are the three most targeted receptors for the treatment of diabetes mellitus (DM)., A key scaffold: 2,4‐Thiazolidinedione is a widely recognised structural motif present in many therapeutic agents used for the treatment of diabetes mellitus. This review summarises some of the methods used to prepare biologically active members of this class and discusses the pharmacological potency of these compounds.

Mycoplasmas are fastidious microorganisms, typically characterised by their restricted metabolism and minimalist genome. Although there is reported evidence that some mycoplasmas can develop biofilms little is known about any differences in metabolism in these organisms between the growth states. A systematic metabolomics approach may help clarify differences associated between planktonic and biofilm associated mycoplasmas. In the current study, the metabolomics of two different mycoplasmas of clinical importance (Mycoplasma pneumoniae and Mycoplasma fermentans) were examined using a novel approach involving nuclear magnetic resonance spectroscopy and principle component analysis. Characterisation of metabolic changes was facilitated through the generation of high-density metabolite data and diffusion-ordered spectroscopy that provided the size and structural information of the molecules under examination. This enabled the discrimination between biofilms and planktonic states for the metabolomic profiles of both organisms. This work identified clear biofilm/planktonic differences in metabolite composition for both clinical mycoplasmas and the outcomes serve to establish a baseline understanding of the changes in metabolism observed in these pathogens in their different growth states. This may offer insight into how these organisms are capable of exploiting and persisting in different niches and so facilitate their survival in the clinical setting.

The development of a semi-automated and rapid analytical technique for dermatological analysis has become a key aim of many medical and commercial entities through greater awareness of people to skin health and its importance in the 21st century. We present a proof-of-concept methodology demonstrating the use of validated non-destructive, in-situ (Nuclear Magnetic Resonance Spectroscopy) NMR techniques for characterisation and quantitation of (Natural Moisturising Factor) NMF compounds and actives from topical formulations. This quantitation is crucial for appropriate diagnosis of atopic dermatitis severity due to its association with reduced NMF abundance. This study is the first to combine diffusion NMR, semi-automated quantitation and ex-vivo skin samples to measure NMF and permeation of actives. We have shown that diffusion NMR allows for resolution between formulation components through determination of self-diffusion coefficients. We also demonstrate how the metabolomics software chenomxtm can be used to identify and quantitate individual NMF components. We show comparable results to previous literature on NMF layers in the skin, alongside reinforcing findings on permeation enhancers and heat effects on transdermal delivery of actives and formulation components. The presented methodology has shown great potential as an effective non-destructive, fast and versatile technique for dermatological analysis of physiology and actives, with future hardware and software developments in NMR making the future of dermatological analysis via NMR very promising.

Suppressing toxic aldehydic lipid oxidation product (LOP) generation in culinary oils is now considered vital, since the deleterious effects arising from their ingestion are implicated in a wide range of disease conditions. Partial substitution involves the replenishment of thermally-stressed culinary oils with corresponding unheated ones. This technique was tested by employing 10%, 25%, 50%, and 75% (v/v) partial substitutions of coconut, olive, rapeseed, and sunflower oils at 180℃ for a 300 min continuous thermo-oxidation duration. Oil samples were analysed by proton nuclear magnetic resonance (

Tracing the geographical origin of chocolate is of increasing importance owing to the market growth of cocoa products of high quality and especially where value is derived from those products being of single origin. The NMR analysis of methanolic/aqueous extracts of dark chocolate samples from Peru, Venezuela and Madagascar is reported and 42 different chemical constituents are identified, quantified and analysed using multivariate techniques. This paper describes a simple non-destructive protocol, which look at the chemical profile for chocolate samples from these three geographical locations and demonstrates potential for assessing the provenance of chocolate products, which has implications in food quality, safety and authenticity.

Infection caused by high-risk human papillomaviruses (HPVs) are implicated in the aetiology of cervical cancer. Although current methods of treatment for cervical cancer can ablate lesions, preventing metastatic disseminations and excessive tissue injuries still remains a major concern. Hence, development of a safer and more efficient treatment modality is of vital importance. Natural products from plants are one of the principal sources of precursors to lead compounds with direct pharmaceutical application across all disease classes. One of these plants is Ficus carica, whose fruit latex, when applied on HPV-induced skin warts, has shown potential as a possible cure for this virus related lesions. This study explores the in vitro biological activities of fig latex and elucidates its possible mechanisms of action on cervical cancer cell lines CaSki and HeLa positive for HPV type 16 and 18, respectively. Our data shows that fig latex inhibits properties that are associated with HPV-positive cervical cancer transformed cells such as rapid growth and invasion and substantially downregulated the expression of p16 and HPV onco-proteins E6, E7. These findings suggest Ficus carica latex has the potential to be used in the development of therapeutic modalities for the possible treatment, cure and prevention of HPV related cervical cancer.

This review intends to act as an overview of fructose malabsorption (FM) and its role in the aetiology of diseases including, but not limited to, irritable bowel syndrome (IBS) and infantile colic and the relationship between fructose absorption and the propagation of some cancers. IBS results in a variety of symptoms including stomach pains, cramps and bloating. Patients can be categorised into two groups, depending on whether the patients’ experiences either constipation (IBS-C) or diarrhoea (IBS-D). FM has been proposed as a potential cause of IBS-D and other diseases, such as infantile colic. However, our knowledge of FM is limited by our understanding of the biochemistry related to the absorption of fructose in the small intestine and FM’s relationship with small intestinal bacterial overgrowth. It is important to consider the dietary effects on FM and most importantly, the quantity of excess free fructose consumed. The diagnosis of FM is difficult and often requires indirect means that may result in false positives. Current treatments of FM include dietary intervention, such as low fermentable oligo-, di-, monosaccharides and polyols diets and enzymatic treatments, such as the use of xylose isomerase. More research is needed to accurately diagnose and effectively treat FM. This review is designed with the goal of providing a detailed outline of the issues regarding the causes, diagnosis and treatment of FM.

Differences in lipid oxidation products (LOPs) and trace metal concentrations of French fry samples found between two global chain fast-food restaurants in the UK were investigated using high-resolution proton nuclear magnetic resonance ( H NMR) and inductively coupled plasma-optical emission spectrometry (ICP-OES) analyses, respectively, of extracts derived therefrom. Over the course of 3 days and 3 different diurnal time periods, samples of French fries (FFs) were analyzed, and comparisons of two different oil extraction methods were undertaken for the two restaurants involved. The magnitude of concentrations of LOPs extracted from FFs is discussed. Significant differences between 6/7 aldehyde classifications, and aluminum, manganese, vanadium, lead, iron, copper and nickel levels between samples from the two restaurants are also reported. Redox-active transition and further trace metal concentrations inversely correlated with FF oil sample LOP contents; this suggested an antioxidant rather than a pro-oxidant role for them. [Abstract copyright: Copyright © 2021 Le Gresley, Ampem, De Mars, Grootveld and Naughton.]

The development and evaluation of a Boc-AL(Boc)Q(Trt)-AMC fluorophore to detect 3C Protease, produced by Foot and Mouth Disease Virus (FMDV) is reported, with a view to a potential use as a rapid screen for FMDV infected livestock The peptide-linked conjugate fluorophore is evaluated in vitro for sensitivity, specificity, stability and rapidity and shows statistically significant increases in fluorescence when exposed to physiologically relevant concentrations of 3C Protease and selectivity when compared with other common proteases likely to be located, typically in the absence of FMDV. The stability of deprotected Boc-AL(Boc)Q(Trt)-AMC is reported as a limitation of this probe.

High-resolution 1H nuclear magnetic resonance (NMR) analysis was employed to molecularly screen the lipid, lipid oxidation product (LOP), and antioxidant compositions of four natural (unrefined) cod liver oil (CLO) products. Products 1&ndash, 3 were non-fermented CLOs, whilst Product 4 was isolated from pre-fermented cod livers. Supporting analytical data that were acquired included biogenic amine, flavanone, tannin, phenolic antioxidant, &alpha, tocopherol, and oxygen radical absorbance capacity (ORAC) determinations by recommended HPLC, LC/MS/MS, or spectrophotometric methods. SDS-PAGE, HPLC, and 1H NMR analyses investigated and determined collagenous antioxidants and their molecular mass ranges. 1H NMR analysis of aldehydic LOPs was employed to explore the susceptibilities/resistivities of each CLO product to peroxidation that is induced by thermal stressing episodes (TSEs) at 180&deg, C, or following prolonged (42 day) storage episodes at 4 and 23 &deg, C. Product 4 displayed extremely high ORAC values, which were much greater than those of Products 1&ndash, 3, and that were predominantly ascribable to significant levels of peroxidation-blocking and/or aldehyde-consuming collagenous polypeptides/peptides and ammoniacal agents therein. Significantly lower levels of toxic aldehydes were generated in the pre-fermented Product 4 during exposure to TSEs, or the above long-term storage episodes. These results confirmed the enhanced peroxidative resistivity of a fermented, antioxidant-fortified natural CLO product over those of non-fermented unrefined products. Product 4: Green Pasture Blue Ice&trade, Fermented Cod Liver Oil.

Herein we describe the synthesis, characterisation and determination of fluorescence and photophysical properties of various novel analogues of the orphan fluorophore class Singapore Green. We equate the fluorescence properties of these novel fluorophores to their molecular structure and address the mechanisms through which their fluorescence is quenched and the effect this has on their quantum yields of fluorescence. Fluorescence quenching via acylation was also achieved, thereby providing conceptual proof of their utility as cores for future fluorescent probes. Additionally, we have produced and examined a number of unexpected acyl intermediates of variable photolytic stability. Furthermore, we have obtained proof of concept that the use of Singapore Greens for protease probe generation is feasible via demonstration of proteolytic cleavage of one of the acylated analogues.

High-resolution NMR analysis has been used, for the first time, to identify, putatively, two new secondary aldehydic lipid oxidation products in culinary oils. The impact of heating and cooling times on the thermal stability, fatty acid composition and lipid oxidation product (LOP) concentrations have been analysed for continuous and discontinuous heating periods (180 °C). The susceptibility of the selected oils to thermal oxidation for the different heating episodes has been evaluated via the detection and determination of LOPs, particularly cytotoxic and genotoxic aldehydes. The identities and quantities of these LOPs evolved throughout a 2.0 hour period. Results acquired indicated that sunflower oil was more resistant to discontinuous oxidation than rapeseed and olive oils, however overall discontinuous heating resulted in more LOPs.

This paper reports on the LGX fluorometric test for enzymatic MRSA/MSSA detection. It highlights the reasons rhodamines have been overlooked and also strategies to improve the synthesis of rhodamine-peptide conjugates. Evaluation of the LGX test for detection of MRSA/MSSA on surfaces is undertaken in the presence of potentially confounding E. coli and S. epidermidis for the first time.

BACKGROUND The accurate determination of vitamin D in skin is of considerable importance in evaluating penetration of skin health products through the different layers of the skin. OBJECTIVE We report on the characterisation and quantitation of vitamin D in an idealised sample and in complex mixtures which mimic that of a typical skin cream, using qNMR, 2D NMR and DOSY techniques. METHODS The characterisation and quantitation conditions were acquired over several heterogeneous samples, allowing for analysis of how the dynamic range and complexity of the different sample mixtures affect the limits of detection (LOD) and limits of quantitation (LOQ) of vitamin D. NMR is of particular value to this task as it is non-destructive, uses a primary ratio method for quantification, and tolerates a wide variety of hydrophilic and hydrophobic components within a given matrix. RESULTS In this investigation, we have attained a trueness level

The bacterial species Neisseria gonorrhoeae (N. gonorrhoeae) and Staphylococcus aureus (S. aureus) are amongst the main microorganisms that cause ophthalmia neonatorum. The current treatment involves the use of various antibiotics such as ciprofloxacin, cephalosporin, ceftriaxone and cefotaxime. However, this treatment strategy is becoming more ineffective due to the antibiotic resistance in N. gonorrhoeae. The current study explores the potential use of fatty acid based microemulsions (ME) to prevent N. gonorrhoeae and S. aureus infections in new-borns’ eyes without harmful side effects such as corneal or conjunctiva irritation. Pseudo-ternary phase diagrams were constructed to evaluate microemulsion regions and six different α-linolenic acid based microemulsions were prepared. The prepared formulations were characterized for α-linolenic acid content, size, transparency, zeta potential, Polarized light Microscopy, antimicrobial activity and ex vivo ocular toxicity. The mean droplet size of the ME formulations was in the range of 190.4 to 350.5 nm and polydispersity index (PDI) values were in the range of 0.102 to 0.561. All formulations were found stable upon storage for at least 8 weeks. In addition, self-diffusion coefficients determined by nuclear magnetic resonance (NMR) reflected that the diffusability of water increased at higher than 30% w/w water, while that of fatty acids and surfactants was in reverse. The antimicrobial efficacy of microemulsions was determined against N. gonorrhoeae and S. aureus. It was concluded that all microemulsions have strong antimicrobial effects against N. gonorrhoeae and S. aureus. Finally, bovine corneal opacity permeability (BCOP) and hen’s egg chorioallantoic (HET-CAM) tests results showed that all microemulsion formulations were not strong ocular irritants.

The application of DOSY (Diffusion Ordered Spectroscopy) NMR as a technique for the virtual separation of toothpaste adjuvants in model saliva is reported for the first time. In addition, the scope and limitations of DOSY NMR are considered using the DOSY Tool Box processing software, as is the quantification of the adjuvants and components of saliva by quantitative NMR (qNMR). These techniques represent a new and powerful tool for the evaluation of complex mixtures of natural products with a view to identifying biomarkers for disease within the oral cavity.

NMR is used extensively for accurate quantitation of simple analytes and can, with careful application, generate SI traceable measurements. Its application for more complex analytes is limited due to spectrum complexity and signal overlap. Due to its higher resolving power, 2D qNMR is starting to emerge as a viable quantitative technique for such complex analytes but brings with it a variety of sources of experimental bias not present in the simple 1D qNMR method. In order to claim SI traceability of 2D NMR techniques, these biases and additional sources of measurement uncertainty need to be quantified. This work evaluates the application of HSQC methods to perform quantitative analysis with minimal bias and using an internally standardised glucose assay as an example, to assess the variation between experimental and theoretical biases and discuss approaches to determine the measurement uncertainty with a minimum of method validation.

The use of the Heck reaction in the synthesis of anthracene-9-monoacrylamide and anthracen-9,10-bisacrylamides as potential G-quadruplex ligands and preliminary biological testing are reported.

The synthesis and self-association of chiral isotopically labeled trianglamine macrocycles under electrospray mass spectrometer conditions in an ion trap are described. A moderate diastereoselectivity in the self-association process was observed providing a synthetic model system for the investigation of chiral self-association in the gas phase. The first non-covalently bound dimer exclusively bonded through aromatic–aromatic interactions was observed in the gas phase. Evidence for self-association in solution was observed by diffusion nuclear magnetic resonance spectroscopy. Copyright © 2007 John Wiley & Sons, Ltd.

We report a comprehensive analysis of the acquisition-related sources of uncertainty for internally and externally standardized qNMR experiments. The impacts of major instrument- and sample-related sources of biases and uncertainties are quantified where possible, and the validity of correction and calibration techniques are also discussed. The application of uncertainty budgets for qNMR is well established for simple, internally standardized systems, but the model is incomplete and does not allow for the additional biases and sources of uncertainty that arise from spectrum complexity and external standardization. This report considers the additional contributions to the uncertainty budget that need to be considered to ensure SI traceability of measurement across a wider range of analytes and NMR methodologies.

The enantiospecific synthesis of chromanes and isochromanes obtained from an intramolecular Nicholas cyclisation reaction is discussed. During the course of this study we observed the formation of chroman-4-ones from a CAN deprotection step of a dioxolane and this is also discussed.

Upper rim substituted tetraiodocalix[4]arenes are coupled to a variety of olefins using the palladium catalysed Heck reaction. Tetraolefinic upper rim substituted calix[4]arenes are obtained in good yields. All of the olefins are coupled with exceptionally high stereoselectivity to produce the all-(E) isomers. The optimisation of reaction conditions as well as the scope and limitation of the reaction with respect to a variety of olefins are discussed.

The synthesis of novel tetra-olefinic calix[4]arene carcerands is described using a synthetic strategy involving palladium catalysed Heck coupling followed by imine formation.

During the attempt to deprotect the dioxolane (I) in order to get an aldehyde structure as precursor of a benzopyran skeleton, formation of a chromanone (II) is observed.

Heck reactions are used for the synthesis of a variety of anthracene-9-monoacrylamide and bisacrylamide derivatives.

The application of DOSY (Diffusion Ordered SpectroscopY) NMR as a technique for the virtual separation of key components of manuka honey and the implications for future discriminatory analysis of honey types is reported for the first time. The scope and the limitations of DOSY NMR are considered using the recently conceived DOSY Tool Box processing software and preliminary anti-bacterial data for the different honey types is reported.

This communication reports the first synthesis of a number of deep cavity tetraformyl calix[4]arene macrocycles and their use as key building blocks in the synthesis of a dynamic and the first static non-peptide macrocyclic library.

This article reports the development of a novel fluorometric indicator which shows a rapid response when exposed to coagulase positive Staphylococcus aureus (SA) bacteria (including methicillin sensitive Staphylococcus aureus (MSSA) and methicillin resistant Staphylococcus aureus (MRSA) bacteria). The test is robust and will detect a wide variety of SA strains and there is no significant fluorescence response observed for other species of bacteria commonly found in clinical specimens, including other Staphylococcus bacteria. This research forms the basis of a prototype SA testing kit for the rapid detection of SA within hospital and healthcare environments as an economical prescreen or alternative to the current PCR based testing methodology. Rapid identification of SA carriers will allow hospital infection control teams to be pre-emptive and could significantly reduce the incidence of hospital acquired infections involving this organism.

Upper rim substituted tetraiodo calix[4]arenes are coupled to a variety of acrylamides using the palladium catalysed Heck reaction. Tetra-acrylamido upper rim substituted calix[4]arenes are obtained in good yields with exceptionally high stereoselectivity, to produce the all-trans isomers. Tetra-acrylamido calix[4]arenes derived from secondary acrylamides are shown to dimerise via eight hydrogen bonds to form dimeric capsules, which are able to include small organic molecules.

Upper rim substituted tetra-acrylamido-calix[4]arenes have been synthesised using the palladium catalysed Heck reaction; the compounds display solvent dependent aggregation in solution to form dimeric capsules stabilised by only eight amide CO–H–N hydrogen bonds and π–π interactions.