Phenolic Core Research Articles

1,2,3-Triazole Hybrids Containing Isatins and Phenolic Moieties: Regioselective Synthesis and Molecular Docking Studies.

The synthesis of hybrid molecules is one of the current strategies of drug discovery for the development of new lead compounds. The 1,2,3-triazole moiety represents an important building block in Medicinal Chemistry, extensively present in recent years. In this paper, we presented the design and the synthesis of new 1,2,3-triazole hybrids, containing both an isatine and a phenolic core. Firstly, the non-commercial azide and the alkyne synthons were prepared by different isatines and phenolic acids, respectively. Then, the highly regioselective synthesis of 1,4-disubstituted triazoles was obtained in excellent yields by a click chemistry approach, catalyzed by Cu(I). Finally, a molecular docking study was performed on the hybrid library, finding four different therapeutic targets. Among them, the most promising results were obtained on 5-lipoxygenase, an enzyme involved in the inflammatory processes.

Linkage and Stereochemistry Characters of Phenolic Antioxidant Product Formation.

The present study developed a smart and novel strategy to elucidate the linkage and stereochemistry characters during phenolic antioxidant product formation. A series of phenolic isomers or analogues were treated with 2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide radical, to create 16 antioxidant dimerization reactions in aqueous solution. The products were rapidly identified by ultraperformance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight tandem mass-spectrometry. Through a systematic function-structure relationship analysis of these reactions and theoretical calculations, it is concluded that the phenolic antioxidant product is formed via linear linkage or furanocyclic linkage. The linear linkage is fulfilled via a radical coupling and controlled by the O-O linkage exclusion, meta-linkage exclusion, and catechol-activated principles. However, when an exocyclic π-bond conjugates with the phenolic core and is affixed at the -OH para-position, the furanocyclic linkage may occur via a subsequent intramolecular Michael addition. The intramolecular addition always lacks Re-attack to show "α,β diastereoselectivity." The α,β diastereoselectivity is the stereochemistry character of furanocyclic linkage during phenolic antioxidant product formation. All these novel findings can benefit not only the field food science but also other fields as well.

Phenolipids, Amphipilic Phenolic Antioxidants with Modified Properties and Their Spectrum of Applications in Development: A Review.

Polyphenols, as secondary metabolites from plants, possess a natural antioxidant capacity and biological activities attributed to their chemical and structural characteristics. Due to their mostly polar character, polyphenols present a low solubility in less polar environments or hydrophobic matrices. However, in order to make polyphenols able to incorporate in oils and fats, a transformation strategy is necessary. For the above, the functionalization of polyphenols through chemical or enzymatic lipophilization has allowed the synthesis of phenolipids. These are amphipilic molecules that preserve the natural phenolic core to which an aliphatic motif is attached by esterification or transesterification reactions. The length of the aliphatic chain in phenolipids allows them to interact with different systems (such as emulsions, oily molecules, micelles and cellular membranes), which would favor their use in processed foods, as vehicles for drugs, antimicrobial agents, antioxidants in the cosmetic industry and even in the treatment of degenerative diseases related to oxidative stress.

Laccase catalyses phytophenol furanocyclic dimerization: Substrate specificity and diastereoselective process

Lacasse can transform phytophenol into furanocyclic dimers, including coumaran linkage dimer and 3,7-dioxabicyclo[3.3.0]octane linkage dimer. However, the substrate specificity and diastereoselective process remain unknown until now. The study therefore selected a series of monomeric phytophenol isomers or analogues as substrates to interact with laccase from Trametes versicolor (Lac TV). The products were rapidly identified by ultra-performance liquid chromatography coupled with high-resolution mass-spectrometry. On this basis, 9 dimerization reactions were established for a systematical structure–function relationship analysis. Through analysis, it can be concluded that, phytophenol furanocyclic dimerization requires a specific substrate structure, i.e., a C=C bond sitting at the -OH para-position and also conjugating with the phenolic core. The coumaran linkage dimerization presents “7,8 diastereoselectivity” character; while the 3,7-dioxabicyclo[3.3.0]octane linkage dimerization shows not only “7,8 diastereoselectivity” character but also “cis- 8H,8′H” character. The former character is attributed to the intramolecular nucleophilic addition which always prevents the Re-attack. The latter character however is caused by a substantial energy gap between normal envelop conformation and twist envelop conformation. All these findings can help to efficiently utilize Lac TV tool for phytophenol biosynthesis in chemistry fields.

Phytophenol Dimerization Reaction: From Basic Rules to Diastereoselectivity and Beyond.

Phytophenol dimerization, which is a radical-mediated coupling reaction, plays a critical role in many fields, including lignin biosynthesis. To understand the reaction, 2,2-diphenyl-1-picrylhydrazyl radical was used to initiate a series of phytophenol dimerization reactions in methanol. The products were identified using ultra-performance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight tandem mass spectrometry (UHPLC-ESI-Q-TOF-MS/MS) analysis in situ. The identified products mainly included biphenols, magnolol, honokiol, gingerol 6,6′-dimers, 3,6-dimethoxylcatechol β,β′ dimer, euphorbetin, bis-eugenol, dehydrodiisoeugenol, trans-ε-viniferin, (+) pinoresinol, and (−) pinoresinol. Structure–function relationship analysis allowed four basic rules to be defined: meta-excluded, C–C bonding domination, ortho-diOH co-activation, and exocyclic C=C involvement. The exocyclic C=C involvement, however, required conjugation with the phenolic core and the para-site of the -OH group, to yield a furan-fused dimer with two chiral centers. Computational chemistry indicated that the entire process was completed via a radical coupling reaction and an intramolecular conjugate addition reaction. Similar results were also found for the horseradish peroxidase (HRP)-catalyzed coniferyl alcohol dimerization, which produced (+) and (−) pinoresinols (but no (−) epipinoresinol), suggesting that the HRP-catalyzed process was essentially an exocyclic C=C-involved phytophenol dimerization reaction. The reaction was highly diastereoselective. This was attributed to the intramolecular reaction, which prohibited Re-attack. The four basic rules and diastereoselectivity can explain and even predict the main products in various chemical and biological events, especially oxidase-catalyzed lignin cyclization.

Hydroxytyrosol fatty acid esters as new candidate markers for detecting olive oil inadequate storage conditions by UHPLC-QqQ-MS/MS

Recently, lipophenols (or phenolipids), which are composed of a fatty acid (FA) and a phenolic core such as hydroxytyrosol (HT), have been detected in extra virgin olive oils (EVOO), promoted by the esterification reaction between FA and HT in a unique lipophenolic molecule (HT-FAs). However, the levels of HT-FAs, as well as potential alterations in their concentrations during the storage of EVOO, are still unexplored. Thus, the present study uncovers, by UHPLC-MS/MS triple quadrupole analyzer, the changes of HT-FA levels in extra virgin olive oil (EVOO) during 12 months of storage, mimicking both commercial temperatures (room temperature (RT)), as well as inappropriate conditions of storage at high temperatures (40 °C). In addition, levels of HT-FAs in olive oils (blends with refined olive oil) compared to EVOO were assessed to investigate the effect of the refining process on lipophenol generation. Free HT concentration in EVOO was increased, after 12 months, by 121.31% and 236.80% at RT and 40 °C, respectively. Additionally, HT-FAs in EVOO samples, mainly, esterified with linoleic acid and oleic acid, enhanced up to 2.6-fold and 5.5-fold, respectively after 12 months at 40 °C. Nonetheless, in blends with refined oils, the levels of free HT decreased by 80.2%, whereas esterified HT augmented significantly. The type of FA linked to HT core, as well as the degree of unsaturation of FA seem to influence the lipophenolic derivative generation. Significant concentration differences found during storage time supported their potential use as candidate markers, but these findings so require further assessment to establish the HT-FAs concentration range for authentication purposes. Likewise, the ratio between esterified/free HT could be employed as freshness or aging indices of the EVOO during its shelf life, when used in conjunction with validated olive quality parameters.

Fatty Acid Hydroxytyrosyl Esters of Olive Oils Are Bioaccessible According to Simulated In Vitro Gastrointestinal Digestion: Unraveling the Role of Digestive Enzymes on Their Stability

Recently, new bioactive compounds were identified in olive oil, lipophenols, which are composed of a fatty acid (FA) and a phenolic core, such as HT (HT-FA). However, their bioaccessibility remains unknown. Thus, the present study uncovers the impact of the separate phases of gastrointestinal digestion on the release and stability of HT-FAs from oily matrices under in vitro simulated conditions. Accordingly, it was found that the bioaccessibility of HT derivatives is largely dependent on the type of FA that esterifies HT, as well as the food matrix. Also, the generation of HT-FAs during intestinal digestion was observed, with pancreatin being the enzyme responsible, to a higher extent, for the de novo formation of lipophenolic derivatives. These findings prompt us to identify new applications to oily matrices and their byproducts as potential functional ingredients for the promotion of health, where the possible formation of new lipophenols during digestion should be taken into consideration.

Construction and Biological Evaluation of Small Libraries Based on the Intermediates within the Total Synthesis of Uvaretin.

Discovering therapeutic agents: New bioactive agents, either as sole or combinational agents, have been constructed through the synthetic manipulation of the intermediates within the total synthesis of the uvaretin class of natural products. It was found that increasing the hydrophobic character of the phenolic core correlates to a decrease in sole agent cytotoxicity. The synthesis of new, small chemical screening libraries (CSL) constructed from the intermediates of our total synthesis route of the uvaretin class of natural products is demonstrated herein. Numerous chalcone-based CSLs with various substitution on the phenolic groups within the chalcone core were assembled. Through cytotoxicity investigations, it was found that the level of hydrophobicity of the phenolic core of the chalcones gives biases: less cytotoxicity with more hydrophobic cores. In addition, it was observed that the potentiation, evaluated with 6-thiopurine in the pancreatic cancer cell line MIA PaCa-2, is tunable by the inclusion of less-hydrophobic character on the phenolic core. The role of the o-hydroxybenzyl group, present within the uvaretin family, was revealed to be cytotoxic in character. Merging all of the structure-activity relationship studies performed on the CSLs constructed in this effort led to the construction of a new chalcone hybrid possessing both a cytotoxic enone group and a small-molecule-potentiating, reduced enone group.

Identification of odorous compounds in oak wood using odor extract dilution analysis and two-dimensional gas chromatography-mass spectrometry/olfactometry.

Over the centuries, oak wood has been used in the maturation process of alcoholic beverages imparting aroma and flavor notes. Whereas several studies have dealt with the impact of oak wood on the chemical composition of, for example, wine aroma, only limited information is available on the odorant composition of unmodified and raw oak wood itself. To close this gap, a combination of human sensory and chemo-analytical techniques was applied for the elucidation of the chemical composition of oak odor, comprising extraction of the volatile fraction of oak wood by means of solvent-assisted flavor evaporation (SAFE) and subsequent mild concentration of the distillate. Odor extract dilution analysis (OEDA), which is based on gas chromatography-olfactometry (GC-O), was then applied for the targeted characterization of the odor-active compounds. Overall, a total of 97 odorants was identified via gas chromatography-mass spectrometry/olfactometry (GC-MS/O) and heart-cut two-dimensional gas chromatography-mass spectrometry/olfactometry (2D-GC-MS/O). The majority of these odorants comprised a series of terpenes, mainly mono- and sesquiterpenes, aldehydes, acids, and lactones, as well as a number of odorants containing a phenolic core moiety. Several odorants are reported here for the first time as volatile organic compounds in oak wood. Identification of the molecular composition of oak wood odor helps to establish a better understanding of the distinctive smell of oak wood, and offers the basis for unveiling its potential effects on humans when being exposed to oak wood smell in daily life. Graphical abstract ᅟ.

Flexural and shear behaviour of layered sandwich beams

A new type of composite beam, referred to as Layered Sandwich Beam (LSB) is introduced in this study. The sandwich system consists of Glass Fiber Reinforced Polymer (GFRP) skins and Phenolic cores, and several layers of sandwich panels are bonded together with epoxy polymer matrix for manufacturing beams. To explore the suitability of this novel concept for structural applications, the flexural and shear behaviour of LSB have been investigated. Eight LSB, with four having layers horizontally oriented and the other four vertically oriented, have been tested under four-point bending and asymmetrical beam shear. A three-dimensional finite element model was developed using Strand7 to further understand the fundamental behaviour of the LSB. The results showed that the LSB has an increased sectional stability by preventing wrinkling and buckling of the composite skins and indentation failure. This improved the bending and shear strengths of the vertical LSB by 25% and 100%, respectively, compared with single sandwich beams in same orientation. While horizontal LSB provided a higher bending stiffness, the vertical beams exhibited higher shear strength due to the orientation of the skins. The finite element model can reliably predict the fundamental behaviour of the LSB in different orientations and loading configurations, within −10% to +14%.

Practical, mild and efficient electrophilic bromination of phenols by a new I(iii)-based reagent: the PIDA-AlBr3 system.

A practical electrophilic bromination procedure for phenols and phenol–ethers was developed under efficient and very mild reaction conditions. A broad scope of arenes was investigated, including the benzimidazole and carbazole core as well as analgesics such as naproxen and paracetamol. The new I(iii)-based brominating reagent PhIOAcBr is operationally easy to prepare by mixing PIDA and AlBr3. Our DFT calculations suggest that this is likely the brominating active species, which is prepared in situ or isolated after centrifugation. Its stability at 4 °C after preparation was confirmed over a period of one month and no significant loss of its reactivity was observed. Additionally, the gram-scale bromination of 2-naphthol proceeds with excellent yields. Even for sterically hindered substrates, a moderately good reactivity is observed.

Acute toxicity and "structure-action" dependence of 4-(R-benzylidenamino)-5-methyl-4H-1,2,4-triazoles 3-tion

The achievements of modern pharmaceutical chemistry allow to develop a wide range of potential new drugs. However, their success in clinical practice depends on their safety. Therefore, the presence of evidence of their safety and efficacy is an integral part of any research.The aim of our study was to investigate acute toxicity of synthesized 1,2,4-triazoles derivatives, studying behavioral reactions to toxic doses and dependence "structure – action".Methods. To install middle lethal dose (LD50) the substance was administered intraperitoneally as an aqueous suspension stabilized by Tween-80. The substance was administrated once to four groups of laboratory animals (white nonlinear rats), 2 animals in each group. Multiple doses were administered, including the dose which does not cause the death of any animal and the dose which causes the death of all animals in the group. After administration of the compounds we conducted surveillance for two weeks to all animals who stayed alive.Results. The least toxic compound among the studied 4-(R-benzylidenamino)-5-methyl-4H-1,2,4-triazoles-3-thiones was compound 1 with an index of 840 mg/kg, which contains 4-methoxybenzilidene substituent on N4-nitrogen atom and the most toxic was compound 5, which has 4-brombenzilidene substituent at the same prosition (LD50 – 284 mg/kg). So we see that replacing bromine atom leads to the reduction of toxic properties. So we can assume that the introduction of a halogen atom to benzilidene phenolic core substituent increases the toxic properties of the synthesized compounds.An interesting pattern is observed for compounds 2–4, which contain two methoxy substituents, and their LD50 almost did not changed and range from 764 to 790 mg/kg.Conclusions. The study has found that 4-(R-benzylidenamino)-5-methyl-4H-1,2,4-triazol-3-tiones belonging to IV Class of toxicity. In addition, these compounds can be subjected to further biological study.

Identification of odorants in wood of Calocedrus decurrens (Torr.) Florin by aroma extract dilution analysis and two-dimensional gas chromatography-mass spectrometry/olfactometry.

General emissions of volatile organic compounds from wood are well investigated, but only limited information is available on the odor-active substances contained therein. To close this gap, we aimed at specifically elucidating the odorous constituents of wood from incense cedar [Calocedrus decurrens (Torr.) Florin]; this material is commonly used for the production of a range of products such as pencils and interior accessories. Targeted odorant analysis requires specialized techniques combining modern odorant analytical tools with human-sensory evaluation. Following this concept, the odor profile of the wood sample was first evaluated by human-sensory analyses. Then, the most potent wood odorants were characterized by means of gas chromatography-olfactometry and ranked according to their odor potency via aroma extract dilution analysis. With use of this approach, more than 60 odorous substances were detected, and the 22 most potent odorants were successfully identified by gas chromatography-mass spectrometry/olfactometry and two-dimensional gas chromatography-mass spectrometry/olfactometry. Among the main odorants found were a series of terpenes, several degradation products of fatty acids, and a number of odorants with a phenolic core moiety. Five odorants are reported here for the first time as wood odorants, such as γ-octalactone and 3-phenylpropanoic acid; thymoquinone was demonstrated for the first time to have a pencil-like odor quality.

Bond behaviour of composite sandwich panel and epoxy polymer matrix: Taguchi design of experiments and theoretical predictions

Structural sandwich panels made of glass fibre reinforced polymer (GFRP) and a phenolic core are used to manufacture a new type of composite railway sleeper. As these sandwich panels are produced in limited thicknesses for production efficiency, they are bonded together by an epoxy-based polymer matrix with structural filler to manufacture the composite railway sleepers. In this paper, an investigation into the effects of the matrix properties, bond length, bond thickness and bond width on the bond behaviour between a composite sandwich panel and polymer matrix is discussed. The experimental program was designed by Taguchi method to minimise the number of required experiments, and the percentage contribution of each variable on the bond strength was evaluated using the analysis of variance (ANOVA). The results indicated that a polymer matrix with 40% filler and 60% resin (by volume) is optimal to satisfactorily bind the sandwich panels together. A bond length of at least 70mm and bond thickness of 5mm are necessary to effectively utilise the strength of the composite sandwich panel. The ANOVA showed that the bond thickness has the greatest influence, contributing 51% to the bond strength, while the properties of the polymer matrix, bond length and bond width contribute 33%, 15% and 1%, respectively. The proposed theoretical equations can reliably predict the failure load and failure mode of the bonded joints.

Effect of beam orientation on the static behaviour of phenolic core sandwich composites with different shear span-to-depth ratios

This study thoroughly investigated the flexural behaviour of phenolic cored sandwich beams with glass fibre composite skins in the horizontal and vertical positions. The beams have a shear span-to-depth ratio (a/d) varying between 0.5 and 12, and tested under 4-point static bending. Their failure load are then predicted theoretically. The results showed that changing the beam orientation from horizontal to vertical changes the failure mode from brittle to progressive. The sandwich beam’s high bending stiffness can be efficiently utilised by placing them vertically. The a/d ratio played a major role on the load capacity and failure mode. In both orientations, the load capacity decreased with the increased of a/d. The beam failed in shear, a combined shear and bending, and bending for a/d≤2, 2<a/d<6, and a/d≥6, respectively. These failure mechanisms can be correlated to the shear-to-bending stress ratio while the failure load can be reasonably predicted using the available theoretical models. The two-way analysis of variance showed that the beam orientation is a more influential parameter than the a/d ratio. From this study, the horizontal beams are preferable for flexural dominated structures while the vertical beams are desirable for shear dominated structures.

Flexural behavior of an FRP sandwich system with glass-fiber skins and a phenolic core at elevated in-service temperature

This paper presents the effects of elevated in-service temperature on the flexural behavior of sandwich composites consisting of glass-fiber-reinforced-polymer (GFRP) skins and a phenolic core. The glass transition temperatures of the GFRP skin and phenolic core were obtained from dynamic mechanical analysis (DMA). Subsequently, the flexural behavior of the GFRP skin and the sandwich beams were assessed with a 3-point static bending test at temperatures ranging from room temperature up to 180°C. The results show that the variation trend of the GFRP skin’s stiffness from 3-point static bending test is in general agreement with the corresponding storage modulus results from the DMA. The GFRP skin, phenolic core, and sandwich beams retained more than 80% of their mechanical properties at 80°C. Moreover, the flexural behavior of the sandwich beams was governed by the GFRP skins up to 80°C, while the phenolic core played a major part on overall behavior beyond this temperature. The full-composite action between the skin and core was lost due to the disintegration of the phenolic core at high temperature.

Dynamic behaviour of debonded GFRP composite beams

A new generation composite sandwich made up of glass fibre reinforced polymer (GFRP) skins and high strength phenolic core material has been developed in Australia. Sandwich structure relies on the adhesive bond between the face-sheet and core for its overall stability and consistency. Although perfect bond between the skin and the core is a common assumption, an important issue that needs to be considered in using a composite beam or slab is the development of debonding between the skin and the core, which is a predominant failure mode of these sandwiches. Debonding can happen during fabrication or under service conditions that leads to changes in free vibration behaviour which in turn can result in resonance. Therefore, it is important to make accurate predictions of changes in natural frequencies in such structural elements. This paper investigates the influence of debonding on dynamic behaviour of sandwich beams of different debonding sizes and end conditions. Numerical model is developed with Strand7 finite element software, and the developed model is used for 3D finite element simulation. Free vibration behaviour reported in the literature for composite beams will first be used to compare the analytical results with the fully bonded and debonded beams. Study is extended to depict the effect of debonding on free vibration behaviour of novel composite beams. It is observed that the decrease in natural frequency with the increase in the extent of debonding is more dependent on the width of debonding across the beam than the length along the beam. The end conditions of the beam are also a governing factor dictating which modes are more affected. It is also perceived that full width debonding leads to increased participation of twisting modes in comparison to half-width debonding in clamped-clamped end condition.

Behaviour of fibre composite sandwich structures under short and asymmetrical beam shear tests

The behaviour of structural fibre composite sandwich beams made up of glass fibre composite skins and phenolic core material was investigated under three-point short beam and asymmetrical beam shear tests. The effect of the shear span-to-depth ratio (a/D) on the strength and failure behaviour of the composite sandwich beams was examined. The results showed that with increasing a/D ratio, the failure load of the sandwich beam is decreasing. On the contrary, the coupling effect of flexural stresses increases with increasing a/D ratio. Noticeably, the fibre composite sandwich beams tested under asymmetrical beam shear exhibited higher failure load compared to beams tested under short beam shear. Analysis showed that the shear stress in the core is more dominant than flexural stress when the a/D ratio is 1 for the sandwich beams under short beam test and 1–3 for the sandwich beams tested under asymmetrical beams shear test. The proposed prediction equation which accounts for the combined effect of shear and flexural stresses due to the changing a/D ratio, presented a good agreement with the experimental results, showing that it can reasonably estimate the failure load of structural fibre composite sandwich beams.

Mechanical properties characterization of the skin and core of a novel composite sandwich structure

This study has investigated the mechanical properties of the constituent materials of a novel structural composite sandwich panel developed for structural applications. Properly designed and carefully conducted experiments using coupon specimens following ISO and ASTM test standards were performed to characterize the flexural, tensile, compressive and shear properties of the fiber composite skins and the modified phenolic core of the composite sandwich structure. As a general behavior, the glass fiber composite skins behaved linearly elastic up to failure in both tension and compression with the tensile strength much higher than the compressive strength. The modified phenolic core behaved linearly elastic in tension but exhibited non-linear behavior in compression. The modified phenolic core material exhibited higher strength and modulus in shear and compression compared to the traditional core material systems. The improved mechanical properties of the core structure combined with the high-strength and lightweight glass fiber composite skins suggest a high potential of the novel composite sandwich panel for structural applications. Furthermore, the results of this study provide an understanding of the fundamental behavior of the constituent materials of a novel sandwich structure providing a base knowledge from which further research could continue.

Behavior of Full-Scale Railway Turnout Sleepers from Glue-Laminated Fiber Composite Sandwich Structures

An experimental study on the flexural and shear behavior of the full-scale glue-laminated composite sandwich beams in three different layouts was conducted to evaluate the suitability of this construction system for railway turnout sleepers. The building block of this innovative beam is a novel composite sandwich structure made up of glass fiber composite skins and modified phenolic core material that has been specifically developed for civil engineering applications. The sandwich beam is produced by gluing layers of fiber composite sandwich structure together in flatwise (horizontal) and in edgewise (vertical) orientations. The glued sandwich beams with edgewise laminations presented appropriate strength and stiffness for replacement turnout timber sleeper. The mechanical properties of these glue-laminated sandwich beams are comparable with the existing timber turnout sleepers, demonstrating that the innovative composite sandwich beam is a viable alternative sleeper material for railway turnouts. From this study, it is concluded that the glue-laminated composite sandwich structures have the potential to be used for replacement railway turnout sleepers. An enhanced understanding of the behavior of fiber composite sandwich structures for potential civil engineering applications is also an outcome of this investigation.