Synthesis of 2-(Trifluoromethyl)-[1,2,4]triazolo[5,1-a]isoquinoline via Cycloaddition of C,N-Cyclic Azomethine Imine with CF3CN.

A [3 + 2] cycloaddition of C,N-cyclic azomethine imine with in situ-generated CF3CN for the construction of 2-(trifluoromethyl)-[1,2,4]triazolo[5,1-a]isoquinoline is reported. Remarkably, this process shows a broad substrate scope with excellent functional group tolerance, which is scalable and enables a practical route to a library of 2-(trifluoromethyl)-[1,2,4]triazolo[5,1-a]isoquinoline derivatives in moderate to good yields.

A color-change fluorescence sensor for oleanolic acid based on chiral camphanic decorated bis-cyanostilbene.

Although various fluorescent sensors for biomolecules had been extensively reported, the effective fluorescent sensor was seldom reported for detecting oleanolic acid up to now. This work reports the first color-change fluorescence sensor for oleanolic acid based on a bridging bis-cyanostilbene derivative with chiral camphanic groups (C-BCS). C-BCS possessed the chartreuse fluorescence in aqueous media, which transferred to strong blue fluorescence in the presence of oleanolic acid. This sensing ability of C-BCS for oleanolic acid exhibited the high selectivity among all kinds of biomolecules and ions. The good linearity between the fluorescence intensity and concentration of oleanolic acid was acquired in the range of 0.2 × 10-6 to 8.0 × 10-6 M with the detecting limitation of 0.0582 µM. The 1:1 binding process was clarified as oleanolic acid located in the opening cavity composed of two bridging cyanostilbene units and two chiral camphanic groups based on multiple hydrogen bonds and hydrophobic interaction. The detecting ability of C-BCS was applied on sensing oleanolic acid in thin-layer chromatography analysis, imprinting experiment, tap water, and tea samples, suggesting the effective on-site sensing abilities of C-BCS for oleanolic acid in real samples and daily life.

An effective long-wavelength fluorescent sensor for Cu2+ based on dibenzylidenehydrazine-bridged biphenylacrylonitrile.

Although numerous fluorescence sensors for Cu2+ have been presented, a long-wavelength sensor in aqueous media has rarely been reported as expected due to practical application requirements. In this work, a novel AIE molecule (DHBB) containing two biphenylacrylonitrile units bridged by dibenzylidenehydrazine was prepared. It possessed the merits of long-wavelength emission, good emission in aqueous media, and multiple functional groups for binding Cu2+. It exhibited good sensing selectivity for Cu2+ among all kinds of tested metal ions. The detection limit was as low as 1.08 × 10-7 M. The sensing mechanism was clarified as 1:1 stoichiometric ratio based on the binding cooperation of O and N functional groups of DHBB. The selective sensing ability for Cu2+ remained stable at pH = 5-9 and was influenced little by other metal ions. The Cu2+ sensing ability of DHBB was applied in real samples with 96% recovery rate. The bio-imaging experiment of living cells suggested that DHBB possessed not only good bio-imaging performance but also sensing ability for Cu2+ in living environments. This work suggested the good application prospect of DHBB to sense Cu2+ in real samples and living environment.

The influence of alkyl lengths on circularly polarized luminescence for non-liquid crystalline binaphthol-based cyanostilbene.

In previous studies, the increasing alkyl length of liquid crystalline molecules enhanced the chiral transfer and resulted in better CPL performance. But no work concerned the influence of alkyl lengths on CPL properties for non-liquid crystalline systems. In this research, three R-binaphthol-based cyanostilbene derivatives with various alkyl chains (BC-5, BC-8 and BC-12) were prepared in yields of 60-69%. They did not exhibit liquid crystalline behavior but were seen as soft materials at room temperature. They displayed excellent AIE fluorescence in aggregated states. Chiroptical investigations suggested good CD and CPL properties for their cyanostilbene units, indicating the successful chiral transfer from the binaphthol moieties to cyanostilbene units. Moreover, the values of gabs for CD signals and glum for CPL signals displayed the changing order of BC-5 > BC-8 > BC-12. These results suggested that the shorter alkyl chains for non-liquid crystalline systems led to stronger CPL emission, which was opposite to the results of the liquid crystalline molecules. This work provided a new strategy for the design and synthesis of chiroptical materials with good CPL properties based on non-liquid crystalline molecules.

Fluorescein-bridged Perylene Bisimide Dimer for Use as Liquid Crystal: Studies on Mesomorphic and Fluorescence Properties.

A novel fluorescein-bridged perylene bisimide (PBI) dimer for liquid crystal (LC) with geometrically symmetric structure was developed. The mesomorphic results indicated that the energetically stable and unstable conformers of fluorescein fragments could lead to the transformation of mesophases from a hexagonal columnar mesophase to an uncertain phase at 136.9 °C in heating, whilst a stable hexagonal columnar mesophase maintained between 175.6 °C and 58.6 °C in cooling. The selectively excited fluorescence characters in THF solution demonstrated that the fluorescence resonance energy transfer (FRET) effect between fluorescein fragments and PBI unites could provide a means to effectively impose strong fluorescence of the dimeric PBIs modified with suitable chromophore at the N-imide position, which alternatively serves as a platform for the further study of multi-functional PBI-based LCs.

A simple "turn-on" fluorescence sensor for salicylaldehyde skeleton based on switch of PET-AIE effect.

The selective detection of salicylaldehyde skeleton is of great significance in phytochemistry and biological research but rarely reported. In this research, a simple and highly selective "turn-on" fluorescence sensor (CDB-Am) for salicylaldehyde skeleton was developed based on switch of photoinduced electron transfer (PET) and aggregation-induced emission (AIE). CDB-Am bearing amino-cyanodistyrene structure responded to salicylaldehyde in the range of 3.1 to 40 µM with a detection limit of 0.94 µM. The sensing process of formation of Schiff-base adduct CDB-SA was confirmed by 1H NMR, MS, and FT-IR spectra, revealing that a recovered AIE property accounted for the turn-on fluorescence response of CDB-Am and the intramolecular hydrogen bonding played a crucial role in the disruption of PET process. This sensing ability was successfully applied for both fluorescence qualitative test of salicylaldehyde skeleton on TLC analysis and quantitative detection of salicylaldehyde skeleton with good accuracy in the root bark of Periploca sepium, suggesting the extensive applications in phytochemistry and traditional Chinese herbal medicine. Furthermore, CDB-Am exhibited the first excellent fluorescence imaging ability in detecting salicylaldehyde skeleton in a living system. This work supplied a new strategy of preparing a novel "turn-on" fluorescence probe for detecting salicylaldehyde skeleton in complex environments and living bodies.

Room-temperature AIE ionic liquid crystals based on diphenylacrylonitrile-imidazole salts.

Although various AIE liquid crystals have been studied, AIE ionic liquid crystals (ILCs) are almost unknown to date. In this work, a series of novel AIE ILCs based on diphenylacrylonitrile-imidazole salts bridged by soft spacers with different anions were prepared in yields of 63-80%. The mesomorphic, photophysical and electrochemical properties were investigated systematically to elucidate the relationship between structures and properties. The results implied that they were the first room-temperature AIE ILCs with wide ranges of mesomorphic temperature, good fluorescence emission in both the solid state and mesophase, and stable electrochemical behaviour. The samples with one alkyl chain possessed the SmA2 mesophase while the samples with two alkyl chains prefered the Colh mesophase. The larger anions resulted in the bigger layer spacing length for the SmA2 mesophase and smaller values of ncell in each slice of Colh mesophase. The fluorescence quantum yields in the mesophase maintained reasonable values (0.15-0.22), which decreased a little in comparison with that in solid films (0.18-0.26) due to the orderly molecular stacking in the mesophase. The cyclic voltammetry experiments confirmed that all of them possessed similar and stable electrochemical behaviour. This research not only presented the first room-temperature AIE ILCs with excellent mesomorphic, photophysical and electrochemical properties, but also elucidated the relationship between structures and properties to a certain degree, contributing to the further construction of novel AIE ILCs with excellent mesomorphic, photophysical and electrochemical properties.

A first porphyrin liquid crystal with strong fluorescence in both solution and aggregated states based on the AIE-FRET effect.

Porphyrins are good near-infrared fluorescent materials, but the strong self-assembly stacking resulted in the aggregation-caused quenching (ACQ) effect, limiting their emissive performance in aggregated states. In this work, a novel diphenylacrylonitrile-porphyrin derivative with multiple polyglycol chains on the periphery was designed and synthesized as an excellent near-infrared-emissive liquid crystalline material in both solution and aggregated states, which was first observed for porphyrin liquid crystals. It exhibited a high self-assembly ability with the ordered hexagonal columnar mesophase between 70 and 120 °C approximately. The strong AIE-FRET effect was produced based on the overlap of the emission wavelength of diphenylacrylonitrile and the absorption wavelength of the porphyrin, resulting in the excellent near-infrared emission in both solution and aggregated states. The pseudo Stokes shift was as large as 210 nm and the fluorescence quantum yield reached 0.12 in the solid state. Moreover, this porphyrin liquid crystal displayed low biotoxicity and excellent fluorescence bio-imaging ability in living cells, opening a new application prospect for porphyrin liquid crystalline materials.

A fluorescent sensor for folic acid based on crown ether-bridged bis-tetraphenylethylene.

Aggregation-induced emission (AIE) provides a new strategy for preparing fluorescent sensors in aggregated state. In this paper, a series of crown ether-bridged bis-tetraphenylethylene compounds were synthesized in 78-84% yield by a simple procedure. The molecules exhibited excellent AIE properties in THF/H2O solutions and solid films. The investigation on sensing abilities for various biomolecules and metal ions suggested that Bis-TPE-1 possessed obvious response to folic acid, with fluorescence enhancement and blue shift of maximum emission wavelength from 380 nm to 365 nm. The detection limit for folic acid was 6.36 × 10-7 M, and the sensor's selectivity for folic acid was little interfered by the other species. The sensor mechanism was studied by FT-IR, 1H NMR, MS spectra and fluorescence Jobs' plot. The selective sensor for folic acid was applied in test paper and the analyses of real samples of mung bean and spinach. The superior bioimaging performance of Bis-TPE-1 for sensing folic acid was confirmed by the live cell imaging experiments, which indicated its good practical application potential for detecting folic acid.

Exploration in the Mechanism of Action of Licorice by Network Pharmacology.

Licorice is a popular sweetener and a thirst quencher in many food products particularly in Europe and the Middle East and also one of the oldest and most frequently used herbs in traditional Chinese medicine. As a wide application of food additive, it is necessary to clarify bioactive chemical ingredients and the mechanism of action of licorice. In this study, a network pharmacology approach that integrated drug-likeness evaluation, structural similarity analysis, target identification, network analysis, and KEGG pathway analysis was established to elucidate the potential molecular mechanism of licorice. First, we collected and evaluated structural information of 282 compounds in licorice and found 181 compounds that met oral drug rules. Then, structural similarity analysis with known ligands of targets in the ChEMBL database (similarity threshold = 0.8) was applied to the initial target identification, which found 63 compounds in licorice had 86 multi-targets. Further, molecular docking was performed to study their binding modes and interactions, which screened out 49 targets. Finally, 17 enriched KEGG pathways (p < 0.01) of licorice were obtained, exhibiting a variety of biological activities. Overall, this study provided a feasible and accurate approach to explore the safe and effective application of licorice as a food additive and herb medicine.

Perylene bisimide with diphenylacrylonitrile on side-chain: strongly fluorescent liquid crystal with large pseudo Stokes shift based on AIE and FRET effect.

A novel perylene bisimide (PBI) derivative with an AIE-active diphenylacrylonitrile unit positioned at the terminal N-imide position through a flexible spacer has been synthesized and characterized. The DSC, POM and XRD studies confirmed that it could self-assemble into a stable hexagonal columnar liquid-crystalline phase between 56 °C and 160 °C. This PBI derivative also exhibited strong fluorescence in solution, thin film and mesophase based on the cooperative mechanism of AIE and FRET between the diphenylacrylonitrile group and perylene moiety. The pseudo Stokes shift was as large as 283 nm, and the fluorescence quantum yields were as high as 0.62-0.79 in solution and 0.68-0.86 in solid state. This study provides a good strategy for converting the columnar liquid crystal with ACQ effect to one with the AIE effect, successfully filling the gap between the excellent columnar mesomorphic properties and strong fluorescence in solid state.

A fluorescent sensor based on aggregation-induced emission: highly sensitive detection of hydrazine and its application in living cell imaging.

Aggregation-induced emission (AIE) molecules eliminate the aggregation-caused quenching (ACQ) phenomenon effectively and exhibit excellent properties of a fluorescent sensor in the aggregated state. In this paper, an allochroic fluorescent sensor based on AIE molecules with a diphenylacrylonitrile structure was prepared in high yield by a simple procedure. This molecule possessed good AIE properties and exhibited a sensitive sensor ability for aliphatic amines with an obvious color change from orange to blue-green. The detailed investigation on the detection of hydrazine suggested that the detection limit for hydrazine was 3.67 × 10-6 M, and the highly sensitive sensor for hydrazine was not influenced by other species. The sensor mechanism was confirmed by using 1H NMR and MS spectra. The sensor for hydrazine was successfully applied in a test paper, exhibiting good practical application potential for detecting hydrazine. The experiment of living cell imaging suggested that this sensor showed superior bioimaging performance and presented sensitive detection for hydrazine with an obvious color change from orange to blue-green.

Discovery of molecular mechanism of a clinical herbal formula upregulating serum HDL-c levels in treatment of metabolic syndrome by in vivo and computational studies.

Decreased HDL cholesterol (HDL-c) is considered as an independent risk factor of cardiovascular disease in metabolic syndrome (Mets). Wendan decoction (WDD), a famous clinical traditional Chinese medicine formula in Mets in China, which can obviously up-regulate serum HDL-c levels in Mets. However, till now, the molecular mechanism of up-regulation still remained unclear. In this study, an integrated approach that combined serum ABCA1 in vivo assay, QSAR modeling and molecular docking was developed to explore the molecular mechanism and chemical substance basis of WDD upregulating HDL-c levels. Compared with Mets model group, serum ABCA1 and HDL-c levels intervened by two different doses of WDD for two weeks were significantly up-regulated. Then, kohonen and LDA were applied to develop QSAR models for ABCA1 up-regulators based flavonoids. The derived QSAR model produced the overall accuracy of 100%, a very powerful tool for screening ABCA1 up-regulators. The QSAR model prediction revealed 67 flavonoids in WDD were ABCA1 up-regulators. Finally, they were subjected to the molecular docking to understand their roles in up-regulating ABCA1 expression, which led to discovery of 23 ABCA1 up-regulators targeting LXR beta. Overall, QSAR modeling and docking studies well accounted for the observed in vivo activities of ABCA1 affected by WDD.

Identfication of Potent LXRß-Selective Agonists without LXRα Activation by In Silico Approaches.

Activating Liver X receptors (LXRs) represents a promising therapeutic option for dyslipidemia. However, activating LXRα may cause undesired lipogenic effects. Discovery of highly LXRß-selective agonists without LXRα activation were indispensable for dyslipidemia. In this study, in silico approaches were applied to develop highly potent LXRß-selective agonists based on a series of newly reported 3-(4-(2-propylphenoxy)butyl)imidazolidine-2,4-dione-based LXRα/ß dual agonists. Initially, Kohonen and stepwise multiple linear regression SW-MLR were performed to construct models for LXRß agonists and LXRα agonists based on the structural characteristics of LXRα/ß dual agonists, respectively. The obtained LXRß agonist model gave a good predictive ability (R²train = 0.837, R²test = 0.843, Q²LOO = 0.715), and the LXRα agonist model produced even better predictive ability (R²train = 0.968, R²test = 0.914, Q²LOO = 0.895). Also, the two QSAR models were independent and can well distinguish LXRß and LXRα activity. Then, compounds in the ZINC database met the lower limit of structural similarity of 0.7, compared to the 3-(4-(2-propylphenoxy)butyl)imidazolidine-2,4-dione scaffold subjected to our QSAR models, which resulted in the discovery of ZINC55084484 with an LXRß prediction value of pEC50 equal to 7.343 and LXRα prediction value of pEC50 equal to -1.901. Consequently, nine newly designed compounds were proposed as highly LXRß-selective agonists based on ZINC55084484 and molecular docking, of which LXRß prediction values almost exceeded 8 and LXRα prediction values were below 0.

Diphenylacrylonitrile-connected BODIPY dyes: fluorescence enhancement based on dark and AIE resonance energy transfer.

This study focuses on the construction of novel diphenylacrylonitrile-connected BODIPY dyes with high fluorescence in both solution and an aggregated state by combining DRET and FRET processes in a single donor-acceptor system. The first BODIPY derivatives with one, two, or three AIE-active diphenylacrylonitrile groups were designed and synthesized in moderate yields. Strong fluorescence emissions were observed in the THF solution under excitation at the absorption wavelength of non-emissive diphenylacrylonitrile chromophores, implying the existence of the DRET process between the dark diphenylacrylonitrile donor and the emissive BODIPY acceptor. In the THF/H2O solution, the fluorescence intensity of the novel BODIPY derivatives gradually increased under excitation at the absorption wavelength of diphenylacrylonitrile chromophores, suggesting a FRET process between diphenylacrylonitrile and BODIPY moieties. A greater number of diphenylacrylonitrile units led to higher energy-transfer efficiencies. The pseudo-Stokes shift for both DRET and FRET processes was as large as 190 nm.

Systematic Understanding of Mechanisms of a Chinese Herbal Formula in Treatment of Metabolic Syndrome by an Integrated Pharmacology Approach.

Metabolic syndrome (MS) is becoming a worldwide health problem. Wendan decoction (WDD)-a famous traditional Chinese medicine formula-has been extensively employed to relieve syndromes related to MS in clinical practice in China. However, its pharmacological mechanisms still remain vague. In this study, a comprehensive approach that integrated chemomics, principal component analysis, molecular docking simulation, and network analysis was established to elucidate the multi-component and multi-target mechanism of action of WDD in treatment of MS. The compounds in WDD were found to possess chemical diversity, complexity and drug-likeness compared to MS drugs. Six nuclear receptors were obtained to have strong binding affinity with 217 compounds of five herbs in WDD. The importance roles of targets and herbs were also identified due to network parameters. Five compounds from Radix Glycyrrhizae Preparata can hit all six targets, which can assist in screening new MS drugs. The pathway network analysis demonstrated that the main pharmacological effects of WDD might lie in maintaining lipid and glucose metabolisms and anticancer activities as well as immunomodulatory and hepatoprotective effects. This study provided a comprehensive system approach for understanding the multi-component, multi-target and multi-pathway mechanisms of WDD during the treatment of MS.

Multi-Layer Identification of Highly-Potent ABCA1 Up-Regulators Targeting LXRß Using Multiple QSAR Modeling, Structural Similarity Analysis, and Molecular Docking.

In this study, in silico approaches, including multiple QSAR modeling, structural similarity analysis, and molecular docking, were applied to develop QSAR classification models as a fast screening tool for identifying highly-potent ABCA1 up-regulators targeting LXRß based on a series of new flavonoids. Initially, four modeling approaches, including linear discriminant analysis, support vector machine, radial basis function neural network, and classification and regression trees, were applied to construct different QSAR classification models. The statistics results indicated that these four kinds of QSAR models were powerful tools for screening highly potent ABCA1 up-regulators. Then, a consensus QSAR model was developed by combining the predictions from these four models. To discover new ABCA1 up-regulators at maximum accuracy, the compounds in the ZINC database that fulfilled the requirement of structural similarity of 0.7 compared to known potent ABCA1 up-regulator were subjected to the consensus QSAR model, which led to the discovery of 50 compounds. Finally, they were docked into the LXRß binding site to understand their role in up-regulating ABCA1 expression. The excellent binding modes and docking scores of 10 hit compounds suggested they were highly-potent ABCA1 up-regulators targeting LXRß. Overall, this study provided an effective strategy to discover highly potent ABCA1 up-regulators.

A "turn-on" fluorescent sensor for herbicide quizalofop-p-ethyl based on cyanostilbene-pyridine macrocycle.

Quizalofop-p-ethyl is a widely used herbicide that also poses a risk to human health and environmental safety. However, there is still a lack of simple and in-situ detecting method for quizalofop-p-ethyl so far. In this work, the fluorescent sensor was firstly developed on detection of quizalofop-p-ethyl based on cyanostilbene-pyridine macrocycle (CPM). CPM was prepared by the "1 + 1" condensation of pyridine-substituted cyanostilbene derivative with 4,4'-Bis(chloromethyl)biphenyl in 68 % yield. The weak fluorescence of CPM in aqueous media transferred to strong orange fluorescence after sensing quizalofop-p-ethyl. This sensing behavior exhibited high selectivity among 28 kinds of herbicides and ions. The limitation of detection (LOD) was 2.98 × 10-8 M and the limitation of quantification (LOQ) was 9.94 × 10-8 M (λex = 390 nm, λem = the maximum emission between 512 nm and 535 nm) with a dynamic range of 0.01-0.9 eq. The binding constant (Ka) of quizalofop-p-ethyl to the sensor CPM was 3.2 × 106 M-1. The 1:1 sensing mechanism was confirmed as that quizalofop-p-ethyl was located in the cavity of CPM, which enhanced aggregating effect and reduced the intramolecular rotation of aromatic groups for better AIE effect. The sensing ability of CPM for quizalofop-p-ethyl had been efficiently applied in test paper experiments, agricultural product tests and real water samples, revealing that CPM has good application prospect for simple and in-situ detection of quizalofop-p-ethyl in real environment.

"Turn-on" fluorescent sensor for oleanolic acid based on o-phenyl-bridged bis-tetraphenylimidazole.

Fluorescent sensors had been extensively applied on sensing various biomolecules effectively, but no fluorescent sensor for oleanolic acid was presented up to now. In this work, the first fluorescent sensor for oleanolic acid was designed and synthesized based on o-phenyl-bridged bis-tetraphenylimidazole (PTPI). PTPI was prepared by bridging two tetraphenylimidazole units and o-phenylenediamine via Schiff-base condensation in yield of 86%. PTPI showed high sensing selectivity for oleanolic acid among 26 biomolecules and ions. The blue fluorescence at 482 nm was enhanced by 4.5 times after sensing oleanolic acid in aqueous media. The fluorescence sensing ability of PTPI for oleanolic acid maintained stable in pH = 5-9. The detecting limitation was as low as 0.032 µM. The detecting mechanism was clarified as 1:1 binding stoichiometry by fluorescence Job's plot, mass spectrometry, 1H nuclear magnetic resonance and fourier transform infrared spectroscopy. The detecting ability of PTPI for oleanolic acid was successfully used for paper test and real samples of grapes and Kuding tea with recoveries in the range of 96.0%-106.0%, indicating the good application potential for on-site detecting oleanolic acid in real samples of fruits and food.

An effective dual sensor for Cu2+ and Zn2+ with long-wavelength fluorescence in aqueous media based on biphenylacrylonitrile Schiff-base.

Although some sensors for Cu2+ and Zn2+ had been reported, the sensor with long-wavelength emission in aqueous media for in-situ detecting Cu2+ and Zn2+ was always expected. Herein, a biphenylacrylonitrile Schiff-base (OPBS) with large aromatic conjugated system was designed and synthesized in yield of 82%. OPBS possessed excellent long-wavelength fluorescence at 550-750 nm in aqueous media, which selectively response to sense Cu2+ with quenched fluorescence and Zn2+ with chromotropic fluorescence from red to yellow. The detection of Cu2+ and Zn2+ were realized without mutual interference in their coexistence system by means of the assistance of ATP. The detection limits were 2.3 × 10-7 M for Cu2+ and 1.8 × 10-6 M for Zn2+, respectively. The sensing mechanism was elucidated by binding MS spectra, fluorescence Job's plot and 1H NMR spectra. Moreover, OPBS exhibited good bioimaging performance and the in-situ sensing abilities for Cu2+ and Zn2+ in living cells, suggesting the application potential for detecting Cu2+ and Zn2+ in both vitro assay and vivo environment.