I2-Mediated [3 + 3] Annulation for the Construction of Indole-Pyrimidine-Pyrazole-Fused Tetracyclic Heteroarenes.

An I2-mediated annulation of 3-aminopyrazoles with indole-3-carboxaldehydes has been demonstrated for the first time. This tandem strategy allows the facile construction of indole-pyrimidine-pyrazole-fused tetracyclic heteroarenes that are otherwise inaccessible by the existing methods. These fused heterocycles exhibited enhanced antifungal activities against Valsa mali and Botryosphaeria dothidea compared with commercial Xemium fungicide.

Synthesis of pyrazino[1,2-b]indazoles via cascade cyclization of indazole aldehydes with propargylic amines.

An efficient intermolecular annulation of indazole aldehydes with propargylic amines has been developed for the synthesis of pyrazinoindazoles under catalyst- and additive-free conditions. This straightforward methodology was found to feature a wide substrate scope, high atom economy and environmental advantages. The bioactivity results of these new pyrazino[1,2-b]indazoles showed that some of them exhibited significant antifungal activity.

Exploring the ring-opening reactions of imidazo[1,5-a]quinolines for the synthesis of imides under photochemical conditions.

The ring-opening reaction of imidazo[1,5-a]quinolines under photoredox conditions has been described. With Eosin Y as the organophotoredox catalyst, synthetically useful and medicinally important imides were obtained in moderate to excellent yields under mild reaction conditions.

Iodine-catalyzed direct C-H thiolation of imidazo[1,5-a]quinolines for the synthesis of 3-sulfenylimidazo[1,5-a]quinolines.

An iodine-catalyzed regioselective sulfenylation of imidazo[1,5-a]quinolines was developed under metal- and oxidant-free reaction conditions. Using disulfides or thiophenols as sulfenylating agents, 3-sulfenylimidazo[1,5-a]quinoline derivatives were obtained in good to excellent yields with broad functional group tolerance. A multi-component reaction to generate 1-sulfenylated imidazo[1,5-a]pyridines is also described. Preliminary biological evaluation showed that some of the 3-sulfenylated imidazo[1,5-a]quinolines had significant anticancer activity.

Copper-Promoted Double Oxidative C-H Amination Cascade for the Synthesis of Imidazo[1,5-a]quinolines.

A copper-promoted cascade reaction of 2-methylazaarenes and benzylamines has been developed via sequential double oxidative C(sp(3))-H aminations. This protocol provides straightforward access to imidazo[1,5-a]quinoline derivatives without employing prefunctionalized substrates.

Ethyl 2-phenyl-5,6-dihydro-pyrrolo-[2,1-a]isoquinoline-3-carboxyl-ate.

In the title compound, C(21)H(19)NO(2), the six-membered heterocycle assumes a screw-boat conformation. The phenyl ring is oriented with respect to the pyrrole ring at a dihedral angle of 64.76 (10)°. An intra-molecular C-H⋯O hydrogen bond helps to stabilize the mol-ecular structure. There are weak C-H⋯π inter-actions between inversion-related mol-ecules in the crystal.

Quantitative Determination of Quercitrin Levels in Rat Plasma Using UHPLC-MS/MS and its Application in a Pharmacokinetic Study after the Oral Administration of Polygoni cuspidati Folium Capsules.

BACKGROUND: Quercitrin is widely found in herbal medicines, and it is particularly important in the design of new therapeutic agents. Because of its wide range of biological activities, methods for detecting quercitrin and its pharmacokinetics in biological samples must be investigated. OBJECTIVES: To develop and validate a sensitive and reliable ultra-high-performance liquid chromatography- tandem mass spectrometry (UHPLC-MS/MS) method for the quantitative determination of quercitrin levels in rat plasma, and test its application in a pharmacokinetic investigation after the oral administration of Polygoni cuspidati folium capsules (HC). METHODS: First, a rapid analytical method implementing UHPLC-MS/MS for the quantification of quercitrin levels in rat plasma was developed and validated. The analyte and internal standard (IS) tinidazole were extracted from rat plasma via protein precipitation with 800 µL of methanol and 50 µL of 1% formic acid solution. Chromatographic separation was performed using an Agilent ZORBAX C18 column within 4 min. Mass spectrometry was performed for quantification using a triple-quadrupole mass spectrometer employing electrospray ionization in the negative ion mode. The MRM transitions for quercitrin and IS were m/z 447.2→229.9 and m/z 246.0→125.8, respectively. The UHPLC-MS/MS method for the quantitative determination of quercitrin levels in rat plasma was then applied to investigate its pharmacokinetics after the oral administration of HC in rats. RESULTS: The developed UHPLC-MS/MS method for detecting quercitrin in rat plasma was linear over the range of 0.1-160 ng/mL. The linear regression equation was Y = (0.7373 ± 0.0023)X - (0.0087 ± 0.0021) (r2 = 0.9978). The intra- and interday precision values were within 7.8%, and the recoveries of quercitrin and IS exceeding 67.3%. The UHPLC-MS/MS method was successfully applied to characterize the pharmacokinetic profile of quercitrin in eight rats after the oral administration of HC. The experimentally obtained values were fit to a one-compartment, first-order pharmacokinetic model, and they appeared to fit the concentration-time curve. CONCLUSION: Quercitrin was proven to be stable during sample storage, preparation, and the analytical procedures. The pharmacokinetic parameters suggested that quercitrin may be present in the peripheral tissues of rats.

Regioselective C-H Phosphorothiolation of (Hetero)arenes Enabled by the Synergy of Electrooxidation and Ultrasonic Irradiation.

An electrochemically regioselective C-H phosphorothiolation of (hetero)arenes with thiocyanate as the S source under ultrasonic irradiation has been developed. The synergistic cooperation of electrooxidation and ultrasonication markedly accelerated the C-H phosphorothiolation reaction. This mechanistically different method is distinguished by its wide substrate scope and transition-metal-free and external-oxidant-free conditions, thus complementing the existing metal-catalyzed or peroxide-mediated protocols for the green synthesis of S-(hetero)aryl phosphorothioates.

Iodide-promoted transformations of imidazopyridines into sulfur-bridged imidazopyridines or 1,2,4-thiadiazoles.

A NaI-promoted sequential double carbon-sulfur bond formation was developed to afford sulfur-bridged imidazopyridines, using Deoxofluor as the sulfur source and requiring only 15 min at room temperature. Using this process, imidazo[1,5-a]pyridines could also be transformed to 1,2,4-thiadiazoles in the presence of ammonium salt with the formation of both carbon-sulfur and nitrogen-sulfur bonds. This mechanistically unique method is distinguished by its wide substrate scope, lack of requirement for transition metals and mild conditions.

Unraveling the Action Mechanism of Buyang Huanwu Tang (BYHWT) for Cerebral Ischemia by Systematic Pharmacological Methodology.

BACKGROUND: Buyang Huanwu Tang (BYHWT) and relevant Traditional Chinese medicine (TCM) has its unique advantages in the treatment of cerebral ischemia. However, its pharmacological mechanism has not been fully explained. OBJECTIVE: Base on the multi-component, also the entire disease network targets, the present study sets out to identify major bioactive ingredients, key disease targets, and pathways of BYHWT against cerebral ischemia disease by systematic pharmacological methodology. METHODS: Both the bioactive compounds from the BYHWT and the positive drugs against cerebral ischemia were fully investigated. The binding targets of the positive drugs were then obtained. A virtual screening protocol was then used to highlight the compound-target interaction and network was constructed to visualize the compound-target binding effect after docking analysis. Moreover, the targets enrichment analysis for biological processes and pathways were performed to further explore the function of bio-targets protein gene and its role in the signal pathway. RESULTS: A total of 382 active ingredients of the BYHWT and 23 candidate disease targets were identified. Virtual screening results indicated that multiple bioactive compounds targeted multiple proteins. Each compound acts on one or more targets. The mechanisms were linked to 20 signaling pathways, and the key mechanism was related to serotonergic synapse, calcium signaling pathway and camp signaling pathways. CONCLUSION: The present study explored the bioactive ingredients and mechanisms of BYHWT against cerebral ischemia by systematic pharmacological methodology. The novel methodology would provide a reference for the lead discovery of precursors, disease mechanism and material base for TCM.

In Silico System Pharmacology for the Potential Bioactive Ingredients Contained in Xingnaojing Injection () and Its Material Basis for Sepsis Treatment.

OBJECTIVE: To elucidate the action mechanism of Xingnaojing Injection (, XNJI) for sepsis, and to target screen the potential bioactive ingredients. METHODS: An integrated protocol that combines in silico target screen (molecular docking) and database mapping was employed to find the potential inhibitors from XNJI for the sepsis-related targets and to establish the compound-target (C-T) interaction network. The XNJI's bioactive components database was investigated and the sepsis-associated targets were comprehensively constructed; the 3D structure of adenosine receptor A2a and 5-lipoxygenase proteins were established and evaluated with homology modeling method; system network pharmacology for sepsis treatment was studied between the bioactive ingredients and the sepsis targets using computational biology methods to distinguish inhibitors from non inhibitors for the selected sepsis-related targets and C-T network construction. RESULTS: Multiple bioactive compounds in the XNJI were found to interact with multiple sepsis targets. The 32 bioactive ingredients were generated from XNJI in pharmacological system, and 21 potential targets were predicted to the sepsis disease; the biological activities for some potential inhibitors had been experimentally confirmed, highlighting the reliability of in silico target screen. Further integrated C-T network showed that these bioactive components together probably display synergistic action for sepsis treatment. CONCLUSIONS: The uncovered mechanism may offer a superior insight for understanding the theory of the Chinese herbal medicine for combating sepsis. Moreover, the potential inhibitors for the sepsis-related targets may provide a good source to find new lead compounds against sepsis disease.

In silico target fishing for the potential bioactive components contained in Huanglian Jiedu Tang (HLJDD) and elucidating molecular mechanisms for the treatment of sepsis.

The present study was designed to target fish for potential bioactive components contained in a Huang Lian Jie Du decoction (HLJDD) and identify the underlying mechanisms of action for the treatment of sepsis at the molecular level. he bioactive components database of HLJDD was constructed and the sepsis-associated targets were comprehensively investigated. The 3D structures of the PAFR and TXA2R proteins were established using the homology modelling (HM) method, and the molecular effects for sepsis treatment were analysed by comparing the bioactive components database and the sepsis targets using computational biology methods. The results of the screening were validated with biological testing against the human oral epidermal carcinoma cell line KB in vitro. We found that multiple bioactive compounds contained in the HLJDD interacted with multiple targets. We also predicted the promising compound leads for sepsis treatment, and the first 28 compounds were characterized. Several compounds, such as berberine, berberrubine and epiberberine, dose-dependently inhibited PGE2 production in human KB cells, and the effects were similar in the presence or absence of TPA. This study demonstrates a novel approach to identifying natural chemical compounds as new leads for the treatment of sepsis.