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Faldaprevir analogue molecule (FAM) has been reported to effectively inhibit the catalytic activity of HCV NS3/4A protease, making it a potential lead compound against HCV. A series of HCV NS3/4A protease crystal structures were analyzed by bioinformatics methods, and the FAM-HCV NS3/4A protease crystal structure was chosen for this study. A 20.4 ns molecular dynamics simulation of the complex consists of HCV NS3/4A protease and FAM was conducted. The key amino acid residues for interaction and the binding driving force for the molecular recognition between the protease and FAM were identified from the hydrogen bonds and binding free energy analyses. With the driving force of hydrogen bonds and van der Waals, FAM specifically bind to the active pocket of HCV NS3/4A protease, including V130-S137, F152-D166, D77-D79 and V55, which agreed with the experimental data. The effect of R155K, D168E/V and V170T site-directed mutagenesis on FAM molecular recognition was analyzed for their effect on drug resistance, which provided the possible molecular explanation of FAM resistance. Finally, the system conformational change was explored by using free energy landscape and conformational cluster. The result showed four kinds of dominant conformation, which provides theoretical basis for subsequent design of Faldaprevir analogue inhibitors based on the structure of HCV NS3/4A protease.

The association rate constant and dissociation rate constant are important parameters of the drug-cyclodextrin supermolecule systems, which determine the dissociation of drugs from the complex and the further in vivo absorption of drugs. However, the current studies of drug-cyclodextrin interactions mostly focus on the thermodynamic parameter of equilibrium constants (K). In this paper, a method based on quantitative high performance affinity chromatography coupled with mass spectrometry was developed to determine the apparent dissociation rate constant (k(off,app)) of drug-cyclodextrin supermolecule systems. This method was employed to measure the k(off,app) of meloxicam and acetaminophen. Firstly, chromatographic peaks of drugs and non-retained solute (uracil) on β-cyclodextrin column at different flow rates were acquired, and the retention time and variance values were obtained via the fitting the peaks. Then, the plate heights of drugs (H(R)) and uracil (H(M,C)) were calculated. The plate height of theoretical non-retained solute (H(M,T)) was calculated based on the differences of diffusion coefficient and the stagnant mobile phase mass transfer between drugs and uracil. Finally, the k(off,app) was calculated from the slope of the regression equation between (H(R)-H(M,T)) and uk/(1+k)2, (0.13 ± 0.00) s(-1) and (4.83 ± 0.10) s(-1) for meloxicam and acetaminophen (control drug), respectively. In addition, the apparent association rate constant (k(on,app)) was also calculated through the product of K (12.53 L x mol(-1)) and k(off,app). In summary, it has been proved that the method established in our study was simple, efficiently fast and reproducible for investigation on the kinetics of drug-cyclodextrin interactions.

The paper is aimed to establish a method of residue analysis for thiamethoxam and to study its degradation dynamic and final residue and its standard of safe application of thiamethoxam on Lonicera japonica. Samples extracted with methanol by ultrasonication were purified with dichloromethane by liquid-liquid extraction and SPE column and analysed by HPLC-UV. The results showed that average rate was 84.91%-94.44% and RSD 1.74%-4.96% with addition of thiamethoxam in respectively diverse concentration, which meets inspection requirement of pesticide residue. Two kinds of dosages of thiamethoxam were treated- varying from recommended dosage (90 g x hm(-2)) to high dosage (135 g x hm(-2)), Results of two years test showed that thiamethoxam was degraded more than 90% seven days after application and the half - life period of thiamethoxam was 1.54-1.66 d. The digestion rate of thiamethoxam was fast in the L. japonica. The recommended MRL of thiamethoxam in the L. japonica is 0.1 mg x kg(-1), the dosage of 25% thiamethoxam WDG from 90-135 g x hm(-2) is sprayed less than three times a year on L. japonica and 14 days is proposed for the safety interval of the last pesticide application's and harvest's date.

A series of novel 2-amino-4-phenylthiazole derivatives were designed and synthesized, furthermore, their inhibition effect on acetylcholinesterase were investigated. 2-Amino-4-phenylthiazoles were prepared from alpha-bromoacetophenones by Hantzsch reaction, acylation reaction and substitution reaction. Moreover, their bioactivities as AChE inhibitors in vitro were measured with Ellman spectrophotometry. The results showed that most of them had a certain inhibition activity on AChE, and the compound 8a was the best of them. The IC50 of 8a to AChE is 3.54 micromol x L(-1), and the value was better than that of rivastigmine. 2-Amino-4-phenylthiazole derivatives showed a certain bioactivity in vitro, which were worth further investigation.

Alzheimer's disease (AD) is a progressive neurodegenerative disease endangering human health seriously. Recent reports have revealed that beta-amyloid aggregates play a key role in the pathogenesis of AD. Thus, targeting the Abeta plaques benzothiazole derivatives were synthesized with the scaffold of the most promising imaging agent PIB ([11C]-6-OH-BTA-1, [11C]-2-(4-(methylamino)phenyl)-6-hydroxybenzothiazole) and C = N as linker to study the binding characteristics with the target protein through surface plasmon resonance (SPR) technique. These derivatives were synthesized through simple yet effective method with high yields and characterized by 1H NMR and FTIR. The binding properties (K(D)) were determined with Biacore X-100 instrument according to the fitting-plot curve. Compounds 3a and 3f showed high binding affinity for Abeta1-40. The results suggest that benzothiazole derivatives could be served as a scaffold to develop novel beta-amyloid imaging agents for the diagnosis of AD.

As an important member of metabotropic glutamate receptors (mGluR), metabotropic glutamate receptor 1 (mGluR1) plays an important role in the signal transduction of central nervous system. Selective mGluR1 antagonists can block the signaling pathway activated by mGluR1 and exert a series of physiological actions including analgesia, antianxiety, antidepression, etc. Currently, the discovery and modification of selective mGluR1 antagonists have become a hot research focus. This paper reviews the structural catalogs of selective mGluR1 antagonists and their structure-activity relationships in the last decade.

This article studies the thermostability and the crystal structure of a new anticancer drug dasatinib. The thermostability of dasatinib was analyzed using the differential scanning calorimeter (DSC) and thermo gravimetric analyzer (TGA), and the structural characteristics of polymorphism and crystalline transformation was determined using the X-ray powder diffractometry (XRD) with in-situ high temperature accessories. The results showed that dasatinib has at least two different crystal forms. The form-I has one crystalline water and form-II one and half, and in a heating-up processing both of them would change their crystal structures. After losing their crystalline water, both would change into the same crystalline form with no crystalline water. Their melting points were almost the same: form-I was 285.68 degrees C and form-II was 285.50 degrees C. The results of the study method would provide a comprehensive reference for the quality evaluation of dasatinib.

In recent years, the incidence and mortality rate of invasive fungal infection have increased dramatically, and it is of great significance to develop novel antifungal agents with new chemical structure and new mode of action. In this review, novel antifungal lead compounds reported from 2007 to 2009 are reviewed. Moreover, their chemical structures, antifungal activities and structure-activity relationships have been summarized, which can provide useful information for future study of antifungal agents.

Apoptosis is an essential factor in keeping homeostasis of the organism. Apoptosis is regulated by a series of cytokines. Bcl-2 family proteins are key regulators of apoptosis. The Bcl-2 family includes both anti- and pro-apoptotic proteins with opposing biological functions. Their interaction regulates the transmission of the apoptosis signal. High expression of anti-apoptotic members such as Bcl-2 and Bcl-xL are commonly found in human cancers. In recent years, following the disclosing of the crystal structures of Bcl-2 family proteins, researchers have paid attention to the development of the small molecule inhibitors of Bcl-2 family proteins. This article reviews the progress in this field from the view of drug design.

A molecular spectroscopic investigation of the interaction of phenacyl thiazolium bromide (PTB) and bovine serum albumin (BSA) or human serum albumin (HSA) is reported employing fluorescence quenching techniques. It is determined that the maximal excitation wavelength is 280 nm for BSA solution, and 290 nm for HAS solution. When PTB was added into these solutions gradually, the emission peaks were decreased obviously, which are typical quenching phenomena. The results obtained reveal that there is a medium-intensity binding affinity for PTB with HSA and BSA. At 15 degrees C, the binding constants of PTB and BSA (HSA) are 3.66 x 10(3) and 3.83 x 10(3), and the numbers of binding sites are 1.02 and 1.06 respectively. At 37 degrees C, the binding constants of PTB and BSA (HSA) are 3.58 x 10(3) and 3.35 x 10(3), and the numbers of binding sites are 0.95 and 0.87 respectively. According to the thermodynamic parameters, the main sort of the binding force between the drug and BSA or HSA was electrostatic force. Based on the Föster non-radiation energy transfer theory, it could be acquired that the distance between BSA or HSA and PTB is 7.5 or 7.9 nm. According to the crystal structure of serum albumin, it can be speculated that subdomain II A was the binding sites for the interaction of PTB and serum albumin, which is the region near Try214.

Aim: To synthesize a series of 2-arylimino-4-thiazolidone derivatives and 2-imidazolino [2,3-b]-4-thiazolidone in order to get some novel potent compounds with nitric oxide synthases (NOS) inhibitory activity., Methods: The target compounds were prepared by reaction of N-chloroacetyl-1,2,3,4-tetrahydroisoquinoline or N-chloroacetylphthalimide with substituted thioureas, their NOS inhibitory activity were measured., Results and Conclusion: The 15 new compounds were synthesized and most of the reaction yields were over 65%. The structures of new compounds were identified by IR, 1H NMR, MS and elemental analyses. Bioassay indicated that, most of 15 new compounds synthesized had confirmed bioactivities inhibition against NOS.

Aim: To investigate the inhibitory effect of 2-aminothiazole derivatives on Neuro-cell apoptosis and QSAR., Methods: The 2-aminothiazole derivatives were designed and synthesized based on the lead compound of PFT-alpha, the protective action of the compounds I and II against and their inhibitory action on PC12 cell apoptosis induced by H2O2 were determined by MTT method and FCM method. The QSAR equation was obtained from Cerius2-QSAR+ module., Results: Eleven novel 2-aminothiazole Schiff base compounds (II) have been designed and synthesized. The structure of the compound II were characterized by IR, MS,1H NMR, 13C NMR. Their protective action against and the inhibitory action on PC12 cell apoptosis induced by H2O2 were found in this experiment. The optimal QSAR equation obtained from the Cerius2-QSAR+ module by using log (1/EC50) with corresponding descriptors is Activity = 6.947 68 - 0.088 72 x "LUMO" - 0.043 018 x "Alogp98" - 0.128 752 x "Rad0fGration" + 0.018 246 x "Dipole-mag". The correlation statistics parameters of the above equation are as follows: r2 = 0.970, F-test = 49. 149, r = 0. 985 and Lse = 0. 001., Conclusion: The 2-aminothiazole derivatives exhibited certain activity in inhibiting PC12 cell apoptosis induced by H2O2. Some compounds such as I-6, I-9 and II-6 have the dual activities, the protective action against and inhibitory action on PC12 cell apoptosis induced by H2O2. The QSAR equation indicated that it is favorable for enhance the activity of 2-aminothiazole derivatives by the reduction of "radius of gyration" and the energy of "LUMO" of the compounds.

Objective: Neuroblastoma (NB) is a pediatric solid tumor derived from neural crest precursor cells. It is resistant to current therapeutic protocols, including high dose chemotherapy. The mechanisms of chemoresistance are very complex. The recent studies have shown that the levels of tyrosine kinase receptor B (TrkB) and brain-derived neurotrophic factor (BDNF) are high in NB tumors with poor prognosis. The aim of this research was to explore the effects of TrkB and BDNF levels on the chemotherapeutic sensitivity in neuroblastoma by using the NB cell line SH-SY5Y in vitro., Methods: The expression of TrkB protein was detected with Western-blot after the treatment with different concentrations of all trans-retinoic acid (ATRA). Cell survival rate was analyzed using MTT. Apoptosis was detected using flow cytometry (FCM) and a transmission electron microscope (TEM)., Results: (1) The expression of TrkB protein was undetectable in SY5Y. It was positive, however, after the treatment with ATRA (1, 10, 100 nmol/L) for five days. The level of TrkB protein was increased with adding of ATRA at different concentrations. (2) The difference of the survival and apoptotic rate between the BDNF (10 ng/ml) + ATRA (10 nmol/L) + cisplatin (CP, 5 microg/ml) group (survival rate 46.51% +/- 13.44%, apoptosis rate 11.79% +/- 1.53%) and the CP alone group (survival rate 38.51% +/- 9.66%, apoptosis rate 14.95% +/- 2.06%) was not statistically significant (P > 0.05). The survival rate of the BDNF (50 ng/ml and 100 ng/ml) + ATRA (10 nmol/L) + CP (5 microg/ml) group (66.85% +/- 18.39%, 94.30% +/- 10.71%) was greatly higher than CP alone group (P < 0.05, P < 0.01), whereas the apoptotic rate (9.36% +/- 1.03%, 5.20% +/- 1.99%) was significantly lower than that of the CP alone group (P < 0.01, P < 0.01). The survival rates of BDNF (100 ng/ml) + ATRA (10 nmol/L) + CP (5 microg/ml) group were higher than those of BDNF (50 ng/ml) + ATRA (10 nmol/L) + CP (5 microg/ml) group (P < 0.01), whereas the apoptotic rates were lower than those of BDNF (50 ng/ml) + ATRA (10 nmol/L) + CP (5 microg/ml) group (P < 0.05). There were no significant difference between the ATRA (1 nmol/L) + BDNF (50 ng/ml) + CP group (survival rate 45.33% +/- 11.83%, apoptosis rate 12.48% +/- 2.48%) and the CP alone group in the survival and apoptotic rates (P > 0.05). The survival rates of the ATRA (10 nmol/L, 100 nmol/L) + BDNF (50 ng/ml) + CP (61.62% +/- 18.53%, 105.02% +/- 5.55%) group were greatly higher than those of the CP alone group (P < 0.05, P < 0.01), whereas the apoptotic rate (9.36% +/- 1.03%, 5.05% +/- 1.88%) was significantly lower than that of the CDDP alone group (P < 0.05, P < 0.01). The survival rates of the ATRA (100 nmol/L) + BDNF (50 ng/ml) + CP group were higher than those of the ATRA (10 nmol/L) + BDNF (50 ng/ml) + CP group (P < 0.01), whereas the apoptotic rates were lower than the ATRA (10 nmol/L) + BDNF (50 ng/ml) + CP group (P < 0.01). (3) Some of the cells showed apoptotic changes in the CP alone group, whereas the intranuclear chromoplasma was well-distributed, the nuclear membrane was clear, and mitochondria, ribosome and solvent were present in the ATRA (10 nmol/L) + BDNF (50 ng/ml) + CP group., Conclusions: The sensitivity of SY5Y to CP was affected by TrkB and BDNF. The higher the level of TrkB and BDNF was, the lower the sensitivity of SY5Y to CP.

The study with high-pressure mercury lamp illuminating showed that after illuminated for 15 min, NO2- and NO3- quenched the photolysis of mefenacet, and NO3- with a concentration ratio 10:1 (mass) had the most obvious effect, its quenching rate being up to 53.3%. Halogen ions inhibited the photolysis of mefenacet by "weight atom effect". When the concentration ratio of I- was 10:1, the quenching rate was 76.9% after illuminated for 15 min. Surfactants Nongru 500, Nongru 404, Nongru 601 and Nongru 603 had different effects on the photodegradation of mefenacet. At concentration ratios 1:5 and 1:1, only Nongru 404 showed a weak photosensitive effect, while in the other cases, all the four surfactants had photoquenching effects. Among the four herbicides benthiocarb, bensulfuron, alachlor and chlorsulfuron, only bensulfuron at low concentration ratio (1 : 10) accelerated the photolysis of mefenacet, with a photosensitive proportion of 18.2% after illuminated for 25 min. Aerified N2 could accelerate the photolysis of mefenacet, and the half-life was shortened from 7.14 min to 6.70 min without aerifying N2.

Benzothiazole compounds with byrazoline group or benximidazole group are new fluorescent compounds. The fluorescent compounds have been used in many fields, but their development has beeo slow. According to Schellhammer theory on the relation between chemical structure and fluorescent quality, the authors designed now fluorescent compounds with benximidazole group or the byrazoline group in the 1-benzothiazole and with biphenyl in the 3,5-benzothiazole, and their possess fluorescent nature. Two new benximidazole and benzothiazole fluorescent compounds were synthesized. All these compounds were characterized by elemental analysis and infrared spectroscopy. The excitation wavelength of the two compounds is about 441-446 nm. The fluorescence spectra show that the compounds have good blue and green fluorescence. The characteristic peaks of t he absorption spectra of these compounds werefound by IR spectral analysis, which can be used to deduce the structures of chemical compounds.

Aim: To build a model of two series of PPAR gamma agonists--thiazolidinedione and aryketo-acid derivatives using 3D-QSAR method, and to reveal the structural features affecting the binding activity to PPAR gamma, which relates to antihyperglycemic and antihyperlipidemic activity and has a potential application to the treatment of type II diabetes., Methods and Results: 48 agonists with selective activity for PPAR gamma were analyzed using CoMFA. Based upon the active conformation of rosiglitazone (BRL) extracted from its complex with PPAR gamma all agonists were aligned. The model from CoMFA showed a high ability to explain and predict the activity of PPAR gamma agonists with cross-validation correlation coefficient R2 = 0.656, that of non-cross-validation R2 = 0.982, F10,37 = 201.1, and SE = 0.115., Conclusion: The CoMFA contour map indicates that the steric fields mainly contribute to the binding effect, and especially a bulk group in the arylketo-acid series favors in the increase of affinity for PPAR gamma, as compared to the thiazolidinedione.