Silica-supported Thionyl Chloride-assisted Synthesis and Bioassay of Novel Tetrazinan-3-thione and 3-Oxo-pyrazolidine-4-carbonitrile Derivatives of Steroids

A series of tetrazinan-3-thione and 3-oxo-pyrazolidine-4-carbonitrile derivatives of steroids（1-3） were synthesized with silica-chloride as a heterogeneous catalyst.The synthesized compounds 4-9 were obtained in substantial yields.In vitro evaluation of anticancer and antioxidant activity of the synthesized compounds was carried out via 3-（4,5-dimethylthiazol-2-yl）-2,5-diphenyltetrazolium bromide（MTT） and 1,1-diphenyl-2-picrylhydrazyl（DPPH）assays,respectively.Compound 6 exhibited promising anti-proliferative activity towards a panel of cancer cell lines.The significant activity of compound 6 was further ascertained on structural,molecular modelling and docking studies.This study may provide a valuable insight into the further design and development of more potent biologically active compounds.     

Molecular Modeling and Design of Arylthioindole Derivatives as Tubulin Inhibitors

Three-dimensional quantitative structure activity relationship （3D-QSAR） and docking studies of a series of arylthioindole derivatives as tubulin inhibitors against human breast cancer cell line MCF-7 have been carried out. An optimal 3D-QSAR model from the comparative molecular field analysis （CoMFA） for training set with significant statistical quality （R2=0.898） and predictive ability （q2=0.654） was established. The same model was further applied to predict pIC50 values of the compounds in test set, and the resulting predictive correlation coefficient R2（pred） reaches 0.816, further showing that this CoMFA model has high predictive ability. Moreover, the appropriate binding orientations and conformations of these compounds interacting with tubulin are located by docking study, and it is very interesting to find the consistency between the CoMFA field distribution and the 3D topology structure of active site of tubulin. Based on CoMFA along with docking results, some important factors improving the activities of these compounds were discussed in detail and were summarized as follows： the substituents R3-R5 （on the phenyl ring） with higher electronegativity, the substituent R6 with higher eleetropositivity and bigger bulk, the substituent R7 with smaller bulk, and so on. In addition, five new compounds with higher activities have been designed. Such results can offer useful theoretical references for experimental works.     

Interactions of Phenanthroline Compounds with i-Motif DNA

The interactions of each of three phenanthroline derivatives 1, 2 and 3 with the human telomeric/-motif DNA were investigated. The results suggest these compounds are potent binders. The compounds could stabilize the structure of i-motif DNA by π-π stacking. Moreover, the binding constants of the compounds with/-motif DNA were （2.71-8.12）×10^4 L·mol^-1, and the binding stoichiometry ratio was 1：1. CD studies reveal that the binding by phenanthroline comoounds perturbs the conformation of i-motif DNA.     

Conventional and microwave irradiated synthesis,biological activity evaluation and molecular docking studies of highly substituted piperazine-azole hybrids

Azole derivatives(3,6) obtained starting from 1-(2-methoxyphenyl) piperazine were converted to the corresponding Mannich bases containing β-lactame or flouroquinolone core via a one pot three component reaction.The synthesis of conazole analogues was carried out starting from triazoles by three steps.Reactions were carried out under conventional and microwave mediated conditions.All the newly synthesized compounds were screened for their antimicrobial,enzyme inhibition and antioxidant activity,and most of them displayed good-moderate activity.Binding affinities and non-covalent interactions between enzyme-ligand complexes were predicted with molecular docking method at molecular level.Docking results complemented well the experimental results on α-glucosidase and urease inhibitory effects of the compounds.Higher binding affinities and much more interaction networks were observed for active compounds in contrary to inactive ones.It was predicted with the docking studies that triazole and anisole moieties in the structure of the synthesized compounds contributed to the stabilization of corresponding enzymes through noncovalent interactions.     

Synthesis and biological evaluation of novel triazole derivatives as antifungal agents

A series of 1-(benzylamino)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-l-yl)propan-2-ols compounds were synthesized and evaluated for their antifungal activities in vitro.The results showed that compounds 6A and 6B exhibited good antifungal activity.Compound 6A8 showed the strongest antifungal activity,which was significantly higher than that of the lead compounds and positive-control drugs Fluconazole and Itraconazole.In particular,the antifungal activity of compound 6A8 against Candida albicans and Candida krusei(MIC80 both at 0.00097μg/mL) was 515 and 64 times that of Fluconazole,respectively.The structure-activity relationships of the synthesized compounds were discussed,and the docking model of the target compounds with fungal lanosterol 14α-demethylase (CYP51) was analyzed.     

Insight into the Structural Requirements of Protoporphyrino- gen Oxidase Inhibitors： Molecular Docking and CoMFA of Di- phenyl Ether, Isoxazole Phenyl, and Pyrazole Phenyl Ether

Protoporphyrinogen oxidase （PPO, EC 1.3.3.4） is one of the most significant targets for a large family of in- hibitors that may be used as herbicide, bactericide, fungicide, or photosensitizing activator to treat cancer through photodynamic therapy （PDT）. Molecular docking and CoMFA were combined in a multistep framework with the ultimate goal of identifying important factor contributing to the activity of PPO inhibitors. As a continuation of the previous research work on the development of new PPO inhibitors, the bioassay results indicated that good PPO in- hibitors were discovered in all of the three chemical series with ICs0 values ranging from 0.010 to 0.061 pmol·L ^-1. Using the crystal structure of tobacco mitochondrial PPO （mtPPO） as template, all the compounds were docked into the enzyme active site. The docking pose of each compound was subsequently used in a receptor-based alignment, leading to the development of a significant CoMFA model with r^2 value of 0.98 and q^2 （cross validation r^2） value of 0.63. This novel multistep framework gives insight into the and it can be extended to other classes of PPO inhibitors. In be particularly applicable in virtual screening procedures. structural characteristics for the binding of inhibitors, addition, the simplicity of the proposed approach may     

鬼臼毒素及其衍生物热分解反应的动力学研究

The thermal behavior and thermal decomposition kinetic parameters of podophyllotoxin （1） and 4 derivatives, picropodophyllin （2）, deoxypodophyllotoxin （3）, fl-apopicropodophyllin （4）, podophyllotoxone （5） in a temperature-programmed mode have been investigated by means of DSC and TG-DTG. The kinetic model functions in differential and integral forms of the thermal decomposition reactions mentioned above for first stage were established. The kinetic parameters of the apparent activation energy Ea and per-exponential factor A were obtained from analy- sis of the TG-DTG curves by integral and differential methods. The most probable kinetic model function of the decomposition reaction in differential form was （1- a）^2 for compounds 1-3,2/3·a^-1/2 for compound 4 and 1/2（1-a）·[-In（1-a）]^-1 for compound 5. The values of Ea indicated that the reactivity of compounds 1-5was increased in the order： 5〈4〈2〈1〈3. The values of the entropy of activation △S^≠, enthalpy of activation △H^≠ and free energy of activation △G^≠ of the reactions were estimated. The values of △G^≠ indicated that the thermal stability of compounds 1-3 with the samef（a） was increased in the order： 2〈3〈1.     

Design and Synthesis of Tri-substituted Chiral Pyrrolidin-2-one Derivatives as CCR4 Antagonists

A series of tri-substituted chiral pyrrolidin-2-one derivatives have been designed and synthesized as CC chemokine receptor 4 （CCR4） antagonists. The structure of CCR4 was built by homology modeling. Asymmetric synthesis was applied to synthesize the R,R configuration chiral pyrrolidin-2-one scaffold. The stereoisomeric con- figurations of the compounds were identified by 2D I H-~H COSY spectroscopy and 1D NOESY spectroscopy. This method was more economical and convenient than traditional X-ray single crystal diffraction. In addition, the inter- actions between these compounds and the N-terminal extracellular tail of CCR4 were studied using capillary zone electrophoresis. The CCR4 chemotaxis inhibition effect was tested in CCR4-transfected HEK293 cells. Several compounds showed potent activities as CCR4 antagonists. Among these compounds, lc is the most active one. Its apparent binding constant of CZE experiment result is （1.569±0.11）× 10s L·mol ^-1, and its percentage inhibition of the HEK293/CCR4 cells migration with the concentration of I gmol·L ^-1 in DMSO is 59%. And compound If has slightly higher affinity to N-terminal of CCR4 according to its apparent binding constant than lb because of the in- troduced ester linkage. Further studies on the mechanism of these compounds are in progress.     

Binding Model and 3D-QSAR of 3-（2-Chloropyrid-5- ylmethylamino）-2-cyanoacrylates as PSⅡ Electron Transport Inhibitor

The binding model of 3-（2-chloropyrid-5-ylmethylamino）-2-cyanoacrylate photosystem Ⅱ （PSⅡ） electron transport inhibitors with the D 1 protein of PSII was built. The high herbicidal activity of this kind of inhibitors was explained by docking studies： in addition to usual factors, the N atom on the pyridine ring could form an H-bond with the backbone amide of Phe265 on the D1 protein. 3D-QSAR analysis on sixteen 3-（2-chloropyrid-5-yl- methylamino）-2-cyanoacrylate compounds was performed using CoMFA method to explain the nature of interactions between the compounds and D1 protein. These studies may provide useful insights for designing new PSII electron transport inhibitors.     

Synthesis,Docking and Biological Evaluation of Isoquinolonic Acid Derivatives

A series of isoquinolonic acid derivatives（4a-4o） was synthesized via one-pot synthesis for their anti-tumor activity. The structures of all the targeted compounds were confirmed by IH nuclear magnetic resonance （IH NMR） spectrometry and mass spectrometry（MS）. The anti-tumor activities of compounds 4a-4o against MG63（human osteosarcoma cells） and B16-F10（mouse melanoma cells） were examined. To evaluate the antitumor effect of the as-synthesized compounds, we compared the half maximal inhibitory concentration（1C50） of compounds 4a--4o to that of camptothecin（CPT） which appeared to be active against a broad range of human cancers. Among all the compounds, compound 41 shows the most potent biological activity against MG63 cells[IC50=（2.16i0.26） μmol/L] and B16-F10 cells[IC50=（6.95±0.24）μmol/L], thus providing useful information for the antitumor activity and potential practical use of isoquinolonic acid compounds. In addition, we screened out an efficient compound（41） that shows potential inhibit activity against Topoisomerase 1（Topo 1） by docking simulation.     

CoMFA 3D-QSAR Analysis of Epothilones Based on Docking Conformation and Alignment

Epothilones belong to a class of novel microtubule stabilizing and anti-mitotic agents, which have a paclitaxel-like mechanism of action. A three-dimensional quantitative structure-activity relationship （3D-QSAR） model was built for epothilones by the method of comparative molecular field analysis （CoMFA） combined with the flexible docking technology. The docking CoMFA model gave a good cross-validated value of q2=0.784 with an optimized component of 6 and the conventional correlation coefficient of r^2=0.985. The statistical results show that the model has good ability to predict the activity of the studied compounds. At last, the docking CoMFA model was analyzed through contour maps complemented with MOLCAD-generated active site potential surface in the α,β-tubulin receptor, which can provide important information for the structure-based drug design.     

Investigation of the Interaction between Isoflavonoids and Bovine Serum Albumin by Fluorescence Spectroscopy

The interactions of bovine serum albumin （BSA） with three structurally related isoflavonoids, genistein, puerarin and daidzein, were studied under physiological conditions by fluorescence spectroscopic technique. The quenching mechanism of these compounds with BSA was suggested as static quenching and the binding constants were determined at different temperatures based on the fluorescence quenching results. The transfer efficiency of energy and distance between the acceptor and BSA were investigated on the basis of the mechanism of the Forster energy transference. According to the thermodynamic parameters it has been suggested that the acting force be mainly hydrophobic force. The comparison of binding potency of the three isoflavonoids to BSA showed that the substitution by 5-OH and 8-Glc could enhance the binding affinity. All these obtained in the work can make us better understand the mode of the action and pharmacological activities of the isoflavonoids.     

Design and synthesis of novel triazole derivatives containing γ-lactam as potential antifungal agents

A series of novel triazole derivatives containing γ-lactam were designed and synthesized, and their structures were confirmed by ~1H NMR,~(13)CNMR and HRMS. The in vitro antifungal activities of the target compounds were evaluated. The results showed that all of the compounds exhibited stronger activity against the six clinically important fungi tested than fluconazole. 3D and 3E showed comparative activity against the fungi tested except for Candida glabrata and Aspergillus fumigatus as voriconazole. In addition,the docking model for 2A and CYP51 was investigated.     

Design, synthesis, insecticidal evaluation and molecular docking studies of cis-nitenpyram analogues bearing diglycine esters

Based on the strategies of receptor structure-guided neonicotinoid design, a series of novel cis-nitenpyram analogues bearing diglycine esters were designed and synthesized. Preliminary bioassays indicated that the insecticidal spectra of the target compounds were expanded compared with our previous work, while all the target compounds presented excellent insecticidal activities against Nilaparvata lugens and Aphis medicagini at 100 mg/L. Among these analogues, 6b showed 100% mortality against Nilaparvata lugens (LC 50 = 0.163 mg/L) and 90% against Aphis medicagini at 4 mg/L. SARs suggested that the insecticidal potency of our designed cis-nitenpyram analogues was dual-controlled by the size and species of the ester groups. The molecular docking simulations revealed that the structural uniqueness of these analogues may lead to a unique molecular recognition and binding mode compared with the previously designed compounds. Introduction of the peptide bond gave rise to more significant hydrogen bonds between the nitenpyram analogues bonding with the amino acid residues of insect nAChRs. The docking results explained the SARs observed in vitro, and shed light on the novel insecticidal mechanism of these cis-nitenpyram analogues.     

CAN catalyzed one-pot synthesis and docking study of some novel substituted imidazole coupled 1,2,4-triazole-5-carboxylic acids as antifungal agents

The present work describes a facile,one-pot three component synthesis of a series of 3-[(4,5-diphenyl-2-substituted aryl/heteryl)-1H-imidazol-1-yl]-1H-1,2,4-triazole-5-carboxylic acid derivatives M(1-15).Benzil,aromatic aldehydes and 3-amino-l,2,4-triazole-5-carboxylic acid was refluxed in ethanol using cerric ammonium nitrate(CAN) as a catalyst to give the title compounds in good yields.The compounds were evaluated for their in vitro antifungal and antibacterial activity.Compounds M1,M9,and M15 were found to be equipotent against Candida albicans when compared with fluconazole.Compounds M2.M5,and M14 showed higher activity against Streptococcus pneumoniae.Escherichia coli and Streptococcus pyogenes,respectively,compared with ampicillin.Docking study of the newly synthesized compounds was performed,and the results showed good binding mode in the active sites of C albicans enzyme cytochrome P450 lanosterol 14α-demethylase.The results of in vitro antifungal activity and docking study showed that synthesized compounds had potential antifungal activity and can be further optimized and developed as a lead compound.     

Asymmetric Synthesis of （R）- and （S）-Moprolol

A simple and effective procedure for the enantioselective synthesis of （R）- and （S）-moprolol was described. The key step was the asymmetric synthesis of enantiopure （R）- and （S）-guaifenesin, which were synthesized from enantioenriched （R）-3-chloro-l,2-propanediol and （S）-epichlorohydrin via kinetics of hydrolysis resolution of racemic epichlorohydrin by chiral Salen-Co^Ⅲ complex. The e.e. values of both the optical compounds were above 98%, and the chemical structures of the target compounds were confirmed by ^1H NMR, ^13C NMR, IR, and MS.     

Molecular Dynamics Simulation of the Binding Interaction between Hormone Glucagon Protein and Self-Assembled Monolayer Molecules

Restrained molecular dynamics simulations were performed to study the binding affinity of the peptide with alkanethiols of different tail-groups, S（CH2）7CH3, S（CH2）7OH and S（CH2）7COOH, which self-assembled on Au（111） surface in the presence of water molecules. The curves of binding affinity were calculated by fixing the center of mass of the peptide at various distances from the assembling surface. Simulation results show that the binding affin- ity is in the order as COOH-SAMs〉OH-SAMs〉CH3-SAMs, while 100% COOH-SAMs〉5% COOH-SAMS in concentration. The effects on binding affinity by different tail-groups were also studied. Results show that the binding affinity between COOH-SAMs and the peptide is bigger than those of the others and increasing the acidity of COOH-SAMs will result in stronger attractive power.     

Synthesis,Crystal Structure and Biological Activity of 6-Arylmethyl-7H-thiazolo[3,2-b]-1,2,4-triazin-7-one Derivatives as Antitumor Agents

In order to explore the novel anti-tumor agents, ten 6-arylmethyl-3-aryl-7 Hthiazolo[3,2-b]-1,2,4-triazin-7-ones were designed and synthesized, and the structures were characterized by ~1H-NMR, MS, IR and X-ray single-crystal diffraction analysis. The biological activity results showed that the target compounds exhibited certain inhibitory activity of osteosarcoma cells U2 OS-EGFP. Compounds 6 a, 6 g and 6 j exhibited more than 70% inhibition ratio at the concentration of 50 μmol·L~(-1), and especially, the IC50 value of compound 6 j was 11.58 μmol·L~(-1). The crystal of 6 h was obtained and analyzed; some related weak interactions were discussed. The molecular docking results showed that the target compounds were supposed to be ERK1/2 inhibitors.     

Synthesis and bioactivity of novel strobilurin derivatives containing the pyrrolidine-2,4-dione moiety简

（E）-Methyl-2-（2-（bromomethyl）phenyl）-3-methoxyacrylate was reacted with substituted 1-acetylpyr-rolidine-2,4-diones and 3-（1-（hydroxylamino）ethylidene）pyrrolidine-2,4-diones respectively to synthesize two series of/%methoxyacrylate derivatives containing the pyrrolidine-2,4-dione moiety. The structures of the targeted compounds were confirmed by IR, 1H NMR, 13C NMR, MS and elemental analysis. The fungicidal activity against Rhizoctonia solani, Botrytis cinerea and Fusarium graminearum was evaluated. The bioassay results demonstrated that these compounds showed visible fungicidal activity.