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Based on molecular simulation, the etravirine-VRX-480773 hybrids previously disclosed by our group were optimized to yield novel pyrimidine sulfonylacetanilides 8 with improved activity against a panel of seven clinically relevant single and double mutant strains of HIV-1. The improvement in potency in this in vitro model of HIV RNA replication partly validates the mechanism by which this class of allosteric pyrimidine derivatives inhibits the reverse transcriptase (RT), and represents a remarkable step forward in the development of anti-HIV drugs.

Black pepper extracts reportedly inhibit food spoilage and food pathogenic bacteria. This study explored the antimicrobial activity of black pepper chloroform extract (BPCE) against Escherichia coli and Staphylococcus aureus. The antibacterial mechanism of BPCE was elucidated by analyzing the cell morphology, respiratory metabolism, pyruvic acid content, and ATP levels of the target bacteria. Scanning electron micrographs showed that the bacterial cells were destroyed and that plasmolysis was induced. BPCE inhibited the tricarboxylic acid pathway of the bacteria. The extract significantly increased pyruvic acid concentration in bacterial solutions and reduced ATP level in bacterial cells. BPCE destroyed the permeability of the cell membrane, which consequently caused metabolic dysfunction, inhibited energy synthesis, and triggered cell death.

A series of new DAPY-DPEs hybrids, combined the important pharmacophores of DAPYs and DPEs, has been synthesized and biologically evaluated for their anti-HIV activities against wild-type HIV-1 strain IIIB, double RT mutant (K103N+Y181C) strain RES056 and HIV-2 strain ROD in MT-4 cell cultures. Many promising candidates with potent inhibitory activity (wild-type) within the EC50 range from 0.16 to 0.013 μM were obtained. In particular, 3c, 3p, 3r and 3s displayed low nM level EC50 values (35, 13, 50 and 17 nM, respectively) and high selectivity (9342, 25131, 2890 and 11338, respectively), which were much more potent than NVP (EC50=0.31 μM, SI=48), 3TC (EC50=2.24 μM, SI>39), DDI (EC50=23.20 μM, SI>9) and DLV (EC50=0.65 μM, SI>67), and comparable to AZT (EC50=0.0071 μM, SI>13144) and EFV (EC50=0.0062 μM, SI>1014). The HIV-1 reverse transcriptase inhibitory assay confirmed that these DAPY-DPEs hybrids targeted HIV-1 RT. Molecular simulation was performed to investigate the potential binding mode of the newly synthesized compounds. And reasonable explanation for the activity results was discussed with docking method.

A new series of 29 diarylpyrimidine analogues featuring a cyclopropylamino group between the pyrimidine scaffold and the aryl wing have been synthesized. All of the new compounds have been characterized by spectra analysis. The target molecules were evaluated for their in vitro anti-HIV activity with FDA-approved drugs as references. Some of the compounds exhibited moderate to potent activities against wild-type HIV-1. The compound 4-((4-((cyclopropylamino)(2,5-difluorophenyl)methyl)pyrimidin-2-yl)amino)benzonitrile (1e) displayed potent anti-HIV-1 activity against WT HIV-1 with an IC50 of 0.099 μM and a selectivity index of 2302. The preliminary structure-activity relationship (SAR) of this new series of compounds was also investigated.

A series of new diarylpyrimidines (DAPYs) characterized by a halogen atom on the methylene linker between wing I and the central pyrimidine ring was synthesized and evaluated for their anti-HIV activity in MT-4 cell cultures. The two most promising compounds 7f and 7g showed excellent activity against wild-type HIV-1 with low nanomolar EC 50 values of 0.005 and 0.009 μM, respectively, which were comparable to or more potent than all the reference drugs zidovudine (AZT), lamivudine (3TC), nevirapine (NEV), efavirenz (EFV), delaviridine (DLV) and etravirine (ETV). In particular, 7g also displayed strong activity against the double mutant strain 103N + 181C with an EC 50 value of 8.2 μM. The preliminary structure–activity relationship (SAR) and molecular docking analysis of this new series of CHX-DAPYs were also investigated.

Here we report the asymmetric amination of 3-(2-oxoindolin-3-ylidene)butanoates catalyzed by a cinchona-derived alkaloid, yielding products with an N-containing stereocenter in high yields and moderate enantioselectivity. The developed process could be an attractive approach for the synthesis of chiral amino acids.

The main aim of the present work was to optimize mead production using Response Surface Methodology. The effects of pH (X1:4–6), diammonium phosphate concentration (X2: 90–150g/hL), and temperature(X3: 24–32°C) on mead quality, concerning the final ethanol, was studied. The results showed that regression equation fit well with experimental data and the optimum extraction conditions determined in order to maximize the combined responses were pH value of 6.5, diammonium phosphate concentration of 150g/hL, temperature of 28°C. The mead produced under these conditions had the following characteristics: ethanol concentration of 9.3% and good flavor.

A series of C6-rigid S-DABO analogs characterized by a substituted benzoyl group at C6 position of the pyrimidine ring has been synthesized and biological evaluation as NNRTIs against wild-type HIV-1 strain IIIB, double RT mutant (K103N + Y181C) strain RES056 as well as HIV-2 strain ROD in MT-4 cell cultures. Most of the compounds exhibited moderate antiviral activities. Among them, compound 7q displayed the highest anti-HIV-1 activity with an EC50 value of 0.26 μM and a selectivity index (SI) of 541. The preliminary structure–activity relationship (SAR) of these new S-DABOs was investigated, the target RT was confirmed and docking study was performed.

Substances from Fructus Alpinia Oxyphylla (AOF) were extracted by using solvent extraction. In accordance with central composited design of response surface methodology system, the extracts were analyzed for the index which is the criteria formula of multiplying OD value by the yield. The optimum conditions obtained were extraction temperature of 60°C, liquid-solid ratio of 9mL/g, and solvent density of 80%. According to Ficks second law of diffusion, experimental parameters of K (rate constant), Ea (activation energy), Gs (effective diffusion coefficient) were gained, which represents a good agreement between the model simulation and the results of the actual process. The results can provide the valuable theory basis for the technical design and further research of extraction process. Antibacterial activities of the extraction were shown through MIC of which represents a significant effect.

A short and cyanide-free enantioselective synthesis of atorvastatin calcium has been achieved starting from a commercially available highly substituted 1,4-diketone in an overall yield of 40%. The key step in this approach is the asymmetric aldol reaction of an aldehyde with diketene in the presence of Ti(O-i-Pr)4–Schiff base complex to create the (5R)-stereochemistry of atorvastatin calcium.

In order to investigate the effect of magnetic field on the antibacterial substances from black pepper, we used shaking and ultrasonic-assisted ethanol extraction with Escherichia coli, Staphylococcus aureus, Bacillus anthracis and Aspergillus niger as indicator bacteria respectively. Meanwhile, extraction rate and diameter of inhibition zone were regarded as the activity monitoring parameters. The results showed the existence of magnetic field can make a difference. It weakened the antibacterial activity of black pepper by shaking extraction. However, the antibacterial activity of substances to Aspergillus niger was proportional to the intensity of the applied magnetic field by ultrasonic-assisted ethanol extraction.

The aim of this work was to optimize extraction procedure of antibacterial compounds from amomum tsao-ko and verify antibacterial ability of yields. Two methods were carried out and compared. One is ethanol reflux extraction, and the other is ultrasonic-assisted ethanol extraction which selected due to better antibacterial efficiency of the extract obtained. In order to improve extraction rate and antibacterial activity which both varied with ultrasonic-assisted extraction conditions, Box-Behnken design was employed. Studies showed that the optimum conditions for extraction antibacterial substances from amomum tsao-ko were determined to be: ethanol density 100%, soaking time 4h, extraction time 120min.

In this study, the volatile compounds of pepper (Piper Nigrum L.) were extracted and analyzed by simultaneous distillation-extraction (SDE) and gas chromatography-mass spectrometry (GC-MS). The differences in volatile compounds were observed by GC-MS data sets. Results showed vinyl compounds were the most dominant volatiles in pepper by simultaneous distillation-extraction (SDE) and GC-MS, and 22 volatile compounds in the white pepper and black pepper were the same.

The microstructures, wettabilities and mechanical properties of Sn–9Zn–xAg (x = 0, 0.1, 0.3, 0.5, 1 wt%) lead-free solders were investigated, respectively in this paper. Results show that, when the quantity of Ag added to the solder is 0.3 wt%, the microstructure of the solder becomes finer and more uniform than Sn–9Zn, and when the quantity of Ag is exceeded 0.3 wt% (upto 0.5–1 wt%), the AgZn3 intermetallic compounds appear in the solder. In particular, adding 0.3 wt% Ag improves the wettability due to the better oxidation resistance of the Sn–9Zn–0.3Ag solder. Results also indicate that adding 0.3 wt% Ag to the solder enhances mechanical property of soldered joint, at which the fracture micrographs show that plenty of small and uniform dimples could be observed on the Sn–9Zn–0.3Ag soldered joints fractures. When the content of Ag is upto 1 wt%, some Cu–Zn and Ag–Zn intermetallic compounds appear on the bottom of dimples, and the mechanical property of the soldered joint decreases.

To investigate the lysophosphatidic acid (LPA) receptors expression situation and their biological significance in human ovarian cancer cell lines and in human epithelial ovarian neoplasms.The reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting were employed to measure the expression levels of LPA(1), LPA(2) and LPA(3) mRNA, LPA(2) and LPA(3) protein expression in cultured human ovarian cancer cell lines (3AO, SKOV3 and OVCAR3) and in human epithelial ovarian neoplasms. The immunocytochemical method was used to detect LPA(2) and LPA(3) protein expression in cultured human ovarian cancer cell lines.RT-PCR revealed that all ovarian cancer cell lines expressed LPA(1), LPA(2) and LPA(3) mRNA. The positive rates (100%; 86.4%; 88.2%) of LPA(1) mRNA in normal ovarian tissue, benign tumor and ovarian cancer were no significant difference (p0.05). The expression level of LPA(1) mRNA was significantly higher in normal ovarian tissue compared with that in benign tumor and in ovarian cancer tissue (p0.01). LPA(1) expression level was no significant difference in both benign tumor and ovarian cancer tissue (p0.05). LPA(2) mRNA-positive rates (92.6%) and expression level were significantly higher in ovarian cancer compared with that in benign tumor (31.8%) and in normal ovarian tissue (31.3%) (p0.01); LPA(2) mRNA-positive rates and expression level were no significant difference in both benign tumor and normal ovarian tissue (p0.05). LPA(3) mRNA-positive rates (92.6%) and expression level were significantly higher in ovarian cancer compared with that in benign tumor (31.8%) and in normal ovarian tissue (31.3%) (p0.01), LPA(3) mRNA-positive rates and expression level were no significant difference in both benign tumor and normal ovarian tissue (p0.05). LPA(1) mRNA expression level was significantly decreased compared with that of LPA(2) and LPA(3) in ovarian cancer (p0.01); Western blotting clearly revealed that all ovarian cancer cell lines showed LPA(2) and LPA(3) protein. The positive rates and expression level of LPA(2) and LPA(3) protein were significantly increased in ovarian cancer (92.6%; 92.6%) compared with that in benign tumor (45.5%; 45.5%) and that in normal ovarian tissue (43.8%; 43.8%) (p0.01); LPA(2) and LPA(3) protein-positive rates and expression level were no significant difference in both benign tumor and normal ovarian tissue (p0.05). Correlation of clinicopathological parameters showed that LPA receptors mRNA and protein expression were associated with FIGO stage and histological grade, except pathologic types and age. The mRNA and protein expression of LPA(2) and LPA(3) in stages III and IV was significantly higher than that in stages I and II epithelial ovarian cancer (p0.05). The mRNA and protein expression of pathologic grade G(3) was significantly higher compared with grade G(1) (p0.05).LPA(1), LPA(2) and LPA(3) mRNA and protein expressed widely in human epithelial ovarian neoplasms. LPA(2) and LPA(3) may be involved in the development and progression of human ovarian cancer. There was a significant correlation between LPA(2), LPA(3) and invasion and metastasis of epithelial ovarian cancer. LPA(2) and LPA(3) may be a prognostic indicator in patients with epithelial ovarian cancer.

A molecular hybridization approach is a powerful tool in the design of new molecules with improved affinity and efficacy. In this context, a series of diarylpyrimidine–quinolone hybrids were synthesized and evaluated against both wt HIV-1 and mutant viral strains. The most active hybrid 5a displayed an EC 50 value of 0.28 ± 0.07 μM against HIV-1 III B . A couple of enzyme-based assays clearly pinpoint a RT-targeted mechanism of action. Docking studies revealed that these hybrids could be well located in the NNIBP of HIV-1 RT despite the bulky and polar properties of a quinolone 3-carboxylic acid moiety in the molecules.

This article reports the design, synthesis and antiviral evaluation of a new series of non-nucleoside reverse transcriptase inhibitors (NNRTIs). The basic skeleton of these target 18 molecules is diarylpyrimidine featuring a substituted amino group between the pyrimidine scaffold and the aryl wing. All of the new compounds have been characterized by spectra analysis. The entire target molecules were evaluated for their in vitro anti-HIV activity with controlling group of FDA approved drugs. Most of them showed good to potent activities against wild-type (WT) HIV-1 with IC50 values in the range of 0.0175–69.21 μM. 2-(4-Cyanophenylamino)-4-(2-cyanovinylphenylhydrazonomethyl)pyrimidine (1d) displayed potent anti-HIV-1 activity against WT HIV-1 with a selectivity index (SI) of 106367 and an IC50 value of 1.75 nM, which was 47 fold lower than that of AZT. Compound 1d also showed a broad-spectrum inhibitory activity, with an IC50 value of 5.33 μM and 5.05 μM against both HIV-1 double-mutated (K103N/Y181C) strain and HIV-2 strain, respectively. The preliminary structure–activity relationship (SAR) was also investigated. The binding modes with HIV-1 RT for both the wild type and mutant type have also been discussed.

A series of CR 2 (OH)-diarylpyrimidine derivatives (CR 2 (OH)-DAPYs) featuring a hydrophobic group at CH(OH) linker between wing I and the central pyrimidine were synthesized and evaluated for their anti-HIV activity in MT-4 cell cultures. All the target compounds except for compound 3k displayed inhibitory activity against HIV-1 wild-type with EC 50 values ranging from 7.21 ± 1.99 to 0.067 ± 0.006 μM. Among them, compound 3d showed the most potent anti-HIV-1 activity (EC 50 = 0.067 ± 0.006 μM, SI > 592), which was approximately 2-fold more potent than the reference drugs nevirapine (NVP) and delaviridine (DLV) in the same assay. In addition, the binding modes with HIV-1 RT and the preliminary SAR studies of these new derivatives were also investigated.

A series of conformationally restricted dihydro-alkylthio-benzyl- oxopyrimidine (S-DABO) hybrids, which combined the structural features of C6-α-methylbenzyl-thio-DABOs (α-methyl-S-DABOs) and C6-α-cyanobenzyl-thio-DABOs (CN-S-DABOs), has been synthesized and biologically evaluated for their anti-HIV activity against wild-type HIV-1 strain IIIB, double RT mutant (K103N + Y181C) strain RES056 and HIV-2 strain ROD in MT-4 cell cultures. Most of these compounds exhibited inhibitory activity (wild-type) within the range of EC50 values from micromolar to nanomolar. Among them, compound 1s displayed the highest anti-HIV-1 activity with an EC50 value of 91 nM and a selectivity index (SI) of 548, which was more potent than zalcitabine and comparable to nevirapine and delavirdine in the same assay. The HIV-1 reverse transcriptase inhibitory (RT) assay confirmed that these conformationally restricted S-DABO hybrids targeted HIV-1 RT. The preliminary structure-activity relationship (SAR) and molecular docking analysis of this new series of conformationally constrained CN-S-DABO hybrids were also investigated. © 2014 the Partner Organisations. ispartof: Medicinal Chemistry Communications vol:5 issue:4 pages:468-473 status: published

Two new tetranuclear iron(III) complexes, [Fe4(TBA)4(μ-O)2(μ4-Suc)](ClO4)4(OH)2·1.5CH3CN·2C2H5OH·6H2O (1) and [Fe4(TBA)4(μ-O)2(μ4-Tp)](ClO4)6·3C2H5OH·6H2O (2) (Suc = succinate, Tp = terephthalate, TBA = tris(2-benzimidazolylmethyl)amine) have been prepared and characterized by various physicochemical techniques. X-Ray crystallography reveals complex 1 contains equivalent two μ-oxo-μ-carboxylate diiron(III) centers bridged by a succinate acting as a tetradentate ligand linked to four iron atoms, forming a tetranuclear core [Fe4(TBA)4(O)2(Suc)]6+, in which each iron atom has an N4O2 donor set with distorted octahedral geometry and each of the two diiron(III) centers contains two iron atoms with a distinct coordination environment. Magnetic behaviors indicate the presence of a stongly antiferromagnetic coupling in the two complexes with the exchange coupling constants J = −114.27(8) cm−1 for 1 and J = −119.52(6) cm−1 for 2. The NMR spectra imply that the structures in the solid state are retained in solution. The two tetranuclear complexes exhibit similar cyclic voltammograms, i.e. there are three irreversible two-electron redox peaks at Ec = 0.247, −0.233 V; Ea = 0.354 V for 1 and Ec = 0.307, −0.166 V; Ea = 0.526 V for 2. The preliminary study on the hydrolysis of adenosine 5′-triphosphate (ATP) followed by 31P NMR spectroscopy shows that the two complexes can catalyze the hydrolysis of ATP.