Penicillixanthone A,a marine-derived dual-coreceptor antagonist as anti-HIV-1 agent

Marine micro-organisms have been proven to be excellent sources of bioactive compounds against HIV-1. Several natural products obtained from marine-derived Aspergillus fungi were screened for their activities to inhibit HIV-1 infection. Penicillixanthone A (PXA), a natural xanthone dimer from jellyfish-derived fungus Aspergillus fumigates, displayed potent anti-HIV-1 activity by inhibiting infection against CCR5-tropic HIV-1 SF162 and CXCR4-tropic HIV-1 NL4-3, with IC₅₀ of 0.36 and 0.26 μM, respectively. Molecular docking study was conducted to understand the possible binding mode of PXA with the CCR5/CXCR4. The results revealed that, the marine-derived PXA, as a CCR5/CXCR4 dual-coreceptor antagonist, presents a new type of potential lead product for the development of anti-HIV therapeutics.     

3D-QSAR,molecular docking and in silico ADMET studies of propiophenone derivatives with anti-HIV-1 protease activity

Structural Chemistry - HIV protease inhibitors are one of the most important agents for the treatment of HIV infection. In this work, molecular modeling studies combining 3D-QSAR, molecular...     

Novel bio compactable silver nanowires and nanocubes: An effective treatment against carbapenem and vancomycin resistant strains isolated from cancer patients

Blood stream infections in the cancer patients are a critical problem which leads to considerable rate of mortality and morbidity. In view of this herein, we account the response of Poly Vinyl Pyrrolidone (PVP) coated silver nanowires (Ag-NWs) and silver nano cubes (Ag-NCs) towards carbapenem (Escherichia coli) and vancomycin (Staphylococcus aureus) resistant strains as well as to human epithelial cells. The prepared PVP capped silver nanomaterials were in the range of 80 nm (Ag-NC) and 25 nm (Ag-NW) as observed from Transmission Electron Microscopy (TEM). Though the selected strains were resistant to carbapenem and vancomycin, PVP capped Ag-NWs and Ag-NCs could inhibit the growth of these strains. These nanomaterials could break the cell wall and damage the genetic material of these strains as observed by death rate assay and alkaline comet assay. Furthermore, we have shown that toxicity of Ag-NWs and Ag-NCs precisely follows the dose retort pattern. Even though the resistant strains were susceptible to a concentration of 10 µg ml^?1 of silver nanomaterials the epithelial cells were not affected by the same concentration. It is also confirmed with live dead staining assay and observed that metabolic activities of epithelial cells were not affected by a concentration of 10 µg ml^?1. Overall, this work suggests that these nanomaterials can be utilized to treat the multiple drug resistant strains from cancer patients.     

Genipin crosslinked microspheres as an effective hemostatic agent

Efficient hemorrhage control is of extreme importance to decrease mortality rates arising from traumatic bleeding. However, traditional hemostatic agents are limited to unsatisfied biocompatibility, inconvenient usage, and high cost. To this end, we have devised a novel hemostatic microsphere from chitosan and gelatin by using appropriate amount of genipin as a crosslinker. The performance of these Cs/Gel MPs was evaluated with experiments in vitro and in vivo. Results in vitro showed that the best hemostatic efficacy was achieved by Cs/Gel‐0.75 MPs (the mass fraction of genipin in Cs/Gel mixture is 8.6 × 10⁻⁶). Skin laceration model indicated that the hemostatic time of Cs/Gel‐0.75 MPs was within 12 seconds, which has been significantly shortened in comparison with commercial available products. Moreover, cytocompatibility results displayed that Cs/Gel‐0.75 MPs caused no obvious cytotoxicity even at the high concentration of 40 μg/ml. Cs/Gel‐0.75 MPs also possess satisfactory fluid absorption ratio and low hemolysis. Therefore, these Cs/Gel‐0.75 MPs are promising candidates for further surgical wound hemostatic agent.     

Magnesium/methanol: an effective reducing agent for peroxides

Magnesium in methanol is an effective reagent for the chemoselective reduction of peroxides, including ozonides. Mg/MeOH is significantly more reactive than Me(2)S or PPh(3) and somewhat more reactive than Zn/HOAc.     

Solid-phase triester synthesis of modified triuridylates using an effective condensing agent

Triuridylates containing 2-deoxyuridine, 5-bromouridine, and 6-azauridine in various positions of the sequence have been synthesized by the use of an O-nucleophilic nucleotide condensation catalyst — 4-ethoxypyridine N-oxide — under the conditions of the solid-phase triester method.Institute of Molecular Biology and Genetics, Ukrainian SSR Academy of Sciences, Kiev. Translated from Khimiya Prirodnykh Soedinenii, No. 3, pp. 416–421, May–June, 1988.     

Three new lignans, longipedunins A-C, from Kadsura longipedunculata and their inhibitory activity against HIV-1 protease

Three new lignans, longipedunins A (1), B (2) and C (3), together with three known compounds, benzoyl-binankadsurin A (4), acetyl-binankadsurin A (5) and schisanlactone A (6), were isolated from Kadsura longipedunculata. Their structures and stereochemistry were determined by spectral and single-crystal X-ray analyses. Compounds 1 and 6 showed appreciable inhibitory activity against HIV-1 protease with IC50 values of 50 and 20 microM, respectively.     

Radiation resistant polypropylene blended with mobilizer,: antioxidants and nucleating agent

Post-irradiation storage of medical disposables prepared from isotactic polypropylene renders them brittle due to degradation. To avoid this, isotactic polypropylene [(is)PP] was blended with a mobilizer, dioctyl pthallate (DOP), three antioxidants (hindered amines and a secondary antioxidant) and benzoic acid to obtain radiation-resistant, thermally-stable and transparent material. Different formulations prepared were subjected to gamma radiation to doses of 25 and 50 kGy. Tests of breakage on bending after ageing in an oven at 70°C up to 12 months have shown that the addition of DOP and the antioxidants imparts improved radiation and thermal stability as compared to (is)PP alone or its blend with DOP. All the formulations irradiated or otherwise demonstrated excellent colour stability even after accelerated ageing at 70°C for prolonged periods.     

Application of the Barton photochemical reaction in the synthesis of 1-dethia-3-aza-1-carba-2-oxacephem: a novel agent against resistant pathogenic microorganisms

Racemic 7-(phenylacetamido)-1-dethia-3-aza-1-carba-2-oxacephem 3 was synthesized and found to possess antibacterial activity against Staphylococcus aureus FDA 209P, Escherichia coli ATCC 39188, Pseudomonas aeruginosa 1101-75 and Klebsiella pneumoniae NCTC 418 as well as the beta-lactamase producing organisms E. coli A9675 and P. aeruginosa 18S-H and the methicillin-resistant organism S. aureus 95. Formation of the carbacephem 3 originated from the Barton photochemical reaction in the conversion of 8 to 10. Intramolecular cyclization of syn-oximino beta-lactam 10 afforded 7-azido-2-oxa-3-azacephem 11, which was reduced and acylated to 12. Enzymatic removal of the methyl group from 12 gave the target molecule 3.     

Absolute configuration of anti-HIV-1 agent (-)-concentricolide: total synthesis of (+)-(R)-concentricolide

The first enantioselective total synthesis of (+)-(R)-concentricolide, the enantiomer of an anti-HIV-1 agent isolated from Daldinia concentrica, from 2-iodophenol in 7 steps reveals the (S)-configuration for the natural form of the furanophthalide. The key features include an anionic ortho-Fries rearrangement to furnish 3-iodosalicylamide, facile construction of the benzofuran system employing the tandem Sonogashira coupling annulation reaction, directed ortho metalation to introduce a propanoyl group, as well as CBS reduction, establishing the stereocenter enantioselectively.     

Synthesis of 9H-pyrrolo[2,1-b][1,3,6]benzothiadiazocin-10(11H)-one 4,4-dioxide,a potential anti-HIV-1 agent

Starting from 2-(2-aminophenylthio)-1-ethoxycarbonylmethyl-1H-pyrrole a four-step synthesis of 9H-pyrrolo[2,1-b][1,3,6]benzothiadiazocin-10(11H)-one 4,4-dioxide, a new heterocycle related to anti-HIV-1 tricyclic non-nucleoside agents, is described.     

Epoxy resin modified with amine as an effective complexing agent of metal cations

A simple synthesis of a material capable of metal cation removal is proposed. The material was a derivative of epoxy resin containing amine groups. It is insoluble in water and in this study it was characterized by elemental analysis and infrared spectroscopy. The sorbent obtained was tested for its ability to remove coper(II), cadmium(II) and lead(II) from water solutions. The tests were performed for different concentrations of metal ions (10–200 mg L^?1) and at different pH (2.0–9.0). The effects of temperature and stirring time, as well as reusability of the sorbent were also studied in batch experiments. In the optimum conditions, the decrease in the cation concentration in aqueous solutions was observed in the order Cu>Pb>Cd but for each ion the decrease was at least 50% of the initial concentration. The sorbent has demonstrated high effectiveness in cation sorption and after regeneration it can be applied repeatedly in the process described.      

Energetic basis for drug resistance of HIV-1 protease mutants against amprenavir

Amprenavir (APV) is a high affinity (0.15 nM) HIV-1 protease (PR) inhibitor. However, the affinities of the drug resistant protease variants V32I, I50V, I54V, I54M, I84V and L90M to amprenavir are decreased 3 to 30-fold compared to the wild-type. In this work, the popular molecular mechanics Poisson-Boltzmann surface area method has been used to investigate the effectiveness of amprenavir against the wild-type and these mutated protease variants. Our results reveal that the protonation state of Asp25/Asp25′ strongly affects the dynamics, the overall affinity and the interactions of the inhibitor with individual residues. We emphasize that, in contrast to what is often assumed, the protonation state may not be inferred from the affinities but requires pK_a calculations. At neutral pH, Asp25 and Asp25′ are ionized or protonated, respectively, as suggested from pK_a calculations. This protonation state was thus mainly considered in our study. Mutation induced changes in binding affinities are in agreement with the experimental findings. The decomposition of the binding free energy reveals the mechanisms underlying binding and drug resistance. Drug resistance arises from an increase in the energetic contribution from the van der Waals interactions between APV and PR (V32I, I50V, and I84V mutant) or a rise in the energetic contribution from the electrostatic interactions between the inhibitor and its target (I54M and I54V mutant). For the V32I mutant, also an increased free energy for the polar solvation contributes to the drug resistance. For the L90M mutant, a rise in the van der Waals energy for APV-PR interactions is compensated by a decrease in the polar solvation free energy such that the net binding affinity remains unchanged. Detailed understanding of the molecular forces governing binding and drug resistance might assist in the design of new inhibitors against HIV-1 PR variants that are resistant against current drugs.     

Purification and characterization of an alkaline protease prot 1 frombotrytis cinerea

Alkaline thiol protease named Prot 1 was isolated from a culture filtrate ofBotrytis cinerea. The enzyme was purified by ammonium sulfate fractionation, gel filtration, and ion-exchange chromatography. Thus, the enzyme was purified to homogeneity with specific activity of 30-fold higher than that of the crude broth. The purified alkaline protease has an apparent molecular mass of 43 kDa under denaturing conditions as estimated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The native molecular mass (45 kDa), determined by gel filtration, indicated that the alkaline protease has a monomeric form. The purified protease was biochemically characterized. The enzyme is active at alkaline pH and has a suitable and high thermostability. The optimal pH and temperature for activity were 9.0–10.0 and 60°C, respectively. This protease was stable between pH 5.0 and 12.0. The enzyme retained 85% of its activity by treatment at 50°C over 120 min; it maintained 50% of activity after 60 min of heating at 60°C. Furthermore, the protease retained almost complete activity after 4 wk storage at 25°C. The activity was significantly affected by thiol protease inhibitors, suggesting that the enzyme belongs to the alkaline thiol protease family. With the aim on industrial applications, we focused on studying the stability of the protease in several conditions. Prot 1 activity was not affected by ionic strength and different detergent additives, and, thus, the protease shows remarkable properties as a biodetergent catalyst.     

Virtual screening for anti-HIV-1 RT and anti-HIV-1 PR inhibitors from the Thai medicinal plants database: a combined docking with neural networks approach

The virtual screening approach for docking small molecules into a known protein structure is a powerful tool for drug design. In this work, a combined docking and neural network approach, using a self-organizing map, has been developed and applied to screen anti-HIV-1 inhibitors for two targets, HIV-1 RT and HIV-1 PR, from active compounds available in the Thai Medicinal Plants Database. Based on nevirapine and calanolide A as reference structures in the HIV-1 RT binding site and XK-263 in the HIV-1 PR binding site, 2,684 compounds in the database were docked into the target enzymes. Self-organizing maps were then generated with respect to three types of pharmacophoric groups. The map of the reference structures were then superimposed on the feature maps of all screened compounds. Only the structures having similar features to the reference compounds were accepted. By using the SOMs, the number of candidates for HIV-1 RT was reduced to six and nine compounds consistent with nevirapine and calanolide A, respectively, as references. For the HIV-1 PR target, there are 135 screened compounds showed good agreement with the XK-263 feature map. These screened compounds will be further tested for their HIV-1 inhibitory affinities. The obtained results indicate that this combined method is clearly helpful to perform the successive screening and to reduce the analyzing step from AutoDock and scoring procedure.     

Magnesium/methanol: an effective reducing agent for chemoselective reduction of pyrimidine-2(1H)-ones

Magnesium in methanol is an effective reagent for the chemoselective reduction of pyrimidine-2(1H)-ones. Other reducible functionalities such as ester and alkene of enamine ester and uriedo carbonyl remain unaffected. This constitutes the first example of the formation of Biginelli 3,4-dihydropyrimidin-2(1H)ones through the reduction of pyrimidine-2(1H)-ones.     

Chemical modification of oleanene type triterpenes and their inhibitory activity against HIV-1 protease dimerization

Oleanolic acid derivatives with different lengths of 3-O-acidic acyl chains were synthesized and evaluated for their inhibitory activity against HIV-1 protease. The lengths of the acidic chains were optimized to 6 and 8 carbons. Changing a 3-ester bond to an amide bond or dimerization of the triterpenes retained their inhibitory activity against HIV-1 protease. Introduction of an additional acidic chain to C-28 of oleanolic acid increased the inhibitory activity appreciably, though a derivative with only one acidic chain linked at C-28 also showed potent activity against HIV-1 protease. The inhibitory mechanism was proved directly by size exclusion chromatography to be inhibition of dimerization of the enzyme polypeptides. The ester bonds of the triterpene derivatives were found to be stable to lipase under mild alkaline conditions.     

Bidentate lactate binding in aqueous solution in a cationic,heptadentate lanthanide complex: an effective chiral derivatising agent

The X-ray crystal structures of cationic, heptadentate lanthanide complexes of holmium and ytterbium bound to lactate are reported and the observed bidentate chelation in the solid state is consistent with near-IR CD (Yb) and solution NMR measurements; the complexes are shown to act as aqueous chiral derivatising agents for alpha-hydroxy acids.     

Nominal and effective strains in severe plastic deformation processes

Severe plastic deformation (SPD) processes may be used for obtaining materials with a nanocrystalline structure and enhanced properties. Recent work on such methods is briefly reviewed, with special emphasis on processes resulting in only minor shape changes, i.e. multi-step forging (MSF), high-pressure torsion (HPT) and equal-channel angular extrusion (ECAE). The nominal strain levels achieved by these processes are discussed, taking into account various possible conditions of deformation (at constant or variable thickness for HPT, according to the exact shape of the die for ECAE). In actual operation, strain values may deviate from the calculated ones, particularly due to strain inhomogeneities (along the sample radius or through the thickness for HPT, longitudinal or transverse inhomogeneities in ECAE). The domains of application for these methods are considered.     

Almotriptan,an antimigraine agent,and its malate salt

The crystal structures of almotriptan {systematic name: N,N‐dimethyl‐2‐[5‐(pyrrolidin‐1‐ylsulfonylmethyl)‐1H‐indol‐3‐yl]ethanamine}, C₁₇H₂₅N₃O₂S, and almotriptan malate {systematic name: N,N‐dimethyl‐2‐[5‐(pyrrolidin‐1‐ylsulfonylmethyl)‐1H‐indol‐3‐yl]ethanaminium malate, C₁₇H₂₆N₃O₂S⁺·C₄H₅O₅⁻, a novel selective serotonin 1B/D agonist, have been determined in order to gain further insight into the structure–activity relationships of triptans. The two structures differ in the orientation of their sulfonylpyrrolidine side chains. A comparison with other triptans reveals that molecules of almotriptan, sumatriptan, zolmitriptan and rizatriptan can adopt two principal conformations. N—H...N, N—H...O and O—H...O hydrogen bonds are responsible for the molecular packing.