Discovery of novel inhibitors for <Emphasis Type="Italic">Leishmania</Emphasis> nucleoside diphosphatase kinase (NDK) based on its structural and functional characterization

Nucleoside diphosphate kinases (NDKs) are ubiquitous enzymes that catalyze the transfer of the γ-phosphate moiety from an NTP donor to an NDP acceptor, crucial for maintaining the cellular level of nucleoside triphosphates (NTPs). The inability of trypanosomatids to synthesize purines de novo and their dependence on the salvage pathway makes NDK an attractive target to develop drugs for the diseases they cause. Here we report the discovery of novel inhibitors for Leishmania NDK based on the structural and functional characterization of purified recombinant NDK from Leishmania amazonensis. Recombinant LaNDK possesses auto-phosphorylation, phosphotransferase and kinase activities with Histidine 117 playing an essential role. LaNDK crystals were grown by hanging drop vapour diffusion method in a solution containing 18% PEG-MME 500, 100 mM Bis-Tris propane pH 6.0 and 50 mM MgCl₂. It belongs to the hexagonal space group P6₃22 with unit cell parameters a?=?b?=?115.18, c?=?62.18 Å and α?=?β?=?90°, γ?=?120°. The structure solved by molecular replacement methods was refined to crystallographic R-factor and R_free values of 22.54 and 26.52%, respectively. Molecular docking and dynamics simulation-based virtual screening identified putative binding compounds. Protein inhibition studies of selected hits identified five inhibitors effective at micromolar concentrations. One of the compounds showed ~45% inhibition of Leishmania promastigotes proliferation. Analysis of inhibitor-NDK complexes reveals the mode of their binding, facilitating design of new compounds for optimization of activities as drugs against leishmaniasis.     

Sensitive detection of endocrine disrupters using ionic liquid--single walled carbon nanotubes modified screen-printed based biosensors

Simple and low cost biosensor based on screen-printed electrode for sensitive detection of some alkylphenols was developed, by entrapment of HRP in a nanocomposite gel based on single-walled carbon nanotubes (SWCNTs) and 1-butyl-3-methylimidazolium hexafluorophosphate ([BMIM][PF₆]) ionic liquid. Raman and FTIR spectroscopy, CV and EIS studies demonstrate the interaction between SWCNTs and ionic liquid. The nanocomposite gel, SWCNT-[BMIM][PF₆] provides to the modified sensor a considerable enhanced electrocatalytic activity toward hydrogen peroxide reduction. The HRP based biosensor exhibits high sensitivity and good stability, allowing a detection of the alkylphenols at an applied potential of −0.2 V vs. Ag/AgCl, in linear range from 5.5 to 97.7 μM for 4-t-octylphenol and respectively, between 5.5 and 140 μM for 4-n-nonylphenol, with a response time of about 5 s. The detection limit was 1.1 μM for 4-t-octylphenol, and respectively 0.4 μM for 4-n-nonylphenol (S/N = 3).     

Determination of aliphatic amines by gas chromatography–mass spectrometry after in-syringe derivatization with pentafluorobenzoyl chloride

A simple and highly sensitive gas chromatographic method has been developed for the determination of low molecular weight short-chain aliphatic amines (SCAAs) after their simultaneous extraction and in-syringe derivatization with pentafluorobenzoyl chloride (PFBOC). Derivatization of the low molecular weight aliphatic amines in bicarbonate buffer of pH 10.5 with PFBOC was followed by immersed solvent microextraction. Derivatization conditions, including reagent concentration, reaction pH, ionic concentration of buffer, reaction time, stirring rate, reaction temperature and extraction solvent, have been investigated for method optimization. Linearity was studied within range of 0.15 pg ml⁻¹–50 ng ml⁻¹. The correlation coefficients were between 0.9934 and 0.9999. Detection limit of derivatized amines proved to be in the range of 0.117–1.527 pg ml⁻¹, and the intraday and interday relative standard deviation (RSD) values were less than 8% with respect to peak area. The method was applied for analysis of lake, river and industrial waste water. The recoveries of extraction from lake, river and industrial waste water samples, which have been spiked with different levels of aliphatic amines, were in the range of 68–99%, 63–102% and 62–105%, respectively.     

Itinerant electron metamagnetism and magnetocaloric effect in Dy(Co,Si)2

Itinerant electron metamagnetism in Dy(Co_1-xSi_x)₂ compounds was studied in the light of a recent theoretical model based on magnetovolume effect and spin fluctuations. The nature of the magnetic transition in these compounds was analyzed within the framework of this model. The magnetocaloric effect in these compounds has been calculated and correlated with the strength of itinerant electron metamagnetism. The domain wall pinning effect was found to be dominant at low temperatures.     

Structures of mixed ligand copper(II) complexes coordinating through S,O and N. E.p.r. studies

Summary The formation of near square planar mixed ligand Cu^II complexes with diethyldithiocarbamate (dtc) as one of the ligands and 8-hydroxyquinolinate (Hy) or salicylaldehydate (Sal) as the second ligand by exchange reactions, has been detected by e.p.r. spectroscopy. The concentrations of the mixed ligand complexes in the reaction mixtures are small compared to those of the reactants. Six different tests were used to identify the m₁=3/2,⁶³Cu hyperfine transition of the near square planar complexes, based upon the relative concentrations of the different Cu^II species in the reaction mixture, ligand hyperfine structures, the minium linewidths observed in a temperature dependent study and the isotropic g₀ estimated from the e.p.r. spectra in solution.     

A versatile route for the synthesis of 3-(1′, 1′-dimethyllallyl)coumarins

Synthesis of 3-(′, 1′-dimethylallyl)herniarin and 3-(′, 1′-dimethylallyl)desmothosyherniarin has been carried out by a versatile route.     

Charged-particle multiplicity density at midrapidity in central Pb-Pb collisions at sqrt[S(NN)] = 2.76 TeV

The first measurement of the charged-particle multiplicity density at midrapidity in Pb-Pb collisions at a center-of-mass energy per nucleon pair √ S NN = 2.76 TeV is presented. For an event sample corresponding to the most central 5% of the hadronic cross section, the pseudorapidity density of primary charged particles at midrapidity is 1584 ± 4(stat) ± 76(syst), which corresponds to 8.3 ± 0.4(syst) per participating nucleon pair. This represents an increase of about a factor 1.9 relative to pp collisions at similar collision energies, and about a factor 2.2 to central Au-Au collisions at √ S NN = 2.76 TeV. This measurement provides the first experimental constraint for models of nucleus-nucleus collisions at LHC energies.