Planning new Trypanosoma cruzi CYP51 inhibitors using QSAR studies

Molecular Diversity - Chagas disease kills over 10,000 people per year, and approximately 8 million people are infected by Trypanosoma cruzi. The reference drug for treatment of the disease,...     

Fluorides of Silver Under Large Compression**

The silver-fluorine phase diagram has been scrutinized as a function of external pressure using theoretical methods. Our results indicate that two novel stoichiometries containing Ag⁺ and Ag²⁺ cations (Ag₃F₄ and Ag₂F₃) are thermodynamically stable at ambient and low pressure. Both are computed to be magnetic semiconductors under ambient pressure conditions. For Ag₂F₅, containing both Ag²⁺ and Ag³⁺, we find that strong 1D antiferromagnetic coupling is retained throughout the pressure-induced phase transition sequence up to 65 GPa. Our calculations show that throughout the entire pressure range of their stability the mixed-valence fluorides preserve a finite band gap at the Fermi level. We also confirm the possibility of synthesizing AgF₄ as a paramagnetic compound at high pressure. Our results indicate that this compound is metallic in its thermodynamic stability region. Finally, we present general considerations on the thermodynamic stability of mixed-valence compounds of silver at high pressure.     

In Silico and Experimental Investigation of the Biological Potential of Some Recently Developed Carprofen Derivatives

The efficient regioselective bromination and iodination of the nonsteroidal anti-inflammatory drug (NSAID) carprofen were achieved by using bromine and iodine monochloride in glacial acetic acid. The novel halogenated carprofen derivatives were functionalized at the carboxylic group by esterification. The regioselectivity of the halogenation reaction was evidenced by NMR spectroscopy and confirmed by X-ray analysis. The compounds were screened for their in vitro antibacterial activity against planktonic cells and also for their anti-biofilm effect, using Gram-positive bacteria (Staphylococcus aureus ATCC 29213, Enterococcus faecalis ATCC 29212) and Gram-negative bacteria (Escherichia coli ATCC 25922 and Pseudomonas aeruginosa ATCC 27853). The cytotoxic activity of the novel compounds was tested against HeLa cells. The pharmacokinetic and pharmacodynamic profiles of carprofen derivatives, as well as their toxicity, were established by in silico analyses.     

Viscoelastic and dielectric behaviour of thin films made from siloxane-containing poly(oxadiazole-imide)s

Siloxane-containing poly(oxadiazole-imide)s were prepared by polycondensation reaction of two aromatic diamino-oxadiazoles with a dianhydride containing tetramethylsiloxane moiety. Free-standing flexible films having good mechanical properties were made therefrom. The polyimides exhibited high thermal stability with initial decomposition temperature being above 440 °C and glass transition in the range of 165-183 °C. The dielectric constant values, measured at room temperature and in the frequency domain of 1 Hz-1 MHz, are in the range of 2.69-2.90, being significantly lower in comparison with that of Kapton HN® film, whose dielectric constant values ranged from 3.13 to 3.24. The dielectric loss values are low, in the same range with those of Kapton HN®. The dielectric spectroscopy data corroborated with the dynamo-mechanical analysis ones showed distinct sub-glass transitions for these polymers: γ relaxations with activation energies of 44 and 45 kJ/mol, and a β relaxation with an activation energy of 107 kJ/mol. The dielectric properties are discussed in comparison with those of Kapton HN® film measured under the same conditions.     

Determination of organic acids in wine by zone electrophoresis on a chip with conductivity detection

An appropriate combination of separation mechanisms (simultaneous use of differences in pK values, host-guest complexations, and the ionic strength dependences of the actual ionic mobilities) provided zone electrophoresis (ZE) resolution of 22 organic and inorganic acids expected in wines on a polymethylmethacrylate (PMMA) chip with integrated conductivity detection. These separating conditions offered a framework for the ZE determination of organic acids responsible for some important organoleptic characteristics of wines (tartrate, malate, succinate, acetate, citrate, and lactate). The ZE procedure developed in this context is simple and rapid (ca. 10 minutes' analysis time), while affording reproducible migration and quantitation data for the acids. For example, 0.8-2.0% RSD values characterized the migration times of the acids for 25 repeated ZE runs with the same sample carried out in 5 days in the background electrolyte solution prepared freshly on a daily basis, while 3-5% RSD values were typical for the accompanying peak area data. The concentration ranges within which the acids of analytical interest could be determined in one ZE run covered all wine samples included in our study (100-400-fold sample dilutions were needed to work under the conditions corresponding to the validities of the calibration data). 90-110% recoveries of the acids as obtained repeatedly for one of the reference wine samples used in our experiments indicate a good predisposition of the present method to provide accurate analytical results. This statement also supports the results from the determination of the acids in reference wine samples with claimed concentrations of malic (five samples), tartaric (one sample), and lactic (one sample) acids.     

Antinociceptive Efficacy of the µ-Opioid/Nociceptin Peptide-Based Hybrid KGNOP1 in Inflammatory Pain without Rewarding Effects in Mice: An Experimental Assessment and Molecular Docking

Opioids are the most effective analgesics, with most clinically available opioids being agonists to the µ-opioid receptor (MOR). The MOR is also responsible for their unwanted effects, including reward and opioid misuse leading to the current public health crisis. The imperative need for safer, non-addictive pain therapies drives the search for novel leads and new treatment strategies. In this study, the recently discovered MOR/nociceptin (NOP) receptor peptide hybrid KGNOP1 (H-Dmt-D-Arg-Aba-β-Ala-Arg-Tyr-Tyr-Arg-Ile-Lys-NH₂) was evaluated following subcutaneous administration in mouse models of acute (formalin test) and chronic inflammatory pain (Complete Freund’s adjuvant-induced paw hyperalgesia), liabilities of spontaneous locomotion, conditioned place preference, and the withdrawal syndrome. KGNOP1 demonstrated dose-dependent antinociceptive effects in the formalin test, and efficacy in attenuating thermal hyperalgesia with prolonged duration of action. Antinociceptive effects of KGNOP1 were reversed by naltrexone and SB-612111, indicating the involvement of both MOR and NOP receptor agonism. In comparison with morphine, KGNOP1 was more potent and effective in mouse models of inflammatory pain. Unlike morphine, KGNOP1 displayed reduced detrimental liabilities, as no locomotor impairment nor rewarding and withdrawal effects were observed. Docking of KGNOP1 to the MOR and NOP receptors and subsequent 3D interaction pattern analyses provided valuable insights into its binding mode. The mixed MOR/NOP receptor peptide KGNOP1 holds promise in the effort to develop new analgesics for the treatment of various pain states with fewer MOR-mediated side effects, particularly abuse and dependence liabilities.     

Refractive Indices Measurement and Correlation for Selected Binary Systems of Various Polarities at 25 °C

New refractive indices at 25 °C were measured and are reported here for 19 binary mixtures of pentan-3-one+1,2-dichloroethane, +1,3-dichloropropane, +1,4-dichlorobutane, +trichloromethane, +1,1,1-trichloroethane, +1,1,2,2-tetrachloroethane; cyclopentanone+1-chlorobutane, +1,1,2,2-tetrachloroethane; cyclohexanone+1,1,2,2-tetrachloroethane; 5-chloro-2-pentanone+n-hexane, +toluene, +ethylbenzene; nitromethane+trichloromethane; and nitromethane or nitroethane, +1,2-dichloroethane, +1,3-dichloropropane, +1,4-dichlorobutane. The experimental refractive index deviations from linear mixing behavior have been evaluated and correlated consistently with the 3-parameter Redlich–Kister equation with good results. The molar refraction was also examined for the systems including pentan-3-one, cyclopentanone, cyclohexanone and 5-chloro-2-pentanone for which densities and excess molar volumes are available from previous works. Different theoretical (n, ρ) mixing rules were tested for these systems. The excess Gibbs energy G ^E and excess enthalpy H ^E values were considered together with the excess molar volumes V ^E, excess refractive indexes $ n_{\text{D}}^{\text{E}} $ , molar refraction R and excess molar refractions R ^E on mixing in the discussion of the influence of the alkyl chain length or of the nature of the second component in the mixture in terms of molecular interactions.     

Comparison of catalytic properties of free and immobilized cellobiase Novozym 188

The enzyme cellobiase from Novo was immobilized in controlled pore silica particles by covalent binding with the silane-glutaraldehyde method with protein and activity yields of 67 and 13.7%, respectively. The activity of the free enzyme (FE) and immobilized enzyme (IE) was determined with 2 g/L of cellobiose, from 40 to 75°C at pH 3.0–7.0 for FE and from 40 to 70°C at pH 2.2–7.0 for IE. At pH 4.8 the maximum specific activity for the FE and IE occurred at 65°C: 17.8 and 2.2 micromol of glucose/(min·mg of protein), respectively. For all temperatures the optimum pH observed for FE was 4.5 whereas for IE it was shifted to 3.5. The energy of activation was 11 kcal/mol for FE and 5 kcal/mol for IE at pH 4.5–5, showing apparent diffusional limitation for the latter. Thermal stability of the FE and IE was determined with 2 g/L of cellobiose (pH 4.8) at temperatures from 40 to 70°C for FE and 40 to 75°C for IE. Free cellobiase maintained its activity practically constant for 240 min at temperatures up to 55°C. The IE has shown higher stability, retaining its activity in the sametest up to 60°C. Half-life experimental results for FE were 14.1, 2.1, and 0.17 h at 60, 65, and 70°C, respectively, whereas IE at the same temperatures had half-lives of 245, 21.3, and 2.9 h. The energy of thermal deactivation was 80.6 k cal/mol for the free enzyme and 85.2 k cal/mol for the IE, suggesting stabilization by immobilization.