Pharmacophore elucidation and 3D-QSAR analysis of a new class of highly potent inhibitors of acid ceramidase based on maximum common substructure and field fit alignment methods

Comparative molecular field analysis (CoMFA) and comparative similarity indices analysis (CoMSIA) studies have been carried on a series of 2,4-dioxopyrimidine-1-carboxamides as acid ceramidase inhibitors. Two alignment rules for the compounds were defined using maximum common substructure and field fit. The best orientation was then searched by all-orientation search strategy, to minimize the effect of the initial orientation of the structures. The Kennard Stone algorithm was used to divide the entire set into training (25 compounds) and test (7 compounds) sets. Pharmacophore model identification was also performed using DISCOtech algorithm and refinement was carried out using GASP, to highlight important structural features that could be responsible for the inhibitory activity. All constructed models showed appropriate statistical parameters in terms of q ² and r _pred ² . Based upon the information obtained from CoMFA, CoMSIA, and developed pharmacophore pattern, some key features that may be used to design new inhibitors for acid ceramidase have been identified.     

Multivariate curve resolution alternating least squares in the quantitative determination of sulfur using overlapped S(Kα)–Mo(Lα) emission peaks by wavelength dispersive X‐ray fluorescence spectrometry

Spectral line overlap is a serious problem in quantitative X‐ray fluorescence analysis. In this study multivariate curve resolution alternating least squares (MCR‐ALS) approach was used to resolve the effect of overlapping S(K_α)–Mo(L_α) emission lines generated by standard‐less software of a wavelength dispersive X‐ray fluorescence spectrometer (WDXRF) for the quantitative monitoring of sulfur in mineral samples. Scan channel set contained Ge crystal, 550‐µm collimator, flow detector (Ar + CH₃) and rhodium (Rh) tube. The 18 calibration and 10 validation samples contain 0.00%–10.98% sulfate (SO₃) and 0.00%–92.40% MoO₃. The digitized spectral data were extracted in the range between 109° and 113.9° (2θ) at every 0.1 degree. Lack of fit percentage (LOF%) for experimental data and the variance explained at the optimum condition () were 2.32 and 99.94, respectively. The values of the root mean square error of prediction (RMSEP) for analyzing of sulfur were 0.23. MCR‐ALS was also compared with partial least squares (PLS) method for determination of sulfur in the presence of molybdenum. To evaluate the resolution and quantification performance of MCR‐ALS procedure, the method was used to determine sulfur in presence of molybdenum in two synthetic soil samples. Copyright © 2015 John Wiley & Sons, Ltd.     

Indigo Carmine as New Label in PNA Biosensor for Detection of Short Sequence of p53 Tumor Suppressor Gene

A new electrochemical PNA hybridization biosensor for detection of a 15‐mer sequence unique to p53 using indigo carmine (IC) as an electrochemical detector is described in this work. This genosensor is based on the hybridization of target oligonucleotide with its complementary probe immobilized on the gold electrode by self‐assembled monolayer formation. Because this label is electroactive in acidic medium, the interaction between IC and short sequence of p53 is studied by differential pulse voltammety (DPV) in 0.1 M H₂SO₄. The results of electrochemical impedance spectroscopy and cyclic voltammetry in the solution of [Fe(CN)₆]^3?/4? shows no breakage in PNA‐DNA duplex. A decrease in the voltammetric peak currents of IC is observed upon hybridization of the probe with the target DNA. The influence of probe concentration on effective discrimination against non‐complementary oligonucleotides is investigated and a concentration of 10^?7 M is selected. The diagnostic performance of the PNA sensor is described and the detection limit is found to be 4.31×10^?12 M.     

Efficient chemoselective alkylation of quinoline 2,4‐diol derivatives in water

Synthesis of various C‐3‐dialkyl derivatives of quinoline 2,4‐diol was achieved by condensation of aniline or substituted anilines with diethyl malonate, followed by chemoselective alkylation at C‐3 in water. The higher yields, easy work up and environmental compatible conditions are the main aspects of our method. J. Heterocyclic Chem., 2011.     

Fractal Inspired Models of quark and gluon distributions and longitudinal structure function FL (x, Q2) at small x

In recent years, Fractal Inspired Models of quark and gluon densities at small x have been proposed. In this paper, we investigate longitudinal structure function F _L (x, Q ²) within this approach. We make predictions using the Quantum Chromodynamics (QCD) based approximate relation between the longitudinal structure function and the gluon density. As the Altarelli-Martinelli equation for the longitudinal structure function cannot be applied to Model I due to the presence of a singularity in the Bjorken x-space we consider Model II only. The qualitative feature of the prediction of Model II is found to be compatible with the QCD expectation.     

Jute as raw material for the preparation of microcrystalline cellulose

Cellulose was extracted at a yield of 59.8% from jute fibres based on the formic acid/peroxyformic acid process at an atmospheric pressure. The amounts of dissolved lignin and hemicelluloses were determined in the spent liquor. The results showed that the spent liquor contained 10.6% total sugars and 10.9% lignin (based on jute). Microcrystalline cellulose (MCC) was further prepared from the jute cellulose based on the acid hydrolysis technique. A very high yield, 48–52.8% (based on the jute raw material) was obtained. The acid hydrolysate of cellulose contained 2.7% glucose and 0.2% xylose. The MCC samples obtained from two different conditions, one at a low acidity and the other at a high acidity, were characterized by means of Thermo Gravimetric Analysis, Fourier Transform Infrared, X-ray detraction, Scanning Electron Micrograph, and Transmission Electron Micrograph techniques.     

Open charm mesons and charmonia in magnetized strange hadronic matter

We investigate the in-medium masses of open charm mesons (D(\begin{document}$ D^0 $\end{document}, \begin{document}$ D^+ $\end{document}), \begin{document}$ \bar{D} $\end{document}(\begin{document}$ \bar{D^0} $\end{document}, \begin{document}$ D^- $\end{document}), \begin{document}$ D_s $\end{document}(\begin{document}$ {D_{s}}^+ $\end{document}, \begin{document}$ {D_{s}}^- $\end{document})) and charmonium states (\begin{document}$ J/\psi $\end{document}, \begin{document}$ \psi(3686) $\end{document}, \begin{document}$ \psi(3770) $\end{document}, \begin{document}$ \chi_{c0} $\end{document}, \begin{document}$ \chi_{c2} $\end{document}) in strongly magnetized isospin asymmetric strange hadronic matter using a chiral effective model. In the presence of a magnetic field, the number and scalar densities of charged baryons have contributions from Landau energy levels. The mass modifications of open charm mesons result from their interactions with nucleons, hyperons, and the scalar fields (the non-strange field σ, strange field ζ, and isovector field δ) in the presence of a magnetic field. The mass modifications of the charmonium states result from the modification of gluon condensates in a medium simulated by the variation in the dilaton field (χ) in the chiral effective model. The effects of finite quark masses are also incorporated in the trace of the energy-momentum tensor in quantum chromodynamics to investigate the mass shifts of charmonium states. The in-medium masses of open charm mesons and charmonia are observed to decrease with an increase in baryon density. The charged \begin{document}$ D^+ $\end{document}, \begin{document}$ D^- $\end{document}, \begin{document}$ {D_{s}}^+ $\end{document}, and \begin{document}$ {D_{s}}^- $\end{document} mesons have additional positive mass shifts due to Landau quantization in the presence of a magnetic field. The effects of the strangeness fraction are observed to be more dominant for \begin{document}$ \bar{D} $\end{document} mesons compared with D mesons. The mass shifts of charmonia are observed to be larger in hyperonic media compared with nuclear media when the effect of the finite quark mass term is neglected. These medium mass modifications can have observable consequences on the production of the open charm mesons and charmonia in high-energy asymmetric heavy-ion collision experiments.     

Structure–Activity Relationships of the Antimalarial Agent Artemisinin 10. Synthesis and Antimalarial Activity of Enantiomers of rac-5β-Hydroxy-d-Secoartemisinin and Analogs: Implications Regarding the Mechanism of Action

An efficient synthesis of rac-6-desmethyl-5β–hydroxy-d-secoartemisinin 2, a tricyclic analog of R-(+)-artemisinin 1, was accomplished and the racemate was resolved into the (+)-2b and (−)-2a enantiomers via their Mosher Ester diastereomers. Antimalarial activity resided with only the artemisinin-like enantiomer R-(−)-2a. Several new compounds 9–16, 19a, 19b, 22 and 29 were synthesized from rac-2 but the C-5 secondary hydroxyl group was surprisingly unreactive. For example, the formation of carbamates and Mitsunobu reactions were unsuccessful. In order to assess the unusual reactivity of 2, a single crystal X-ray crystallographic analysis revealed a close intramolecular hydrogen bond from the C-5 alcohol to the oxepane ether oxygen (O-11). All products were tested in vitro against the W-2 and D-6 strains of Plasmodium falciparum. Several of the analogs had moderate activity in comparison to the natural product 1. Iron (II) bromide-promoted rearrangement of 2 gave, in 50% yield, the ring-contracted tetrahydrofuran 22, while the 5-ketone 15 provided a monocyclic methyl ketone 29 (50%). Neither 22 nor 29 possessed in vitro antimalarial activity. These results have implications in regard to the antimalarial mechanism of action of artemisinin.     

Exploring the potential of fluoro-flavonoid derivatives as anti-lung cancer agents: DFT,molecular docking,and molecular dynamics techniques

The present investigation utilized in silico methodologies to explore the diverse pharmacological activities, toxicity profiles, and chemical reactivity of a series of fluoro-flavonoid compounds ( 1 – 14 ), which are secondary metabolites of plants known for their broad range of biological effects. A comprehensive strategy is utilized, incorporating methods such as prediction of activity spectra for substances (PASS) prediction, absorption, distribution, metabolism, excretion, and toxicity (ADMET) assessments, and density functional theory (B3LYP) calculations using three basis sets: 6-31G(d,p), 6-311G(d,p), and 6-311++G(d,p). Furthermore, the study employed molecular docking technique to identify target proteins, including HER2 (7JXH), EGFR (4UV7), FPPS (1YQ7), HPGDS (1V40), DCK (1P60), and KEAP1 on Nrf2 (1X2J), for the investigated compounds, with cianidanol and genistein serving as reference drugs for the docking process. The investigated fluoro-flavonoid compounds exhibited significantly greater binding affinities (ranging from −8.3 to −10.6 kcal mol⁻¹) toward HER2, HPGDS, and KEAP1 compared to the reference drugs, cianidanol and genistein, which displayed binding affinities ranging from −8.4 to −9.4 kcal mol⁻¹. Furthermore, molecular dynamics simulations were conducted to assess the stability of the protein-ligand interaction, using the root-mean-square deviation (RMSD), root-mean-square fluctuation (RMSF), Radius of gyration (Rg) parameters and principle component analysis (PCA). Among the tested fluoro-flavonoid analogs, analog 11 showed a RMSD value of .15 nm with the HER2 protein target, indicating a stable interaction. Based on in silico results, it appears that the fluoro-flavonoid compound 11 has the potential to serve as a targeted anti-lung cancer drug. However, additional in vivo and in vitro studies are necessary to confirm this hypothesis.