Synthesis and biological evaluation of 2,3-diarylpyrazines and quinoxalines as selective COX-2 inhibitors

Several 2,3-diaryl pyrazines and quinoxalines with 4-sulfamoyl (SO(2)NH(2))/methylsulfonyl (SO(2)Me)-phenyl pharmacophores have been synthesized and evaluated for the cyclooxygenase (COX-1/COX-2) inhibitory activity. Smaller groups such as methoxy, methyl and fluoro when substituted at/around position-4 of the adjacent phenyl ring, have great impact on the selective COX-2 inhibitory activity of the series. Many potential compounds were obtained from a brief structure-activity relationship (SAR) study. Two of these, compounds 11 and 25 exhibited excellent in vivo activity in the established animal model of inflammation. Since compound 25 possessed an amenable sulfonamide group, two of its prodrugs 48 and 49 were also synthesized. Both of them have excellent in vivo potential, and represent a new class of COX-2 inhibitor.     

Liquid chromatographic separation and thermodynamic investigation of lorcaserin hydrochloride enantiomers on immobilized amylose–based chiral stationary phase

A novel liquid chromatographic method was developed for enantiomeric separation of lorcaserin hydrochloride on Chiralpak IA column containing chiral stationary phase immobilized with amylose tris (3.5‐dimethylphenylcarbamate) as chiral selector. Baseline separation with resolution greater than 4 was achieved using mobile phase containing mixture of n‐hexane/ethanol/methanol/diethylamine (95:2.5:2.5:0.1, v/v/v/v) at a flow rate of 1.2 mL/min. The limit of detection and limit of quantification of the S‐enantiomer were found to be 0.45 and 1.5 μg/mL, respectively; the developed method was validated as per ICH guideline. The influence of column oven temperatures studied in the range of 20°C to 50°C on separation was studied; from this, retention, separation, and resolution were investigated. The thermodynamic parameters ΔH°, ΔS°, and ΔG° were evaluated from van't Hoff plots,(Ink′ _versus 1/T) and used to explain the strength of interaction between enantiomers and immobilized amylose–based chiral stationary phase     

SAR and factor IXa crystal structure of a dual inhibitor of factors IXa and Xa

Modifications to the P4 moiety and pyrazole C3 substituent of factor Xa inhibitor SN-429 provided several new compounds, which are 5-10nM inhibitors of factor IXa. An X-ray crystal structure of one example complexed to factor IXa shows that these compounds adopt a similar binding mode to that previously observed with pyrazole inhibitors in the factor Xa active site both with regard to how the inhibitor binds and the position of Tyr99.     

Zinc regulates the activity of kinase-phosphatase pair (BasPrkC/BasPrpC) in Bacillus anthracis

Bacillus anthracis Ser/Thr protein kinase PrkC (BasPrkC) is important for virulence of the bacterium within the host. Homologs of PrkC and its cognate phosphatase PrpC (BasPrpC) are the most conserved mediators of signaling events in diverse bacteria. BasPrkC homolog in Bacillus subtilis regulates critical processes like spore germination and BasPrpC modulates the activity of BasPrkC by dephosphorylation. So far, biochemical and genetic studies have provided important insights into the roles of BasPrkC and BasPrpC; however, regulation of their activities is not known. We studied the regulation of BasPrkC/BasPrpC pair and observed that Zn²⁺ metal ions can alter their activities. Zn²⁺ promotes BasPrkC kinase activity while inhibits the BasPrpC phosphatase activity. Concentration of Zn²⁺ in growing B. anthracis cells was found to vary with growth phase. Zn²⁺ was found to be lowest in log phase cells while it was highest in spores. This variation in Zn²⁺ concentration is significant for understanding the antagonistic activities of BasPrkC/BasPrpC pair. Our results also show that BasPrkC activity is modulated by temperature changes and kinase inhibitors. Additionally, we identified Elongation Factor Tu (BasEf-Tu) as a substrate of BasPrkC/BasPrpC pair and assessed the impact of their regulation on BasEf-Tu phosphorylation. Based on these results, we propose Zn²⁺ as an important regulator of BasPrkC/BasPrpC mediated phosphorylation cascades. Thus, this study reveals additional means by which BasPrkC can be activated leading to autophosphorylation and substrate phosphorylation.     

Accumulation of Trace Metals by Mangrove Plants in Indian Sundarban Wetland: Prospects for Phytoremediation

The work investigates on the potential of ten mangrove species for absorption, accumulation and partitioning of trace metal(loid)s in individual plant tissues (leaves, bark and root/pneumatophore) at two study sites of Indian Sundarban Wetland. The metal(loid) concentration in host sediments and their geochemical characteristics were also considered. Mangrove sediments showed unique potential in many- fold increase for most metal(loid)s than plant tissues due to their inherent physicochemical properties. The ranges of concentration of trace metal(loid)s for As, Cd, Co, Cr, Cu, Fe, Hg, Mn, Ni, Pb and Zn in plant tissue were 0.006–0.31, 0.02–2.97, 0.10–4.80, 0.13–6.49, 4.46–48.30, 9.2–938.1, 0.02–0.13, 9.8–1726, 11–5.41, 0.04–7.64, 3.81–52.20 μg g ^?1respectively. The bio- concentration factor (BCF) showed its maximum value (15.5) in Excoecaria agallocha for Cd, suggesting that it can be considered as a high-efficient plant for heavy metal bioaccumulation. Among all metals, Cd and Zn were highly bioaccumulated in E. agallocha (2.97 and 52.2 μg g ^?1 respectively. Our findings suggest that the species may be classified as efficient metal trap for Cd in aerial parts, as indicated by higher metal accumulation in the leaves combined with BCF and translocation factor (TF) values.     

Determining bioclimatic space of Himalayan alder for agroforestry systems in Nepal

Himalayan alder species are proven to be very useful in traditional as well as contemporary agroforestry practice. These nitrogen-fixing trees are also useful in the land restoration. Therefore, understanding the distribution of Himalayan alder and the potential zone for plantation is meaningful in the agroforestry sector. Suitable climatic zones of Alnus spp. were modelled in MaxEnt software using a subset of least correlated bioclimatic variables for current conditions (1950-2000), topographic variables (DEM derived) and Landuse Landcover (LULC) data. We generated several models and selected the best model against random models using ANOVA and t-test. The environmental variables that best explained the current distribution of the species were identified and used to project into the future. For future projections, ensemble scenarios of climate change projection derived from the results of 19 Earth System Models (ESM) were used. Our model revealed that the most favorable conditions for Alnus nepalensis are in central Nepal in the moist north-west facing slope, whereas for Alnus nitida they are in western Nepal. The major climatic factor that contributes to Alnus species distribution in Nepal appears to be precipitation during the warmest quarter for A. nepalensis and precipitation during the driest quarter for A. nitida. Future projections revealed changes in the probability distribution of these species, as well as where they need conservation and where they can be planted. Also, our model predicts that the distribution of Alnus spp. in hilly regions will remain unchanged, and therefore may represent sites that can be used to revitalize traditional agroforestry systems and extract source material for land restoration.     

Human and Mouse Type I Natural Killer T Cell Antigen Receptors Exhibit Different Fine Specificities for CD1d-Antigen Complex

Human and mouse type I natural killer T (NKT) cells respond to a variety of CD1d-restricted glycolipid antigens (Ags), with their NKT cell antigen receptors (NKT TCRs) exhibiting reciprocal cross-species reactivity that is underpinned by a conserved NKT TCR-CD1d-Ag docking mode. Within this common docking footprint, the NKT TCR recognizes, to varying degrees of affinity, a range of Ags. Presently, it is unclear whether the human NKT TCRs will mirror the generalities underpinning the fine specificity of the mouse NKT TCR-CD1d-Ag interaction. Here, we assessed human NKT TCR recognition against altered glycolipid ligands of α-galactosylceramide (α-GalCer) and have determined the structures of a human NKT TCR in complex with CD1d-4′,4″-deoxy-α-GalCer and CD1d-α-GalCer with a shorter, di-unsaturated acyl chain (C20:2). Altered glycolipid ligands with acyl chain modifications did not affect the affinity of the human NKT TCR-CD1d-Ag interaction. Surprisingly, human NKT TCR recognition is more tolerant to modifications at the 4′-OH position in comparison with the 3′-OH position of α-GalCer, which contrasts the fine specificity of the mouse NKT TCR-CD1d-Ag recognition (4′-OH > 3′-OH). The fine specificity differences between human and mouse NKT TCRs was attributable to differing interactions between the respective complementarity-determining region 1α loops and the Ag. Accordingly, germline encoded fine-specificity differences underpin human and mouse type I NKT TCR interactions, which is an important consideration for therapeutic development and NKT cell physiology.     

Availability of substratum enhances ethanol production in <Emphasis Type="Italic">Saccharomyces cerevisiae</Emphasis>

Novel additives that act as substratum for attachment of the yeast cells, increased ethanol production in Saccharomyces cerevisiae. The addition of 2 g rice husk, straw, wood shavings, plastic pieces or silica gel to 100 ml medium enhanced ethanol production by 30–40 (v/v). Six distillery strains showed an average enhancement of 34 from 4.1 (v/v) in control to 5.5 (v/v) on addition of rice husk. The cell wall bound glycogen increased by 40–50 mg g ^–1 dry yeast while intracellular glycogen decreased by 10–12 mg g^–1 dry yeast in cells grown in presence of substratum