Synthesis and pharmacological activity of 4-(4'-(chlorophenyl)-4-hydroxypiperidine) derivatives

A new series of 4-(4'-chlorophenyl)-4-hydroxypiperidine derivatives (2-5), substituted at nitrogen, were synthesized and tested as potential analgesic compounds as well as evaluated for their effect on hypotensive activity. Results showed that all the derivatives exhibit significant analgesic activity in male Wistar rats at a dose of 50 mg/kg of body weight after intramuscular injection, when tested by thermal stimuli (tail flick test). Pethidine was used as reference drug. Compounds 2, 3 and 5 produced reduction in blood pressure in normotensive rat.     

A Novel Anti-Inflammatory d-Peptide Inhibits Disease Phenotype Progression in an ALS Mouse Model

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterised by selective neuronal death in the brain stem and spinal cord. The cause is unknown, but an increasing amount of evidence has firmly certified that neuroinflammation plays a key role in ALS pathogenesis. Neuroinflammation is a pathological hallmark of several neurodegenerative disorders and has been implicated as driver of disease progression. Here, we describe a treatment study demonstrating the therapeutic potential of a tandem version of the well-known all-d-peptide RD2 (RD2RD2) in a transgenic mouse model of ALS (SOD1*G93A). Mice were treated intraperitoneally for four weeks with RD2RD2 vs. placebo. SOD1*G93A mice were tested longitudinally during treatment in various behavioural and motor coordination tests. Brain and spinal cord samples were investigated immunohistochemically for gliosis and neurodegeneration. RD2RD2 treatment in SOD1*G93A mice resulted not only in a reduction of activated astrocytes and microglia in both the brain stem and lumbar spinal cord, but also in a rescue of neurons in the motor cortex. RD2RD2 treatment was able to slow progression of the disease phenotype, especially the motor deficits, to an extent that during the four weeks treatment duration, no significant progression was observed in any of the motor experiments. Based on the presented results, we conclude that RD2RD2 is a potential therapeutic candidate against ALS.     

C—H⋯N and C—H⋯π interactions in 2‐ethoxy‐4,6‐diphenylpyridine‐3‐carbonitrile

The title compound, C₂₀H₁₆N₂O, has two mol­ecules in the asymmetric unit and the crystal structure shows that the central pyridine ring of each mol­ecule has a flat boat conformation. The terminal C atom in one of the mol­ecules is disordered over two positions, with relative occupancies of 0.594 (14) and 0.398 (14). Intermolecular C—H?N and C—H?π interactions and π–π stacking, along with intramolecular C—H?N and C—H?π interactions, help to stabilize the structure.     

Speciation of cationic selenium compounds in Brassica juncea leaves by strong cation-exchange chromatography with inductively coupled plasma mass spectrometry

Strong cation-exchange chromatography (SCX-HPLC) was used in conjunction with inductively coupled plasma mass spectrometry (ICP-MS) to investigate cationic selenium species present in leaf extract of wild-type Brassica juncea supplemented with selenite. Total amount of Se accumulated by the leaves was found to be 352 microg g(-1). Cation-exchange solid-phase extraction (SCX-SPE) was used to pre-concentrate the cationic species present in the leaf extract. Methylselenomethionine (MeSeMet) and dimethylselenoniumproprionate (DMSeP) were synthesized and characterized by electrospray quadrupole time-of-flight MS (ESI-QTOF-MS). Laboratory synthesized and commercially available standards were used in chromatographic studies to identify the Se species in the leaf extract through retention time comparisons and standard addition method. Major cationic selenium species identified in the present study were MeSeMet and methylselenocysteine (MeSeCys) while selenomethionine (SeMet) was found in minor quantities.     

Synthesis and S-methylation of 2-thioxopyrido[3′,2′:4,5]thieno[3,2-d]-pyrimidin-4(3H)-ones with and without a phase transfer catalyst

A number of 2-thioxopyrido[3′,2′:4,5]thieno[3,2-H]pyrimdin-4(3H-ones (5) have been synthesized by cyclocondensation of 2-carbethoxy-3-amino-4-phenyl-6-substituted-thieno[2,3-b]pyridines (3) with various isothiocyanates. Compounds 5 were S-methylated routinely and the reactions compared under solid-liquid phase transfer conditions to obtain 2-methylthiopyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4(3H)-^ones (6). The new triheterocyclic pyridothienopyrimidines were prepared with the objective to study their pharmacological properties.     

High performance liquid chromatographic-mass spectrometric assay for the quantitation of BMS-204352 in dog K(3)EDTA plasma

A high performance liquid chromatographic-mass spectrometric (LC/MS) assay was developed and validated for the determination of BMS-204352 in dog K(3)EDTA plasma. A 0.5 mL aliquot of control plasma was spiked with BMS-204352 and internal standard (IS) and buffered with 1 mL of 5 mM ammonium acetate. The mixture was then extracted with 3 mL of toluene. After separation and evaporation of the organic phase to dryness using nitrogen at 40 degrees C, the residue was reconstituted in the mobile phase and 25 microL of the sample were injected onto a Hypersil C(18) column (2 x 50 mm; 3 microm) at a flow rate of 0.5 mL/min. The mobile phase was consisted of two solvent mixtures (A and B). Solvent A was composed of 5 mM ammonium acetate and 0.1% triethylamine in 75:25 v/v water:methanol, pH adjusted to 5.5 with glacial acetic acid, and solvent B was 5 mM ammonium acetate in methanol. A linear gradient system was used to elute the analytes. The mass spectrometer was programmed to admit the de-protonated molecules at m/z 352.7 (IS) and m/z 357.9 (BMS-204352). Standard curves of BMS-204352 were linear (r(2) > or = 0.998) over the concentration range of 0.5-1000 ng/mL. The mean predicted quality control (QC) concentrations deviated less than 5.1% from the corresponding nominal values (ie 4, 80, 400 and 2000 ng/mL); the within- and between-assay precision of the assay were within 5.5% relative standard deviation. Stability of BMS-204352 was confirmed after at least three freeze/thaw cycles and BMS-204532 was stable in dog plasma when stored frozen at or below -20 degrees C for at least 16 weeks in spiked QC samples and for at least 4 1/2 weeks for in vivo study samples. BMS-204352 and IS were stable in the injection solvent at room temperature for at least 24 h. The assay was applied to delineate the pharmacokinetic disposition of BMS-204352 in dogs following a single intravenous dose administration. In conclusion, the assay is accurate, precise, specific, sensitive and reproducible for the pharmacokinetic analysis of BMS-204532 in dog plasma.     

Seed Priming with Devosia sp. Cell-Free Supernatant (CFS) and Citrus Bioflavonoids Enhance Canola and Soybean Seed Germination

Climate change, environmental pollution and associated abiotic stresses are beginning to meaningfully affect agricultural production worldwide. Salt stress is, however, one of the most important threats that significantly impairs plant growth and development. Plants in their early growth stages such as seed germination, seed emergence and early seedling growth are very sensitive to salt stress. Among the range of sustainable techniques adopted to improve seed germination and early plant growth is seed priming; however, with the use of ecofriendly substances, this is one of the most effective and economically viable techniques to improve seed tolerance against such environmental stresses. For instance, priming with appropriate non-synthetic compounds including microbial biostimulants are prominent ways to sustainably address these challenges. Therefore, in this research, by using the “priming technique”, two biostimulants were tested for their potential as sustainable approaches to improve canola and soybean seed germination under salt stress and optimal growth conditions. Canola and soybean seeds were primed with flavonoids extracted from citrus fruits (flavopriming) and cell-free supernatant (CFS; produced by a novel strain of Devosia sp.—SL43), alone and in combination, and exposed to low–higher levels of salt stress and ideal growth conditions. Both biostimulants showed promising effects by significantly improving seed germination of soybean and canola under both ideal and stressful conditions. However, increases in seed germination were greater under salinity stress as flavonoids and CFS with stress amelioration effects showed substantial and statistically significant improvements in seed germination under varying levels of salt stress. In addition, combinations (mixtures) of both biostimulants were tested to determine if their effects might be more additive or multiplicative than the individual applications. However, results suggested incompatibility of both biostimulants as none of the combinations showed better results than that of the individual applications of either flavonoids or CFS. Conceivably, the use of flavonoids and this novel Devosia sp. CFS could be significant plant growth enhancers, perhaps much better than the few other biostimulants and bacterial-based compounds currently in use.     

Evaluation of Phytochemistry and Pharmacological Properties of Alnus nitida

In the current study, the anti-inflammatory and analgesic potential of Alnus nitida (leaves and fruits) was evaluated in the Sprague-Dawley rat. Traditionally, A. nitida was used for the treatment of inflammatory ailments. However, A. nitida leaves and fruits have not been yet reported regarding any potential medicinal effects. Leaves/fruits of A. nitida were extracted with methanol and fractionated to attain n-hexane, chloroform, ethyl acetate and aqueous fractions. These extracts were then evaluated for in vivo analgesic and anti-inflammatory potential. For in vivo anti-inflammatory activity, carrageenan-induced paw edema assay, Freunds’ complete adjuvant-induced edema, xylene-induced ear edema and histamine-induced paw edema models were used in rats, which showed significant (p < 0.01) reduction (70–80%) in edema in comparison of inflammatory controls. On other hand, for the analgesic assessment, hot plate assay and acetic acid-induced writhing tests were used, which showed a significant (p < 0.01) rise in latency time (40–60%) as compared with pain-induced controls. These results were comparable with standard drugs in a concentration-dependent manner and no mortality or toxicity was observed during all experiments. Then, for the identification of chemical constituents gas chromatography–mass spectrometry (GC-MS) analysis was performed, which indicated the presence of neophytadiene, 3,7,11,15-Tetramethyl-2-hexadecen-1-ol, phytol and vitamin E, justifying the use of A. nitida to treat inflammatory disorders.     

Friedelin Attenuates Neuronal Dysfunction and Memory Impairment by Inhibition of the Activated JNK/NF-κB Signalling Pathway in Scopolamine-Induced Mice Model of Neurodegeneration

Oxidative stress (OS) and c-Jun N-terminal kinase (JNK) are both key indicators implicated in neuro-inflammatory signalling pathways and their respective neurodegenerative diseases. Drugs targeting these factors can be considered as suitable candidates for treatment of neuronal dysfunction and memory impairment. The present study encompasses beneficial effects of a naturally occurring triterpenoid, friedelin, against scopolamine-induced oxidative stress and neurodegenerative pathologies in mice models. The treated animals were subjected to behavioural tests i.e., Y-maze and Morris water maze (MWM) for memory dysfunction. The underlying mechanism was determined via western blotting, antioxidant enzymes and lipid profile analyses. Molecular docking studies were carried out to predict the binding modes of friedelin in the binding pocket of p-JNK protein. The results reveal that scopolamine caused oxidative stress by (1) inhibiting catalase (CAT), peroxidase enzyme (POD), superoxide dismutase (SOD), and reduced glutathione enzyme (GSH); (2) the up-regulation of thiobarbituric acid reactive substances (TBARS) in mice brain; and (3) affecting the neuronal synapse (both pre- and post-synapse) followed by associated memory dysfunction. In contrast, friedelin administration not only abolished scopolamine-induced oxidative stress, glial cell activation, and neuro-inflammation but also inhibited p-JNK and NF-κB and their downstream signaling molecules. Moreover, friedelin administration improved neuronal synapse and reversed scopolamine-induced memory impairment accompanied by the inhibition of β-secretase enzyme (BACE-1) to halt amyloidogenic pathways of amyloid-β production. In summary, all of the results show that friedelin is a potent naturally isolated neuro-therapeutic agent to reverse scopolamine-induced neuropathology, which is characteristic of Alzheimer’s disease.