Synthesis of 3-substituted 4-piperidinones via a one-pot tandem oxidation-cyclization-oxidation process: stereodivergent reduction to 3,4-disubstituted piperidines

A novel approach to 3-substituted 4-piperidinones is described. The one-pot tandem oxidation-cyclization-oxidation of unsaturated alcohols 1a-e by PCC or PCC and trifluoromethanesulfonic acid affords piperidinones 2a-e in good yield. Reduction of 2a-e by L-Selectride gives the corresponding cis 3,4-disubstituted piperidines with diastereomeric ratios of >99:1. By contrast, reduction of 2a-e by Al-isopropoxydiisobutylalane gives the trans products with diastereomeric ratios of up to 99:1.     

Glutamine: fructose-6-phosphate amidotransferase (GFAT): homology modelling and designing of new inhibitors using pharmacophore and docking based hierarchical virtual screening protocol

Glutamine: fructose-6-phosphate amidotransferase (GFAT), also termed GFPT1 and GFAT1, catalyzes the first committed step of the hexosamine biosynthesis pathway in mammals and consequently plays an important role in type 2 diabetes. In the present study, a combination of pharmacophore modelling, homology modelling, and molecular docking analysis was performed to design new glutamine competitive inhibitors of human GFAT, and to investigate important interaction details of inhibitor molecules. A pharmacophore model of GFAT inhibitors was developed, subsequently validated, and utilized for the screening by the PHASE database to identify new molecules. Afterwards, homology modelling was performed to construct the glutamine-binding site of the GFAT protein. The modelled active site was utilized to dock the studied molecules to investigate important receptor-ligand interactions and to scrutinize database-screened molecules on the basis of essential interactions. This systematic in silico protocol helped us to identify new molecules that would be explored for the treatment of type 2 diabetes and its complications.     

Three Validated Methods for Simultaneous Determination of Ofloxacin and Dexamethasone in Binary Mixture

JPC – Journal of Planar Chromatography – Modern TLC - Three selective, precise, and accurate methods were developed and validated for the simultaneous determination of ofloxacin and...     

Simultaneous Densitometric TLC Analysis of Olmesartan Medoxomil and Hydrochlorothiazide in the Tablet Dosage Form

JPC – Journal of Planar Chromatography – Modern TLC - A simple, rapid, and selective densitometric thin-layer chromatographic (TLC) method has been established and validated for...     

Chemical composition of the essential oil of Pituranthos scoparius

The essential oils obtained by hydro distillation of the aerial parts of Pituranthos scoparius were collected from different regions of Algeria and gave various yields ranging from 0.6 up to 2.8% (v/w). These samples were analyzed by GC and GC-MS showing the occurrence of monoterpene hydrocarbons and some oxygenated compounds. The major components were alpha-pinene (4.4-35.8%), limonene (0.8-66.5%), bornyl acetate (tr-9.6%), myristicin (tr-31.1) and dill apiole (0.4-47.3%). The aerial parts of P. scoparius could be either very rich or very poor in limonene, myristicin or dill apiole. Cluster analysis shows differences in essential oil compositions of samples coming from the different area collected.     

Multivariate optimization of a GC-MS method for determination of sixteen priority polycyclic aromatic hydrocarbons in environmental samples

This paper describes the development and optimization, by using multivariate analysis, of a GC-MS-SIM method for evaluation of the 16 polyaromatic hydrocarbons considered as priority pollutants in atmospheric particulate material by the US EPA. In order to assure an adequate separation in the shortest analysis time, a multivariate design was used to set the conditions of the oven temperature program. The optimization process was carried out using factorial fractional design and Box-Behnken design. The following factors were evaluated: initial temperature, temperature rate #1, intermediary temperature, temperature rate #2, and final temperature. The optimized conditions were set at: 70 degrees C (2 min) --> 200 degrees C (30 degrees C/min, 5 min) --> 300 degrees C (5 degrees C/min, 1.67 min). Moreover, we have also optimized the injector temperature as 310 degrees C and sampling time as 0.8 min. The total analysis time was 33 min. Validation of GC-MS-SIM yielded satisfactory results for repetitivity of the detector response and retention times, and linearity of calibration curves. LOD were established as 0.13-0.34 ng/mL (peak area) and 0.18-0.72 ng/mL (peak height). The method has been shown to be appropriate for the analysis of samples of atmospheric particulate material and/or other environmental matrices.     

A validated RP‐HPLC method for the evaluation of the influence of grapefruit juice on liver S9 activation of sacubitril

Grapefruit juice inhibits esterase enzyme. Therefore, a possible interaction with ester prodrugs should be taken into consideration. In this study, the influence of grapefruit juice on sacubitril (SAC) rat liver S9 activation by esterase enzyme was evaluated. An RP‐HPLC method was developed and validated for estimation of SAC in rat liver S9 fraction using a C₁₈ Cyano column as stationary phase and acetonitrile–sodium di‐hydrogen phosphate buffer (0.02 m , pH 4 adjusted by o‐phosphoric acid, 40:60, v/v), as mobile phase at a flow rate of 1 mL/min and UV detection at 254 nm. The method was successfully applied to an in vitro study in which SAC was incubated with rat liver S9 fraction prepared from rats that had previously ingested grapefruit juice for a week. The calculated SAC concentration after incubation was compared with that of SAC incubated with rat liver S9 fraction from the rat control group. The statistical significance between the results of test and control incubation sets was assessed. In conclusion, the current study demonstrated that grapefruit juice decreased SAC hydrolysis, hence delaying its activation to sacubitrilat (active form) in gut lumen. Based on this food–drug interaction, it may be required that grapefruit juice should be consumed with caution in patients receiving SAC.     

Rescoring of docking poses under Occam’s Razor: are there simpler solutions?

Ligand affinity prediction from docking simulations is usually performed by means of highly empirical and diverse protocols. These protocols often involve the re-scoring of poses generated by a force field (FF) based Hamiltonian to provide either estimated binding affinities—or alternatively, some empirical goodness score. Re-scoring is performed by so-called scoring functions—typically, a reweighted sum of FF terms augmented by additional terms (e.g., desolvation/entropic penalty, hydrophobicity, aromatic interactions etc.). Sometimes, the scoring function actually drives ligand positioning, but often it only operates on the best scoring poses ranked top by the initial ligand positioning tool. In either of these rather intricate scenarios, scoring functions are docking-specific models, and most require machine-learning-based calibration. Therefore, docking simulations are less straightforward when compared to “standard” molecular simulations in which the FF Hamiltonian defines the energy, and affinity emerges as an ensemble average property over pools of representative conformers (i.e., the trajectory). Paraphrasing on Occam’s Razor principle, additional model complexity is only acceptable if demonstrated to bring a significant improvement of prediction quality. In this work we therefore examined whether the complexity inherent to scoring functions is indeed justified. For this purpose we compared sampler for multiple protein–ligand entities, a general purpose conformation sampler based on the AMBER/GAFF FF, complemented with continuum solvation terms, with several state of the art docking tools that rely on calibrated scoring functions (Glide, Gold, Autodock-Vina) in terms of its ability to top-rank the actives from large and diverse ligand series associated with various proteins. There is no clear winner of this study, where each program performed well on most of the targets, but also failed with respect to at least one of them. Therefore, a well-parameterized force field with a simple, energy-based ligand ranking protocol appears to be an as effective docking protocol as intricate rescoring strategies based on scoring functions. A tool that can sample the conformational space of the free ligand, the bound ligand and the protein binding site using the same force field may avoid many of the approximations common to contemporary docking protocols and allow e.g., for docking into highly flexible active sites, when current scoring functions are not well suited to estimate receptor strain energies.     

A simple procedure for hydrodynamic injection in flow injection analysis applied to the atomic absorption spectrometry of chromium in steels

The proposed technique for hydrodynamic injection is based on commutation in a simple flow-injection system with only one peristaltic pump. Precise results (usually r.s.d. < 1%) are attained even when injected volumes are small (1–10 μl). Dead-volume effects are associated with the mechanical flexibility of the system and with diffusion; differences between effective sample size and the dimensions of the injection duct are emphasized, particularly for small volumes. The proposed technique is checked for a spectrophotometric model system and confirmed by the atomic absorption spectrometry of chromium in steels. With a sampling rate of 120 h^?1, the precision is better than 99% for chromium contents in the 0.0–30.0% (w/w) range. The results agree well with those obtained by i.c.p./a/e/s. and conventional a.a.s.     

Synthesis of 3,4-disubstituted piperidines by carbonyl ene and Prins cyclizations: a switch in diastereoselectivity between Lewis and Brønsted acid catalysts

[reaction: see text] A novel diastereoselective approach to cis and trans 3,4-disubstituted piperidines is described. Carbonyl ene cyclization of aldehydes 6a-e catalyzed by the Lewis acid methyl aluminum dichloride in refluxing chloroform affords trans piperidines 8a-e with diastereomeric ratios of up to 93:7. By contrast, Prins cyclization of 6a-e catalyzed by hydrochloric acid at low temperatures affords cis products 7a-e with diastereomeric ratios of up to 98:2.