Studies in werner clathrates. Part 2. Structures of bis (isothiocyanato) tetra (4-phenylpyridine) nickel (II)· 4-dimethylsulphoxide,bis (isothiocyanato) tetra (3-methylpyridine) nickel (II)· chloroform and bis (isothiocyanato) tetra (3,5-dimethylpyridine) nickel (II)

The structures of Ni(NCS)₂(4-PhPy)₄·4DMSO and Ni(NCS)₂(3-MePy)₄·CHCl₃ have been elucidated. Movement of guest molecules through channels in the host structure was simulated by potential energy calculations. Ni(NCS)₂(3,5-diMePy)₄ does not form inclusion compounds. An intra-molecular potential energy study shows that theortho-hydrogens on the 3,5-dimethylpyridine ligands control the conformation of the molecule. The same result is obtained with the 4-methylpyridine ligand, which suggests that the extent of rotation of substituted pyridines about the Ni–N bounds is not a factor governing clathrate formation. Supplementary Data relating to this article are deposited with the British Library as Supplementary Publication No. SUP 82030 (43 pages).     

Reactions of organocobaloximes with aryldisulfonyl chlorides

Photochemical reactions of benzyl, heteroaromaticmethyl and allylcobaloximes with aryldisulfonyl chlorides yield symmetrical disulfones. Allyl cobaloximes yield allyldisulfones as the major product whereas bibenzyl is the major product in benzylcobaloximes. A time dependent ¹H NMR studies show that bibenzyl is formed from O-benzyldimethylglyoxime - a predominant product in the initial stage of the reaction.     

Synthesis of new pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidines and related heterocycles

The reaction between 5-amino-4-imino-1(2)-substituted-1(2)H-4,5-dihydropyrazolo[3,4-d]pyrimidines and several commercially available reactants afforded new heterocycles with a conserved pyrazolo[3,4-d]pyrimidine nucleus. The key intermediates employed proved to be suitable compounds by virtue of their two vicinal amino and imino groups that were used to obtain five, six and seven-membered rings.     

A revised quantum chemistry-based potential for poly(ethylene oxide) and its oligomers in aqueous solution

We have conducted a high-level quantum chemistry study of the interactions of 1,2-dimethoxyethane (DME) with water for complexes representing both hydrophilic and hydrophobic hydration. It was found that our previous quantum chemistry-based force field for poly(ethylene oxide) (PEO) and its oligomers in aqueous solution did a poor job in describing the hydrophobic binding of water to the ether, consistent with our recent calculations of the excess free energy and entropy of hydration of DME. Our original force field was revised to more accurately reproduce the interaction of water with the carboneous portions of DME. Molecular dynamics simulations of aqueous DME solutions using the revised quantum chemistry-based potential yielded good agreement with experiment for excess free energy, enthalpy, and volume as well as excess solution viscosity and the self-diffusion of water. Comparison with our original potential revealed that the relatively hydrophobic ether-water interactions in the new potential strongly reduced the favorable excess free energy and enthalpy but have relatively little influence on the excess entropy for dilute DME solutions. Other properties of DME and PEO solutions including conformational populations and dynamics, solution viscosity, hydrogen bonding, water translational and rotational diffusion and neutron structure factor as a function of solution composition were found to be largely unchanged from those obtained using the original potential.     

Simultaneous Determination of Enalapril and Enalaprilat in Human Plasma by LC-MS: Application to a Bioequivalence Study

A rapid, simple and specific liquid chromatography-electrospray ionization mass spectrometry (LC-ESI-MS) method has been developed and validated for the simultaneous determination of enalapril and its major active metabolite enalaprilat in human plasma. Benazepril hydrochloride was used as the internal standard. Plasma was deproteinized with acetone and centrifuged. The supernatant was transferred and evaporated to dryness and the residue dissolved in mobile phase. Samples were separated on a C18 column with a mobile phase of methanol–20 mM ammonium acetate (53:47, v/v) containing 0.15% trifluoracetic acid (v/v) with a pH of 3.0. Enalapril, enalaprilat and the internal standard were measured by electrospray positive selective ion monitoring mode. The method was validated over a linear range of 1.56–400 ng mL⁻¹ and the limits of quantification were 1.56 ng mL⁻¹ for both enalapril and enalaprilat using 0.1 mL plasma. Extraction efficiency was more than 84% and recoveries were in range of 93.65–101.17%. The intra-day relative standard deviations (RSD) were less than 8.16 and 7.05% and inter-day RSDs were within 8.42 and 5.72% for enalapril and enalaprilat, respectively. The storage stability of QC samples was investigated under various conditions. The method was successfully applied for the evaluation of the pharmacokinetics and bioequivalence of enalapril and enalaprilat in 20 healthy volunteers after an oral dose of 20 mg enalapril maleate.     

Spectroscopic and quantum chemical studies on the structure of 2-arylquinoline-4(1H)-thione derivatives

The geometries of the title compounds were probed in solution, solid and gas states using spectroscopic methods, X-ray crystallography and quantum chemical techniques. The exclusive existence of the NH-4-thiones in solution (NMR and PCM-B3LYP(MP2)/6-31+G(d) calculations) and solid state (FT-IR and X-ray) is also corroborated by comparison of their spectroscopic data with those of the corresponding 2-aryl-1-methylquinoline-4(1H)-thione derivatives. The co-existence of the quinoline-4-thione and quinoline-4-thiol (4-mercaptoquinoline) isomers in the gas phase is confirmed by mass spectrometry and the preponderance of the 4-thiol is supported by quantum chemical techniques (PM3, MP2 and B3LYP).     

Schiff bases of nickel(II), copper(II) porphyrins and dibenzo-18-crown-6 interspersed bis -metal porphyrins. Protonation studies

Schiff-base (SB) derivatives of Ni(II) and Cu(II) porphyrins endowed with various amine functions (R−NH₂),n-butylamine,p-anisidine andm-nitroaniline have been prepared from corresponding formyl porphyrins. Protonation studies of these SB derivatives reveal a marked red shift of the optical absorption bands in the visible region relative to the unprotonated imines. The magnitude of the observed red shifts in the protonated derivatives, (SBH⁺) are found to depend on the electron-withdrawing or electron-donating nature of the R group of the amines. The results of the optical absorption,¹H NMR, EPR, and cyclicovoltammetric studies are illustrative of the fact that protonation of the SB derivatives results in a localized positive charge, in the periphery of the porphyrin (p) system. The dibenzo-18-crown-6 interspersedbisporphyrin schiff bases have been prepared fromtrans 4,4′-diamino dibenzo-18-crown-6 and formyl porphyrins. The protonation of these SB derivatives is found to proceed in a concerted fashion. The cation complexation studies by the crown ether entity in thebisporphyrin systems have been investigated using optical absorption, magnetic resonance and electrochemical methods. The redox characteristics of the protonated dimeric SB porphyrins reveal that the first oxidation step involves a two-electron transfer reaction. This is important in view of their possible usage in multielectron transfer reactions of biological and catalytic interest.     

Improving (Q)SAR predictions by examining bias in the selection of compounds for experimental testing

ABSTRACT

Existing data on structures and biological activities are limited and distributed unevenly across distinct molecular targets and chemical compounds. The question arises if these data represent an unbiased sample of the general population of chemical-biological interactions. To answer this question, we analyzed ChEMBL data for 87,583 molecules tested against 919 protein targets using supervised and unsupervised approaches. Hierarchical clustering of the Murcko frameworks generated using Chemistry Development Toolkit showed that the available data form a big diffuse cloud without apparent structure. In contrast hereto, PASS-based classifiers allowed prediction whether the compound had been tested against the particular molecular target, despite whether it was active or not. Thus, one may conclude that the selection of chemical compounds for testing against specific targets is biased, probably due to the influence of prior knowledge. We assessed the possibility to improve (Q)SAR predictions using this fact: PASS prediction of the interaction with the particular target for compounds predicted as tested against the target has significantly higher accuracy than for those predicted as untested (average ROC AUC are about 0.87 and 0.75, respectively). Thus, considering the existing bias in the data of the training set may increase the performance of virtual screening.     

High-Throughput Analysis of Sofalcone in Human Plasma by Use of Automated 96-Well Protein Precipitation and LC-MS-MS

A sensitive and selective method for the determination of sofalcone in human plasma was established by use of protein precipitation and liquid chromatography-tandem mass spectrometry. Plasma samples were transferred into 96-well plate using an automated sample handling system and spiked with 10 L of 2 g mL^–1 internal standard solution (d₃-sofalcone). 0.5 mL of acetonitrile was added to the 96-well plate and the plasma samples were then vortexed for 30 sec. After centrifugation, the supernatant was transferred into another 96-well plate and completely evaporated at 40 °C under a stream of nitrogen. The dry residue was reconstituted with mobile phase. All sample transfer and protein precipitation was automated through the application of both the PerkinElmer MultiPROBE II HT and TOMTEC Quadra 96 workstation. The limit of quantitation of sofalcone was 2 ng mL^–1 using a sample volume of 0.2 mL for the analysis. The reproducibility of the method was evaluated by analyzing five samples at nine quality control (QC) levels over the nominal concentration range from 2 ng mL^–1 to 1000 ng mL^–1. Validation of the method showed that the assay has good precision and accuracy. Sofalcone and internal standard produced a protonated precursor ion ([M+H]⁺) at m/z 451 and 454, and both gave a corresponding product ion at m/z 315. The high sample throughput of the method has been successfully applied to a pharmacokinetic study of sofalcone in human plasma.