Structural changes by sulfoxidation of phenothiazine drugs

Summary The side-chain conformations of psychoactive phenothiazine drugs in crystals are different from those of biologically inactive ring sulfoxide metabolites. This study examines the potential energies, molecular conformations and electrostatic potentials in chlorpromazine, levomepromazine (methotrimeprazine), their sulfoxide metabolites and methoxypromazine. The purpose of the study was to examine the significance of the different crystal conformations of active and inactive phenothiazine derivatives, and to determine why phenothiazine drugs lose most of their biological activity by sulfoxidation. Quantum mechanics and molecular mechanics calculations demonstrated that conformations with the side chain folded over the ring structure had lowest potential energy in vacuo, both in the drugs and in the sulfoxide metabolites. In the sulfoxides, side chain conformations corresponding to the crystal structure of chlorpromazine sulfoxide were characterized by stronger negative electrostatic potentials around the ring system than in the parent drugs. This may weaken the electrostatic interaction of sulfoxide metabolites with negatively charged domains in dopamine receptors, and cause the sulfoxides to be virtually inactive in dopamine receptor binding and related pharmacological tests.     

LC-MS–MS Determination of Pregabalin in Human Plasma

A rapid, sensitive and specific method to quantify pregabalin in human plasma using metaxalone as the internal standard is described. Sample preparation involved simple protein precipitation by using acetronitrile as solvent. The extract was analyzed by high-performance liquid chromatography coupled to electrospray tandem mass spectrometry (LC-MS–MS). Chromatography was performed isocratically on Thermo Hypurity C₁₈ 5 μm analytical column, (50 mm × 4.6 mm i.d.). The assay of pegabalin was linear calibration curve over the range 10.000–10000.000 ng mL^?1. The lower limit of quantification was 10.000 ng mL^?1 in plasma. The method was successfully applied to the bioequivalence study of pregabalin capsules (150.0 mg) administered as a single oral dose.     

Electronic, cyclic voltammetry, IR and EPR spectral studies of copper(II) complexes with 12-membered N4, N2O2 and N2S2 donor macrocyclic ligands

A new series of copper(II) complexes have been synthesized with macrocyclic ligands having three different donating atoms in the macrocyclic ring. It has been shown that the stereochemistry of complexes is dependent on the coordinated anions. These complexes are characterized by various physicochemical techniques, viz. elemental analysis, molar conductance, magnetic susceptibility measurements, IR, electronic, 1H NMR and EPR spectral studies. Cyclic voltammetric behavior of the complexes has also been discussed. The observed anisotropic g-values indicate that the chloro and acetato complexes are six-coordinate tetragonal. Whereas the sulfato and nitrato complexes are found to have five-coordinate square-pyramidal and four-coordinate square-planar geometry, respectively.     

The ionization of sulfurous acid in Na−Mg−Cl solutions at 25°C

The stoichiometric pK ₁ ^* and pK ₂ ^* for the ionization of sulfurous acid has been determined from emf measurements in NaCl solutions with varying concentrations of added MgCl₂ (m=0.1, 0.2 and 0.3) from I=0.5 to 6.0 molal at 25°C. These experimental results have been treated using both the ion pairing and Pitzer's specific ion-interaction models. The Pitzer parameters for the interaction of Mg²⁺ with SO₂ and HSO ₃ ^– yielded =0.085±0.004, ⁽⁰⁾ = 0.35±0.02, ⁽¹⁾ = 1.2±0.04, and C = –0.072±0.007. The Pitzer parameters ⁽⁰) = –2.8±0.4, ⁽¹⁾ = 12.9±2.9 and ⁽²⁾ = –2071±57 have been determined for the interactions of Mg²⁺ with SO ₃ ^2– . The calculated values of pK ₁ ^* and pK ₂ ^* using Pitzer's equations reproduce the measured values to within ±0.04 pK units. The ion pairing model with log K_MgSO3=2.36±0.02 and log_MgSO3 = 0.1021, reproduces the experimental values of pK ₂ ^* to ±0.01. These results demonstrate that treating the data by considering the formation of MgSO₃ yields a better fit of the experimental measurements with fewer adjustable parameters. With these derived coefficients obtained from the Pitzer equations and the ion pairing model, it is possible to make reliable estimates of the activity coefficients of HSO ₃ ^– and SO ₃ ^2– in seawater, brines and marine aerosols containing Mg²⁺ ions.     

Simulation of aerated lagoon using artificial neural networks and multivariate regression techniques

The aim of this study was to develop an empirical model that provides accurate predictions of the biochemical oxygen demand of the output stream from the aerated lagoon at International Paper of Brazil, one of the major pulp and paper plants in Brazil. Predictive models were calculated from functional link neural networks (FLNNs), multiple linear regression, principal components regression, and partial least-squares regression (PLSR). Improvement in FLNN modeling capability was observed when the data were preprocessed using the PLSR technique. PLSR also proved to be a powerful linear regression technique for this problem, which presents operational data limitations.     

A di-μ-oxomolybdenum(V) complex of 6-acetonylisoxanthopterin,undergoing oxygen atom transfer with dimethyl sulphoxide

The new compound, Na[(Mo₂ ^VO₄)(pte)(OMe)(MeOH)₂] (pte = anion of 6-acetonylisoxanthopterin), has been prepared using the redox non-innocent title ligand in MeOH–H₂O, and characterized by elemental analysis and physico-chemical methods including e.s.m.s., i.r., u.v.–vis. and ¹H-n.m.r. spectra. Rate constants data (1.4 × 10^–3 s^–1 at 300 K) for its oxygen atom transfer with dimethyl sulphoxide tally with those of synthetic analogue systems reported earlier by different authors. The negative activation entropy (–206.3 J mol^–1 deg^–1) is consistent with an associative mechanism for this reaction.     

Second Dissociation Constants of 4-[N-morpholino]butanesulfonic Acid and N-[2-hydroxyethyl]piperazine-N′-4-butanesulfonic Acid from 5 to 55°C

The values of the second dissociation constant, pK ₂, for the dissociation of the NH⁺ charge center of the zwitterionic buffer compounds 4-(N-morpholino)butanesulfonic acid (MOBS), and N-(2-hydroxyethyl)piperazine-N-4-butanesulfonic acid (HEPBS) have been determined from 5 to 55°C, including, 37°C at intervals of 5°C. The electromotive-force (emf) measurements have been made utilizing hydrogen electrodes and silver–silver chloride electrodes. The value of pK ₂ for MOBS was found to be 7.702 ± 0.0005, and 8.284 ± 0.0004 for HEPBS, at 25°C, respectively. The related thermodynamic quantities, G ^o, H ^o, S ^o, and C _p ^o for the dissociation processes of MOBS and HEPBS have been derived from the temperature coefficients of pK ₂. Both the MOBS and HEPBS buffer materials are useful as primary pH standards for the control of pH 7.3 to 8.6 in the region close to that of physiological fluids.