Conformational polymorphic changes in the crystal structure of the chiral antiparasitic drug praziquantel and interactions with calcium carbonate.

Praziquantel is an antiparasitic drug used for decades. Currently, the praziquantel commercial preparation is a racemic mixture, in which only the levo-enantiomer possesses anthelmintic activity. The knowledge of its properties in the solid state and other chemical-physical properties is necessary for improving its efficacy and applications. Drug solid dispersions were prepared with calcium carbonate at 1:5 drug to excipient weight ratio by solvent evaporation method. Then, the modification of the crystal structure of the racemic polymorph of praziquantel in presence of calcium carbonate has been studied by means of several analytical techniques (DSC, TGA, XRD, SEM, FTIR, Raman spectroscopy and chiral liquid chromatography). This study has been completed with atomistic calculations based on empirical interatomic force fields and quantum mechanics methods applied to the crystal structure of praziquantel and of intermolecular interactions. The results evidenced that calcium carbonate provoked a conformational change in the praziquantel molecule yielding the formation of different polymorphs of praziquantel crystal. These alterations were not observed replacing calcium carbonate with colloidal silica as excipient in the solid dispersion.

A DFT study of the carboxymethyl-phosphatidylethanolamine formation from glyoxal and phosphatidylethanolamine surface. Comparison with the formation of N(ε)-(carboxymethyl)lysine from glyoxal and L-lysine.

Mechanisms of the generation of carboxymethyl compounds Nε-(carboxymethyl)lysine (CML) and carboxymethyl-phosphatidylethanolamine (CM-PE) from the reactions between glyoxal and L-lysine, and glyoxal and phosphatidylethanolamine (PE) were studied using the DFT method at the PBE/DNP level of theory. In order to study the reaction with PE, a periodic model of the PE surface was built. The starting surface model includes two molecules of PE, a molecule of monohydrated form of glyoxal, and five water molecules as explicit solvent that form a hydrogen bond network, which are involved in the reactions by stabilizing reaction intermediates and transition states and as proton-transfer carriers, important in all steps of reactions. Both reactions take place in three steps, namely, (1) carbino-diol-amine formation; (2) dehydration; and (3) rearrangement into carboxymethyl final products. The rate-limiting step for the formation of CML/CM-PE was the dehydration stage. The comparison of both reactions in their equivalent stages showed a catalytic role of the PE surface; it is highlighted in the case of dehydration step where its relative free energy barrier had a value of 5.3 kcal mol(-1) lower than that obtained in the L-lysine-glyoxal system. This study gives insights into the active role of the phospholipid surface in some chemical reactions that occur above it. Our results also give support to consider the pathway of formation of CML and CM-PE from the reactions between glyoxal and L-lysine, and glyoxal and PE as an alternative pathway for generation of these advanced glycation end-products (AGEs).

Theoretical study on the influence of the Mg2+ and Al3+ octahedral cations on the vibrational spectra of the hydroxy groups of dioctahedral 2:1 phyllosilicate models.

The effect on the vibrational spectrum of the hydroxy groups in dioctahedral 2:1 phyllosilicates of the isomorphous cation substitution of Mg(2+) by Al(3+) in the octahedral sheet was investigated at the DFT level. Ortho, meta and para Mg(2+) configurational polymorphs were defined. The theoretical vibration frequencies of OH groups depend significantly on the nature of the cations they are joined with. Theoretical values are spread out over narrow ranges: 3,612-3,626 cm(-1) for ν(AlOHMg), 3,604-3,606 cm(-1) for ν(AlOHAl), and 3,657-3,660 cm(-1) for ν(MgOHMg); 803-830 cm(-1) for δ(AlOHMg), 877 cm(-1) for δ(AlOHAl), and 693-711 cm(-1) for δ(MgOHMg), in agreement with known experimental values. From the intensities of the XOHY bands, we observe that the vibrational adsorptivities of the ν(OH) vibrations are not the same for all XOHY groups, and that ν(MgOHMg) absorptivity is much lower than that of ν(AlOHAl). These theoretical results should be taken into account in quantitative analysis of experimental vibrational studies in clay minerals, introducing different molar extinction coefficients in the Lambert-Beer law to determine the relative concentrations of both cationic arrangements.

Adsorption Mechanism and Structure of the Montmorillonite Complexes with (CH(3))(2)XO (X=C, and S), (CH(3)O)(3)PO, and CH(3)-CN Molecules.

The formation of complexes with different ligands in the interlayer space of montmorillonite saturated in Na(+), Mg(2+), Ca(2+), Co(2+), Cu(2+), Ni(2+), Fe(3+), and Cr(3+) was studied. Acetone, acetonitrile, dimethyl sulfoxide, and trimethylphosphate were used as ligands. The nature of the complexes was studied by means of X-ray diffraction, infrared spectroscopy, thermogravimetric analysis, microcalorimetry, and ab initio quantum mechanical methods. In all cases, the organic ligands penetrate into the interlayer space at room temperature, forming complexes stable in vacuum with the interlayer cations. The ligand-cation ratio depends on the valence of the saturating cation. The cation-ligand interaction in these complexes has an ion-dipole electrostatic nature. The complexes are formed by the direct interaction of the oxygen or nitrogen atom of ligand and the interlayer cation. Using the quantum mechanical approach, allow us to determine the disposition of the ligand in these complexes. In all cases, only one layer of ligands is present in the stable complexes. Copyright 2000 Academic Press.

Adsorption of Water Vapor by Homoionic Montmorillonites. Heats of Adsorption and Desorption

Adsorption isotherms for water vapor, basal spacing, and immersion heats and water desorption heats of Li+, Na+, Mg2+, Ca2+, Cu2+, and Fe3+ montmorillonite are measured at various relative humidities (r.h.). The amount of water adsorbed as a function of r.h. is found to increase gradually, whereas basal spacing increases and the adsorption heat decreases in steps. The water desorption heat also decreases in steps. The entropy of adsorbed water appears to be negative with respect to the entropy of liquid water. A theoretical model is proposed to describe the hydration process of Li+, Na+, Mg2+, Ca2+, Cu2+, and Fe3+ montmorillonites. The experimental adsorption heats are found to have a direct relationship with the sum of the hydration energy of the cations plus expansion energy.

Quantum mechanical study and nuclear magnetic resonance measurements of some alpha-arylcarboxyalkyl acids as anti-inflammatory agents.

The CNDO/2 quantum mechanical conformation method of analysis, charge density and protonation energy calculations, as well as 13C and 1H NMR measurements were carried out for ibufenac, ibuprofen, methylibuprofen, and for a series of alpha-arylpropionic acids. It was found that the nature of the terminal lipophilic residue does not significantly influence the conformation of the alpha-arylcarboxyalkyl acid side chain. The preferred conformational angle, for the torsion of the phenyl-C alpha bond, was found to be 90, 120, and 180 degrees in ibufenac, ibuprofen, and methylibuprofen, respectively. This conformational angle is calculated to be the same in all the alpha-arylpropionic acids. The protonation energies of the alpha-arylpropionic acids are correlated with the anti-inflammatory activity. It was found that the smaller the protonation energy, the larger the anti-inflammatory activity.

Self-consistent field-molecular orbital (SCF-MO) calculations and nuclear magnetic resonance measurements for fosfomycin and related compounds.

In the present work, the mechanism of action of fosfomycin [(-)-(1R,2S)-(1,2-epoxypropyl)phosphonic acid] as an antibiotic agent is studied by "ab initio" quantum mechanical calculations and by 1H, 13C, and 31P NMR measurements. Attention is focused on the relative charge density and chemical shift of the C(2) atom of the epoxy ring, which seems to be closely related with the activity of this antibiotic. The theoretical results suggest that the sulfhydryl addition should be preceded by a necessary anchoring of the phosphonate moiety on a positive group of the receptor.

Quantum mechanical calculations useful for determining the mechanism of action of fosfomycin.

CNDO/2 calculations were performed to determine at the molecular level the mechanism of action of the antibiotic fosfomycin, (--)-(1R,2S)-(1,2-epoxypropyl)phosphonic acid. Fosfomycin, a bacterial cell wall inhibitor, is known to act as a competitive inhibitor of N-acetylglucosamine-3-O-enolpyruvyl transferase, the normal substrate of which is phosphoenolpyruvate. Both compounds were studied, and the theoretical calculations revealed that the preferred conformations of phosphoenolpyruvate and fosfomycin presented the same spatial charge distributions on the active sites, the values of which are in complete agreement with the experimental observations. These results permit the projection of some details of the receptor, with implications for the modification of fosfomycin to increase its antibiotic activity.