Pseudorotaxane formation affected by stereo-electronic effects. A theoretical and experimental study.

We report a theoretical and experimental study on different complexes of pseudorotaxanes possessing pyridine axles. In order to evaluate the stereo-electronic effects of the methyl substituents in the pyridine ring, complexes with different substitution patterns were synthesized. In this way, it was possible to analyze the different behaviors of these complexes according to the positions of their methyl substituents. Combined techniques of molecular dynamics and quantum mechanical calculations with the help of molecular electrostatic potentials for a simpler visualization of the electronic effects were employed. We have sought experimental support of NMR spectroscopy analysis to corroborate the conclusions obtained from the molecular simulations. Our results not only clearly demonstrate that both electronic and steric effects play key roles in the feasibility of the formation of such complexes, but also the simulations reported here might predict the degree of difficulty of their formation. The combination of computational techniques employed here seems to be an excellent approach to be able to predict whether or not a complex can be formed and with what degree of difficulty. In addition, our experimental and theoretical results have allowed us to visualize the formation of external complexes in the rotaxanes reported here. In this case, the use of bolaforms with trimethylammonium groups at both ends was very useful to evaluate in detail the formation of the so-called external complexes in these systems.

Spectroscopic study of solvent effects on the electronic absorption spectra of flavone and 7-hydroxyflavone in neat and binary solvent mixtures.

The solvatochromic characteristics of flavone and 7-hydroxyflavone were investigated in neat and binary solvent mixtures. The spectral shifts of these solutes were correlated with the Kamlet and Taft parameters (α, ß and π*) using linear solvation energy relationships. The multiparametric analysis indicates that both specific hydrogen bond donor ability and non-specific dipolar interactions of the solvents play an important role in absorption maxima of flavone in pure solvents. The hydrogen bond acceptor ability of the solvent was the main parameter affecting the absorption maxima of 7-hydroxyflavone. The simulated absorption spectra using a TD-DFT method were in good agreement with the experimental ones for both flavones. Index of preferential solvation was calculated as a function of solvent composition. Preferential solvation by ethanol was detected in cyclohexane-ethanol and acetonitrile-ethanol mixtures for flavone and in acetonitrile-ethanol mixtures for 7-hydroxyflavone. These results indicate that intermolecular hydrogen bonds between solute and solvent are responsible for the non-linear variation of the solvatochromic shifts on the mole fraction of ethanol in the analyzed binary mixtures.

Experimental and Theoretical Study of the Stability of the Complex Fisetin-Cu(II) and A Comparative Study of Free Ligand and Complex Interaction with Molecular Singlet Oxygen.

In this work, the flavonol fisetin was selected in order to study its reactivity against Cu(II), a metal ion of interest in biological media and industry. The stoichiometry and apparent formation constant of the complex in ethanolic medium at 25°C were evaluated using spectrophotometric techniques. The resulting stoichiometry was a 1:1 ligand:metal complex, and a log K = 5.17 ± 0.12 was determined. Since two possible chelation sites can be proposed for the complex formation, quantum chemistry calculations were performed on these structures. Calculations suggest that the hydroxyl-keto site is more stable for the complex formation than the catechol site. Flavonoids could exert protection against oxidative damage caused by reactive oxygen species, and this biological activity could be affected by chelation with metal ions. This led us to perform a study on the interaction of both, free flavonoid and complex, with reactive oxygen species. Our results showed both compounds quench molecular singlet oxygen photogenerated with visible light, mainly in a physical fashion. In order to analyze a possible protective effect of flavonoid and its complex against oxidative damage in biological environments, the amino acid tryptophan was selected as a model oxidation system. Free flavonoid does not have a marked protective effect, whereas its complex showed a relevant protective effect.

In vitro and in vivo inhibition of Hass avocado polyphenol oxidase enzymatic browning by paeonol, ß-cyclodextrin, and paeonol:ß-cyclodextrin inclusion complex.

Polyphenol oxidase (PPO) was extracted from Hass avocados and its physicochemical properties were analyzed. The optimum pH and temperature of the enzyme were pH 7.5 and 20°C. This PPO showed a high thermal stability, since 26% of the initial activity was retained by the enzyme after heating at 60°C for 40 min. Inhibition studies were performed using different chemical reagents, and the order in the inhibition efficiency was paeonol > 4-hydroxybenzaldehyde > ß-cyclodextrin (ß-CD). The first two inhibitors presented a non-competitive mechanism while the inhibition by ß-CD results from a mixed type mechanism. Since the aqueous solubility of paeonol (a natural compound) is very low, the inclusion complex between this drug and ß-CD was obtained in solution and solid state. The stoichiometry of the paeonol:ß-CD complex was 1:1 and its ΔG° of formation was -26 kJ/mol. The complexation of paeonol by ß-CD not only enhances the aqueous solubility and thermal stability of the drug, but also improves the in vitro inhibition efficiency against PPO. Colorimetric analysis on avocados pulp (in vivo) showed that the inclusion complex does not increase the inhibitory effect of paeonol, remaining practically unchanged. However, the formulation of paeonol:ß-CD inclusion complex allows employing this compound as PPO inhibitor in aqueous solutions.

Encapsulation of methyl and ethyl salicylates by beta-cyclodextrin HPLC, UV-vis and molecular modeling studies.

The complexation of methyl salicylate (MS) and ethyl salicylate (ES), non-steroidal analgesic, anti-inflammatory and antirrheumatic drugs with beta-cyclodextrin (betaCD) has been studied from thermodynamic and structural points of view. The complexation with betaCD has been investigated using reversed-phase liquid chromatography. Retention behavior has been analyzed on a reverse-phase column Luna 18(2) 5 microm. The mobile-phase was methanol:water in different ratios (55:45 to 70:30) in which betaCD (1-9 mM) was incorporated as a mobile-phase additive. The decrease in retention times with increasing concentrations of betaCD enables the determination of the apparent stability constant of the complexes. Values at 30 degrees C with 55% methanol were K(MS:betaCD): 15.84 M(-1) and K(ES:betaCD): 12.73 M(-1) for MS and ES, respectively. The apparent stability constants decrease as the polarity of the solvent decreases. The low solubility of MS and ES in aqueous solution has been improved by complexation with betaCD (1-9 mM). The stability constants of the complexes obtained from the phase-solubility diagrams using a UV-vis spectrophotometric method were K(MS:betaCD): 229 M(-1) and K(ES:betaCD): 166 M(-1). In addition, semi-empirical quantum mechanics calculations using AM1 and PM3 methods in vacuum were performed. The energetically favorable inclusion structures were identified and the most favorable orientation for the inclusion process was found to be the head-down orientation for both complexes. Enthalpy for encapsulation processes was found to be favorable (DeltaH degrees <0), while entropy (DeltaS degrees <0) and Gibbs free energy were unfavorable (DeltaG degrees >0). By means of HPLC and UV-vis measurements and quantum mechanics calculations, it was found that MS and ES form a 1:1 inclusion complex with betaCD. The theoretical results are in agreement with the experimental parameters associated with the encapsulation process.

Theoretical and Experimental Study of Inclusion Complexes of ß-Cyclodextrins with Chalcone and 2',4'-Dihydroxychalcone.

The inclusion complexes formed by chalcone and 2',4'-dihydroxychalcone with ß-cyclodextrin have been studied combining experimental (phase solubility diagrams, Fourier transform infrared spectroscopy) and molecular modeling (molecular dynamics, quantum mechanics/molecular mechanics calculations) techniques. The formation constants of the complexes were determined at different temperatures, and the thermodynamic parameters of the process were obtained. The inclusion of chalcone in ß-cyclodextrin is an exothermic process, while the inclusion of 2',4'-dihydroxychalcone is endothermic. Free energy profiles, derived from umbrella sampling using molecular dynamics simulations, were constructed to analyze the binding affinity and the complexation reaction at a molecular level. Hybrid QM/MM calculations were also employed to obtain a better description of the energetic and structural aspects of the complexes. The intermolecular interactions that stabilize both inclusion complexes were characterized by means of quantum atoms in molecules theory and reduce density gradient method. The calculated interactions were experimentally observed using FTIR.

Looking for the interactions between omeprazole and amoxicillin in a disordered phase. An experimental and theoretical study.

In this paper, co-grinding mixtures of omeprazole-amoxicillin trihydrate (CGM samples) and omeprazole-anhydrous amoxicillin (CGMa samples) at 3:7, 1:1 and 7:3 molar ratios, respectively, were studied with the aim of obtaining a co-amorphous system and determining the potential intermolecular interactions. These systems were fully characterized by differential scanning calorimetry (DSC), FT-infrared spectroscopy (FTIR), X-ray powder diffraction (PXRD), scanning electron microscopy (SEM) and solid state Nuclear Magnetic Resonance (ssNMR). The co-grinding process was not useful to get a co-amorphous system but it led to obtaining the 1:1 CGMa disordered phase. Moreover, in this system both FTIR and ssNMR analysis strongly suggest intermolecular interactions between the sulfoxide group of omeprazole and the primary amine of amoxicillin anhydrous. The solubility measurements were performed in simulated gastric fluid (SGF) to prove the effect of the co-grinding process. Complementarily, we carried out density functional theory calculations (DFT) followed by quantum theory of atoms in molecules (QTAIM) and natural bond orbital (NBO) analyses in order to shed some light on the principles that guide the possible formation of heterodimers at the molecular level, which are supported by spectroscopic experimental findings.

Physicochemical characterization of 2-hydroxybenzophenone with ß-cyclodextrin in solution and solid state.

The characterization of the inclusion complex between 2-hydroxybenzophenone (2OHBP) and ß-cyclodextrin (ßCD) in the solid state was performed using Fourier transform infrared spectroscopy (FTIR), powder X-ray diffractometry (PXRD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and transmission electron microscopy (TEM). The apparent formation constant of the complex was determined by phase solubility diagrams and liquid chromatography (HPLC) at different temperatures. The formation of the inclusion complex induced slight shifts in the FTIR spectrum while by PXRD a new crystalline phase was observed. TEM studies revealed that the complex forms aggregates of nanometric size. The inclusion complex showed a higher solubility in the tested dissolution media than free 2OHBP. Moreover, the freeze-dried solid complex exhibits a higher thermal stability than the solid free drug. The thermodynamic analysis allowed us to conclude that the encapsulation process is endothermic in water and exothermic in methanol-water.

Inclusion complex of 2-chlorobenzophenone with cyclomaltoheptaose (ß-cyclodextrin): temperature, solvent effects and molecular modeling.

A thermodynamic study of the inclusion process between 2-chlorobenzophenone (2ClBP) and cyclomaltoheptaose (ß-cyclodextrin, ß-CD) was performed using UV-vis spectroscopy, reversed-phase liquid chromatography (RP-HPLC), and molecular modeling (PM6). Spectrophotometric measurements in aqueous solutions were performed at different temperatures. The stoichiometry of the complex is 1:1 and its apparent formation constant (K(c)) is 3846M(-1) at 30°C. Temperature dependence of K(c) values revealed that both enthalpy (ΔH°=-10.58kJ/mol) and entropy changes (ΔS°=33.76J/Kmol) are favorable for the inclusion process in an aqueous medium. Encapsulation was also investigated using RP-HPLC (C18 column) with different mobile-phase compositions, to which ß-CD was added. The apparent formation constants in MeOH-H(2)O (K(F)) were dependent of the proportion of the mobile phase employed (50:50, 55:45, 60:40 and 65:35, v/v). The K(F) values were 419M(-1) (50% MeOH) and 166M(-1) (65% MeOH) at 30°C. The thermodynamic parameters of the complex in an aqueous MeOH medium indicated that this process is largely driven by enthalpy change (ΔH°=-27.25kJ/mol and ΔS°=-45.12J/Kmol). The results of the study carried out with the PM6 semiempirical method showed that the energetically most favorable structure for the formation of the complex is the 'head up' orientation.