Fabrizio Melani

Interaction between naproxen and chemically modified β-cyclodextrins in the liquid and solid state

Abstract The complexation between naproxen and some chemically modified β-cyclodextrins (hydroxyethyl β-cyclodextrin with average substitution degree per anhydroglucose unit 0.6, 1.0 and 1.6; hydroxyproyl β-cyclodextrin with average substitution degree per anhydroglucose unit 0.6 and 0.9) was studied using phase-solubility analysis and molecular modelling. The amorphous carriers exhibit similar solubilizing effects and complexing abilities, which are reflected by a comparable increase in drug dissolution rate to about the same extent from equimolar blends with each chemically modified β-cyclodextrin. X-ray diffractometry and differential scanning calorimetry data indicate a role of the degree of substitution of the carrier in the decrease in crystallinity of naproxen in equimolar blends with chemically modified β-cyclodextrins.

Computer-aided molecular modeling techniques for predicting the stability of drug–cyclodextrin inclusion complexes in aqueous solutions

Molecular modeling was used to investigate factors influencing complex formation between cyclodextrins and guest molecules and predict their stability through a theoretical model based on the search for a correlation between experimental stability constants (Ks) and some theoretical parameters describing complexation (docking energy, host– guest contact surfaces, intermolecular interaction fields) calculated from complex structures at a minimum conformational energy, obtained through stochastic methods based on molecular dynamic simulations. Naproxen, ibuprofen, ketoprofen and ibuproxam were used as model drug molecules. Multiple Regression Analysis allowed identification of the significant factors for the complex stability. A mathematical model (r ¼ 0:897) related log Ks with complex docking energy and lipophilic molecular fields of cyclodextrin and drug. 2002 Elsevier Science B.V. All rights reserved.

1H-NMR and molecular modelling techniques for the investigation of the inclusion complex of econazole with α-cyclodextrin in the presence of malic acid.

Carrying on a study where the combination of alpha-cyclodextrin and malic acid was found to be the most effective in improving the solubility of econazole, an antifungal drug very poorly water soluble, in the present work 1H-NMR and nuclear overhauser effect (NOE) experiments and molecular modelling studies were performed to gain insight into the interactions in solution between such three components and the structure of the supposed multicomponent complex. Findings demonstrated that two different complexes can be simultaneously present in solution involving, respectively, the inclusion of econazole monochloro-phenyl group within the host cavity from the primary hydroxyl side of the cyclodextrin cavity, or that of the other phenyl group through the opposite side of the cavity. It was shown that also malic acid is strictly involved in the molecular assembly of the complex, particularly through interactions with primary hydroxyl groups of the cyclodextrin molecule. Molecular modelling studies allowed to elaborate possible geometric models of the multicomponent complex and to select the more energetically favourable conformations which complied better with experimental data. Results suggested the possible formation in solution of stable oligomeric aggregates constituted by the repeated concatenation of the three components.

1H-NMR NOE and molecular modelling to characterize thymol and carvacrol β-cyclodextrin complexes

Abstract In this study the structural conformations of the complexes between β-cyclodextrin and the geometrical isomers, thymol and carvacrol, were investigated using 1 H-NMR and molecular modelling techniques. The NOE experiments were performed in aqueous solutions and showed the presence of only one complex with a well-defined orientation either for thymol or for carvacrol. Molecular modelling investigations were useful to clarify the structural conformation of the supramolecular edifice. To develop graphic simulations closer to the experimental conditions, the studies were performed in dynamic at 300 K with and without evaluating the dielectric constant, D. The best agreement of 1 H-NMR NOE findings with the theoretical data was obtained after the evaluation of the dielectric constant parameter and these results confirmed the inclusion of thymol and carvacrol inside the βCD hydrophobic cavity.

GRIND-derived pharmacophore model for a series of α-tropanyl derivative ligands of the sigma-2 receptor

A pharmacophore model for the sigma-2 receptor was derived using GRIND (GRid INdependent Descriptors) descriptors arising from a 3D-level procedure whose main prerogative is that it does not require ligand alignment. PLS models for sigma-2 affinity (sigma-2 model: r2=0.83, q2=0.63) and sigma-1/sigma-2 selectivity (r2=0.72, q2=0.46) were derived using a series of α-tropanyl derivatives. The models provide pictures of the virtual receptor site (VRS) significant enough to attain a qualitative pharmacophoric representation of the sigma receptor. They give the internal geometrical relationships within two hydrophobic areas (hydrophobic-1 and -2) and a H-bond donor receptor region with which ligands establish non-covalent bonds.

Synthesis and A1 and A2A adenosine binding activity of some pyrano [2,3-c] pyrazol-4-ones

A series of pyrano[2,3-c]pyrazol-4-ones was synthesized and evaluated for bovine brain adenosine A1 and A2A receptor binding affinity. Substituents at positions 5 and/or 6 were varied in order to define the structure-activity relationships in these new kinds of adenosine receptor ligands. The most selective and potent ligand among the reported compounds was the 1,4-dihydro-1-phenyl-3-methyl-6-(3-aminophenyl)-pyrano[2,3-c]pyraz ol-4-one 11 which showed a 27-fold selectivity for A1 receptor and a Ki value of 84 nM.

Enhancement of viniferin production in Vitis vinifera L. cv. alphonse lavallée cell suspensions by low-energy ultrasound alone and in combination with methyl jasmonate

This study examined for the first time the effect of low-energy ultrasound (US), used alone or in combination with methyl jasmonate (MeJA), on viniferin production in cell cultures of Vitis vinifera L. cv Alphonse Lavallée. Cell suspensions were exposed for 2 min to US (power 30, 60, and 90 mW cm(-3)). The highest viniferin production was obtained at 30 mW cm(-3). When sonication was performed twice, the effect on viniferin production was negligible, whereas triple sonication slightly increased production. US treatment at 30 mW cm(-3) for 5 min decreased viniferin production and induced cellular death. The combined use of MeJA and US (2 min) increased the production of δ-viniferin, the dominant stilbene, more than each elicitor used alone. These results suggest that low-energy US, alone and in combination with MeJA, can act as a physical elicitor to stimulate viniferin production in V. vinifera cell cultures.

Pyrazolo[4,5-c]quinolines. 2. Synthesis and specific inhibition of benzodiazepine receptor binding.

A series of 1-aryl-3,5-dimethyl-4,5-dihydro-1H-pyrazolo[4,5-c]quinolin-4-ones (2a-e) and 1-aryl-3-methyl-1H-pyrazolo[4,5-c]quinolines (3-7a-e) bearing different substituents at position 4 were prepared and tested for their ability to displace specific [3H]flunitrazepam binding from bovine brain membranes. The 5-N-methyl derivatives 2a-c,e were the compounds that bound with the highest affinity within this class. The replacement of the carbonyl group with other substituents and the resulting aromatization of the pyridine moiety greatly decreased the binding affinity. From a Lineweaver-Burk analysis on the most active compound 2b, it appears that the inhibition is a competitive one.

The correct synthesis of 2,3-dihydro-2-aryl-4-r-[1]benzopyrano[4,3-c]pyrazole-3-ones.

Abstract The correct synthesis of the title compounds 1a–b and 2a–b is described. The claimed synthesis of 2a from 2-methyl-3-chromonecarbonitrile is shown not to lead to 2a , as previously reported but to 1,4-dihydro-1-phenyl-3-methyl[1]benzopyrano[3,4-d]pyrazole-4-one 10a.

Interaction of naproxen with alpha-cyclodextrin and its noncyclic analog maltohexaose.

AbstractPurpose. To study the effect of mechanical grinding on crystallinity changes of naproxen (NAP) in mixtures with α-cyclodextrin (αCd), amorphous αCd, and maltohexaose (M6); and the possible formation of a pseudo-inclusion complex between NAP and M6 in aqueous solution. Methods. NAP-additive physical mixtures at 0.30,0.18, and 0.10 mass fraction of drug were tested, after increasing grinding times, by differential scanning calorimetry (DSC) and X-ray powder diffractometry (XRD). Interaction in aqueous solution was examined by phase-solubility and fluorescence analyses supported by molecular modelling. Results. In the mixtures with each additive the fusion enthalpy per unit mass of NAP decreased and the half width at half maximum of selected X-ray diffraction peaks of NAP increased with the progress of grinding time following the loss of crystallinity of the samples. The mechanical treatment apparently did not affect the chemical integrity of the drug. Particularly active in the equimolar mixture was the best amorphizing agent, M6. Solution studies and molecular modelling confirmed M6 may have the feature of a supermolecule for NAP, which forms a 1:1 pseudo-inclusion complex that was as stable as the true inclusion complex with αCd. Conclusions. The intrinsically amorphous linear analog of αCd might be a potential amorphism-inducing agent and solubilizer for scarcely water soluble drugs.