Publications

Abstract The host-guest chemistry of ferrocene derivatives was explored by a combined experimental and theoretical study. Several 1-arylferrocenes and 1,1'-diarylferrocenes were synthesized by the Suzuki-Miyaura cross-coupling reaction. The ability of these compounds to bind small cations in the gas phase was investigated experimentally by electrospray ionization mass spectrometry (ESI-MS). The results evidenced a noticeable ability of all 1,1'-diarylferrocenes studied to bind cations, while the same was not observed for the corresponding 1-arylferrocenes nor ferrocene. The 1,1'-diarylferrocene center dot center dot center dot cation relative interaction energies were evaluated by ESI-MS and quantum chemical calculations and showed that cation binding in these systems follows electrostatic trends. It was found that, due to their unique molecular shape and smooth torsional potentials, 1,1'-diarylferrocenes can act as molecular tweezers of small-sized cations in the gas phase.

Abstract Freeze-drying has widely been applied to improve the stabilization of colloidal drug carriers. In the present study, the effect of cryoprotectants on the physicochemical characteristics of silica nanoparticles (SiNP) during the freeze-drying process has been extensively investigated. SiNP were synthesized by sol-gel technology and freeze-dried in the presence of sorbitol, trehalose, and/or mannitol at different concentrations and ratios. Dynamic light scattering (DLS), atomic force microscopy (AFM), X-ray diffraction analysis (XRD), and differential scanning calorimetry (DSC) have been used for particle characterization after freeze-drying. Based on the obtained results, SiNP in the presence of mannitol showed a more crystalline behavior in comparison to nanoparticles with sorbitol or trehalose (confirmed by DSC and XRD). SiNP in the presence of trehalose showed a more crystalline structure than SiNP in the presence of sorbitol. However, trehalose was more efficient in preserving the particle size of nanoparticles during the freeze-drying process. The optimal concentration of trehalose for preserving silica nanoparticles was 10 % at a ratio of (1:1). During the freeze-drying process, trehalose is able to replace water molecules due to the strong interaction via hydrogen bounds between silanol groups present in SiNP surface and the sugar, forming a stable layer around the particle and thus preserving the particle physical properties.

Abstract The use of resistance-modifying agents is a potential strategy that is used to prolong the effective life of antibiotics in the face of increasing antibiotic resistance. Since certain flavonoids are potent bacterial efflux pump inhibitors, we assessed morin, rutin, quercetin, hesperidin, and (+)-catechin for their combined activity with the antibiotics ciprofloxacin, tetracycline, erythromycin, oxacillin, and ampicillin against drug-resistant strains of Staphylococcus aureus, including methicillin-resistant S. aureus. Four established methods were used to determine the combined efficacy of each combination: microdilution checkerboard assays, time-kill determinations, the Etest, and dual disc-diffusion methods. The cytotoxicity of the flavonoids was additionally evaluated in a mouse fibroblast cell line. Quercetin and its isomer morin decreased by 3- to 16-fold the minimal inhibitory concentration of ciprofloxacin, tetracycline, and erythromycin against some S. aureus strains. Rutin, hesperidin, and (+)-catechin did not promote any potentiation of antibiotics. Despite the potential cytotoxicity of these phytochemicals at a high concentration (fibroblast IC50 of 41.8 and 67.5mg/L, respectively), quercetin is commonly used as a supplement for several therapeutic purposes. All the methods, with exception of the time-kill assay, presented a high degree of congruence without any apparent strain specificity.

Abstract The thermochemistry of samples of amorphous cellulose, cellulose I, cellulose II, and cellulose III was studied by using oxygen bomb calorimetry, solution calorimetry in which the solvent was cadoxen (a cadmium ethylenediamine solvent), and with a Physical Property Measurement System (PPMS) in zero magnetic field to measure standard massic heat capacities C-p,C-w degrees over the temperature range T = (2 to 302) K. The samples used in this study were prepared so as to have different values of crystallinity indexes CI and were characterized by X-ray diffraction, by Karl Fischer moisture determination, and by using gel permeation chromatography to determine the weight average degree of polymerization DPw. NMR measurements on solutions containing the samples dissolved in cadoxen were also performed in an attempt to resolve the issue of the equivalency or non-equivalency of the nuclei in the different forms of cellulose that were dissolved in cadoxen. While large differences in the NMR spectra for the various cellulose samples in cadoxen were not observed, one cannot be absolutely certain that these cellulose samples are chemically equivalent in cadoxen. Equations were derived which allow one to adjust measured property values of cellulose samples having a mass fraction of water w(H2O) to a reference value of the mass fraction of water w(ref). The measured thermodynamic properties (standard massic enthalpy of combustion Delta H-c(w)degrees, standard massic enthalpy of solution Delta H-sol(w)degrees, and C-p,C-w degrees) were used in conjunction with the measured CI values to calculate values of the changes in the standard massic enthalpies of reaction Delta H-r(w)degrees*, the standard massic entropies of reaction Delta S-r(w)degrees*, the standard massic Gibbs free energies of reaction Delta(r)G(w)degrees*, and the standard massic heat capacity Delta C-r(p,w)degrees, for the interconversion reactions of the pure (CI = 100) cellulose allomorphs, i.e., cellulose(am), cellulose I(cr), cellulose II(cr), and cellulose II(cr), at the temperature T = 298.15 K, the pressure p degrees = 0.1 MPa, and w(H2O) = 0.073. The "*"' denotes that the thermodynamic property pertains to pure cellulose allomorphs. Values of standard massic enthalpy differences Delta H-T(0)w degrees, standard massic entropy differences Delta S-T(0)w degrees, and the standard massic thermal function Phi(w)degrees = Delta S-T(0)w degrees - Delta H-T(0)w degrees/T were calculated from the measured heat capacities for the cellulose samples and for the pure cellulose allomorphs. The extensive literature pertinent to the thermodynamic properties of cellulose has been summarized and, in many cases, property values have been calculated or recalculated from previously reported data. The thermodynamic property data show that cellulose(am) is the least stable of the cellulose allomorphs considered in this study. However, due to the uncertainties in the measured property values, it is not possible to use these values to order the relative stabilities of the cellulose (I, II, and III) crystalline allomorphs with a reasonable degree of certainty. Nevertheless, based on chemical reactivity information, the qualitative order of stability for these three allomorphs is cellulose III(cr) > cellulose II(cr) > cellulose I beta(cr) at T = 298.15 K. However, as evidenced by the fact that cellulose I(cr) can be reformed by the application of heat and water to a sample of cellulose III(cr), the differences in the stabilities of these three allomorphs appear to be small and may be temperature dependent. Standard thermodynamic formation properties as well as property values for the conversion reactions of the cellulose allomorphs to alpha-D-glucose(cr) have been calculated on the assumption that S-w degrees -> 0 as T -> 0. The values for the standard massic Gibbs free energy of reaction Delta(r)G(w)degrees for the conversion of the cellulose allomorphs to alpha-D-glucose(cr), with the exception of anhydrous cellulose(am), all have positive values and thus are thermodynamically not favored for mass fractions of water w(H2O) < 0.073.

Abstract The standard (p(o) = 0.1 MPa) molar energies of combustion, Delta U-c(m)o, of 2-phenylindole, 1-methyl-2-phenylindole and 1-ethyl-2-phenylindole, in the crystalline state, were determined, at T = 298.15 K, using a static bomb combustion calorimeter. The vapour pressures as a function of the temperature for these compounds were measured by the Knudsen effusion technique and the standard molar enthalpies of sublimation were derived. From the experimental results, the standard (p(o) = 0.1 MPa) molar enthalpies of formation in the condensed and gaseous phases, at T = 298.15 K, of 2-phenylindole, 1-methyl-2-phenylindole and 1-ethyl-2-phenylindole were calculated. Additionally, the gas-phase enthalpies of formation of these compounds and also for 1-ethylindole were estimated by G3(MP2) calculations. Enthalpies of formation, obtained using appropriate working reactions, were calculated and compared with the experimental data. The results were also analysed in terms of structural enthalpic group contributions.

Abstract Telomeres and telomerase are key players in tumorogenesis. Among the various strategies proposed for telomerase inhibition or telomere uncapping, the stabilization of telomeric G-quadruplex (G4) structures is a very promising one. Additionally, G4 stabilizing ligands also act over tumors mediated by the alternative elongation of telomeres. Accordingly, the discovery of novel compounds able to act on telomeres and/or inhibit the telomerase enzyme by stabilizing DNA telomeric G4 structures as well as the development of approaches efficiently prioritizing such compounds constitute active areas of research in computational medicinal chemistry and anticancer drug discovery. In this direction, we applied a virtual screening strategy based on the rigorous application of QSAR best practices and its harmonized integration with structure-based methods. More than 600,000 compounds from commercial databases were screened, the first 99 compounds were prioritized, and 21 commercially available and structurally diverse candidates were purchased and submitted to experimental assays. Such strategy proved to be highly efficient in the prioritization of G4 stabilizer hits, with a hit rate of 23.5%. The best G4 stabilizer hit found exhibited a shift in melting temperature from FRET assay of +7.3 degrees C at 5 mu M, while three other candidates also exhibited a promising stabilizing profile. The two most promising candidates also exhibited a good telomerase inhibitory ability and a mild inhibition of HeLa cells growth. None of these candidates showed antiproliferative effects in normal fibroblasts. Finally, the proposed virtual screening strategy proved to be a practical and reliable tool for the discovery of novel G4 ligands which can be used as starting points of further optimization campaigns.

Abstract Personal care products (PCPs) have been found in surface water, wastewater, tap water, and swimming pool water. The chlorine used in the disinfection process of water reacts with these compounds generating chlorinated byproducts that may possess enhanced toxicity. In the case of swimming pool water chlorine also reacts with organic material released by swimmers such as amino acids and other nitrogen compounds yielding chlorinated compounds. Besides this organic material, sunscreen cosmetics used by swimmers are also released into pool water and react with chlorine. UV-Filters 2-ethylhexyl-p-dimethylaminobenzoate (EHDPABA), benzophenone-3 (BP-3), benzophenone- 4 (BP-4), 2-ethylhexyl-4-methoxycinnamate (EHMC), and 4-tert-butyl- 40-methoxy-dibenzoylmethane (BDM) are known to suffer an electrophilic aromatic substitution of one or two atoms of hydrogen per one or two chlorine atoms leading to mono- and di-chlorinated byproducts. It has also been observed the presence of halobenzoquinones (HBQs) in pool water that results from the chlorination of UV-filters such as BDM, octocrylene, and terephthalilidene dicamphor sulfonic acid. The chlorination of some parabens has also been studied. It is known that some of the formed chlorinated byproducts are genotoxic. In this chapter we present a review on the work done so far to determine the stability of PCPs in chlorinated water and to identify the chlorinated byproducts. © Springer International Publishing Switzerland 2014.

Abstract Plants contain numerous components that are important sources of new bioactive molecules with antimicrobial properties. Isothiocyanates (ITCs) are plant secondary metabolites found in cruciferous vegetables that are arising as promising antimicrobial agents in food industry. The aim of this study was to assess the antibacterial activity of two isothiocyanates (ITCs), allylisothiocyanate (AITC) and 2-phenylethylisothiocyanate (PEITC) against Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus and Listeria monocytogenes. The antibacterial mode of action was also characterized by the assessment of different physiological indices: membrane integrity, intracellular potassium release, physicochemical surface properties and surface charge. The minimum inhibitory concentration (MIC) of AITC and PEITC was 100 mu g/mL for all bacteria. The minimum bactericidal concentration (MBC) of the ITCs was at least 10 times higher than the MIC. Both AITC and PEITC changed the membrane properties of the bacteria decreasing their surface charge and compromising the integrity of the cytoplasmatic membrane with consequent potassium leakage and propidium iodide uptake. The surface hydrophobicity was also non-specifically altered (E. coli and L. monocytogenes become less hydrophilic; P. aeruginosa and S. aureus become more hydrophilic). This study shows that AITC and PEITC have strong antimicrobial potential against the bacteria tested, through the disruption of the bacterial cell membranes. Moreover, phytochemicals are highlighted as a valuable sustainable source of new bioactive products.

Abstract Bacterial resistance has been increasingly reported worldwide and is one of the major causes of failure in the treatment of infectious diseases. Natural-based products, including plant secondary metabolites (phytochemicals), may be used to surpass or reduce this problem. The objective of this study was to determine the antibacterial effect and mode of action of selected essential oils (EOs) components: carveol, carvone, citronellol, and citronellal, against Escherichia coli and Staphylococcus aureus. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) were assessed for the selected EOs components. Moreover, physicochemical bacterial surface characterization, bacterial surface charge, membrane integrity, and K+ leakage assays were carried out to investigate the antimicrobial mode of action of EOs components. Citronellol was the most effective molecule against both pathogens, followed by citronellal, carveol, and carvone. Changes in the hydrophobicity, surface charge, and membrane integrity with the subsequent K+ leakage from E. coli and S. aureus were observed after exposure to EOs. This study demonstrates that the selected EOs have significant antimicrobial activity against the bacteria tested, acting on the cell surface and causing the disruption of the bacterial membrane. Moreover, these molecules are interesting alternatives to conventional antimicrobials for the control of microbial infections.

Abstract The self-association equilibrium, i.e. formation of noncovalent dimers; in two triphenylamine derivative TPD (N,N'-bis(3-methylphenyl)-N,N'-diphenylbenzidine) and mMTDAB (1,3,5-tri[(3-methylphenyl)phenylamino]benzene), in solution was evaluated by H-1 NMR. spectroscopy. The gas-phase energetics of the respective dimerization processes was explored by computational quantum chemistry: The results indicate that self-association is significantly more extensive in TPB than in TDAB. It is proposed that this fact helps to explain why TPB presents a stability, higher than expected in the liquid phase, which is reflected in a lower melting temperature, a less volatile liquid, and possibly a higher tendency to form a glass. These results highlight the influence of self-association on the phase equilibria and thermodynamic properties of pure organic substances.