Publications

Abstract Nature is an ancient pharmacy that is largely used as an inspiring source for drug discovery processes for the early eras. Several drugs used nowadays are of natural product origin or inspired on the basis of natural product structures and approximately half of the 20 best-selling non-protein drugs are related to natural products. However, a largely unexplored marine world that presumably harbors the most biodiversity may be the vastest resource to discover compounds with remarkable biological properties. Marine based drug discovery research has been mainly focused on crude extracts. The purpose of this review is to summarize the findings reported in this area, particularly focuses on marine-derived coumarincontaining compounds.

Abstract A comprehensive study on the phase behaviour of two sets of ionic liquids (ILs) and their interactions with water is here presented through combining experimental and theoretical approaches. The impact of the alkyl side chain length and the cation symmetry on the water solubility in the asymmetric [C-N (-) (1)C(1)im][NTf2] and symmetric [C-N (-) (1)C(1)im][NTf2] series of Rs (N up to 22), from 288.15 K to 318.15 K and at atmospheric pressure, was studied. The experimental data reveal that the solubility of water in ILs with an asymmetric cation is higher than in those with the symmetric isomer. Several trend shifts on the water solubility as a function of the alkyl side chain length were identified, namely at [C(6)C(1)im][NTf2] for asymmetric ILs and at [C(4)C(4)im][NTf2] and [C(7)C(7)im]INTf2] for the symmetric ILs. To complement the experimental data and to further investigate the molecular-level mechanisms behind the dissolution process, density functional theory calculations, using the Conductor-like Screening Model for Real Solvents (COSMO-RS) and the electrostatic potential-derived CHelpG, were performed. The COSMO-RS model is able to qualitatively predict water solubility as a function of temperature and alkyl chain lengths of both symmetric and asymmetric cations. Furthermore, the model is also capable to predict the somewhat higher water solubility in the asymmetric cation, as well as the trend shift as a function of alkyl chain lengths experimentally observed. Both COSMO-RS and the electrostatic potential-derived CHelpG show that the interactions of water and the IL cation take place on the IL polar region, namely on the aromatic head and adjacent methylene groups that explains the differences in water solubility observed for cations with different chain lengths. Furthermore, the CHelpG calculations for the isolated cations in the gas phase indicates that the trend shift of water solubility as a function of alkyl chain lengths and the difference of water solubility in symmetric may also result from the partial positive charge distribution/contribution of the cation.

Abstract Potential bioactive 3-arylquinolin-4(1H)-ones were synthesized under ohmic heating using an efficient, reusable, and ligand-free protocol developed for the Suzuki-Miyaura coupling of 1-substituted-3-iodoquinolin-4(1H)-ones with several boronic acids in water using Pd(OAc)(2) as a catalyst and tetrabutylammonium bromide (TBAB) as the phase transfer catalyst. Good substrate generality, ease of execution, short reaction time, and practicability make this method exploitable for the generation of libraries of B ring-substituted 3-arylquinolin-4(1H)-ones. After a simple workup, the Pd/catalyst-H2O-TBAB system could be reused for at least seven cycles without significant loss of activity.

Abstract Although previous studies attempted to characterize the liquidliquid phase behaviour between water and ionic liquids (ILs), the impact of non-cyclic cations on the solubilities is poorly studied and yet to be understood. In this work, the mutual solubilities between water and ILs containing the anion bis(trifluoromethylsulfonyl)imide, [NTf2]-, combined with the cations diethylmethylsulfonium, [S-221][NTf2], triethylsulfonium, [S-222][NTf2], butyltrimethylammonium, [N-4111][NTf2], tributylmethylammonium, [N-4441][NTf2], methyltrioctylammonium, [N-1888][NTf2], and methyltrioctylphosphonium, [P-1888][NTf2], from (288.15 to 318.15) K and at 0.1 MPa, were experimentally measured and further compared with predictions from the COnductor-like Screening MOdel for Real Solvents (COSMO-RS). All the studied phase diagrams display an upper critical solution temperature (UCST). The binary system composed of [P-1888][NTf2] exhibits the widest immiscibility gap, followed by [N-18888][NTf2], [N-4441][NTf2], [S-222][NTf2], [N-4111][NTf2], and [S-221][NTf2]. The COSMO-RS is able to correctly predict the experimental UCST behaviour and the cation impact on the immiscibility regimes observed. Natural Population Analysis (NPA) calculations were additionally performed for the isolated cations in the gas phase indicating that the differences in the water-IL mutual miscibilities might not result only from the hydrophobicity of the cation (derived from the increase of the alkyl chains length) but also from the charge distribution of the central atom and attached methylene groups. This fact explains the enhanced solubility of ammonium-based ILs in water here identified

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.