Ana Borrego-Sánchez

Two derivatives of the group of 7-azaindoles, 1-benzyl-3-(piperidin-1-ylmethyl)-1H-pyrrolo [2,3-b] pyridine, and 1-benzyl-5-methoxy-3-(piperidin-1-ylmethyl)-1H-pyrrolo [2,3-b] pyridine as mono-oxalate salts are studied in this work as potential neuroprotective drugs for the treatment of Alzheimer’s disease. Previously, we studied the use of a natural montmorillonite clay mineral as a candidate for a drug delivery system, finding that these drugs can be intercalated into the confined interlayer space of montmorillonite and subsequently released in a human medium for therapeutic use. However, some aspects of this study could not be explained. This work has studied this process at the atomic and molecular levels by using the Interface force field (FF). Initially, this methodology was validated in this work, reproducing the experimental crystal structure of these 7-azaindole drugs. Then, this FF was applied to calculate the intercalation of these drugs by cation exchange into montmorillonite according to the experimental results. Our calculations have reproduced this intercalation at the cation exchange capacity at the molecular level, finding that the experimental structure can only be justified with the intercalation of five drug molecules per 4 × 2 × 1 supercell of clay mineral inside the confined interlayer space. In addition, this intercalation does not produce a monolayer disposition postulated initially from experiments. On the contrary, our molecular dynamics simulations show that the intercalated molecules adopt a disordered disposition with a certain tendency to form a bilayer configuration in the confined interlayer space of montmorillonite. Besides, the spectroscopic infrared properties are useful for monitoring the preparation and encapsulation processes of pharmaceutical drugs. Then, these properties were studied experimentally and calculated theoretically. The calculated frequencies of the crystal structure of these 7-azaindole drugs allowed assignments of the experimental FT-IR spectra. This collaborative work with experimental and theoretical research enhances the knowledge for a promising drug delivery system for anti-Alzheimer therapy.

La falsificación e identificación incorrecta de productos farmacéuticos supone un reto creciente para la salud pública. Para fomentar el pensamiento crítico y la capacidad de análisis normativo, se diseñó una actividad de innovación docente en la asignatura de Legislación y Deontología Farmacéutica de la Universitat de València. Participaron estudiantes de cuarto curso del Grado en Farmacia y de quinto del Doble Grado en Farmacia y Nutrición Humana y Dietética. La actividad se desarrolló en cuatro fases: (1) pretest con siete preguntas tipo test, (2) visualización de un vídeo explicativo sobre tipos de productos farmacéuticos, (3) dinámica grupal con rol de inspector/a de sanidad para clasificar productos según su etiquetado, y (4) postest y encuesta de valoración. Los resultados evidenciaron una mejora significativa en la comprensión del contenido (aumento del 68,6% en la puntuación media), una reducción del 31,2% en el tiempo de respuesta y una alta satisfacción del alumnado. Esta experiencia destaca la utilidad de las metodologías activas y la simulación en el aprendizaje profundo y el compromiso estudiantil.

Hydroperoxymethyl thioformate (or HPMTF) is a compound relevant to the chemistry of sulfur in the marine atmosphere. The chemical cycling of this molecule in the atmosphere is still uncertain due in part to the lack of accurate knowledge of its photolytic behavior. Only approximations based on the properties of its chromophores are used in previous studies. In this work, we calculated the absorption spectra of the molecule in gas and aqueous phases using the Nuclear Ensemble Approach (NEA) and the CASPT2 method. Furthermore, we used such information to obtain relative photolysis rates. We found that the chromophore approximation overestimates the photolysis rates in the gas phase by twice the value obtained with the NEA-CASPT2 protocol. Furthermore, for the aqueous phase, we predict a lower role of photolysis as compared to the gas phase.

The development of fluorescent materials that can act as sensors for the determination of metal ions in biological fluids is important since they show, among others, high sensitivity and specificity. However, most of the molecules that are used for these purposes possess a very low solubility in aqueous media, and, thus, it is necessary to adopt some derivation strategies. Clay minerals, for example, hectorite, as natural materials, are biocompatible and available in large amounts at a very low cost that have been extensively used as carrier systems for the delivery of different hydrophobic species. In the present work, we report the synthesis and characterization of a hectorite/phenanthroline nanomaterial as a potential fluorescent sensor for Zn ion detection in water. The interaction of phenanthroline with the Ht interlaminar space was thoroughly investigated, via both theoretical and experimental studies (i.e., thermogravimetry, FT-IR, UV-vis and fluorescence spectroscopies and XRD measurements), while its morphology was imaged by scanning electron microscopy. Afterwards, the possibility to use it as sensor for the detection of Zn²⁺ ions, in comparison to other metal ions, was investigated through fluorescent measurements, and the stability of the solid Ht/Phe/Zn complex was assessed by different experimental and theoretical measurements.

The healing process of chronic wounds continues to be a current clinical challenge, worsened by the risk of microbial infections and bacterial resistance to the most frequent antibiotics. In this work, non-antibiotic nanohybrids based on chlorhexidine dihydrochloride and clay minerals have been developed in order to design advanced therapeutic systems aimed to enhance wound healing in chronic lesions. To prepare the nanohybrids, two methodologies have been compared: the intercalation solution procedure and the spray-drying technique, the latter as a one-step process able to reduce preparation times. Nanohybrids were then fully studied by solid state characterization techniques. Computational calculations were also performed to assess the interactions between the drug and the clays at the molecular level. In vitro human fibroblast biocompatibility and antimicrobial activity against Staphylococcus aureus and Pseudomonas aeruginosa were assessed to check biocompatibility and potential microbicidal effects of the obtained nanomaterials. The results demonstrated the effective organic/inorganic character of the nanohybrids with homogeneous drug distribution into the clayey structures, which had been confirmed by classical mechanics calculations. Good biocompatibility and microbicidal effects were also observed, especially for the spray-dried nanohybrids. It was suggested that it could be due to a greater contact area with target cells and bacterial suspensions.

Sulfathiazole is an antimicrobial belonging to the family of sulfonamides, which were the first antibiotics to be discovered. Sulfathiazole is generally administered orally, and its main disadvantage is that it has low aqueous solubility, requiring high doses for its administration. This fact has led to side effects and the generation of bacterial resistance to the drug over time. The improvement of its solubility would mean not having to administer such high doses in its treatment. At the same time, montmorillonite is a natural, low-cost, non-toxic, biocompatible clay with a high adsorption capacity. It is potentially useful as a nanocarrier to design sulfathiazole dosage forms. In this work, the interaction between the drug and the clay mineral has been studied from an experimental and computational atomistic point of view to improve the drug’s biopharmaceutical profile. The results showed the potential enhancement of the drug solubility due to the correct adsorption of the sulfathiazole in the clay interlayer space. As a result of the inclusion of sulfathiazole in the interlayer of the clay mineral, the solubility of the drug increased by 220% concerning the pristine drug. Experimentally, it was not possible to know the number of drug molecules adsorbed in the interlayer space or the external surface of the carrier. Theoretical studies will enable the knowledge of the stoichiometry of the drug/clay hybrids, with three molecules in the interlayer space being the most favorable process. The resultant basal spacing was in agreement with the experimental results.

A key step in the development of a new drug, is the design of drug–excipient complexes that lead to optimal drug release kinetics. Computational chemistry and specifically enhanced sampling molecular dynamics methods can play a key role in this context, by minimizing the need for expensive experiments, and reducing cost and time. Here we show that recent advances in enhanced sampling methodologies can be brought to fruition in this area. We demonstrate the potential of these methodologies by simulating the drug release kinetics of the complex praziquantel–montmorillonite in water. Praziquantel finds promising applications in the treatment of schistosomiasis, but its biopharmaceutical profile needs to be improved, and a cheap material such as the montmorillonite clay would be a very convenient excipient. We simulate the drug release both from surface and interlayer space, and find that the diffusion of the praziquantel inside the interlayer space is the process that limits the rate of drug release.

If life developed in hydrothermal vents, it would have been within mineral membranes. The first proto-cells must have evolved to manipulate the mineral membranes that formed their compartments in order to control their metabolism. There must have occurred a biological takeover of the self-assembled mineral structures of the vents, with the incorporation of proto-biological molecules within the mineral membranes to alter their properties for life's purposes. Here, we study a laboratory analogue of this process: chemical-garden precipitation of the amino acids arginine and tryptophan with the metal salt iron chloride and sodium silicate. We produced these chemical gardens using different methodologies in order to determine the dependence of the morphology and chemistry on the growth conditions, as well as the effect of the amino acids on the formation of the iron-silicate chemical garden. We compared the effects of having amino acids initially within the forming chemical garden, corresponding to the internal zones of hydrothermal vents, or else outside, corresponding to the surrounding ocean. The characterization of the formed chemical gardens using X-ray diffraction, Fourier transform infrared spectroscopy, elemental analysis, and scanning electron microscopy demonstrates the presence of amino acids in these structures. The growth method in which the amino acid is initially in the tablet with the iron salt is that which generated chemical gardens with more amino acids in their structures.

Recently, mineral healing clays have gained much attention for wound-dressing applications. Here, we selected halloysite (HAL) clay as a biocompatible, non-toxic material that is useful as a drug delivery system to enhance the healing properties of water-soluble terpenoids 1-3 (T1-3). Terpenoids-loaded HAL clay (TH1-3) was prepared and characterized by adsorption equilibrium studies, X-ray powder diffraction (XRPD), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), Fourier-transform infrared (FTIR) spectroscopy, and release studies. The results reveal that T1-3 were adsorbed at the HAL surface with good efficiency. The prevalent mechanism of drug retention is due to the adsorption via electrostatic interactions between the cationic groups of the T1-3 and the HAL’s external surface. Release studies demonstrated that T3 was released in a higher percentage (>60%) compared to T1-2 (≈50%). Additionally, TH1-3 were assessed for their antimicrobial activity and capability to promote the re-epithelialization of scratched HaCat monolayers, through the time-kill test and the wound-healing assays, respectively. The results reveal that all the tested formulations were able to reduce the microbial growth after 1 h of incubation and that they ensured complete wound closure after 48 h. Furthermore, at the concentration of 1 µg/mL, TH3 exhibited 45% wound closure at 24 h, compared to TH1 (27%) and TH2 (30%), proving to be the best candidate in making the tissue-repair process easier and faster.