Publications

Abstract Two series of novel cationic gemini surfactants based on the amino acid serine have been synthesized. These compounds contain long alkyl chains linked to the nitrogen atoms of the amino acid residues, as well as spacers interconnecting two carboxylic acid groups, through amide or ester bonds. The most efficient synthetic pathway was established; it involves the introduction of the spacers into the N, N-dialkylated monomeric precursors by peptide condensation methods with diamines or diols, with subsequent methylation and deprotection to yield the final target surfactants. The effects of molecular structure, type of spacer linkage, and spacer length on the interfacial and cytotoxic properties of these gemini surfactants are reported and discussed; studies on gemini surfactants with amine linkages and other relevant homologous compounds (conventional bis-quat gemini and monomeric surfactants) are also included. Overall, it is shown that cationic serine-based gemini surfactants have enhanced interfacial properties and low cytotoxicities, offering potential use in technical and biological applications.

Abstract Sol-gel molecularly imprinted materials (MIMs) are traditionally obtained by grinding and sieving of a monolith formed by bulk polymerization. However, this process has several drawbacks that can be overcome if these materials are synthesized directly in the spherical format. This work aimed at the development of two efficient methods to prepare spherical glycylglycine-templated silica ("whole-imprinted" and surface-imprinted) through a combination of sol-gel and emulsion techniques. The synthesis of the microspheres was optimized regarding emulsion and sol-gel parameters. Imprinting efficiency of the prepared materials was studied by solid phase extraction and flow microcalorimetry. The particles prepared with glycylglycine and functional monomer, in basic medium (using cyclohexane as non-polar continuous medium) presented the highest imprinting factor - 2.5 - and the respective surface-imprinted material presented an imprinting factor of 1.5. The results of flow microcalorimetry confirmed the action of different mechanisms of glycylglycine adsorption: entropically-controlled interactions were present for the "whole-imprinted" material, indicating adsorption inside small imprinted pores; enthalpically-controlled interactions were observed for the surface-imprinted material, a behaviour more compatible with a template/surface-only interaction. Globally, the two approaches allowed for a successful imprinting effect which was more extensive for the "whole-imprinted" material, whereas the surface-imprinting feature confers to the surface-imprinted xerogel advantages regarding mass transfer kinetics. Overall, the spherical particles obtained by both approaches presented characteristics, such as sphericity, mesoporosity, easy/fast accessibility to imprinted sites, important indicators that these materials maybe candidates for stationary phases for efficient, selective chromatographic separation.

Abstract The cytotoxicity of three lysine-derived surfactants with a gemini-like structure was evaluated on HeLa cells. The half maximal effective concentration (EC50) was estimated from the dose-response curves and the values indicated an increase in toxicity with the increase in alkyl chain length. The shorter chain length surfactant (C-6) was shown to be less cytotoxic than sodium dodecyl sulfate (SDS), and all the lysine-derived surfactants were less toxic than the cationic cetyl trimethylammonium bromide (CTAB). The presence of ethyl (hydroxyethyl) cellulose (EHEC), shown previously to form thermoresponsive gels in combination with these surfactants, was found to contribute to a lower toxicity on HeLa cells. The conjecture is that the polymer-surfactant interactions in forming mixed micelles are the key contributors to the enhanced biocompatibility of the hydrogels. The most promising results were obtained in the presence of either the most hydrophilic surfactant or in the presence of the longest chain-length surfactant. For the latter, very low concentrations are needed to induce a sol-gel transition of EHEC semi-dilute solutions.

Abstract Due to their role in the metabolism of monoamine neurotransmitters, MAO-A and MAO-B present a significant pharmacological interest. For instance the inhibitors of human MAO-B are considered useful tools for the treatment of Parkinson Disease. Therefore, the rational design and synthesis of new MAOs inhibitors is considered of great importance for the development of new and more effective treatments of Parkinson Disease. In this work, Quantitative Structure Activity Relationships (QSAR) has been developed to predict the human MAO inhibitory activity and selectivity. The first step was the selection of a suitable dataset of heterocyclic compounds that include chromones, coumarins, chalcones, thiazolylhydrazones, etc. These compounds were previously synthesized in one of our laboratories, or elsewhere, and their activities measured by the same assays and for the same laboratory staff. Applying linear discriminant analysis to data derived from a variety of molecular representations and feature selection algorithms, reliable QSAR models were built which could be used to predict for test compounds the inhibitory activity and selectivity toward human MAO. This work also showed how several QSAR models can be combined to make better predictions. The final models exhibit significant statistics, interpretability, as well as displaying predictive power on an external validation set made up of chromone derivatives with unknown activity (that are being reported here for first time) synthesized by our group, and coumarins recently reported in the literature.

Abstract Objectives With the aim of finding the structural features governing binding activity and selectivity against adenosine receptors (ARs), several 3-subtituted coumarins with amide (compounds 36) and carbamate (79) functions were synthesized. To study its possible influence on the binding activity and selectivity, a hydroxyl substituent was also introduced at position 4 of the coumarin moiety. Methods A new series of coumarins (39) were synthesized and evaluated by radioligand binding studies towards ARs. Key findings None of the 4-hydroxy derivatives (4, 8 and 9) showed binding affinity for any of the ARs. None of the compounds interacted with the hA2B AR (Ki > 100 000 nm). Compounds 3, 5, 6 and 7 had different activity profiles with dissimilar binding affinity and selectivity towards human A1, A2A and A3 ARs. Conclusions The most remarkable derivative is compound 7, which presents the best affinity and selectivity for the A3 adenosine receptor (Ki = 5500 nm).

Abstract In the present work we synthesized a series of hydroxy-3-arylcoumarins (compounds 1-9), some of them previously described as MAO-B selective inhibitors, with the aim of evaluating their antioxidant properties. Theoretical evaluation of ADME properties of all the derivatives was also carried. out. From the ORAC-FL, ESR and CV data it was concluded that these derivatives are very good antioxidants, with a very interesting hydroxyl, DPPH and superoxide radicals scavenging profiles. In particular compound 9 is the most active and effective antioxidant of the series (ORAC-FL = 13.5, capacity of scavenging hydroxyl radicals = 100%, capacity of scavenging DPPH radicals = 65.9% and capacity of scavenging superoxide radicals = 71.5%). Kinetics profile for protection fluorescein probe against peroxyl radicals by addition of antioxidant molecule 9 was also performed. Therefore, it can operate as a potential candidate for preventing or minimizing the free radicals overproduction in oxidative-stress related diseases.

Abstract N-phenyl-4-oxo-4H-2-chromone carboxamides were found to be inactive as MAO inhibitors in contrast with their N-phenyl-4- oxo-4H-3-chromone carboxamide isomers. In order to obtain a close insight into the docking mechanism for this family of compounds, the molecular and supramolecular structures of nine N-phenyl-4-oxo-4H-2-chromone carboxamides were determined. It was found that, in most of the secondary structures, the N(amido) and the O(carboxyl) of the carboxamide residue participate in strong intramolecular interactions, with the O atom of the chromene ring and with the H(ortho)-C (phenyl), respectively. When the phenyl ring had accessible acceptors as substituents a third intramolecular hydrogen bond was also observed. As a consequence, rotations of the chromone and phenyl rings around the N-C(alpha) and C(alpha')-C=O are constrained and the compounds were found to be more planar than would otherwise be expected. The deviation from planarity of the whole molecule can be quantified by the dihedral angles between mean planes of the aromatic rings and it was found that they were mainly affected by the degree of torsion of the phenyl ring with respect to the amide residue. The molecular conformations assumed by the secondary amides clearly contrast with that of a related tertiary amide that was also determined in this study. The unavailability of the N in this compound as a donor strongly influences the molecular isomerism and conformation. This analysis demonstrates that the molecules can be classified into four groups depending on the types of interactions formed as described above. If the secondary N(amido) of the carboximide is involved in two intramolecular interactions then this atom does not form any intermolecular contacts. In all other cases it does and the supramolecular structure formed is in most cases supplemented by weak C-H center dot center dot center dot O interactions.