Publications

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.

Abstract Chromones are heterocyclic compounds of natural or synthetic origin that possess relevant pharmacological activities. Versatile functionalization of the chromone nucleus allows attaining of a chemical diversity suitable to perform structure-activity relationships in drug discovery and development programs. Accordingly, the synthesis and identification of novel chromone carboxamide derivatives with electron-donating and electron-withdrawing substituents in different positions of the exocyclic ring are reported in this work. Their complete structural characterization was performed using one-dimensional and two-dimensional resonance techniques. The data acquired are useful for a prompt analysis of related compounds that encompass our integrated medicinal chemistry sketch. Copyright (C) 2013 John Wiley & Sons, Ltd.

Abstract Phenolic acids are ubiquitous antioxidants accounting for approximately one third of the phenolic compounds in our diet. Their importance was supported by epidemiological studies that suggest an inverse relationship between dietary intake of phenolic antioxidants and the occurrence of diseases, such as cancer and neurodegenerative disorders. However, until now, most of natural antioxidants have limited therapeutic success a fact that could be related with their limited distribution throughout the body and with the inherent difficulties to attain the target sites. The development of phenolic antioxidants based on a hybrid concept and structurally based on natural hydroxybenzoic (gallic acid) and hydroxycinnamic (caffeic acid) scaffolds seems to be a suitable solution to surpass the mentioned drawbacks. Galloyl cinnamic hybrids were synthesized and their antioxidant activity as well as partition coefficients and redox potentials evaluated. The structure property activity relationship (SPAR) study revealed the existence of a correlation between the redox potentials and antioxidant activity. The galloyl cinnamic acid hybrid stands out as the best antioxidant supplementing the effect of a blend of gallic acid plus caffeic acid endorsing the hypothesis that the whole is greater than the sum of the parts. In addition, some hybrid compounds possess an appropriate lipophilicity allowing their application as chain-breaking antioxidant in biomembranes or other type of lipidic systems. Their predicted ADME properties are also in accordance with the general requirements for drug-like compounds. Accordingly, these phenolic hybrids can be seen as potential antioxidants for tackling the oxidative status linked to the neurodegenerative, inflammatory or cancer processes.

Abstract ObjectivesIn the present communication, we report the synthesis, pharmacological evaluation, theoretical evaluation of absorption, distribution, metabolism and excretion properties and structure-activity relationship study of a selected series of 3-arylcoumarins (compounds 1-9). Adenosine receptors (ARs) binding activity and selectivity of the synthesized compounds 1-9 were evaluated in this study. Different substituents were introduced in both benzene rings of the evaluated scaffold, at positions 6 and 3 or 4 of the moiety. The lack of data on the 3-arylcoumarin scaffold encouraged us to explore the ARs' binding activity of a selected series of derivatives. MethodsA new series of coumarins (compounds 1-9) were synthesized and evaluated by radioligand binding studies towards ARs. Key findingsAnalysing the experimental data, it can be observed that neither the simple 3-arylcoumarin nor the 4-nitro derivatives presented detectable binding affinity for the evaluated receptors, although most of the other substituted derivatives have good binding affinity profiles, especially against the hA(1)/hA(3) or only hA(3) AR. ConclusionsThe most remarkable derivative is compound 2, presenting the best affinity for hA(3) AR (K-i=2680 nM) and significant selectivity for this subtype.

Abstract The therapeutic potential of natural phenolic antioxidants in human diseases associated with oxidative damage has received great attention to date. Appraisal of literature evidences that, in general, antioxidant therapy has enjoyed relative successes in preclinical studies but little benefits in human intervention studies or clinical trials. In fact, despite the huge, largely untapped potential therapeutic benefit of natural phenolic antioxidants, such as vitamins, non-flavonoid and flavonoid compounds, they appear not to be suitable drug candidates. The problem may be related, among others, to their non-drug-likeness properties. Though controversial the results obtained so far confirm the importance of exploring phenolic natural systems as safe templates for the design of new antioxidants. To support the assumption an outlook of the lead structural optimization process to improve ADME properties was given by means of natural hydroxycinnamic acids as a case study. The optimization of drug physicochemical properties and the development of appropriate delivery antioxidant systems can provide in the next future a way out to attain effective therapeutic antioxidant agents.

Abstract Hydroxycinnamic acids (such as ferulic, caffeic, sinapic, and p-coumaric acids) are a group of compounds highly abundant in food that may account for about one-third of the phenolic compounds in our diet. Hydroxycinnamic acids have gained an increasing interest in health because they are known to be potent antioxidants. These compounds have been described as chain-breaking antioxidants acting through radical scavenging activity, that is related to their hydrogen or electron donating capacity and to the ability to delocalize/stabilize the resulting phenoxyl radical within their structure. The free radical scavenger ability of antioxidants can be predicted from standard one-electron potentials. Thus, voltammetric methods have often been applied to characterize a diversity of natural and synthetic antioxidants essentially to get an insight into their mechanism and also as an important tool for the rational design of new and potent antioxidants. The structure-property-activity relationships (SPARs) correlations already established for this type of compounds suggest that redox potentials could be considered a good measure of antioxidant activity and an accurate guideline on the drug discovery and development process. Due to its magnitude in the antioxidant field, the electrochemistry of hydroxycinnamic acid-based antioxidants is reviewed highlighting the structure-property-activity relationships (SPARs) obtained so far.

Abstract 4-Oxo-N-phenyl-4H-chromene-2-carboxamide, C16H11NO3, crystallizes in the space group P2(1)/n and its derivative 7-methoxy-4-oxo-N-p-tolyl-4H-chromene-2-carboxamide, C18H15NO4, forms two polymorphs which crystallize in the space groups P2(1)/c and P (1) over bar. The structures have an anti-rotamer conformation about the C-N bond; however, the amide O atom can be either trans-or cis-related to the O atom of the pyran ring. The latter compound also crystallizes as a hemihydrate, C18H15NO4 center dot 0.5H(2)O, in the space group C2/c. This compound has a similar structure to that of the unsolvated compound.