Alexandra Gaspar

Chromone: a valid scaffold in Medicinal Chemistry

This work was supported by the Foundation for Science and Technology (FCT), Portugal (projects PTDC/QUI-QUI/113687/2009 and PEst-C/QUI/UI0081/2013). A.G. (SFRH/BD/43531/2008) and M.J.M. (SFRH/BD/61262/2009) thank FCT for grants.

Chromone, a Privileged Scaffold for the Development of Monoamine Oxidase Inhibitors

Two series of novel chromone derivatives were synthesized and investigated for their ability to inhibit the activity of monoamine oxidase. The SAR data indicate that chromone derivatives with substituents in position 3 of γ-pyrone nucleus act preferably as MAO-B inhibitors, with IC(50) values in the nanomolar to micromolar range. Almost all chromone 3-carboxamides display selectivity toward MAO-B. Identical substitutions on position 2 of γ-pyrone nucleus result in complete loss of activity in both isoforms (chromones 2-12 except 3 and 5). Notably, chromone (19) exhibits an MAO-B IC(50) of 63 nM, greater than 1000-fold selectivity over MAO-A, and behaves as a quasi-reversible inhibitor. Docking experiments onto the MAO binding of the most active compound highlight different interaction patterns among the isoforms A and B. The differential analysis of the solvation effects among the chromone isomers gave additional insight about the superior outline of the 3-substituted chromone derivatives.

Hydroxycinnamic acid antioxidants: an electrochemical overview

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.

Alkyl esters of hydroxycinnamic acids with improved antioxidant activity and lipophilicity protect PC12 cells against oxidative stress.

Hydroxycinnamic acids (HCAs) are phenolic compounds present in dietary plants, which possess considerable antioxidant activity. In order to increase the lipophilicity of HCAs, with the aim of improving their cellular absorption and expansion of their use in lipophilic media, methyl, ethyl, propyl and butyl esters of caffeic acid and ferulic acid have been synthesized. All caffeate esters had a slightly lower DPPH IC(50) (13.5-14.5 μM) and higher ferric reducing antioxidant power (FRAP) values (1490-1588 mM quercetin/mole [mMQ/mole]) compared to caffeic acid (16.6 μM and 1398 mMQ/mole, respectively) in antioxidant assays. In contrast, ferulate esters were less active in DPPH (56.3-74.7 μM) and FRAP assays (193-262 mMQ/mole) compared to ferulic acid (44.6 μM and 324 mMQ/mole, respectively). Redox properties of HCAs were in line with their antioxidant capacities, so that compounds with higher antioxidant activities had lower oxidation potentials. Measurement of partition coefficients disclosed the higher lipophilicity of the esters compared to parent compounds. All esters of caffeic acid significantly inhibited hydrogen peroxide-induced neuronal PC12 cell death assessed by MTT assay at 5 and 25 μM. However, caffeic acid, ferulic acid and ferulate esters were not able to protect the cells. In conclusion, these findings suggest that alkyl esterification of some HCAs augments their antioxidant properties as well as their lipophilicity and as a consequence, improves their cell protective activity against oxidative stress. These compounds could have useful applications in conditions where oxidative stress plays a pathogenic role.

Dietary Phenolic Acids and Derivatives. Evaluation of the Antioxidant Activity of Sinapic Acid and Its Alkyl Esters

The action of sinapic acid and its alkyl esters as potential antioxidants has been investigated. For this purpose, a series of sinapic acid ester derivatives was synthesized and their antioxidant activities were evaluated using distinctive analytical methods, namely, 2,2-diphenyl-1-picrylhydrazyl (DPPH) and FRAP UV-vis methods and differential scanning calorimetry. The electron-donating activity and lipophilicity of these phenolic compounds were also evaluated. From the overall results it was concluded that alkyl ester sinapates (linear alkyl esters) present almost the same antioxidant activity, albeit slightly lower, exhibited by the parent compound (sinapic acid). Furthermore, the addition of an alkyl ester side chain has a positive effect on the partition coefficient of sinapic acid, improving its utility as an antioxidant in a more lipophilic medium. The data on the antioxidant activity obtained by different analytical methods correlated well with each other and have revealed interesting antioxidant data of alkyl esters of sinapic acid.

Chromone 3-phenylcarboxamides as potent and selective MAO-B inhibitors.

Monoamine oxidase (MAO) is an enzyme, present in mammals in two isoforms MAO-A and MAO-B. These isoforms have a crucial role in neurotransmitters metabolism, representing an attractive drug target in the therapy of neurodegenerative diseases (MAO-B) and depression (MAO-A). In this context, our work has been focused on the discovery of new chemical entities (NCEs) for MAO inhibition, based on the development of chromone carboxamides. Chromone derivatives with a carboxamide function located in position 2- and 3- of the benzo-γ-pyrone core, (compounds 2-6 and 8-12) were synthesized, with moderate/good yields, by a one-pot condensation reaction using phosphonium salts as coupling reagents. The synthetic compounds were screened towards human MAO isoforms (hMAO) to evaluate their potency and selectivity. The chromone-3-carboxamides show high selectivity to hMAO-B, with compounds 9 and 12 displaying IC(50) values at nanomolar range.

New insights into the antioxidant activity of hydroxycinnamic acids: Synthesis and physicochemical characterization of novel halogenated derivatives

An interdisciplinary research project was developed combining the synthesis of a series of hydroxycinnamic acid derivatives and the evaluation of their physicochemical parameters (namely redox potentials and partition coefficients), along with the corresponding antioxidant activity. A structure-property-activity relationship (SPAR) approach was then applied aiming at establishing a putative relation between the physicochemical parameters of the compounds under study and their antioxidant activity. The results gathered allow concluding that the redox potentials could contribute to the understanding of the antioxidant activity and that the presence of an electron withdrawing group (EWG) of halogen type, namely a bromo atom, in an ortho position to a phenolic group of the cinnamic scaffold does not influence the antioxidant activity. On the other hand after the introduction of this type of substituent a significant increase on the lipophilicity of cinnamic derivatives was observed, which is a feature of extreme importance in the development of novel lipophilic antioxidants. The SPAR results revealed a relation between the redox potentials and the antioxidant activity of hydroxycinnamic acids and derivatives. The data obtained operate as a positive reinforce of the tendency to use redox properties as a guideline of the rational design of this type of compounds.

Chromone-2- and -3-carboxylic acids inhibit differently monoamine oxidases A and B

Chromone carboxylic acids were evaluated as human monoamine oxidase A and B (hMAO-A and hMAO-B) inhibitors. The biological data indicated that only chromone-3-carboxylic acid is a potent hMAO-B inhibitor, with a high degree of selectivity for hMAO-B compared to hMAO-A. Conversely the chromone-2-carboxylic acid resulted almost inactive against both MAO isoforms. Docking experiments were performed to elucidate the reasons of the different MAO IC(50) data and to explain the absence of activity versus selectivity, respectively.

Discovery of novel A3 adenosine receptor ligands based on chromone scaffold.

A project focused on the discovery of new chemical entities (NCEs) as AR ligands that incorporate a benzo-γ-pyrone [(4H)-1-benzopyran-4-one] substructure has been developed. Accordingly, two series of novel chromone carboxamides placed at positions C2 (compounds 2-13) and C3 (compounds 15-26) of the γ-pyrone ring were synthesized using chromone carboxylic acids (compounds 1 or 14) as starting materials. From this study and on the basis of the obtained structure-activity relationships it was concluded that the chromone carboxamide scaffold represent a novel class of AR ligands. The most remarkable chromones were compounds 21 and 26 that present a better affinity for A3AR (Ki = 3680 nM and Ki = 3750 nM, respectively). Receptor-driven molecular modeling studies provide information on the binding/selectivity data of the chromone. The data so far acquired are instrumental for future optimization of chromone carboxamide as a selective A3AR antagonist.

Antioxidant Versus Cytotoxic Properties of Hydroxycinnamic Acid Derivatives – A New Paradigm in Phenolic Research

Trihydroxycinnamic derivatives were synthesized and evaluated for their antioxidant and cytotoxic activities. The ester derivatives exhibited a higher radical‐scavenging activity, when liposomes were used as target systems, a fact which may be related to their lipophilicity and conformational preferences. These compounds were found to display significant growth inhibition and cytotoxic effects towards a human cervix adenocarcinoma cell line (HeLa). The partition coefficients presently obtained for the trihydroxycinnamic derivatives correlate well both with their structural characteristics and with their antioxidant/cytotoxic activities. A positive structure‐activity‐property relationship between cytotoxic and antioxidant activities, which is intrinsically related with physico‐chemical and conformational properties, is anticipated, as a noteworthy study that must be done for phenolic systems. As damage events are frequently correlated with oxidative stress, the prevalence of both properties in a single compound could be beneficial in terms of rationale preventive or therapeutic purposes.