Dolores Viña

Synthesis and study of a series of 3-arylcoumarins as potent and selective monoamine oxidase B inhibitors.

New series of 6-substituted-3-arylcoumarins displaying several alkyl, hydroxyl, halogen, and alkoxy groups in the two benzene rings have been designed, synthesized, and evaluated in vitro as human monoamine oxidase A and B (hMAO-A and hMAO-B) inhibitors. Most of the studied compounds showed a high affinity and selectivity to the hMAO-B isoenzyme, with IC(50) values on nanomolar and picomolar range. Ten of the 22 described compounds displayed higher MAO-B inhibitory activity and selectivity than selegiline. Coumarin 7 is the most active compound of this series, being 64 times more active than selegiline and also showing the highest hMAO-B specificity. In addition, docking experiments were carried out on hMAO-A and h-MAO-B structures. This study provided new information about the enzyme-inhibitor interaction and the potential therapeutic application of this 3-arylcoumarin scaffold.

A new series of 3-phenylcoumarins as potent and selective MAO-B inhibitors

6-Methyl-3-phenylcoumarins 3-6 were designed, synthesized and evaluated as monoamine oxidase A and B (MAO-A and MAO-B) inhibitors. The synthesis of these new compounds (resveratrol-coumarin hybrids) was carried out with good yield by a Perkin reaction, from the 5-methylsalicylaldehyde and the corresponding phenylacetic acid. They show high selectivity to the MAO-B isoenzyme, with IC(50) values in the nanomolar range. Compound 5 is the most active compound and is several times more potent and selective than the reference compound, R-(-)-deprenyl.

Quantitative structure-activity relationship and complex network approach to monoamine oxidase A and B inhibitors.

The work provides a new model for the prediction of the MAO-A and -B inhibitor activity by the use of combined complex networks and QSAR methodologies. On the basis of the obtained model, we prepared and assayed 33 coumarin derivatives, and the theoretical prediction was compared with the experimental activity data. The model correctly predicted 27 compounds, and most of the active derivatives showed IC 50 values in the muM-nM range against both the MAO-A and MAO-B isoforms. Compound 14 shows the same MAO-A inhibitory activity (IC 50 = 7.2 nM), as clorgyline used as a reference inhibitor and has the highest MAO-A specificity (1000-fold higher compared to MAO-B). On the other hand, compounds 24 (IC 50 = 1.2 nM) and 28 (IC 50 = 1.5 nM) show higher activity than selegiline (IC 50 = 19.6 nM) and high MAO-B selectivity with 100-fold and 1600-fold inhibition levels, with respect to the MAO-A isoform.

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.

Synthesis and evaluation of 6-methyl-3-phenylcoumarins as potent and selective MAO-B inhibitors.

A series of 6-methyl-3-phenylcoumarins 3-6 were synthesized and evaluated as monoamine oxidase A and B (MAO-A and MAO-B) inhibitors. A comparative study between the three possible mono methoxy 3-phenyl derivatives and the p-hydroxy analogue is reported. The synthesis of these new resveratrol-coumarin hybrids was carried out by a Perkin reaction between the 5-methylsalicylaldehyde and the corresponding phenylacetic acids. The p-methoxy substituted compound 3 was hydrolyzed to 6 by a traditional reaction with hydriodic acid. The prepared compounds show high selectivity to the MAO-B isoenzyme, some of them with IC(50) values in the low nanomolar range. Compound 4, with the methoxy group in meta position, is the most active of this series, with an IC(50) against MAO-B of 0.80 nM, and is several times more potent and MAO-B selective than the R-(-)-deprenyl (reference compound).

Alignment-Free Prediction of a Drug-Target Complex Network Based on Parameters of Drug Connectivity and Protein Sequence of Receptors

There are many drugs described with very different affinity to a large number of receptors. In this work, we selected drug-receptor pairs (DRPs) of affinity/nonaffinity drugs to similar/dissimilar receptors and we represented them as a large network, which may be used to identify drugs that can act on a receptor. Computational chemistry prediction of the biological activity based on quantitative structure-activity relationships (QSAR) substantially increases the potentialities of this kind of networks avoiding time- and resource-consuming experiments. Unfortunately, most QSAR models are unspecific or predict activity against only one receptor. To solve this problem, we developed here a multitarget QSAR (mt-QSAR) classification model. Overall model classification accuracy was 72.25% (1390/1924 compounds) in training, 72.28% (459/635) in cross-validation. Outputs of this mt-QSAR model were used as inputs to construct a network. The observed network has 1735 nodes (DRPs), 1754 edges or pairs of DRPs with similar drug-target affinity (sPDRPs), and low coverage density d = 0.12%. The predicted network has 1735 DRPs, 1857 sPDRPs, and also low coverage density d = 0.12%. After an edge-to-edge comparison (chi-square = 9420.3; p < 0.005), we have demonstrated that the predicted network is significantly similar to the one observed and both have a distribution closer to exponential than to normal.

New halogenated 3-phenylcoumarins as potent and selective MAO-B inhibitors.

With the aim to find out the structural features for the MAO inhibitory activity and selectivity, in the present communication we report the synthesis and pharmacological evaluation of a new series of bromo-6-methyl-3-phenylcoumarin derivatives (with bromo atom in both different benzene rings of the skeleton) with and without different number of methoxy substituent at the 3-phenyl ring. The methoxy substituents were introduced, in this new scaffold, in the meta and/or para positions of the 3-phenyl ring. The synthesized compounds 3-7 were evaluated as MAO-A and B inhibitors using R-(-)-deprenyl (selegiline) and iproniazide as reference inhibitors, showing, most of them, MAO-B inhibitory activities in the low nanomolar range. Compounds 4 (IC(50)=11.05 nM), 5 (IC(50)=3.23 nM) and 6 (IC(50)=7.12 nM) show higher activity than selegiline (IC(50)=19.60 nM) and higher MAO-B selectivity, with more than 9050-fold, 30,960-fold and 14,045-fold inhibition levels, with respect to the MAO-A isoform.

3-Substituted coumarins as dual inhibitors of AChE and MAO for the treatment of Alzheimer's disease

The complex etiology of Alzheimers disease (AD) has encouraged active research in the development of multi-target drugs with two or more complementary biological activities, since they may represent an important advance in the treatment of this disease. A series of 3-substituted coumarins were synthesized and evaluated as monoamino oxidases (MAO) and acetylcholinesterase (AChE) inhibitors. Most of the 3-benzamide coumarin derivatives inhibited both MAO-B and AChE with values in the micromolar range. It might be a promising direction for developing novel drugs as potential agents for the treatment of AD patients.

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.

Synthesis and Vasorelaxant and Platelet Antiaggregatory Activities of a New Series of 6-Halo-3-phenylcoumarins †

A series of 6-halo-3-hydroxyphenylcoumarins (resveratrol-coumarins hybrid derivatives) was synthesized in good yields by a Perkin reaction followed by hydrolysis. The new compounds were evaluated for their vasorelaxant activity in intact rat aorta rings pre-contracted with phenylephrine (PE), as well as for their inhibitory effects on platelet aggregation induced by thrombin in washed human platelets. These compounds concentration-dependently relaxed vascular smooth muscle and some of them showed a platelet antiaggregatory activity that was up to thirty times higher than that shown by trans-resveratrol and some other previously synthesized derivatives.