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.

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.

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.

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Alzheimer’s disease (AD) is a neurodegenerative disorder representing the leading cause of dementia and is affecting nearly 44 million people worldwide. AD is characterized by a progressive decline in acetylcholine levels in the cholinergic systems, which results in severe memory loss and cognitive impairments. Expression levels and activity of butyrylcholinesterase (BChE) enzyme has been noted to increase significantly in the late stages of AD, thus making it a viable drug target. A series of hydroxylated 2-phenylbenzofurans compounds were designed, synthesized and their inhibitory activities toward acetylcholinesterase (AChE) and BChE enzymes were evaluated. Two compounds (15 and 17) displayed higher inhibitory activity towards BChE with IC50 values of 6.23 μM and 3.57 μM, and a good antioxidant activity with EC50 values 14.9 μM and 16.7 μM, respectively. The same compounds further exhibited selective inhibitory activity against BChE over AChE. Computational studies were used to compare protein-binding pockets and evaluate the interaction fingerprints of the compound. Molecular simulations showed a conserved protein residue interaction network between the compounds, resulting in similar interaction energy values. Thus, combination of biochemical and computational approaches could represent rational guidelines for further structural modification of these hydroxy-benzofuran derivatives as future drugs for treatment of AD.

The complex etiology of Alzheimer's 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.