Coumarin-Chalcone Hybrids as Inhibitors of MAO-B: Biological Activity and In Silico Studies.

Guillermo Moya-Alvarado,Angélica Fierro,Marco Tulio Núñez,Nicole Morales,Osvaldo Yañez,Olimpo García-Beltrán,Angélica González-González,Carlos Areche

doi:10.3390/molecules26092430

Abstract

Fourteen coumarin-derived compounds modified at the C3 carbon of coumarin with an α,β-unsaturated ketone were synthesized. These compounds may be designated as chalcocoumarins (3-cinnamoyl-2H-chromen-2-ones). Both chalcones and coumarins are recognized scaffolds in medicinal chemistry, showing diverse biological and pharmacological properties among which neuroprotective activities and multiple enzyme inhibition, including mitochondrial enzyme systems, stand out. The evaluation of monoamine oxidase B (MAO-B) inhibitors has aroused considerable interest as therapeutic agents for neurodegenerative diseases such as Parkinson’s. Of the fourteen chalcocumarins evaluated here against MAO-B, ChC4 showed the strongest activity in vitro, with IC50 = 0.76 ± 0.08 µM. Computational docking, molecular dynamics and MM/GBSA studies, confirm that ChC4 binds very stably to the active rMAO-B site, explaining the experimental inhibition data.

Highlights

Coumarins (α-benzopyrones, 2H-chromen-2-ones) are a large family of compounds, of natural and synthetic origin, that show numerous biological [1,2,3,4,5,6] and medicinal chemistry activities, such as anticoagulant, anticancer, antioxidant, antiviral, anti-diabetic, antiinflammatory, antibacterial, antifungal and anti-neurodegerative properties [7,8,9], among which recent studies have paid special attention to enzyme inhibition
The results show that all the chalcocoumarins settle in the active site of rat MAO-B (rMAO-B) (Supplementary Materials; Figure S18), with the benzene ring of the coumarin moiety close to the FAD, the central N-5, at a distance of about 4.0 Å
Fourteen compounds derived from chalcocoumarins were synthesized and evaluated against monoamine oxidase enzyme isoforms

Summary

Introduction

Coumarins (α-benzopyrones, 2H-chromen-2-ones) are a large family of compounds, of natural and synthetic origin, that show numerous biological [1,2,3,4,5,6] and medicinal chemistry activities, such as anticoagulant, anticancer, antioxidant, antiviral, anti-diabetic, antiinflammatory, antibacterial, antifungal and anti-neurodegerative properties [7,8,9], among which recent studies have paid special attention to enzyme inhibition. With regard to monoamine oxidase (MAO) inhibition, recent findings have revealed that MAO affinity and selectivity can be efficiently modulated by appropriate substitutions on the coumarin ring system [1,10,11,12,13]. Using oxygen (O2 ) as electron acceptor. In humans they exist in two isoforms called MAOA and MAO-B. The high resolution crystal structures of both human isoforms A and B (hMAO) rat MAO-A (rMAO-A) have made it possible to analyze binding modes of ligands inside these macromolecules [14]. Serotonin and noradrenaline are substrates of MAO-A which is selectively inhibited by clorgyline, while MAO-B oxidizes β-phenylethylamines and benzylamines and is selectively inhibited by l-deprenyl. In the brain, both isoforms are widely distributed, MAO-B is expressed in high concentrations in the hypothalamus, striatum, globus pallidus and thalamus, and mainly in serotonergic cells while the A isoform is rather evenly distributed, mainly in the cortex, and in nuclei containing preferably catecholaminergic and glial cells [16,17,18,19,20,21]

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Results

Conclusion