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

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.

Keywords: MAO-B; chalcocoumarin; in silico studies; molecular dynamics; neurodegenerative diseases.

Scheme 1

Hybrids of chalcocoumarin.

Figure 1

(A) NCIplot of the non-covalent interaction regions with isosurface gradient (0.6 au) for ChC2 (left) and ChC4 (right). (B) Electrostatic potential (in a.u.) of ChC2 (left) and ChC4 (right) mapped on the 0.001 a.u. isodensity surface for the selected structure computed at the M05-2X-D3/6-31G(d,p) level of theory.

Figure 2

(A) Root Mean Square Deviation (RMSD) and (B) Radius of gyration (R_Gyr) as a function of simulation times for the complexes formed between rMAO-B and ChC2 and ChC4.

Figure 3

(A) Last frame of the molecular simulation showing the positions between the FAD molecule and ChC2–ChC4 compounds interacting with rMAO-B. (B) Distance as a function of simulation time, between the nitrogen atom of the aloxazine planar ring of FAD and the center of the benzaldehyde aromatic ring, for compounds ChC2 and ChC4. Dashed lines represent the position of the nitrogen atom of the aloxazine planar ring.

Figure 4

Frequency of the appearance of residues at a distance of 3.0 Å or closer from ligands (A) ChC2 and (B) ChC4 calculated using MD procedures.

Figure 5

Fraction (in %) of intermolecular hydrogen bonds for rMAO-B interacting with (A) ChC2 and (B) ChC4. The graph bar shows the most common hydrogen bonds formed between the residues on the pocket and the inhibitors.

Figure 6

Schematic representations at the end (100 ns) of their respective production runs for ligands (A) ChC2 and (B) ChC4 bound to rMAO-B. (I) The surrounding amino acid residues in the binding pocket of rMAO-B within 4Å from ligands. (II) Two-dimensional interaction map of ChC2 and ChC4 and rMAO-B. The arrows indicate potential interactions between amino acid residues and the ligands.

Figure 7

Predictive human intestinal absorption (HIA) model and blood-brain barrier permeation (BBB) method (boiled-egg plot) of the 14 compounds.