Coumarin Derivative Hybrids: Novel Dual Inhibitors Targeting Acetylcholinesterase and Monoamine Oxidases for Alzheimer's Therapy

Abstract

Multi-target-directed ligands (MTDLs) represent a promising frontier in tackling the complexity of multifactorial pathologies like Alzheimer's disease (AD). The synergistic inhibition of MAO-B, MAO-A, and AChE is believed to enhance treatment efficacy. A novel coumarin-based molecule substituted with O-phenylpiperazine via three- and four-carbon linkers at the 5- and 7-positions, has been identified as an effective MTDL against AD. Employing a medicinal chemistry approach, combined with molecular docking, molecular dynamic simulation, and ΔG_bind estimation, two series of derivatives emerged as potent MTDLs: 8-acetyl-7-hydroxy-4-methylcoumarin (IC₅₀: 1.52-4.95 μM for hAChE, 6.97-7.65 μM for hMAO-A) and 4,7-dimethyl-5-hydroxycoumarin (IC₅₀: 1.88-4.76 μM for hMAO-B). They displayed binding free energy (ΔG_bind) of -76.32 kcal/mol (11) and -70.12 kcal/mol (12) against AChE and -66.27 kcal/mol (11) and -62.89 kcal/mol (12) against MAO-A. It is noteworthy that compounds 11 and 12 demonstrated efficient binding to both AChE and MAO-A, while compounds 3 and 10 significantly reduced MAO-B and AChE aggregation in vitro. These findings provide structural templates for the development of dual MAO and AChE inhibitors for the treatment of neurodegenerative diseases.

Keywords: Alzheimer’s disease; coumarin derivatives; hAChE/hMAO-B dual-targeted inhibitor; molecular docking; molecular dynamic simulation.

Figure 1

Design strategy for Ensaculin–coumarin hybrids.

Scheme 1

Synthetic route of new coumarin derivatives 1 and 2.

Figure 2

Superimposed coumarin derivatives docked into the binding pocket of hAChE. (A) The hydrophobic and hydrophilic amino acid residues surround the ligands. Surface hydrophobicity was depicted by the shaded colors: brown—the hydrophobic and blue—the lipophilic regions. (B) Shared binding orientation of compounds 1 (green), 3 (turquoise), 4 (orange), 5 (dark blue), 6 (yellow), 7 (dark pink), 9 (brown), and 11 (pink). (C) Superposition of compounds: 2 (red), 8 (dark green), 10 (blue), and 12 (gray).

Figure 3

Superimposed coumarin derivatives docked into the binding pocket of hMAO-A. (A) The hydrophobic and hydrophilic amino acid residues surround the ligands. Surface hydrophobicity was depicted by the shaded colors: brown-hydrophobic region; blue-lipophilic region. The hMAO-A residues that make up the active site of the receptor are labeled in black. (B) Shared binding orientation of 5-hydroxy-substituted coumarins is displayed in 1 (green), 2 (red), 3 (turquoise), 4 (orange), 5 (dark blue), 6 (yellow), 7 (dark pink), and 8 (dark green). (C) Binding orientation of 7-hydroxy-substituted coumarins of 9 (brown), 10 (blue), 11 (pink), and 12 (gray) within the binding pocket.

Figure 4

Superimposed coumarin derivatives docked into the binding pocket of hMAO-B. (A) The hydrophobic and hydrophilic amino acid residues surround the ligands. Surface hydrophobicity was depicted by the shaded colors: brown—hydrophobic region; blue—lipophilic region. (B) Shared binding orientation of compounds 4 (orange), 5 (dark blue), 7 (dark pink), 8 (dark green), 9 (brown), 10 (blue), 11 (pink), and 12 (gray). (C) Superposition of compounds: 1 (green), 2 (red), 3 (turquoise), and 6 (yellow).

Figure 5

Structures of the 10–hAChE, 11–hAChE, and 12–hAChE complexes and 2D view of all hAChE residues interacting with the ligands resulting from MD simulations (residues involved in hydrogen bonding marked as green and cyan circles; residues involved in hydrophobic interactions marked as pink circles; and electrostatic interactions marked as orange circles).

Figure 6

Trajectory analysis of the MD simulation of complexes of AChE with compounds 10, 11, and 12. (A) Plots of root mean square deviation (RMSD) and (B–D) root mean square fluctuation (RMSF) over 120 ns o protein-ligand complexes.

Figure 7

Structures of the 11–hMAO-A and 12–hMAO-A complexes and 2D view of all hMAO-A residues interacting with the ligands resulting from MD simulations (residues involved in hydrogen bonding marked as green and cyan circles; residues involved in hydrophobic interactions marked as pink circles; and electrostatic interactions marked as orange circles).

Figure 8

Structures of the 1–MAO-B, 3–MAO-B, and 4–MAO-B complexes and 2D view of all MAO-B residues interacting with the ligands resulting from MD simulations (residues involved in hydrogen bonding marked as green and cyan circles; residues involved in hydrophobic interactions marked as pink circles; and electrostatic interactions marked as orange circles).

Figure 9

Trajectory analysis of the MD simulation of complexes of MAO-B with compounds 1, 3, and 4. (A) Plots of root mean square deviation (RMSD) and (B–D) root mean square fluctuation (RMSF) over 120 ns o protein-ligand complexes.