Are Terminal Alkynes Necessary for MAO-A/MAO-B Inhibition? A New Scaffold Is Revealed
Panagiou Mavroeidi1, Leandros P Zorba1, Nikolaos V Tzouras1
1Laboratory of Organic Chemistry, Department of Chemistry, National and Kapodistrian University of Athens, 15771 Athens, Greece.
Molecules (Basel, Switzerland)
|June 19, 2024
Summary
Researchers developed novel propargylamines using a multicomponent reaction. These compounds show significant inhibitory activity against human monoamine oxidase (hMAO)-A and hMAO-B enzymes, offering potential for neurodegenerative disease treatments.
Area of Science:
- Medicinal Chemistry
- Neuroscience
- Organic Synthesis
Background:
- Human monoamine oxidase (hMAO)-A and hMAO-B enzymes are crucial targets for treating neurodegenerative disorders.
- Propargylamines are a class of compounds with known biological activities, but their potential against MAO enzymes remains underexplored.
Purpose of the Study:
- To synthesize a novel family of quaternary propargylamines using a sustainable multicomponent reaction.
- To evaluate the inhibitory potential of these compounds against human monoamine oxidase (hMAO)-A and hMAO-B.
- To investigate the binding interactions of these propargylamines with hMAO-A and hMAO-B using computational methods.
Main Methods:
- KA² multicomponent reaction for single-step synthesis of propargylamines.
- Enzyme inhibition assays to determine IC50 values against hMAO-A and hMAO-B.
- Lipinski's rule of five and toxicity predictions.
- Molecular docking, all-atom molecular dynamics (MD) simulations, and MM/GBSA calculations for binding analysis.
Main Results:
- A versatile family of quaternary propargylamines was successfully synthesized.
- Significant inhibitory activity was observed against both hMAO-A (IC50: 765.6–861.6 nM) and hMAO-B (IC50: 152.1–164.7 nM).
- Compounds adhere to Lipinski's rule of five with no predicted toxicity, and computational studies elucidated key binding interactions.
Conclusions:
- The synthesized propargylamines demonstrate potent inhibition of hMAO-A and hMAO-B.
- This study reports the first propargylamine scaffold with an internal alkyne showing activity against monoamine oxidases.
- These findings highlight the potential of these propargylamines as therapeutic agents for neurodegenerative diseases like Parkinson's disease.
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