Are Terminal Alkynes Necessary for MAO-A/MAO-B Inhibition? A New Scaffold Is Revealed

Autor: Panagiou Mavroeidi, Leandros P. Zorba, Nikolaos V. Tzouras, Stavros P. Neofotistos, Nikitas Georgiou, Kader Sahin, Murat Şentürk, Serdar Durdagi, Georgios C. Vougioukalakis, Thomas Mavromoustakos
Jazyk: angličtina
Rok vydání: 2024
Předmět:
Zdroj: Molecules, Vol 29, Iss 11, p 2486 (2024)
Druh dokumentu: article
ISSN: 29112486
1420-3049
DOI: 10.3390/molecules29112486
Popis: A versatile family of quaternary propargylamines was synthesized employing the KA2 multicomponent reaction, through the single-step coupling of a number of amines, ketones, and terminal alkynes. Sustainable synthetic procedures using transition metal catalysts were employed in all cases. The inhibitory activity of these molecules was evaluated against human monoaminoxidase (hMAO)-A and hMAO-B enzymes and was found to be significant. The IC50 values for hMAO-B range from 152.1 to 164.7 nM while the IC50 values for hMAO-A range from 765.6 to 861.6 nM. Furthermore, these compounds comply with Lipinski’s rule of five and exhibit no predicted toxicity. To understand their binding properties with the two target enzymes, key interactions were studied using molecular docking, all-atom molecular dynamics (MD) simulations, and MM/GBSA binding free energy calculations. Overall, herein, the reported family of propargylamines exhibits promise as potential treatments for neurodegenerative disorders, such as Parkinson’s disease. Interestingly, this is the first time a propargylamine scaffold bearing an internal alkyne has been reported to show activity against monoaminoxidases.
Databáze: Directory of Open Access Journals
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