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

Panagiou Mavroeidi, Leandros P. Zorba, Nikolaos V. Tzouras, Stavros P. Neofotistos, Nikitas Georgiou, Kader Sahin, Murat Şentürk, Serdar Durdagi, Georgios C. Vougioukalakis, Thomas Mavromoustakos

Araştırma sonucu: Dergi katkısıMakalebilirkişi

Özet

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.

Orijinal dilİngilizce
Makale numarası2486
DergiMolecules
Hacim29
Basın numarası11
DOI'lar
Yayın durumuYayınlanan - Haz 2024
Harici olarak yayınlandıEvet

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