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

Overview

Journal Molecules

Publisher MDPI

Specialty Biology

Date 2024 Jun 19

PMID 38893361

Authors

Panagiou Mavroeidi

Leandros P Zorba

Nikolaos V Tzouras

Stavros P Neofotistos

Nikitas Georgiou

Kader Sahin

Murat Senturk

Serdar Durdagi

Georgios C Vougioukalakis

Thomas Mavromoustakos

Affiliations

Soon will be listed here.

Abstract

A versatile family of quaternary propargylamines was synthesized employing the KA 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 IC values for hMAO-B range from 152.1 to 164.7 nM while the IC 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.

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