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Molecules 2019, 24(1), 189; https://doi.org/10.3390/molecules24010189

Synthesis of diN-Substituted Glycyl-Phenylalanine Derivatives by Using Ugi Four Component Reaction and Their Potential as Acetylcholinesterase Inhibitors

1
Organic Synthesis Laboratory and Biological Activity (LSO-Act-Bio), Institute of Chemistry of Natural Resources, Universidad de Talca, Casilla 747, Talca 3460000, Chile
2
Departamento de Química Orgánica, Facultad de Ciencias Químicas, Universidad de Concepción, Concepción 4030000, Chile
3
Centro de Bioinformática y Simulación Molecular (CBSM), Universidad de Talca, Casilla 747, Talca 3460000, Chile
*
Author to whom correspondence should be addressed.
Academic Editor: Pawel Kafarski
Received: 24 November 2018 / Revised: 25 December 2018 / Accepted: 28 December 2018 / Published: 6 January 2019
(This article belongs to the Special Issue Design and Synthesis of Bioactive Compounds)
Full-Text   |   PDF [10130 KB, uploaded 6 January 2019]   |  

Abstract

Ugi four component reaction (Ugi-4CR) isocyanide-based multicomponent reactions were used to synthesize diN-substituted glycyl-phenylalanine (diNsGF) derivatives. All of the synthesized compounds were characterized by spectroscopic and spectrometric techniques. In order to evaluate potential biological applications, the synthesized compounds were tested in computational models that predict the bioactivity of organic molecules by using only bi-dimensional molecular information. The diNsGF derivatives were predicted as cholinesterase inhibitors. Experimentally, all of the synthesized diNsGF derivatives showed moderate inhibitory activities against acetylcholinesterase (AChE) and poor activities against butyrylcholinesterase (BuChE). Compound 7a has significant activity and selectivity against AChE, which reveals that the diNsGF scaffold could be improved to reach novel candidates by combining other chemical components of the Ugi-4CR in a high-throughput combinatorial screening experiment. Molecular docking experiments of diNsGF derivatives inside AChE suggest that these compounds placed the phenylalanine group at the peripheral site of AChE. The orientations and chemical interactions of diNsGF derivatives were analyzed, and the changeable groups were identified for future exploration of novel candidates that could lead to the improvement of diNsGF derivative inhibitory activities. View Full-Text
Keywords: acetylcholinesterase inhibitors; molecular docking; multicomponent reactions; N-substituted phenylalanine derivatives; Ugi-4CR acetylcholinesterase inhibitors; molecular docking; multicomponent reactions; N-substituted phenylalanine derivatives; Ugi-4CR
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Prent-Peñaloza, L.; De la Torre, A.F.; Velázquez-Libera, J.L.; Gutiérrez, M.; Caballero, J. Synthesis of diN-Substituted Glycyl-Phenylalanine Derivatives by Using Ugi Four Component Reaction and Their Potential as Acetylcholinesterase Inhibitors. Molecules 2019, 24, 189.

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