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

Luis Prent-Peñaloza,Alexander F De La Torre,José L Velázquez-Libera,Julio Caballero,Margarita Gutiérrez

doi:10.3390/molecules24010189

Luis Prent-Peñaloza, Alexander F De La Torre + Show 3 more

Open Access

https://doi.org/10.3390/molecules24010189

Copy DOI

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.

Highlights

Multicomponent reactions (MCRs) have clear advantages with respect to conventional multistep reactions due to their potential to synthesize complicated organic molecules with low costs and quick reaction times [1,2]
Two different elements of diversity were varied for the preparation of these compounds, i.e., the carboxylic acid and the amino components, while the DL-Phenylalanine ethyl ester isocyanide and paraformaldehyde were unchanged as shown in Scheme 1
A solution-phase Ugi-4CR protocol was employed for the synthesis of diNsGF derivatives, which proved to be suitable for β, γ, and δ amino acids but gave poor results when all reagents were added in one step

Summary

Introduction

Multicomponent reactions (MCRs) have clear advantages with respect to conventional multistep reactions due to their potential to synthesize complicated organic molecules with low costs and quick reaction times [1,2]. There are many successful reports that have obtained relevant biological scaffolds by using isocyanoacetate-based Ugi-4CRs [9,10]. The same authors synthesized fully protected natural and unnatural N-acetylcysteine, dipeptide Cys–Gly, glutathione, and homoglutathione derivatives by the Ugi-4CR using various benzylthio aldehydes and ketones as carbonyl building blocks. They used the ethyl isocyanoacetate as a peptide synthesis precursor, but they replaced it by the OBO-ester of the isocyanoacetic acid in cases where higher reactivity of an isocyanide was required [13].

Methods

Results

Conclusion