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

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.

Keywords: N-substituted phenylalanine derivatives; Ugi-4CR; acetylcholinesterase inhibitors; molecular docking; multicomponent reactions.

Scheme 1

The Ugi four component reaction (Ugi-4CR) for the synthesis of diNsGF derivatives.

Figure 1

The Lineweaver–Burk plot of AChE (0.02 U) with an acetylthiocholine substrate in the absence and presence of inhibitor 7a.

Figure 2

Molecular docking models for diNsGF derivatives inside the AChE binding site. Docking poses of all the compounds (A); Docking poses of compounds 7a (B), 7b (C), 7c (D), 6d (E), and 6e (F), where R and S enantiomers are represented in green and yellow, respectively. Protein residues that form the main interactions with the inhibitors are in stick representation.