Structural Insight of New Butyrylcholinesterase Inhibitors Based on Benzylbenzofuran Scaffold.

Giovanna L Delogu,Amit Kumar,Chinmayi Goyal,Maria J Matos,Francesca Pintus,Benedetta Era,Antonella Fais

doi:10.3390/ph15030304

Giovanna L Delogu, Amit Kumar + Show 5 more

Open Access

https://doi.org/10.3390/ph15030304

Copy DOI

Abstract

In the present work, we use a merger of computational and biochemical techniques as a rational guideline for structural modification of benzofuran derivatives to find pertinent structural features for the butyrylcholinesterase inhibitory activity and selectivity. Previously, we revealed a series of 2-phenylbenzofuran compounds that displayed a selective inhibitory activity for BChE. Here, in an effort to discover novel selective BChE inhibitors with favorable physicochemical and pharmacokinetic profiles, 2-benzylbenzofurans were designed, synthesized, and evaluated as BChE inhibitors. The 2-phenylbenzofuran scaffold structure is modified by introducing one methylene spacer between the benzofuran core and the 2-phenyl ring with a hydroxyl substituent in the para or meta position. Either position 5 or 7 of the benzofuran scaffold was substituted with a bromine or chlorine atom. Further assessment of the selected list of compounds indicated that the substituent’s nature and position determined their activity and selectivity. 5-bromo-2-(4-hydroxybenzyl)benzofuran 9B proved to be the most potent butyrylcholinesterase inhibitor (IC50 = 2.93 µM) of the studied series. Computational studies were carried out to correlate the theoretical and experimental binding affinity of the compounds to the BChE protein.

Highlights

The design of enzyme inhibitors has been a topic of accelerated research, especially concerning the discovery of lead compounds as new therapeutic agents owing to the weak pharmacokinetic properties of several bioactive molecules
We reported that 2-phenylbenzofuran derivatives display promising enzymatic inhibition properties against BChE [8–10] and monoamine oxidase (MAO) [11–13] enzymes
Ortho-hydroxybenzyl alcohols Ia–Id [19] were taken as the starting material

Summary

Introduction

The design of enzyme inhibitors has been a topic of accelerated research, especially concerning the discovery of lead compounds as new therapeutic agents owing to the weak pharmacokinetic properties of several bioactive molecules.Molecular docking is a popular tool in computer-aided drug discovery for rapid screening and predicting the binding characteristics of small molecules to a target protein using its available three-dimensional structure. The design of enzyme inhibitors has been a topic of accelerated research, especially concerning the discovery of lead compounds as new therapeutic agents owing to the weak pharmacokinetic properties of several bioactive molecules. The action as inhibitors of several molecules is related to their target enzyme interaction. The rational drug design strategy is supported by a detailed understanding of interactions between small molecules and proteins [1,2]. The beginning for the rational design of inhibitors of enzymes is existing drugs and known pharmacophores. In this regard, benzofuran scaffolds have drawn considerable attention over the last few years due to their deep biological properties, as well as their widespread occurrence in nature

Objectives

Methods

Results