Structural Insight of New Butyrylcholinesterase Inhibitors Based on Benzylbenzofuran Scaffold

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.

Identification of new benzofuran derivatives as STING agonists with broad-spectrum antiviral activity

“…BZFs have been shown to posses several biologically interesting activities, including anticancer and antiviral activities ( Delogu et al, 2022 ; Duncan et al, 2021 ; Era et al, 2020 ; Fais et al, 2019 ; Ferino et al, 2013 ; Galal et al, 2009 ; Geldenhuys et al, 2012 ; Jiang et al, 2008 ; Kumar et al, 2018 ; Pisani et al, 2013 ; Van Dyk et al, 2015 ; Xu et al, 2019 ). Firstly, BZFs can be isolated from natural products such as: Machilus glaucescens, Ophryosporus charua, Ophryosporus lorentzii, Krameria ramosissima, Ammi majus L., and Zanthoxylum ailanthoidoland presenting antihyperglycemic, analgesic, antiparasitic, antimicrobial, antitumor and kinase inhibitory properties ( Khanam and Shamsuzzaman, 2015 ); secondly, BZFs are included in commonly used medicines all of them showing a good bioavailability among the species tested: amiodarone, ailanthoidol, bufurarol β-adrenoceptor antagonist, opioids (i.e.…”

“…Methoxylated 2-phenylbenzofurans and hydroxylated 2-phenylbenzofurans were obtained following the procedures reported in previous studies ( Delogu et al, 2022 , 2021 , 2016 ).…”

“…Furthermore, BZF is a common moiety present in many biologically active natural and therapeutic compounds representing a suitable scaffold for the development of novel bioactive molecules ( Duncan et al, 2021 ; Khanam and Shamsuzzaman, 2015 ; Miao et al, 2019 ; Naik et al, 2015 ; Nevagi et al, 2015 ; Pan et al, 2020 ; Xu et al, 2019 ). Hence, thirteen in house BZF derivatives bearing different substituents were selected ( Delogu et al, 2022 , 2021 , 2016 ), and subjected to biological assay to assess their ability to induce IFN and to inhibit viral replication.…”

Discovery of promising cholinesterase inhibitors for Alzheimer's disease treatment through DFT, docking, and molecular dynamics studies of eugenol derivatives

“…In addition, as revealed in previous studies, the residues with which the studied compounds interacted are among the relevant sites governing the inhibition of BuChE and AChE. [ 19,20,49–51 ]…”

Recent Advancement of Benzofuran in Treatment of Alzheimer’s Disease

“…Trauma to the head, traumatic brain injury has been associated with a higher risk for dementia [34] . However, whether AD is more likely to lead to pathologic outcomes than other neurodegenerative disease processes such as the recently discovered chronic traumatic encephalopathy [35][36][37][38][39][40][41][42][43][44] .…”