Novel 2-pheynlbenzofuran derivatives as selective butyrylcholinesterase inhibitors for Alzheimer’s disease

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disorder representing the leading cause of dementia and is affecting nearly 44 million people worldwide. AD is characterized by a progressive decline in acetylcholine levels in the cholinergic systems, which results in severe memory loss and cognitive impairments. Expression levels and activity of butyrylcholinesterase (BChE) enzyme has been noted to increase significantly in the late stages of AD, thus making it a viable drug target. A series of hydroxylated 2-phenylbenzofurans compounds were designed, synthesized and their inhibitory activities toward acetylcholinesterase (AChE) and BChE enzymes were evaluated. Two compounds (15 and 17) displayed higher inhibitory activity towards BChE with IC50 values of 6.23 μM and 3.57 μM, and a good antioxidant activity with EC50 values 14.9 μM and 16.7 μM, respectively. The same compounds further exhibited selective inhibitory activity against BChE over AChE. Computational studies were used to compare protein-binding pockets and evaluate the interaction fingerprints of the compound. Molecular simulations showed a conserved protein residue interaction network between the compounds, resulting in similar interaction energy values. Thus, combination of biochemical and computational approaches could represent rational guidelines for further structural modification of these hydroxy-benzofuran derivatives as future drugs for treatment of AD.

Benzofuran and Indole: Promising Scaffolds for Drug Development in Alzheimer's Disease

“…In molecular dynamics studies, compound 25 a expresses the best binding energy by showing interactions at the CAS and PAS of BuChE. Recently, a series of 2‐phenylbenzofuran derivatives with either two or three hydroxy substituents on the phenyl ring have been evaluated as selective inhibitors of BuChE . Among these derivatives, compounds 25 b and 25 c show maximum inhibitory activity against BuChE with IC 50 values of 6.23 and 3.57 μ m , respectively.…”

Exploring the Multi–Target Neuroprotective Chemical Space of Benzofuran Scaffolds: A New Strategy in Drug Development for Alzheimer’s Disease

“…This class of chemical motifs have been shown to display antibacterial, antifungal, antioxidant, antitumoral, antiinflammatory, anticonvulsant, and anti-HIV bioactivities (Hiremathad et al, 2015;Khanam, 2015;Nevagi et al, 2015). Interestingly, benzofurans have also been found to have neuroprotective activity, inhibiting the important events involved in the AD process (Howlett et al, 1999;Allsop et al, 2001;Ono et al, 2002;Ono et al, 2006;Rizzo et al, 2008;Rizzo et al, 2012;Sashidhara et al, 2014;Ha et al, 2017;González-Ramírez et al, 2018;Kumar et al, 2018). Our research group has also investigated the role of natural fungal benzofurans in synaptic failure, decay of intracellular Ca 2+ transients and synaptic disorganization (González-Ramírez et al, 2018).…”

“…Thus, chemical probes containing benzofuran cores have yet to become approved drugs to control AD, mainly due to their modest potency. The lack of drug development could be attributed to the limited knowledge of protein-ligand interactions between benzofurans and important protein targets involved in AD progression (Howlett et al, 1999;Allsop et al, 2001;Kumar et al, 2018). In order to increase their efficacy, chemical transformation can be employed to tune their biological properties.…”

“…Such chemical modifications could be achieved either by hemi-synthesis or total synthesis of natural benzofuran cores. In addition to blocking the Ab fibril formation process, benzofuran compounds have proven to be efficient inhibitors of butyrylcholinesterase (Kumar et al, 2018), which is another important target for drug development to control AD. Given the importance of developing multitarget probes to control AD (Bajda et al, 2011;Leon et al, 2013;Prati et al, 2016;Unzeta et al, 2016), the dual activity displayed by benzofuran scaffolds against different mechanisms of AD make them worthwhile ligand targets for drug development.…”

Benzofuran hydrazones as potential scaffold in the development of multifunctional drugs: Synthesis and evaluation of antioxidant, photoprotective and antiproliferative activity

“…Benzofurans find application in a variety of drugs and in other field of chemistry and agriculture [1]. Therefore, benzofuran derivatives are the important scaffold for drug discovery and possess broad spectrum biological activity like antimicrobial [2][3][4][5][6], anti-viral [7,8] anti-cancer [9][10][11][12][13][14][15][16], anti-Alzheimer [17][18][19][20], anti-hyperlipidemic [21], antinflammatory and anticonvulsivant [22], anti-tubercular [23], anti-pyretic [24] and protein tyrosine phosphatase inhibitors [25]. The benzofuran core is widely distributed in nature, mainly contained in products of secondary plant metabolism.…”