Novel 2-pheynlbenzofuran derivatives as selective butyrylcholinesterase inhibitors for Alzheimer\u2019s disease

Amit Kumar,Giovanna L Delogu,Enrico Pieroni,Amalia Di Petrillo,Benedetta Era,Paola Caria,Francesco Delogu,Antonella Fais,Rosaria Medda,Francesca Pintus,Maria João Matos,Dolores Viña

doi:10.1038/s41598-018-22747-2

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.

Highlights

Being a multifactorial neurodegenerative brain disorder, the exact pathophysiology of Alzheimer’s disease (AD) is not yet entirely known[5]
We recently developed a series of 2-phenylbenzofuran derivatives[34], which exhibited selective inhibitory property for BChE enzyme and with an inhibition IC50 value similar to that of galantamine (~30 μM)
In our recent study[34], we reported that the contemporary presence of a hydroxyl group in the para position of the 2-phenyl ring and a halogen substitution at position 7 (R1) of the benzofuran scaffold resulted in a good and selective BChE inhibition, with best inhibitor displaying an IC50 of 30 μM

Summary

Introduction

Being a multifactorial neurodegenerative brain disorder, the exact pathophysiology of AD is not yet entirely known[5]. Butyrylcholinesterase (BChE) and Acetylcholinesterase (AChE) belong to ChEs family of enzymes and play a role in ACh regulation and in the cholinergic signalling[17]. AChE is substrate specific in nature and is found in high concentrations in the brain, while BChE is non-specific and is distributed throughout the body[14]. Current Food and Drug Administration (FDA) approved cholinesterase inhibitors namely: donepezil, rivastigmine and galantamine, help only in controlling the symptoms of AD and do not treat the underlying disease or delay its progression. In this scenario, a continuous research related to development of more potent and highly efficacious cholinesterase inhibitors becomes even more essential

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