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Novel 2-pheynlbenzofuran derivatives as selective butyrylcholinesterase inhibitors for Alzheimer's disease.
Sci Rep. 2018 03 13; 8(1):4424.SR

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.

Authors+Show Affiliations

Department of Mechanical, Chemical and Materials Engineering, University of Cagliari, via Marengo 2, 09123, Cagliari, Italy. amit369@gmail.com. Modeling and Simulations group, Biosciences Sector, Center for advanced study research and development in Sardinia (CRS4), Loc. Piscina Manna, 09010, Pula, Italy. amit369@gmail.com.Department of Life and Environmental Sciences, University of Cagliari, 09042, Monserrato, Cagliari, Italy.Department of Life and Environmental Sciences, University of Cagliari, 09042, Monserrato, Cagliari, Italy.Department of Life and Environmental Sciences, University of Cagliari, 09042, Monserrato, Cagliari, Italy.Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy.Department of Organic Chemistry, University of Santiago de Compostela, Santiago de Compostela, Spain.Department of Pharmacology, CIMUS University of Santiago de Compostela, Santiago de Compostela, Spain.Modeling and Simulations group, Biosciences Sector, Center for advanced study research and development in Sardinia (CRS4), Loc. Piscina Manna, 09010, Pula, Italy.Department of Mechanical, Chemical and Materials Engineering, University of Cagliari, via Marengo 2, 09123, Cagliari, Italy.Department of Life and Environmental Sciences, University of Cagliari, 09042, Monserrato, Cagliari, Italy.Department of Life and Environmental Sciences, University of Cagliari, 09042, Monserrato, Cagliari, Italy.Department of Life and Environmental Sciences, University of Cagliari, 09042, Monserrato, Cagliari, Italy.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29535344

Citation

Kumar, Amit, et al. "Novel 2-pheynlbenzofuran Derivatives as Selective Butyrylcholinesterase Inhibitors for Alzheimer's Disease." Scientific Reports, vol. 8, no. 1, 2018, p. 4424.
Kumar A, Pintus F, Di Petrillo A, et al. Novel 2-pheynlbenzofuran derivatives as selective butyrylcholinesterase inhibitors for Alzheimer's disease. Sci Rep. 2018;8(1):4424.
Kumar, A., Pintus, F., Di Petrillo, A., Medda, R., Caria, P., Matos, M. J., Viña, D., Pieroni, E., Delogu, F., Era, B., Delogu, G. L., & Fais, A. (2018). Novel 2-pheynlbenzofuran derivatives as selective butyrylcholinesterase inhibitors for Alzheimer's disease. Scientific Reports, 8(1), 4424. https://doi.org/10.1038/s41598-018-22747-2
Kumar A, et al. Novel 2-pheynlbenzofuran Derivatives as Selective Butyrylcholinesterase Inhibitors for Alzheimer's Disease. Sci Rep. 2018 03 13;8(1):4424. PubMed PMID: 29535344.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Novel 2-pheynlbenzofuran derivatives as selective butyrylcholinesterase inhibitors for Alzheimer's disease. AU - Kumar,Amit, AU - Pintus,Francesca, AU - Di Petrillo,Amalia, AU - Medda,Rosaria, AU - Caria,Paola, AU - Matos,Maria João, AU - Viña,Dolores, AU - Pieroni,Enrico, AU - Delogu,Francesco, AU - Era,Benedetta, AU - Delogu,Giovanna L, AU - Fais,Antonella, Y1 - 2018/03/13/ PY - 2017/10/19/received PY - 2018/02/27/accepted PY - 2018/3/15/entrez PY - 2018/3/15/pubmed PY - 2019/9/21/medline SP - 4424 EP - 4424 JF - Scientific reports JO - Sci Rep VL - 8 IS - 1 N2 - 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. SN - 2045-2322 UR - https://www.unboundmedicine.com/medline/citation/29535344/Novel_2_pheynlbenzofuran_derivatives_as_selective_butyrylcholinesterase_inhibitors_for_Alzheimer's_disease_ L2 - https://doi.org/10.1038/s41598-018-22747-2 DB - PRIME DP - Unbound Medicine ER -