Design, synthesis, biological evaluation and docking study of 4-isochromanone hybrids bearing N-benzyl pyridinium moiety as dual binding site acetylcholinesterase inhibitors

Chaolei Wang; Zheng Wu; Hao Cai; Shengtao Xu; Jie Liu; Jieyun Jiang; Hequan Yao; Xiaoming Wu; Jinyi Xu

doi:10.1016/j.bmcl.2015.09.063

Design, synthesis, biological evaluation and docking study of 4-isochromanone hybrids bearing N-benzyl pyridinium moiety as dual binding site acetylcholinesterase inhibitors

Chaolei Wang, Zheng Wu, Hao Cai, Shengtao Xu, Jie Liu, Jieyun Jiang, Hequan Yao, Xiaoming Wu, Jinyi Xu

Microbiology, Immunology, and Molecular Genetics

Research output: Contribution to journal › Article › peer-review

39 Scopus citations

Abstract

A series of novel 4-isochromanone hybrids bearing N-benzyl pyridinium moiety as dual binding site acetylcholinesterase inhibitors have been designed and synthesized. The screening results showed that most of the compounds exhibited potent anti-AChE activity in the range of nM concentrations. The 1-(4-fluorobenzyl) substituted derivative 9d exhibited the most potent anti-AChE activity with IC₅₀ value of 8.9 nM and high AChE/BuChE selectivity (SI >230). Kinetic and molecular modeling studies suggested that compound 9d was mixed-type inhibitor, binding simultaneously to CAS and PAS of AChE. Besides, the preliminary structure-activity relationships were discussed.

Original language	English
Pages (from-to)	5212-5216
Number of pages	5
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	25
Issue number	22
DOIs	https://doi.org/10.1016/j.bmcl.2015.09.063
State	Published - Nov 15 2015

Bibliographical note

Publisher Copyright:
© 2015 Elsevier Ltd. All rights reserved.

Funding

This study was financially supported by Grants from ‘National Natural Science Fund’ (No. 81302635), the Project Program of State Key Laboratory of Natural Medicines, China Pharmaceutical University (No. SKLNMZZCX201404) and the Project for Research and Innovation of Graduates in Colleges and Universities of Jiangsu Province (KYLX_0611).

Funders	Funder number
Project for Research and Innovation of Graduates in Colleges and Universities of Jiangsu Province	KYLX_0611
National Natural Science Foundation of China (NSFC)	81302635
State Key Laboratory of Natural Medicines, China Pharmaceutical University	SKLNMZZCX201404

Keywords

4-Isochromanone
Acetylcholinesterase
Alzheimer's disease
Dual binding site
Hybrids

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

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10.1016/j.bmcl.2015.09.063

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title = "Design, synthesis, biological evaluation and docking study of 4-isochromanone hybrids bearing N-benzyl pyridinium moiety as dual binding site acetylcholinesterase inhibitors",

abstract = "A series of novel 4-isochromanone hybrids bearing N-benzyl pyridinium moiety as dual binding site acetylcholinesterase inhibitors have been designed and synthesized. The screening results showed that most of the compounds exhibited potent anti-AChE activity in the range of nM concentrations. The 1-(4-fluorobenzyl) substituted derivative 9d exhibited the most potent anti-AChE activity with IC50 value of 8.9 nM and high AChE/BuChE selectivity (SI >230). Kinetic and molecular modeling studies suggested that compound 9d was mixed-type inhibitor, binding simultaneously to CAS and PAS of AChE. Besides, the preliminary structure-activity relationships were discussed.",

keywords = "4-Isochromanone, Acetylcholinesterase, Alzheimer's disease, Dual binding site, Hybrids",

author = "Chaolei Wang and Zheng Wu and Hao Cai and Shengtao Xu and Jie Liu and Jieyun Jiang and Hequan Yao and Xiaoming Wu and Jinyi Xu",

year = "2015",

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day = "15",

doi = "10.1016/j.bmcl.2015.09.063",

language = "English",

volume = "25",

pages = "5212--5216",

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Wang, C, Wu, Z, Cai, H, Xu, S, Liu, J, Jiang, J, Yao, H, Wu, X & Xu, J 2015, 'Design, synthesis, biological evaluation and docking study of 4-isochromanone hybrids bearing N-benzyl pyridinium moiety as dual binding site acetylcholinesterase inhibitors', Bioorganic and Medicinal Chemistry Letters, vol. 25, no. 22, pp. 5212-5216. https://doi.org/10.1016/j.bmcl.2015.09.063

Design, synthesis, biological evaluation and docking study of 4-isochromanone hybrids bearing N-benzyl pyridinium moiety as dual binding site acetylcholinesterase inhibitors. / Wang, Chaolei; Wu, Zheng; Cai, Hao et al.
In: Bioorganic and Medicinal Chemistry Letters, Vol. 25, No. 22, 15.11.2015, p. 5212-5216.

Research output: Contribution to journal › Article › peer-review

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T1 - Design, synthesis, biological evaluation and docking study of 4-isochromanone hybrids bearing N-benzyl pyridinium moiety as dual binding site acetylcholinesterase inhibitors

AU - Wang, Chaolei

AU - Wu, Zheng

AU - Cai, Hao

AU - Xu, Shengtao

AU - Liu, Jie

AU - Jiang, Jieyun

AU - Yao, Hequan

AU - Wu, Xiaoming

AU - Xu, Jinyi

PY - 2015/11/15

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AB - A series of novel 4-isochromanone hybrids bearing N-benzyl pyridinium moiety as dual binding site acetylcholinesterase inhibitors have been designed and synthesized. The screening results showed that most of the compounds exhibited potent anti-AChE activity in the range of nM concentrations. The 1-(4-fluorobenzyl) substituted derivative 9d exhibited the most potent anti-AChE activity with IC50 value of 8.9 nM and high AChE/BuChE selectivity (SI >230). Kinetic and molecular modeling studies suggested that compound 9d was mixed-type inhibitor, binding simultaneously to CAS and PAS of AChE. Besides, the preliminary structure-activity relationships were discussed.

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KW - Acetylcholinesterase

KW - Alzheimer's disease

KW - Dual binding site

KW - Hybrids

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Design, synthesis, biological evaluation and docking study of 4-isochromanone hybrids bearing N-benzyl pyridinium moiety as dual binding site acetylcholinesterase inhibitors

Abstract

Bibliographical note

Funding

Keywords

ASJC Scopus subject areas

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