Design, synthesis, and biological evaluation of novel xanthone-alkylbenzylamine hybrids as multifunctional agents for the treatment of Alzheimer's disease

Zhipeng Zhang; Jie Guo; Maojun Cheng; Weixin Zhou; Yang Wan; Rikang Wang; Yuanying Fang; Yi Jin; Jing Liu; Sai-Sai Xie

doi:10.1016/j.ejmech.2021.113154

Design, synthesis, and biological evaluation of novel xanthone-alkylbenzylamine hybrids as multifunctional agents for the treatment of Alzheimer's disease

Eur J Med Chem. 2021 Mar 5:213:113154. doi: 10.1016/j.ejmech.2021.113154. Epub 2021 Jan 11.

Authors

Zhipeng Zhang¹, Jie Guo¹, Maojun Cheng¹, Weixin Zhou¹, Yang Wan¹, Rikang Wang¹, Yuanying Fang¹, Yi Jin¹, Jing Liu², Sai-Sai Xie³

Affiliations

¹ National Pharmaceutical Engineering Center for Solid Preparation in Chinese Herbal Medicine, Jiangxi University of Traditional Chinese Medicine, Nanchang, 330006, PR China.
² School of Pharmacy, Jiangxi University of Traditional Chinese Medicine, Nanchang, 330006, PR China. Electronic address: liujing860828@163.com.
³ National Pharmaceutical Engineering Center for Solid Preparation in Chinese Herbal Medicine, Jiangxi University of Traditional Chinese Medicine, Nanchang, 330006, PR China. Electronic address: xiesaisainanchang@hotmail.com.

PMID: 33476932
DOI: 10.1016/j.ejmech.2021.113154

Abstract

In this study, a series of multifunctional hybrids against Alzheimer's disease were designed and obtained by conjugating the pharmacophores of xanthone and alkylbenzylamine through the alkyl linker. Biological activity results demonstrated that compound 4j was the most potent and balanced dual ChEs inhibitor with IC₅₀ values 0.85 μM and 0.59 μM for eeAChE and eqBuChE, respectively. Kinetic analysis and docking study indicated that compound 4j was a mixed-type inhibitor for both AChE and BuChE. Additionally, it exhibited good abilities to penetrate BBB, scavenge free radicals (4.6 trolox equivalent) and selectively chelate with Cu²⁺ and Al³⁺ at a 1:1.4 ligand/metal molar ratio. Importantly, after assessments of cytotoxic and acute toxicity, we found compound 4j could improve memory function of scopolamine-induced amnesia mice. Hence, the compound 4j can be considered as a promising lead compound for further investigation in the treatment of AD.

Keywords: Alzheimer’s disease; Antioxidant; Cholinesterase; Metal chelator; Xanthone.

MeSH terms

Acetylcholinesterase / metabolism
Alzheimer Disease / drug therapy*
Alzheimer Disease / pathology
Animals
Antioxidants / chemical synthesis
Antioxidants / chemistry
Antioxidants / pharmacology*
Benzothiazoles / antagonists & inhibitors
Benzylamines / chemistry
Benzylamines / pharmacology*
Biphenyl Compounds / antagonists & inhibitors
Butyrylcholinesterase / metabolism
Cell Survival / drug effects
Cells, Cultured
Cholinesterase Inhibitors / chemical synthesis
Cholinesterase Inhibitors / chemistry
Cholinesterase Inhibitors / pharmacology*
Dose-Response Relationship, Drug
Drug Design
Electrophorus
Horses
Male
Mice
Mice, Inbred Strains
Molecular Structure
Neuroprotective Agents / chemical synthesis
Neuroprotective Agents / chemistry
Neuroprotective Agents / pharmacology*
Picrates / antagonists & inhibitors
Rats
Structure-Activity Relationship
Sulfonic Acids / antagonists & inhibitors
Xanthones / chemistry
Xanthones / pharmacology*

Substances

Antioxidants
Benzothiazoles
Benzylamines
Biphenyl Compounds
Cholinesterase Inhibitors
Neuroprotective Agents
Picrates
Sulfonic Acids
Xanthones
2,2'-azino-di-(3-ethylbenzothiazoline)-6-sulfonic acid
xanthone
benzylamine
1,1-diphenyl-2-picrylhydrazyl
Acetylcholinesterase
Butyrylcholinesterase