Design, synthesis and evaluation of flurbiprofen-clioquinol hybrids as multitarget-directed ligands against Alzheimer's disease

Ziyi Yang; Qing Song; Zhongcheng Cao; Guangjun Yu; Zhuoling Liu; Zhenghuai Tan; Yong Deng

doi:10.1016/j.bmc.2020.115374

Design, synthesis and evaluation of flurbiprofen-clioquinol hybrids as multitarget-directed ligands against Alzheimer's disease

Bioorg Med Chem. 2020 Apr 1;28(7):115374. doi: 10.1016/j.bmc.2020.115374. Epub 2020 Feb 13.

Authors

Ziyi Yang¹, Qing Song¹, Zhongcheng Cao¹, Guangjun Yu¹, Zhuoling Liu¹, Zhenghuai Tan², Yong Deng³

Affiliations

¹ Department of Medicinal Chemistry, Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, PR China.
² Institute of Traditional Chinese Medicine Pharmacology and Toxicology, Sichuan Academy of Chinese Medicine Sciences, Chengdu 610041, PR China.
³ Department of Medicinal Chemistry, Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, PR China. Electronic address: dengyong@scu.edu.cn.

PMID: 32089390
DOI: 10.1016/j.bmc.2020.115374

Abstract

A series of novel flurbiprofen-clioquinol hybrids were designed and synthesized as multifunctional agents for Alzheimer's disease therapy, and their potential was evaluated through various biological experiments. In vitro studies showed that most target compounds exhibited significant ability to inhibit self- and Cu²⁺-induced β-amyloid aggregation. Furthermore, some target compounds, especially 7i and 7r, also showed biometal chelating abilities, antioxidant activity, anti-neuroinflammatory activity and appropriate BBB permeability. These biological activities indicated that the representative compound 7i and 7r might be promising multifunctional agents for AD treatment.

Keywords: Alzheimer’s disease; Anti-Aβ-aggregation; Anti-neuroinflammation; Antioxidantion; Biometal chelating; Flurbiprofen-clioquinol hybrids.

Publication types

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

MeSH terms

Alzheimer Disease / chemically induced*
Alzheimer Disease / drug therapy*
Amyloid beta-Peptides / chemistry*
Amyloid beta-Peptides / metabolism
Clioquinol / chemistry*
Drug Discovery
Flurbiprofen / chemistry*
Humans
Ligands
Membranes, Artificial
Models, Molecular
Molecular Structure
Protein Conformation
Structure-Activity Relationship

Substances

Amyloid beta-Peptides
Ligands
Membranes, Artificial
Flurbiprofen
Clioquinol