Design, synthesis and evaluation of 4'-OH-flurbiprofen-chalcone hybrids as potential multifunctional agents for Alzheimer's disease treatment

Zhongcheng Cao; Jie Yang; Rui Xu; Qin Song; Xiaoyu Zhang; Hongyan Liu; Xiaoming Qiang; Yan Li; Zhenghuai Tan; Yong Deng

doi:10.1016/j.bmc.2018.01.030

Design, synthesis and evaluation of 4'-OH-flurbiprofen-chalcone hybrids as potential multifunctional agents for Alzheimer's disease treatment

Bioorg Med Chem. 2018 Mar 1;26(5):1102-1115. doi: 10.1016/j.bmc.2018.01.030. Epub 2018 Feb 2.

Authors

Zhongcheng Cao¹, Jie Yang¹, Rui Xu¹, Qin Song¹, Xiaoyu Zhang¹, Hongyan Liu¹, Xiaoming Qiang¹, Yan Li¹, Zhenghuai Tan², Yong Deng³

Affiliations

¹ Department of Medicinal Chemistry, Key Laboratory of Drug Targeting and Drug Delivery System of the Education Ministry, West China School of Pharmacy, Sichuan University, Chengdu 610041, China.
² Institute of Traditional Chinese Medicine Pharmacology and Toxicology, Sichuan academy of Chinese Medicine Sciences, Chengdu 610041, China.
³ Department of Medicinal Chemistry, Key Laboratory of Drug Targeting and Drug Delivery System of the Education Ministry, West China School of Pharmacy, Sichuan University, Chengdu 610041, China. Electronic address: dengyong@scu.edu.cn.

PMID: 29409707
DOI: 10.1016/j.bmc.2018.01.030

Abstract

A series of 4'-OH-flurbiprofen-chalcone hybrids were designed, synthesized and evaluated as potential multifunctional agents for the treatment of Alzheimer's disease. The biological screening results indicated that most of these hybrids exhibited good multifunctional activities. Among them, compounds 7k and 7m demonstrated the best inhibitory effects on self-induced Aβ_1-42 aggregation (60.0% and 78.2%, respectively) and Cu²⁺-induced Aβ_1-42 aggregation (52.4% and 95.0%, respectively). Moreover, these two representative compounds also exhibited good antioxidant activities, MAO inhibitions, biometal chelating abilities and anti-neuroinflammatory activities in vitro. Furthermore, compound 7m displayed appropriate blood-brain barrier permeability. These multifunctional properties highlight compound 7k and 7m as promising candidates for further development of multi-functional drugs against AD.

Keywords: Alzheimer’s disease; Anti-inflammatory agents; Aβ aggregation inhibitors; Flurbiprofen-chalcone hybrids; Monoamine oxidase inhibitors; Multifunctional agents.

Publication types

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

MeSH terms

Alzheimer Disease / drug therapy
Alzheimer Disease / pathology
Amyloid beta-Peptides / antagonists & inhibitors
Amyloid beta-Peptides / metabolism
Antioxidants / chemistry*
Antioxidants / pharmacology
Antioxidants / therapeutic use
Blood-Brain Barrier / drug effects
Blood-Brain Barrier / metabolism
Cell Line
Cell Survival / drug effects
Chalcones / chemistry*
Chelating Agents / chemical synthesis
Chelating Agents / chemistry
Copper / chemistry
Drug Design*
Flurbiprofen / chemistry*
Humans
Lipopolysaccharides / toxicity
Monoamine Oxidase / chemistry
Monoamine Oxidase / genetics
Monoamine Oxidase / metabolism
Monoamine Oxidase Inhibitors / chemistry
Monoamine Oxidase Inhibitors / pharmacology
Monoamine Oxidase Inhibitors / therapeutic use
Nitric Oxide / metabolism
Peptide Fragments / antagonists & inhibitors
Peptide Fragments / metabolism
Recombinant Proteins / biosynthesis
Recombinant Proteins / chemistry
Recombinant Proteins / genetics
Structure-Activity Relationship

Substances

Amyloid beta-Peptides
Antioxidants
Chalcones
Chelating Agents
Lipopolysaccharides
Monoamine Oxidase Inhibitors
Peptide Fragments
Recombinant Proteins
amyloid beta-protein (1-42)
Nitric Oxide
Flurbiprofen
Copper
Monoamine Oxidase