Discovery of novel 2,5-dihydroxyterephthalamide derivatives as multifunctional agents for the treatment of Alzheimer's disease

Qing Song; Yan Li; Zhongcheng Cao; Hongyan Liu; Chaoquan Tian; Ziyi Yang; Xiaoming Qiang; Zhenghuai Tan; Yong Deng

doi:10.1016/j.bmc.2018.11.015

Discovery of novel 2,5-dihydroxyterephthalamide derivatives as multifunctional agents for the treatment of Alzheimer's disease

Bioorg Med Chem. 2018 Dec 15;26(23-24):6115-6127. doi: 10.1016/j.bmc.2018.11.015. Epub 2018 Nov 13.

Authors

Qing Song¹, Yan Li¹, Zhongcheng Cao¹, Hongyan Liu¹, Chaoquan Tian¹, Ziyi Yang¹, Xiaoming Qiang¹, Zhenghuai Tan², Yong Deng³

Affiliations

¹ Department of Medicinal Chemistry, Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, 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, 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: 30470598
DOI: 10.1016/j.bmc.2018.11.015

Abstract

A series of 2,5-dihydroxyterephthalamide derivatives were designed, synthesized and evaluated as multifunctional agents for the treatment of Alzheimer's disease. In vitro assays demonstrated that most of the derivatives exhibited good multifunctional activities. Among them, compound 9d showed the best inhibitory activity against both RatAChE and EeAChE (IC₅₀ = 0.56 μM and 5.12 μM, respectively). Moreover, 9d exhibited excellent inhibitory effects on self-induced Aβ_1-42 aggregation (IC₅₀ = 3.05 μM) and Cu²⁺-induced Aβ_1-42 aggregation (71.7% at 25.0 μM), and displayed significant disaggregation ability to self- and Cu²⁺-induced Aβ_1-42 aggregation fibrils (75.2% and 77.2% at 25.0 μM, respectively). Furthermore, 9d also showed biometal chelating abilities, antioxidant activity, anti-neuroinflammatory activities and appropriate BBB permeability. These multifunctional properties highlight 9d as promising candidate for further studies directed to the development of novel drugs against AD.

Keywords: 2,5-Dihydroxyterephthalamide derivatives; Acetylcholinesterase inhibitors; Alzheimer’s disease; Anti-neuroinflammatory agents; Antioxidant; Aβ aggregation inhibitors.

Publication types

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

MeSH terms

Acetylcholinesterase / metabolism
Alzheimer Disease / drug therapy*
Alzheimer Disease / metabolism
Amyloid beta-Peptides / antagonists & inhibitors
Amyloid beta-Peptides / metabolism
Animals
Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis
Anti-Inflammatory Agents, Non-Steroidal / chemistry
Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
Antioxidants / chemical synthesis
Antioxidants / chemistry
Antioxidants / pharmacology*
Butyrylcholinesterase / metabolism
Chelating Agents / chemical synthesis
Chelating Agents / chemistry
Chelating Agents / pharmacology*
Cholinesterase Inhibitors / chemical synthesis
Cholinesterase Inhibitors / chemistry
Cholinesterase Inhibitors / pharmacology*
Dose-Response Relationship, Drug
Drug Discovery
Humans
Models, Molecular
Molecular Structure
Peptide Fragments / antagonists & inhibitors
Peptide Fragments / metabolism
Phthalimides / chemical synthesis
Phthalimides / chemistry
Phthalimides / pharmacology*
Protein Aggregates / drug effects
Structure-Activity Relationship

Substances

Amyloid beta-Peptides
Anti-Inflammatory Agents, Non-Steroidal
Antioxidants
Chelating Agents
Cholinesterase Inhibitors
Peptide Fragments
Phthalimides
Protein Aggregates
amyloid beta-protein (1-42)
Acetylcholinesterase
Butyrylcholinesterase