Synthesis and evaluation of 1,2,3,4-tetrahydro-1-acridone analogues as potential dual inhibitors for amyloid-beta and tau aggregation

Peng Lv; Chun-Li Xia; Ning Wang; Zhen-Quan Liu; Zhi-Shu Huang; Shi-Liang Huang

doi:10.1016/j.bmc.2018.08.007

Synthesis and evaluation of 1,2,3,4-tetrahydro-1-acridone analogues as potential dual inhibitors for amyloid-beta and tau aggregation

Bioorg Med Chem. 2018 Sep 1;26(16):4693-4705. doi: 10.1016/j.bmc.2018.08.007. Epub 2018 Aug 4.

Authors

Peng Lv¹, Chun-Li Xia², Ning Wang¹, Zhen-Quan Liu¹, Zhi-Shu Huang¹, Shi-Liang Huang³

Affiliations

¹ School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, People's Republic of China.
² School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, People's Republic of China; Department of Bioengineering, Zhuhai Campus of Zunyi Medical University, Zhuhai 519041, People's Republic of China.
³ School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, People's Republic of China. Electronic address: lsshsl@mail.sysu.edu.cn.

PMID: 30107970
DOI: 10.1016/j.bmc.2018.08.007

Abstract

Amyloid-β (Aβ) and tau protein are two crucial hallmarks in Alzheimer's disease (AD). Their aggregation forms are thought to be toxic to the neurons in the brain. A series of new 1,2,3,4-tetrahydro-1-acridone analogues were designed, synthesized, and evaluated as potential dual inhibitors for Aβ and tau aggregation. In vitro studies showed that compounds 25-30 (20 μM) with N-methylation of the quinolone ring effectively inhibited Aβ_1-42 aggregation by 84.7%-99.5% and tau aggregation by 71.2%-101.8%. Their structure-activity relationships are discussed. In particular, 30 could permeate the blood-brain barrier, bind to Aβ_1-42 and tau, inhibit Aβ_1-42 β-sheets formation, and prevent tau aggregation in living cells.

Keywords: 1,2,3,4-Tetrahydro-1-acridone analogues; Aggregation inhibitors; Alzheimer’s disease; Amyloid β; Tau protein.

Publication types

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

MeSH terms

Acridones / chemistry*
Acridones / metabolism
Acridones / pharmacology
Amyloid beta-Peptides / antagonists & inhibitors
Amyloid beta-Peptides / metabolism*
Animals
Blood-Brain Barrier / metabolism
Central Nervous System Agents / chemical synthesis*
Central Nervous System Agents / metabolism
Central Nervous System Agents / pharmacology
Drug Design
HEK293 Cells
Humans
Microscopy, Confocal
Microscopy, Electron, Transmission
Peptide Fragments / antagonists & inhibitors
Peptide Fragments / metabolism*
Protein Aggregates / drug effects
Structure-Activity Relationship
Surface Plasmon Resonance
Swine
Tacrine / chemistry
tau Proteins / antagonists & inhibitors
tau Proteins / metabolism*

Substances

Acridones
Amyloid beta-Peptides
Central Nervous System Agents
Peptide Fragments
Protein Aggregates
amyloid beta-protein (1-42)
tau Proteins
Tacrine