Synthesis and pharmacological evaluation of novel chromone derivatives as balanced multifunctional agents against Alzheimer's disease

Fan Li; Jia-Jia Wu; Jin Wang; Xue-Lian Yang; Pei Cai; Qiao-Hong Liu; Ling-Yi Kong; Xiao-Bing Wang

doi:10.1016/j.bmc.2017.05.027

Synthesis and pharmacological evaluation of novel chromone derivatives as balanced multifunctional agents against Alzheimer's disease

Bioorg Med Chem. 2017 Jul 15;25(14):3815-3826. doi: 10.1016/j.bmc.2017.05.027. Epub 2017 May 17.

Authors

Fan Li¹, Jia-Jia Wu¹, Jin Wang¹, Xue-Lian Yang¹, Pei Cai¹, Qiao-Hong Liu¹, Ling-Yi Kong², Xiao-Bing Wang³

Affiliations

¹ State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, People's Republic of China.
² State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, People's Republic of China. Electronic address: cpu_lykong@126.com.
³ State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, People's Republic of China. Electronic address: xbwang@cpu.edu.cn.

PMID: 28549891
DOI: 10.1016/j.bmc.2017.05.027

Abstract

In a continuing effort to develop multitargeted compounds as potential treatment agents against Alzheimer's disease (AD), a series of chromone derivatives were designed, synthesized and evaluated. In vitro assay indicated that most of the target compounds have both MAOs inhibition activities, antioxidant activity and biometal chelating ability. Especially, compound s19 exhibits good inhibitory potency for inhibition of MAOs (IC₅₀ value of 5.12μM for hMAO-A and 0.816μM for hMAO-B), moderate inhibition of Aβ aggregation (75.1% at 20μM), metal chelation, control of ROS generation and antioxidant activity (ORAC=3.62). In addition, s19 could reduce PC12 cells death induced by oxidative stress and penetrate the blood-brain barrier (BBB). Taken together, these results suggested that s19 might be a promising multitargeted compound for AD treatment.

Keywords: Alzheimer’s disease; Chromone; Metal chelator; Monoamine oxidase; The blood–brain barrier.

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
Animals
Antioxidants / metabolism
Apoptosis / drug effects
Binding Sites
Blood-Brain Barrier / drug effects
Blood-Brain Barrier / metabolism
Chromones / chemistry*
Chromones / pharmacology
Chromones / therapeutic use
Copper / chemistry
Copper / metabolism
Humans
Hydrogen Peroxide / toxicity
Inhibitory Concentration 50
Molecular Docking Simulation
Monoamine Oxidase / chemistry
Monoamine Oxidase / metabolism*
Monoamine Oxidase Inhibitors / chemical synthesis*
Monoamine Oxidase Inhibitors / pharmacology
Monoamine Oxidase Inhibitors / therapeutic use
Neuroprotective Agents / chemical synthesis
Neuroprotective Agents / pharmacology
Neuroprotective Agents / therapeutic use
Oxidative Stress / drug effects
PC12 Cells
Protein Structure, Tertiary
Rats
Reactive Oxygen Species / metabolism
Structure-Activity Relationship

Substances

Amyloid beta-Peptides
Antioxidants
Chromones
Monoamine Oxidase Inhibitors
Neuroprotective Agents
Reactive Oxygen Species
Copper
Hydrogen Peroxide
Monoamine Oxidase