Synthesis and evaluation of selegiline derivatives as monoamine oxidase inhibitor, antioxidant and metal chelator against Alzheimer's disease

Shishun Xie; Jie Chen; Xiruo Li; Tao Su; Yali Wang; Zhiren Wang; Ling Huang; Xingshu Li

doi:10.1016/j.bmc.2015.04.009

Synthesis and evaluation of selegiline derivatives as monoamine oxidase inhibitor, antioxidant and metal chelator against Alzheimer's disease

Bioorg Med Chem. 2015 Jul 1;23(13):3722-9. doi: 10.1016/j.bmc.2015.04.009. Epub 2015 Apr 10.

Authors

Shishun Xie¹, Jie Chen¹, Xiruo Li¹, Tao Su¹, Yali Wang¹, Zhiren Wang¹, Ling Huang², Xingshu Li³

Affiliations

¹ Institute of Drug Synthesis and Pharmaceutical Process, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
² Institute of Drug Synthesis and Pharmaceutical Process, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China. Electronic address: huangl72@mail.sysu.edu.cn.
³ Institute of Drug Synthesis and Pharmaceutical Process, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China. Electronic address: lixsh@mail.sysu.edu.cn.

PMID: 25934229
DOI: 10.1016/j.bmc.2015.04.009

Abstract

A series of compounds with monoamine oxidase inhibition and biometal chelation activities were designed, synthesised and evaluated as agents against Alzheimer's disease. The in vitro assay shows that most target compounds exhibit good MAO-B activities with submicromolar IC50 values and antioxidant activity (1.49-5.67 ORAC-FL values). The selected compounds were used to determine the biometal chelating ability using UV-vis spectrometry and high-resolution mass spectrometry, which confirm that they can effectively interact with copper(II), iron(II) and zinc(II). The ThT fluorescence binding assay indicates that the synthetic compounds can inhibit Cu(II)-induced Aβ1-42 aggregation. The parallel artificial membrane permeation assay shows that most target compounds can cross the BBB. Based on these results, compound 8a was selected as a potential multifunctional agent for the treatment of AD.

Keywords: Alzheimer’s disease; Metal chelator; Monoamine oxidase inhibitor.

Publication types

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

MeSH terms

Alzheimer Disease / drug therapy
Amyloid beta-Peptides / antagonists & inhibitors
Amyloid beta-Peptides / chemistry
Antioxidants / chemical synthesis*
Antioxidants / pharmacology
Cations, Divalent
Cell Membrane Permeability
Chelating Agents / chemical synthesis*
Chelating Agents / pharmacology
Copper / chemistry
Humans
Iron / chemistry
Membranes, Artificial
Molecular Docking Simulation
Monoamine Oxidase / chemistry*
Monoamine Oxidase Inhibitors / chemical synthesis*
Monoamine Oxidase Inhibitors / pharmacology
Peptide Fragments / antagonists & inhibitors
Peptide Fragments / chemistry
Protein Aggregates / drug effects
Reactive Oxygen Species / antagonists & inhibitors
Selegiline / chemical synthesis*
Selegiline / pharmacology
Solutions
Zinc / chemistry

Substances

Amyloid beta-Peptides
Antioxidants
Cations, Divalent
Chelating Agents
Membranes, Artificial
Monoamine Oxidase Inhibitors
Peptide Fragments
Protein Aggregates
Reactive Oxygen Species
Solutions
amyloid beta-protein (1-42)
Selegiline
Copper
Iron
Monoamine Oxidase
Zinc