Multitarget drug design strategy against Alzheimer's disease: Homoisoflavonoid Mannich base derivatives serve as acetylcholinesterase and monoamine oxidase B dual inhibitors with multifunctional properties

Yan Li; Xiaoming Qiang; Li Luo; Xia Yang; Ganyuan Xiao; Yunxiaozhu Zheng; Zhongcheng Cao; Zhipei Sang; Fu Su; Yong Deng

doi:10.1016/j.bmc.2016.11.048

Multitarget drug design strategy against Alzheimer's disease: Homoisoflavonoid Mannich base derivatives serve as acetylcholinesterase and monoamine oxidase B dual inhibitors with multifunctional properties

Bioorg Med Chem. 2017 Jan 15;25(2):714-726. doi: 10.1016/j.bmc.2016.11.048. Epub 2016 Nov 28.

Authors

Yan Li¹, Xiaoming Qiang¹, Li Luo¹, Xia Yang¹, Ganyuan Xiao¹, Yunxiaozhu Zheng¹, Zhongcheng Cao¹, Zhipei Sang², Fu Su³, Yong Deng⁴

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 College of Chemistry and Pharmaceutical Engineering, Nanyang Normal University, Nanyang 473061, 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: sufu@scu.edu.cn.
⁴ 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: 27923535
DOI: 10.1016/j.bmc.2016.11.048

Abstract

A series of homoisoflavonoid Mannich base derivatives were designed, synthesized and evaluated as multifunctional agents against Alzheimer's disease. It demonstrated that most of the derivatives were selective AChE and MAO-B dual inhibitors with good multifunctional properties. Among them, compound 10d displayed the comprehensive advantages, with excellent AChE and MAO-B inhibitory activities (IC₅₀=2.49±0.08nM and 1.74±0.0581μM, respectively), good self- and Cu²⁺-induced Aβ_1-42 aggregation inhibitory potency, antioxidant activity, biometal chelating ability and high BBB permeability. These multifunctional properties make 10d as an excellent candidate for the development of efficient drugs against AD.

Keywords: Acetylcholinesterase inhibitors; Alzheimer’s disease; Homoisoflavonoid; Mannich base derivatives; Monoamine oxidase B inhibitors; Multifunctional properties.

Publication types

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

MeSH terms

Acetylcholinesterase / metabolism
Alzheimer Disease / drug therapy*
Alzheimer Disease / metabolism
Cholinesterase Inhibitors / chemical synthesis
Cholinesterase Inhibitors / pharmacology*
Dose-Response Relationship, Drug
Drug Design*
Humans
Isoflavones / chemical synthesis
Isoflavones / chemistry
Isoflavones / pharmacology*
Mannich Bases / chemical synthesis
Mannich Bases / pharmacology
Molecular Docking Simulation
Molecular Structure
Monoamine Oxidase / metabolism
Monoamine Oxidase Inhibitors / chemical synthesis
Monoamine Oxidase Inhibitors / pharmacology*
Structure-Activity Relationship

Substances

Cholinesterase Inhibitors
Isoflavones
Mannich Bases
Monoamine Oxidase Inhibitors
Monoamine Oxidase
Acetylcholinesterase