Design, synthesis and evaluation of chalcone Mannich base derivatives as multifunctional agents for the potential treatment of Alzheimer's disease

Xiaoyu Zhang; Qing Song; Zhongcheng Cao; Yan Li; Chaoquan Tian; Ziyi Yang; Heng Zhang; Yong Deng

doi:10.1016/j.bioorg.2019.03.043

Design, synthesis and evaluation of chalcone Mannich base derivatives as multifunctional agents for the potential treatment of Alzheimer's disease

Bioorg Chem. 2019 Jun:87:395-408. doi: 10.1016/j.bioorg.2019.03.043. Epub 2019 Mar 19.

Authors

Xiaoyu Zhang¹, Qing Song¹, Zhongcheng Cao¹, Yan Li¹, Chaoquan Tian¹, Ziyi Yang¹, Heng Zhang¹, Yong Deng²

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 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: [email protected].

PMID: 30921741
DOI: 10.1016/j.bioorg.2019.03.043

Abstract

A series of chalcone Mannich base derivatives were designed, synthesized and evaluated as multifunctional agents for the treatment of Alzheimer's disease based on the multi-target directed ligands design strategy. In vitro assays demonstrated that most of the derivatives exerted potent selective inhibitory potency on AChE with good multifunctional properties. Among them, representative compound 7c exhibited moderate inhibitory potency for EeAChE (IC₅₀ = 0.44 μM) and MAO-B inhibition (IC₅₀ = 1.21 μM), good inhibitory effect on self-induced Aβ_1-42 aggregation (55.0%, at 25 μM), biometal chelating property, moderate antioxidant activity with a value 1.93-fold of Trolox. Moreover, both kinetic analysis of AChE inhibition and molecular modeling study revealed that 7c showed a mixed-type inhibition, binding simultaneously to CAS and PAS of AChE. In addition, 7c also displayed high BBB permeability. These properties indicated 7c may be a promising multifunctional agent for the treatment of AD.

Keywords: Acetylcholinesterase inhibitors; Alzheimer’s disease; Antioxidant; Aβ aggregation inhibitors; Chalcone Mannich base derivatives; MAO-B inhibitors; Multifunctional agents.

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
Animals
Chalcones / chemical synthesis
Chalcones / chemistry
Chalcones / pharmacology*
Cholinesterase Inhibitors / chemical synthesis
Cholinesterase Inhibitors / chemistry
Cholinesterase Inhibitors / pharmacology*
Dose-Response Relationship, Drug
Drug Design
Eels
Humans
Kinetics
Mannich Bases / chemical synthesis
Mannich Bases / chemistry
Mannich Bases / pharmacology*
Models, Molecular
Molecular Structure
Monoamine Oxidase / metabolism
Monoamine Oxidase Inhibitors / chemical synthesis
Monoamine Oxidase Inhibitors / chemistry
Monoamine Oxidase Inhibitors / pharmacology*
Neuroprotective Agents / chemical synthesis
Neuroprotective Agents / chemistry
Neuroprotective Agents / pharmacology*
Peptide Fragments / antagonists & inhibitors
Protein Aggregates / drug effects
Structure-Activity Relationship

Substances

Amyloid beta-Peptides
Chalcones
Cholinesterase Inhibitors
Mannich Bases
Monoamine Oxidase Inhibitors
Neuroprotective Agents
Peptide Fragments
Protein Aggregates
amyloid beta-protein (1-42)
Monoamine Oxidase
Acetylcholinesterase