Discovery of potent glycogen synthase kinase 3/cholinesterase inhibitors with neuroprotection as potential therapeutic agent for Alzheimer's disease

Xueyang Jiang; Yang Wang; Chang Liu; Caiyi Xing; Yingming Wang; Weiping Lyu; Saisai Wang; Qihang Li; Tingkai Chen; Yao Chen; Feng Feng; Wenyuan Liu; Haopeng Sun

doi:10.1016/j.bmc.2020.115940

Discovery of potent glycogen synthase kinase 3/cholinesterase inhibitors with neuroprotection as potential therapeutic agent for Alzheimer's disease

Bioorg Med Chem. 2021 Jan 15:30:115940. doi: 10.1016/j.bmc.2020.115940. Epub 2020 Dec 11.

Authors

Xueyang Jiang¹, Yang Wang², Chang Liu³, Caiyi Xing⁴, Yingming Wang³, Weiping Lyu³, Saisai Wang⁵, Qihang Li⁶, Tingkai Chen⁷, Yao Chen⁸, Feng Feng⁹, Wenyuan Liu¹⁰, Haopeng Sun¹¹

Affiliations

¹ Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing 211198, China; School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China.
² Department of Pharmaceutical Analysis, Key Laboratory of Drug Quality Control and Pharmacovigilance, China Pharmaceutical University, Nanjing 211198, China; School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China.
³ Department of Pharmaceutical Analysis, Key Laboratory of Drug Quality Control and Pharmacovigilance, China Pharmaceutical University, Nanjing 211198, China.
⁴ School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China.
⁵ College of Life Science and Technology, China Pharmaceutical University, Nanjing 211198, China.
⁶ Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 211198, China.
⁷ Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing 211198, China.
⁸ School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China.
⁹ Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing 211198, China; Jiangsu Food and Pharmaceutical Science College, No.4 Meicheng Road, Huai'an 223003, China. Electronic address: fengfeng@cpu.edu.cn.
¹⁰ Department of Pharmaceutical Analysis, Key Laboratory of Drug Quality Control and Pharmacovigilance, China Pharmaceutical University, Nanjing 211198, China. Electronic address: liuwenyuan8506@163.com.
¹¹ Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 211198, China. Electronic address: sunhaopeng@163.com.

PMID: 33340937
DOI: 10.1016/j.bmc.2020.115940

Abstract

In the present work, a novel series of pyridinethiazole bearing benzylpiperidine hybrids were designed and synthesized as dual-target inhibitors of GSK-3β/AChE. Among them, GD29 was the most promising candidate, with an IC₅₀ value of 0.3 μM for hAChE and an IC₅₀ value of 0.003 μM for hGSK-3β, respectively. The compounds exhibited good drug-like properties with optimal inhibitory enzyme activities. Moreover, GD29 showed anti-inflammatory properties at micromolar concentrations and displayed interesting neuroprotective profiles in an in vitro model of oxidative stress-induced neuronal death. Notably, the compounds also exhibited good permeability across the blood-brain-barrier (BBB) both in vitro. Central cholinomimetic activity was confirmed using a scopolamine-induced cognition impairment model in Institute of Cancer Research (ICR) mice upon oral administration. The current work identified optimized compounds and explored the therapeutic potential of glycogen synthase kinase 3/cholinesterase inhibition for the treatment of AD.

Keywords: Cognition; GSK-3β/AChE inhibitor; Inflammation; Neuroprotection.

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 / chemistry
Cholinesterase Inhibitors / pharmacology*
Dose-Response Relationship, Drug
Drug Discovery
Glycogen Synthase Kinase 3 beta / antagonists & inhibitors
Glycogen Synthase Kinase 3 beta / metabolism
Humans
Molecular Structure
Neuroprotective Agents / chemical synthesis
Neuroprotective Agents / chemistry
Neuroprotective Agents / pharmacology*
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Pyridines / chemical synthesis
Pyridines / chemistry
Pyridines / pharmacology*
Structure-Activity Relationship
Thiazoles / chemical synthesis
Thiazoles / chemistry
Thiazoles / pharmacology*
Tumor Cells, Cultured

Substances

Cholinesterase Inhibitors
Neuroprotective Agents
Protein Kinase Inhibitors
Pyridines
Thiazoles
Glycogen Synthase Kinase 3 beta
Acetylcholinesterase
pyridine