Multifunctional tacrine-trolox hybrids for the treatment of Alzheimer's disease with cholinergic, antioxidant, neuroprotective and hepatoprotective properties

Sai-Sai Xie; Jin-Shuai Lan; Xiao-Bing Wang; Neng Jiang; Ge Dong; Zhong-Rui Li; Kelvin D G Wang; Ping-Ping Guo; Ling-Yi Kong

doi:10.1016/j.ejmech.2015.01.058

Multifunctional tacrine-trolox hybrids for the treatment of Alzheimer's disease with cholinergic, antioxidant, neuroprotective and hepatoprotective properties

Eur J Med Chem. 2015 Mar 26:93:42-50. doi: 10.1016/j.ejmech.2015.01.058. Epub 2015 Jan 28.

Authors

Sai-Sai Xie¹, Jin-Shuai Lan¹, Xiao-Bing Wang¹, Neng Jiang¹, Ge Dong¹, Zhong-Rui Li¹, Kelvin D G Wang¹, Ping-Ping Guo¹, Ling-Yi Kong²

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.

PMID: 25656088
DOI: 10.1016/j.ejmech.2015.01.058

Abstract

Combining tacrine with trolox in a single molecule, novel multifunctional hybrids have been designed and synthesized. All these hybrids showed ChE inhibitory activity in nanomolar range and strong antioxidant activity close to the parent compound trolox. Among them, compound 6d was the most potent inhibitor against AChE (IC50 value of 9.8 nM for eeAChE and 23.5 nM for hAChE), and it was also a strong inhibitor to BuChE (IC50 value of 22.2 nM for eqBuChE and 20.5 nM for hBuChE). Molecular modeling and kinetic studies suggested that 6d was a mixed-type inhibitor, binding simultaneously to CAS and PAS of AChE. In vivo hepatotoxicity assays indicated that 6d was much less toxic than tacrine. In addition, it showed neuroprotective effect and good ability to penetrate the BBB. Overall, all these results highlighted 6d a promising multifunctional agent for AD treatment.

Keywords: Alzheimer's disease; Antioxidant; Cholinesterase; Hepatotoxicity; Tacrine; Trolox.

Publication types

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

MeSH terms

Alzheimer Disease / drug therapy*
Alzheimer Disease / enzymology
Alzheimer Disease / metabolism
Animals
Antioxidants / adverse effects
Antioxidants / chemical synthesis*
Antioxidants / pharmacokinetics
Antioxidants / pharmacology
Biphenyl Compounds / chemistry
Blood-Brain Barrier / metabolism
Cell Survival / drug effects
Chemical and Drug Induced Liver Injury / prevention & control*
Cholinesterase Inhibitors / adverse effects
Cholinesterase Inhibitors / chemical synthesis*
Cholinesterase Inhibitors / pharmacokinetics
Cholinesterase Inhibitors / pharmacology
Chromans / adverse effects
Chromans / chemistry
Chromans / pharmacokinetics
Chromans / pharmacology*
Drug Design
In Vitro Techniques
Kinetics
Male
Molecular Docking Simulation
Molecular Structure
Neuroprotective Agents / adverse effects
Neuroprotective Agents / chemical synthesis*
Neuroprotective Agents / pharmacokinetics
Neuroprotective Agents / pharmacology
PC12 Cells
Picrates / chemistry
Rats
Swine
Tacrine / adverse effects
Tacrine / chemistry
Tacrine / pharmacokinetics
Tacrine / pharmacology*

Substances

Antioxidants
Biphenyl Compounds
Cholinesterase Inhibitors
Chromans
Neuroprotective Agents
Picrates
Tacrine
1,1-diphenyl-2-picrylhydrazyl
6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid