Design, synthesis and biological evaluation of dual acetylcholinesterase and phosphodiesterase 5A inhibitors in treatment for Alzheimer's disease

Li-Yun Zhou; Yao Zhu; Yu-Ren Jiang; Xiong-Jie Zhao; Dong Guo

doi:10.1016/j.bmcl.2017.07.013

Design, synthesis and biological evaluation of dual acetylcholinesterase and phosphodiesterase 5A inhibitors in treatment for Alzheimer's disease

Bioorg Med Chem Lett. 2017 Sep 1;27(17):4180-4184. doi: 10.1016/j.bmcl.2017.07.013. Epub 2017 Jul 4.

Authors

Li-Yun Zhou¹, Yao Zhu¹, Yu-Ren Jiang², Xiong-Jie Zhao¹, Dong Guo¹

Affiliations

¹ Department of Pharmaceutical Engineering, College of Chemistry and Chemical Engineering, Central South University, Changsha 410083, China.
² Department of Pharmaceutical Engineering, College of Chemistry and Chemical Engineering, Central South University, Changsha 410083, China. Electronic address: jiangyr@mail.csu.edu.cn.

PMID: 28751142
DOI: 10.1016/j.bmcl.2017.07.013

Abstract

With the recent research advances in molecular biology and technology, multiple credible hypotheses about the progress of Alzheimer's disease (AD) have been proposed; multi-target drugs have emerged as an innovative therapeutic approach for AD. Current clinical therapy for AD patients is mainly palliative treatment targeting acetylcholinesterase (AChE). Inhibition of phosphodiesterase 5A (PDE5A) has recently been validated as a potentially novel therapeutic approach for Alzheimer's disease (AD). In this work, series of new compounds were designed, synthesized and evaluated as dual cholinesterase and PDE5A inhibitor. Biological results revealed that some of these compounds display good biological activities against AChE with IC₅₀ values about 44.67-169.80nM (donepezil IC₅₀ 50.12nM). Notably, compound 12 presented potent activities against PDE5A with IC₅₀ values about 50μM (sildenafil IC₅₀ 12.59μM), and some of these compounds showed low cell toxicity to A549 cells in vitro.

Keywords: Acetylcholinesterase; Alzheimer’s disease; Biological; Inhibitor; Phosphodiesterase 5A.

Publication types

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

MeSH terms

Acetylcholinesterase / metabolism*
Alzheimer Disease / drug therapy*
Alzheimer Disease / metabolism
Cell Line, Tumor
Cell Survival / drug effects
Cholinesterase Inhibitors / chemical synthesis
Cholinesterase Inhibitors / chemistry
Cholinesterase Inhibitors / pharmacology*
Cyclic Nucleotide Phosphodiesterases, Type 5 / metabolism*
Dose-Response Relationship, Drug
Drug Design*
Humans
Molecular Structure
Phosphodiesterase Inhibitors / chemistry
Phosphodiesterase Inhibitors / pharmacology*
Structure-Activity Relationship

Substances

Cholinesterase Inhibitors
Phosphodiesterase Inhibitors
Acetylcholinesterase
Cyclic Nucleotide Phosphodiesterases, Type 5
PDE5A protein, human