Nature-based molecules combined with rivastigmine: A symbiotic approach for the synthesis of new agents against Alzheimer's disease

Giulia Nesi; Qiuhe Chen; Simona Sestito; Maria Digiacomo; Xiaohong Yang; Shengnan Wang; Rongbiao Pi; Simona Rapposelli

doi:10.1016/j.ejmech.2017.10.006

Nature-based molecules combined with rivastigmine: A symbiotic approach for the synthesis of new agents against Alzheimer's disease

Eur J Med Chem. 2017 Dec 1:141:232-239. doi: 10.1016/j.ejmech.2017.10.006. Epub 2017 Oct 4.

Authors

Giulia Nesi¹, Qiuhe Chen², Simona Sestito¹, Maria Digiacomo¹, Xiaohong Yang³, Shengnan Wang³, Rongbiao Pi⁴, Simona Rapposelli⁵

Affiliations

¹ Department of Pharmacy, University of Pisa, Via Bonanno 6, Pisa 56126, Italy.
² Department of Pharmacology & Toxicology, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 5100060, China; International Joint Laboratory (SYSU-PolyU HK) of Novel Anti-dementia Drugs of Guangdong, Guangzhou 510006, China.
³ Department of Pharmacology & Toxicology, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 5100060, China.
⁴ Department of Pharmacology & Toxicology, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 5100060, China; International Joint Laboratory (SYSU-PolyU HK) of Novel Anti-dementia Drugs of Guangdong, Guangzhou 510006, China; Guangdong Province Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China. Electronic address: pirb@mail.sysu.edu.cn.
⁵ Department of Pharmacy, University of Pisa, Via Bonanno 6, Pisa 56126, Italy. Electronic address: simona.rapposelli@unipi.it.

PMID: 29031070
DOI: 10.1016/j.ejmech.2017.10.006

Abstract

Starting from nature as original source, new potential agents with pleiotropic activities have been synthesized and evaluated as neuroprotective agents. In this work, novel nature-based hybrids, combining antioxidant motifs with rivastigmine, have been designed and synthesized. The biological results revealed that the new compounds inhibit both AChE and BuChE. In particular, lipoic acid hybrids LA1, LA2, LA3 resulted to be the most potent inhibitors of BuChE showing IC₅₀ values ranging from 340 to 378 nM. Analogously, all the compounds were able to inhibit the self β-amyloid_1-42 aggregation. The gallic acid hybrid GA2 as well as the 2-chromonecarboxylic acid hybrids CA1 and CA2 prevented the self-mediated Aβ aggregation with percentages of inhibition ranging from 53% to 59%. Finally, some of them also show potent neuroprotective effects against glutamate-induced cell death and low toxicity in HT22 cells.

Keywords: Alzheimer's disease; Gallic acid; Lipoic acid; Multifunctional agents; Neuroprotective agents; Rivastigmine.

MeSH terms

Acetylcholinesterase / metabolism
Alzheimer Disease / drug therapy*
Amyloid beta-Peptides / antagonists & inhibitors
Amyloid beta-Peptides / metabolism
Biological Products / chemical synthesis
Biological Products / chemistry
Biological Products / pharmacology*
Butyrylcholinesterase / metabolism
Cell Death / drug effects
Cell Line, Tumor
Cell Survival / drug effects
Cholinesterase Inhibitors / chemical synthesis
Cholinesterase Inhibitors / chemistry
Cholinesterase Inhibitors / pharmacology*
Dose-Response Relationship, Drug
Free Radical Scavengers / metabolism
Glutamic Acid / pharmacology
Humans
Molecular Structure
Neuroprotective Agents / chemical synthesis
Neuroprotective Agents / chemistry
Neuroprotective Agents / pharmacology*
Peptide Fragments / antagonists & inhibitors
Peptide Fragments / metabolism
Protein Aggregates / drug effects
Rivastigmine / chemical synthesis
Rivastigmine / chemistry
Rivastigmine / pharmacology*
Structure-Activity Relationship

Substances

Amyloid beta-Peptides
Biological Products
Cholinesterase Inhibitors
Free Radical Scavengers
Neuroprotective Agents
Peptide Fragments
Protein Aggregates
amyloid beta-protein (1-42)
Glutamic Acid
Acetylcholinesterase
Butyrylcholinesterase
Rivastigmine