Bioorganic & Medicinal Chemistry Letters
Design, synthesis and biological evaluation of benzylisoquinoline
derivatives as multifunctional agents against Alzheimer’s disease
⇑
Zi-Chen Xu, Xiao-Bing Wang, Wen-Ying Yu, Sai-Sai Xie, Su-Yi Li, Ling-Yi Kong
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
a r t i c l e i n f o
a b s t r a c t
Article history:
A
novel series of benzylisoquinoline derivatives were designed, synthesized, and evaluated as
Received 30 December 2013
Revised 1 March 2014
Accepted 18 March 2014
Available online 3 April 2014
multifunctional agents against Alzheimer’s disease (AD). The screening results showed that most of
the compounds significantly inhibited cholinesterases (ChEs), human cholinesterases (h-ChEs) and
self-induced b-amyloid (Ab) aggregation. In particular, compound 9k showed the strongest acetylcholin-
esterase (AChE) inhibitory activity, being 1000-fold and 3-fold more potent than its precursor benzyliso-
quinoline (10) and the positive control galanthamine, respectively. In addition, 9k was a moderately
Keywords:
Benzylisoquinoline derivatives
Alzheimer’s disease
Cholinesterase inhibitors
Human cholinesterase inhibitors
b-Amyloid aggregation
Low cell toxicity
potent inhibitor for h-ChEs. Compared with precursor benzylisoquinoline (36.0% at 20
lM), 9k (78.4%
at 20 M) could further inhibit Ab aggregation. Moreover, 9k showed low cell toxicity in human SH-
l
SY5Y neuroblastoma cells. Therefore, compound 9k might be a promising lead compound for AD
treatment.
Ó 2014 Elsevier Ltd. All rights reserved.
Alzheimer’s disease (AD), a progressive, neurodegeneration dis-
ease, is the most common cause of dementia among the elderly.1,2
Data of 2010 reported that approximately 36 million people world-
wide suffered from AD. By 2050, it is estimated that the figure is
going to rise beyond 100 million. AD was first defined by the Ger-
man psychiatrist and neuropathologist Alois Alzheimer in 1906.
Over 100 years, the etiology of AD remains elusive. Several factors
such as low levels of acetylcholine (ACh)3,4 and amyloid b-peptide
(Ab) deposits5 play significant roles in the pathophysiology of AD.6
Cholinergic hypothesis is one of the classical hypothesis of AD,
based on which, the decline in cognitive and mental functions
associated with AD is related to the weakened cortical cholinergic
neurotransmission.7 One rational way to enhance cholinergic neu-
rotransmission is to break down the process of metabolism of ACh.
ACh can be degraded by two types of cholinesterases (ChE), namely
acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE).8
Compared with BuChE, AChE attracts more attention from the
pharmaceutical academics since it accounts for nearly 80% ACh
hydrolysis in normal brains.9 The crystallographic structure of
AChE indicates that it includes two separate ligand binding sites,
a peripheral cationic site (PAS) at the entrance and a catalytic ac-
tive site (CAS) at the bottom.10–12 Inhibitors binding to either site
can restrain the activity of AChE. Besides its catalytic function,
AChE can further bind to Ab and act as a promoter of Ab fibril for-
mation. PAS was associated with this action and several ligands
that bind to this site have been shown to prevent Ab aggrega-
tion.13,14 Therefore, the design of dual-site inhibitors that interact
simultaneously with both CAS and PAS appears to be a promising
therapeutic strategy. Furthermore, in healthy brains, the ability
of BuChE to hydrolyze ACh is inferior to that of AChE. While as
AD progresses, the ability of BuChE significantly increases, and that
of AChE diminishes in the hippocampus and temporal cortex.14,15
Consequently, inhibition of both enzymes is beneficial to the treat-
ment of AD.
Recent studies indicate another hypothesis, called amyloid
hypothesis, may contribute to AD pathology. The amyloid hypoth-
esis states that the accumulation and aggregation of Ab is a pivotal
factor to induce AD, as its accumulation in the brain may result in
senile plaques, neurofibrillary tangles, neuronal cell death, and
ultimately dementia.16,17 Ab is formed from a larger amyloid pre-
cursor protein (APP) via sequential proteolytic cleavage by b- and
c
-secretases.18 The cleavage of APP by b-secretase generates a sol-
uble version of APP and a resultant membrane-bound C-terminal
domain. Subsequent intramembrane proteolysis of the C-terminal
domain by c
-secretase produces Ab40 and Ab42 peptides.19 Ab42 is
more prone to self-assembly into fibrils and is the major Ab com-
ponent in amyloid plaques.20 Therefore, preventing this peptide
from aggregation is a potential therapy for AD.
⇑
Up to now, several AChE inhibitors have been launched for
treating AD including tacrine, rivastigmine, donepezil, and
Corresponding author. Tel./fax: +86 25 8327 1405.
0960-894X/Ó 2014 Elsevier Ltd. All rights reserved.