Design, synthesis and evaluation of flavonoid derivatives as potential multifunctional acetylcholinesterase inhibitors against Alzheimer's disease

Article abstract of DOI:10.1016/j.bmcl.2013.02.095

A new series of flavonoid derivatives were designed, synthesized and evaluated as potential multifunctional AChE inhibitors against Alzheimer's disease. Most of them exhibited potent AChE inhibitory activity, high selectivity for AChE over BuChE, and mode

Full text of DOI:10.1016/j.bmcl.2013.02.095

Bioorganic & Medicinal Chemistry Letters 23 (2013) 2636–2641
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Design, synthesis and evaluation of flavonoid derivatives as potential
multifunctional acetylcholinesterase inhibitors against Alzheimer’s
disease
⇑
Ren-Shi Li, Xiao-Bing Wang, Xiao-Jun Hu, 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 new series of flavonoid derivatives were designed, synthesized and evaluated as potential multifunc-
tional AChE inhibitors against Alzheimer’s disease. Most of them exhibited potent AChE inhibitory activ-
ity, high selectivity for AChE over BuChE, and moderate to good inhibitory potency toward Ab
aggregation. Specifically, compound 12c was the strongest AChE inhibitor, being 20-fold more potent
than galanthamine and twofold more potent than tacrine, and it also had ability to inhibit Ab aggregation
(close to the reference compound) and to function as a metal chelator. Molecular modeling and enzyme
kinetic study revealed that it targeted both the catalytic active site and the peripheral anionic site of
AChE. Consequently, this class of compounds deserved to be thoroughly and systematically studied for
the treatment of Alzheimer’s disease.
Received 21 December 2012
Revised 9 February 2013
Accepted 21 February 2013
Available online 1 March 2013
Keywords:
Flavonoid derivatives
Acetylcholinesterase inhibitors
Anti-b-amyloid aggregation
Biometal-chelating agents
Molecular modeling
Ó 2013 Elsevier Ltd. All rights reserved.
Alzheimer’s disease (AD), characterized by memory loss, lan-
guage impairment, personality changes and decline in intellectual
ability, is a highly complex and progressive neurodegenerative dis-
order in the elderly population.1 Many factors are considered as
the key pathological hallmarks of AD, such as cholinergic system
dysfunction, accelerated aggregation of b-amyloid (Ab) peptides
and the dyshomeostasis of biometals.2–6 These factors provide a
basis for the cholinergic, amyloid and biometal hypotheses for
AD pathology, respectively.
According to the cholinergic hypothesis, the cognitive and
memory symptoms of AD are caused by the drastic decline of ace-
tylcholine,7 and recent reports suggest that increasing acetylcho-
linesterase (AChE) inhibition and simultaneously improving
selectivity for AChE over butyrylcholinesterase (BuChE) would be
a promising direction for AD treatment.8 Furthermore, the crystal-
lographic structure of AChE reveals that it contains two separate li-
gand binding sites—a catalytic active site (CAS) at the bottom of
deep narrow gorge and a peripheral cationic site (PAS) at the en-
trance.9,10 Hence, the simultaneous binding to both the CAS and
PAS has been advocated to design potent and selective AChE
inhibitors.11,12
The amyloid cascade hypothesis attributes the pathogenesis of
AD to the accelerated aggregation of Ab in the brain resulting in
the formation of senile plaques and then to neurofibrillary tangles,
neuronal cell death, and ultimately dementia.13,14 Ab40 and Ab42
are the most common peptides found in amyloid plaques. Though
the amount of secreted Ab42 is only 10% of Ab40, Ab42 is more
prone to aggregation and more neurotoxic compared with
Ab40.15,16 Therefore, preventing this peptide from aggregation is
a potential therapy for AD.
It has been reported that biometals also play a very important
role in many critical aspects of AD.17 The gradual accumulation
of Cu(II) and Fe(II) in the neuropil and plaques of the brain linked
to the production of reactive oxygen species and oxidative stress
contributes to AD pathology.18 Direct evidences show that metal
ion levels in AD individuals are three to sevenfolds higher than
those in healthy people.19 Thus, the modulation of these biometals
in the brain is also a potential therapeutic strategy for AD patients.
Up to now, most of therapies for AD focus on increasing cholin-
ergic neurotransmission by acetylcholinesterase inhibitors
(AChEIs), including tacrine, donepezil, rivastigmine and galanta-
mine.20 These drugs can only improve symptoms for most patients
but do not address the etiology of AD. Therefore, searching for
Abbreviations: AD, Alzheimer’s disease; Ab, b-amyloid; AChE, acetylcholinester-
ase; BuChE, butyrylcholinesterase; CAS, catalytic anionic site; PAS, peripheral
anionic site; AChEI, acetylcholinesterase inhibitor; ChEs, cholinesterases; MOE,
Molecular Operating Environment; SI, selectivity index; MD, molecular dynamic.
⇑
Corresponding author. Tel./fax: +86 25 8327 1405.
E-mail address: cpu_lykong@126.com (L.-Y. Kong).
0960-894X/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2013.02.095

R.-S. Li et al. / Bioorg. Med. Chem. Lett. 23 (2013) 2636–2641
2637
more efficient strategies to combat this disease is highly needed.21
Due to the complex multifactorial nature of AD, molecules that
modulate the activity of a single protein target are incapable of sig-
nificantly altering the progression of the disease. In contrast, mul-
tifunctional molecules with two or more complementary biological
activities might represent an important advance in the treatment
of AD. Accordingly, we are devoted to the study of multifunctional
AChEIs that not just inhibit AChE, but decrease Ab42 aggregation
and chelate metals.
dride and boron fluoride ethyl ether (BF3ÁEt2O) as Lewis acid, which
led to a high yield of 1-(2,4-dihydroxy-3-methylphenyl)ethanone
2.28 Then, compound 2 was condensed with benzoyl chloride to
produce b-diketone 3 through our modified Baker–Venkataraman
transformation method by using K2CO3 in acetone.29 The obtained
b-diketone 3 was treated with NaOAc/HOAc to obtain 8-methyl-4-
oxo-2-phenyl-4H-chromen-7-yl benzoate 4. After removing the
benzoyl group of 4, flavonoid scaffold 5 was acquired in 93% yield.
The alkylation of 5 with different a,x-dibromoalkanes in DMF pro-
Flavonoids, ubiquitously presented in fruits and vegetables, are
well-known natural compounds, and have attracted increasingly
widespread attention in present-day society as they possess a wide
range of pharmacological properties related to a variety of neuro-
logical disorders, like neuro-protective effect,22 AChE inhibitory
activity,23 Ab fibril formation inhibitory activity,24 free radical
scavenging effect,25 and metal-chelating ability.26 Thus, the design
and synthesis of new effective flavonoid derivatives are an inter-
esting strategy for the research on anti-AD drugs. According to
the structure of AChE, in order to design dual binding site AChEIs,
we decided to connect flavonoid scaffold with terminal amine
groups through carbon spacers of different lengths. The terminal
amine groups, protonated at physiological pH, could occupy the
vided 6a–6e in 68–80% yields. Finally, the target products 7a–15d
were gained by the reaction of 6a–6e with commercially available
secondary amines (e.g., pyrrolidine and diethylamine) in 66–85%
yields. The purities of all final compounds were confirmed to be
higher than 95% by HPLC (shown in Supplementary data).
To determine the potential anti-AD effects of compounds 7a–
15d, the inhibition of AChE (from electric eel) and BuChE (from
equine serum) were tested using the method of Ellman et al. with
galanthamine and tacrine as reference compounds.30,31 The IC50
values for ChEs inhibition and selectivity index (SI) for the inhibi-
tion of AChE over BuChE were summarized in Table 1. These results
indicated that all of the compounds gave higher inhibitory activi-
ties against AChE than the precursor compound 5 (IC50 value:
CAS via cation–
p
interaction, while flavonoid scaffold could inter-
87.05
was linked to flavonoid scaffold by a four-carbon spacer, was the
most potent inhibitor with an IC50 value of 0.13 M, being 20-fold
more potent than galanthamine (IC50 value: 2.67 M) and twofold
more potent than tacrine (IC50 value: 0.269 M). Hence, the intro-
lM). Specifically, compound 12c, whose diethylamine group
act with the PAS of AChE via aromatic stacking interactions. Flexi-
ble carbon spacer was lodged in the narrow mid-gorge,27 and the
length of carbon spacer was changed aiming to obtain optional
conformation that could make the designed compounds interact
with both the CAS and PAS of AChE.
l
l
l
duction of the aminoalkyl-substituted groups could significantly
Here, a series of flavonoid derivatives with different basic side-
chains (n = 2–6) were designed, synthesized and evaluated for their
cholinesterases (ChEs) inhibition, anti-Ab42 aggregation and me-
tal-chelating ability. The structure–activity relationships were dis-
cussed based on the pharmacological activities.
The synthetic pathways of the flavonoid derivatives were out-
lined in Scheme 1. At the first stage, 2-methylbenzene-1,3-diol 1
was acetylated by a Friedel–Crafts type reaction with acetic anhy-
increase the inhibitory activities of derivatives.
Changing the length of the alkyl chain could affect their ability
to contact both sites of AChE and thereby influence the AChE inhib-
itory potency. Based on the screening data (Fig. 1), compounds
7a–7e, combining pyrrolidine group with flavonoid scaffold by a
two- to six-carbon spacer, exhibited different levels of inhibitory
activities against AChE (7a, n = 2, IC50 value: 2.04
l
M; 7b, n = 3,
0.952
lM; 7c, n = 4, 0.238
lM; 7d, n = 5, 0.243 lM; 7e, n = 6,
HO
OH
HO
OH
O
I
O
OH
II
O
O
O
3
1
2
O
O
IV
VI
HO
O
O
III
O
O
4
5
Br
O
n
O
O
R
V
O
n
O
O
6a-6e, n 2~6
7a-15d
=
Scheme 1. Reagents and conditions: (I) Ac2O (1.1 equiv), BF3ÁEt2O (2.4 equiv), 80 °C, 6 h, 95%; (II) benzoyl chloride, K2CO3, acetone, reflux; (III) NaOAc/HOAc, reflux; (IV)
K2CO3, MeOH/CH2Cl2, rt; (V) Br(CH2)nBr, K2CO3, DMF; (VI) NHR, K2CO3, DMF, KI. (‘R-‘ were showed in Table 1)

2638
R.-S. Li et al. / Bioorg. Med. Chem. Lett. 23 (2013) 2636–2641
Table 1
Inhibition of AChE, BuChE and self-induced Ab42 aggregation activities of the synthesized compounds
Compound
R
n
IC50a
(
lM)
Selectivity Indexc
Ab42 aggregation inhibitiond (%)
AChE
BuChE
5
87.05
>100
n.a.b
7a
7b
7c
7d
7e
2
3
4
5
6
2.04 0.21
2.71 0.36
2.78 0.41
5.70 0.63
1.91 0.12
3.28 0.39
1.3
2.9
23.8
7.8
42.03 0.95
27.12 3.56
21.83 2.78
39.29 1.21
38.12 1.14
N
0.952 0.024
0.238 0.006
0.243 0.011
0.764 0.014
4.3
8a
8b
2
3
2.10 0.17
0.590 0.022
>100
5.84 0.54
>47.5
9.9
30.54 2.35
41.67 1.01
8c
8d
8e
N
N
4
5
6
0.225 0.017
0.216 0.008
1.89 012
>100
2.77 0.22
3.74 0.27
>442.9
12.8
2.0
37.32 1.18
36.74 1.28
43.23 1.12
9a
9b
9c
9d
9e
2
3
4
5
6
1.83 0.18
2.94 0.25
0.607 0.031
0.604 0.034
3.15 0.31
3.21 0.19
4.12 0.31
>100
4.85 0.53
3.93 0.42
1.7
1.4
>164.7
8.0
26.89 3.76
21.35 4.56
22.08 3.96
37.38 1.58
39.04 1.36
1.2
OH
N
10c
10d
4
5
0.234 0.005
0.329 0.009
>100
1.41 0.11
>427.2
4.3
37.48 1.24
41.67 1.06
11c
11d
4
5
1.66 0.26
1.87 0.51
5.75 0.38
4.87 0.61
3.5
2.6
31.14 2.02
39.94 1.17
N
N
N
N
N
O
12c
12d
4
5
0.130 0.002
0.264 0.004
4.82 0.32
>100
37.1
>377.7
38.95 1.57
40.87 1.09
13c
13d
4
5
0.328 0.008
0.210 0.003
>100
2.54 0.20
>304.7
12.1
34.29 2.16
37.86 1.73
14c
14d
4
5
2.88 0.37
8.63 0.84
>100
>100
>34.7
>4.8
20.42 6.56
24.59 4.56
O
15c
15d
4
5
25.3 1.7
19.6 1.1
3.82 0.39
3.93 0.35
0.2
0.2
n.a.b
n.a.b
O
N
Tacrine
Galantamine
Curcumin
0.269 0.023
2.67 0.15
n.a.b
0.054 0.001
12.7 0.2
n.a.b
0.2
4.8
n.a.b
n.a.b
50.12 0.88
a
b
c
IC50: 50% inhibitory concentration (means SEM of three experiments).
Not available.
Selectivity Index = IC50 (BuChE)/IC50 (AChE).
d
Inhibition of self-mediated Ab42 aggregation, the measurements were carried out in the presence of 20 lM compounds (means SEM of three experiments).
Figure 1. Effects of alkyl chain lengths on anti-AChE activities.
0.764
l
M). The compounds with a four- or five-carbon spacer (7c
determined experimentally for inhibiting AChE were the four-
and five-carbon spacers.
With the optimal length of the linker in hand, we introduced
different terminal amine groups to flavonoid scaffold to further
and 7d) displayed higher inhibitory potency. The same trend was
observed for compounds linked with 2-methylpiperidine (8a–8e)
and piperidin-4-ol (9a–9e). Clearly, the optimal chain lengths

R.-S. Li et al. / Bioorg. Med. Chem. Lett. 23 (2013) 2636–2641
2639
Figure 2. Molecular modeling of compound 12c with AChE (A and C) and BuChE (B and D) generated with MOE.
explore structure–activity relationship. Obviously, flavonoid
derivatives with cyclic monoamine groups (pyrrolidine, 2-meth-
ylpiperidine and piperidine) in the optimal side chains showed
high inhibitory activity against AChE similar to those with chain
monoamine groups (diethylamine and dimethylamine), indicat-
ing that both the open-loop and closed-loop groups had the abil-
ity to occupy the CAS of AChE. On the other hand, compounds
9c, 9d, 11c, 11d and 14c–15d, possessing additional nitrogen
or oxygen atom in the terminal group, exhibited much weaker
AChE inhibitory potency than the compounds containing only
one nitrogen atom (e.g., 10c and 10d). These results suggested
electron-withdrawing effects of nitrogen or oxygen atom might
reduce the electronic density of the terminal amine, thereby
impacting on protonation at physiological pH, which could
Operating Environment (MOE) software package. The X-ray crys-
tallographic structures of AChE (PDB code: 1EVE) and BuChE
(PDB code: 1P0I) were obtained from protein data bank. 3D struc-
ture of the strongest AChE inhibitor 12c was built using the builder
interface of MOE program, and docked into the active site of the
protein after energy minimized. The Dock scoring in MOE software
was done using ASE scoring function. Finally, the geometries of
resulting complex were displayed in Figure 2. Compound 12c man-
ifested multiple binding modes (Fig. 2, A and C) with AChE. The fla-
vonoid moiety adopted an appropriate orientation for its binding
to PAS via the p–p stacking interactions with Trp279 and Tyr334,
and their ring-to-ring distance was between 4.12 and 4.16 Å.
Moreover, the conformation of the side chain conformed to the
shape of the mid-gorge, and in the bottom of the gorge, the charged
nitrogen of diethylamine group was observed to bind to the CAS
diminish the cation–p interaction between the terminal nitrogen
and the CAS of AChE. Besides, the length of the alkyl chain could
affect the selectivity for AChE. The compounds with a four-car-
bon spacer showed higher selectivity than the compounds with
via a cation–
(5.01 Å). In contrast, the binding only involved
p
interaction between Trp84 (5.03 Å) and Phe330
cation–
a
p
interaction between Trp82 (4.03 Å) and the nitrogen of diethyl-
amine with BuChE, and no other obvious interactions were
observed (Fig. 2, B and D). These results might explain why com-
pound 12c had strong AChE inhibitory activity and high selectivity
for AChE over BuChE.
a
five-carbon length (e.g., 7c, SI: 23.8 > 7d, SI: 7.8; 8c, SI:
442.9 > 8d, SI: 12.8).
To further investigate the interaction modes and selectivity to
two ChEs, molecular modeling was carried out by Molecular

2640
R.-S. Li et al. / Bioorg. Med. Chem. Lett. 23 (2013) 2636–2641
Figure 3. Lineweavere–Burk plot for the inhibition of AChE by compound 12c.
Figure 4. UV–vis (200–400 nm) absorption spectra of 12c (35
lM) in methanol after addition of ascending amounts of CuCl2 (1–50 lM) (a) and differential spectra due to
12c–Cu2+ complex formation obtained by numerical subtraction from the above spectra of those of CuCl2 and 12c at the corresponding concentrations (b).
After molecular docking, molecular dynamic (MD) simulations
were performed using MOE software to evaluate the stability of
12c-AChE complex.32,33 The root-mean-square deviation (RMSD)
was observed and remained at about 1.055 Å, very stable and much
lower, in the end of the MD. The results showed the complex was
stable during the MD simulation.
Kinetics of compound 12c was further examined to determine
the nature of AChE inhibition by graphical analysis of steady-state
inhibition data.34 As shown in Figure 3, the Lineweavere–Burk
plots showed both increasing slopes and increasing intercepts on
the y-axis at higher inhibitor concentration, which revealed a
mixed-type inhibition. Hence, the enzyme kinetic study also sug-
gested that the inhibitor 12c bound to both sites of AChE, consis-
tent with the results of molecular modeling studies.
ate to good potencies (20.42–43.23% at 20 lM). Interestingly, the
anti-Ab aggregation activity seemed to depend on the length of
the side chain. The compounds with a five-carbon spacer (e.g.,
12d, 40.87%) showed better anti-Ab aggregation activity than the
compounds with a four-carbon length (e.g., 12c, 38.95%). However,
the current data were inadequate to derive a structure–activity
relationship for predicting the activity toward anti-Ab aggregation,
and further research was required.
In addition, compound 12c was also taken as an example to test
for its metal-chelating effect using difference UV–vis spectra re-
corded in methanol at 298 K with wavelength ranging from 200
to 400 nm.4,19 The absorption of 12c (35
l
M) decreased along with
the increasing concentration of Cu2+ from 1 to 50
l
M in Figure 4a.
And the increase in absorbance, better estimated by an inspection
of differential spectra in Figure 4b, implied that there was an inter-
action between copper ion and 12c. The result using Fe2+ was sim-
Subsequently, we evaluated these compounds for their poten-
tial to inhibit the self-induced Ab42 aggregation using thioflavin
T assay (Table 1).35 Compared with the reference compound curcu-
ilar to that using Cu2+
.
These observations indicated that
min (50.12% at 20 lM), these flavonoid derivatives showed moder-
compound 12c could chelate Cu2+ and Fe2+. Therefore, from these

R.-S. Li et al. / Bioorg. Med. Chem. Lett. 23 (2013) 2636–2641
2641
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AD by a chelation mechanism.
In conclusion, a new series of flavonoid derivatives were de-
signed, synthesized and subjected to biological evaluation. Most
of these compounds were potent inhibitors of AChE, with IC50 val-
ues ranging from micromolar to submicromolar, and showed mod-
erate to good potencies toward inhibition of self-mediated Ab42
aggregation. Among them, compound 12c, which contained a
diethylamine group linked to flavonoid scaffold by a four-carbon
spacer, exhibited the most potent AChE inhibitory activity, high
selectivity for AChE over BuChE, anti-Ab42 aggregation, as well
as biometal-chelating effect. The molecular modeling study and
inhibition kinetic analysis indicated that compound 12c bound to
both the CAS and PAS of AChE. Overall, compound 12c had strong
potential to serve as a multifunctional AChEI for the treatment of
AD and this type of multifunctional flavonoid compounds might
provide a useful template for the development of new anti-AD
agents with multiple potencies.
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Acknowledgements
We acknowledge the financial supports from the Program for
Changjiang Scholars and Innovative Research Team in University
(PCSIRT-IRT1193), the Project Founded by the Priority Academic
Program Development of Jiangsu Higher Education Institutions
(PAPD), the Cultivation Fund of the Key Scientific and Technical
Innovation Project, Ministry of Education of China (No. 707033).
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095. These data include MOL files and InChiKeys of the most
important compounds described in this article.
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