Design, synthesis and evaluation of novel ferulic acid-memoquin hybrids as potential multifunctional agents for the treatment of Alzheimer's disease

Article abstract of DOI:10.1016/j.bmcl.2016.03.086

A novel series of ferulic acid-memoquin hybrids were designed, synthesized and evaluated as multifunctional agents for the treatment of Alzheimer's disease (AD). The in vitro studies showed that most of the compounds exhibited a significant ability to inhibit acetylcholinesterase (AChE) (IC₅₀ of 3.2-34.7 μM) and self-induced β-amyloid (Aβ_1-42) aggregation (30.8-39.1%, 25 μM), to act as potential antioxidants (ORAC-FL value of 0.9-1.3). In particular, compound 17d had the greatest ability to inhibit AChE (IC₅₀ = 3.2 μM), and Aβ_1-42 aggregation (30.8%) was also an excellent antioxidant and neuroprotectant. Moreover, it is capable of disaggregating self-induced Aβ aggregation. Furthermore, 17d could cross the blood-brain barrier (BBB) in vitro. The results showed that compound 17d is a potential multifunctional agent for the treatment of AD.

Full text of DOI:10.1016/j.bmcl.2016.03.086

Accepted Manuscript
Design, synthesis and evaluation of novel ferulic acid-memoquin hybrids as
potential multifunctional agents for the treatment of Alzheimer’s disease
Wanli Pan, Ke Hu, Ping Bai, Lintao Yu, Qinge Ma, Tao Li, Xu Zhang,
Changzhong Chen, Kelin Peng, Wenmin Liu, Zhipei Sang
PII:
S0960-894X(16)30318-3
DOI:
http://dx.doi.org/10.1016/j.bmcl.2016.03.086
BMCL 23729
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
7 November 2015
4 March 2016
25 March 2016
Please cite this article as: Pan, W., Hu, K., Bai, P., Yu, L., Ma, Q., Li, T., Zhang, X., Chen, C., Peng, K., Liu, W.,
Sang, Z., Design, synthesis and evaluation of novel ferulic acid-memoquin hybrids as potential multifunctional
agents for the treatment of Alzheimer’s disease, Bioorganic & Medicinal Chemistry Letters (2016), doi: http://
dx.doi.org/10.1016/j.bmcl.2016.03.086
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Design, synthesis and evaluation of novel ferulic acid-memoquin hybrids as
potential multifunctional agents for the treatment of Alzheimer’s disease
Wanli Pana, Ke Hub, Ping Baic, Lintao Yua, Qinge Maa, Tao Lia, Xu Zhanga,
Changzhong Chena, Kelin Penga , Wenmin Liua, *, Zhipei Sanga, *
a College of Chemistry and Pharmaceutical Engineering, Nanyang Normal
University, Nanyang, 473061, China
b Nanyang City Center Hospital, Nanyang, 473061, China
c West China Hospital, Sichuan University, Chengdu, 610041, China
*Corresponding authors.
E-mail: sangzhipei@163.com (Z. Sang), liuwm1969@163.com (W. Liu).
Abstract: A novel series of ferulic acid-memoquin hybrids were designed,
synthesized and evaluated as multifunctional agents for the treatment of Alzheimer’s
disease (AD). The in vitro studies showed that most of the compounds exhibited a
significant ability to inhibit acetylcholinesterase (AChE) (IC50 of 3.2-34.7 μM) and
self-induced β–amyloid (Aβ1-42) aggregation (30.8-39.1%, 25 μM), to act as potential
antioxidants (ORAC-FL value of 0.9-1.3). In particular, compound 17d had the
greatest ability to inhibit AChE (IC50 = 3.2 μM), and Aβ1-42 aggregation (30.8%) was
also an excellent antioxidant and neuroprotectant. Moreover, it is capable of
disaggregating self-induced Aβ aggregation. Furthermore, 17d could cross the
blood-brain barrier (BBB) in vitro. The results showed that compound 17d is a
potential multifunctional agent for the treatment of AD.
Keywords: Alzheimer’s disease; Hybrids; AChE inhibitor; antioxidant; Aβ
aggregation inhibitor; neuroprotectant.
Abbreviations: AD, Alzheimer’s disease; AChE, acetylcholinesterase; BuChE,
butyrylcholinesterase; Aβ, β-amyloid peptide; BBB, blood-brain barrier; ACh,
acetylcholine; MTDL, multitarget-directed ligand; EeAChE, electric eel AChE; CAS,
catalytic anionic site; PAS, peripheral anionic site; ORAC-FL, Oxygen Radicals
Absorbance Capacity by Fluorescence; ThT, thioflavin T; PAMPA-BBB, parallel

artificial membrane permeation assay of the blood−brain barrier.
1. Introduction.
Alzheimer’s disease (AD) is the most common age-related neurodegenerative
disorder with noticeable impairment of cognitive function.1 Today, over 46 million
people live with dementia worldwide, the total estimated worldwide cost is US$818
billion, and the dementia number is estimated to increase to 131.5 million by 2050.2
Although the etiology of AD is not completely known until now, several factors,
including low levels of acetylcholine (ACh), oxidative stress, dyshomeostasis of
biometals and amyloid-β (Aβ) deposits, have been considered to play key roles in the
pathogenesis of AD.3 Current therapeutic options for the treatment of AD focuses on
cholinesterases inhibitors (donepezil, rivastigmine, and galantamine) and one
N-methyl-D-aspartate receptor antagonist (memantine).4 These drugs show modest
improvement in memory and cognitive function, however, they do not prevent
progressive neurodegeneration.5
The production and accumulation of soluble amyloid oligomers of Aβ are a central
event in the neuropathology of AD according to the ''amyloid hypothesis'', as they are
thought to be able to initiate the pathogenic cascade, ultimately leading to neuronal
loss and dementia.6 Aβ could enter the mitochondria where it would increase the
generation of ROS and induce oxidative stress that damage biological molecules such
as proteins, DNA, and lipids.7 Therefore, reducing the aggregation of Aβ in the brain
appears to be a rational therapeutic approach for treating AD.
AChE and BuChE play a role in cholinergic signaling. BuChE can hydrolyze ACh
and compensate for AChE when levels are depleted. AChE activity decreases
progressively in the brain of AD patient, while BuChE activity shows some increase.
Moreover, BuChE genotype may influence AD risk and rate of disease progression.
Strategies that increase ACh levels indicate symptomatic efficacy in AD.8 In view of
BuChE mainly present in serum peripheral tissues9, the potential advantage of
selective AChE over BuChE inhibitor may decrease associated side effects due to
peripheral inhibition of cholinesterase enzyme.

The multifaceted factors of the AD state have encouraged active research in the
development of multi-target-directed ligands (MTDLs)10 to act as agents for the
treatment of this disease. These drugs, which possess two or more complementary
biological activities, may represent an important clinical advance in the future.
Memoquin is the successful molecule of the first AD multitarget-drug discovery
efforts, it interacts with three molecular targets involved in AD pathology, namely,
acetylcholinesterase (AChE), β-amyloid (Aβ), and β-secretase (BACE-1).11 It has
been widely followed and got significant progress.12-14 The alkyl-2-methoxy-benzyl
fragments play a key role in AChE inhibitory activity. Ferulic acid
(4-hydroxy-3-methoxy cinnamic acid, FA) is a widely distributed constituent of plants,
and was first isolated from Ferula foetida. FA, a bioactive component of Traditional
Chinese Medicine, has antioxidant and anti-inflammatory effects, inhibits Aβ fibril
aggregation, and prevents Aβ-mediated toxicity both in vitro and in vivo[15]. Moreover,
tacrine-ferulic hybrids, multifunction FA derivatives, have additional AChE and
BuChE inhibitory activities in relation to FA[16-18], and exhibit multifunctional in vitro
and improve cognitive ability in vivo[19, 20]. However, according to Lipinski's rules, the
target compounds seem not good leading compound for the treatment of AD. In order
to improve the molecular weight and blood-brain penetration ability, FA was selected
to combine with different alkylbenzylamines fragments to design a series of novel
ferulic acid-memoquin hybrids, to test whether these novel molecules might possess
more potency in various multifunctional activities and improve the shortcomings.
In this article, based on the multi-target-directed ligands strategy (MTDLs), we
report the study of the design, synthesis and evaluation of a novel series of ferulic
acid-memoquin hybrids that are found to show potentially applicable biological
activities, including AChE and BuChE inhibition, the kinetics of enzyme inhibition,
antioxidant activities, effects on Aβ aggregation and disaggregation, and protective
effect against H2O2-induced PC12 cell injury. The design strategy for ferulic
acid-memoquin hybrids are depicted in Figure 1.

Figure 1. Design strategy for ferulic acid-memoquin hybrids.
2. Results and discussion.
2.1 Chemistry
The synthesis of ferulic acid-memoquin hybrids (15-17) was shown in Scheme 1.
The starting material 1 was treated with 1,3-dibromopropane, 1,4-dibromobutane or
1,6-dibromohexane to give the intermediates 2-4, and then reacted with secondary
amines 7a-d which were obtained by reductive amination of methylamine or
ethylamine with benzaldehydes in the presence of NaBH4 to afford the key
intermediates 8-10. The key primary amines 11-13 were synthesized through the
hydrazinolysis of compounds 8-10. Finally, the target compounds 15-17 were
obtained by the condensation of ferulic acid with compounds 11-13 in the presence of
EDCI and HOBt.

Scheme 1. Synthesis of ferulic acid-memoquin hybrids (15-17). Reagents and conditions: (i)
Br(CH2)nBr, acetone, reflux for 6-10 h. (ii) R1R2NH, K2CO3, CH3CN, 65°C, for 6-8 h. (iii)
H2NNH2.H2O, EtOH, reflux for 3 h. (iv) CH2Cl2, EDCI, HOBT, room temperature, overnight. (v)
NaBH4, CH3OH, room temperature, 6-10 h.
Target compounds 15a-d~17a-d were tested in vitro for inhibition of AChE from
electrophorus electricus (EeAChE) and BuChE from equine serum, using the Ellman
assay.5 The inhibitory activities of ferulic acid and memoquin were also evaluated for
comparative purposes. As shown in Table 1, all the target compounds exhibited more
potent inhibitory activities than ferulic acid (IC50 > 100 μM), but lower inhibitory
activities than memoquin (IC50 = 0.0067 μM). All the derivatives indicated weak
BuChE inhibitory activity. The compound 17d showed the strongest inhibitory
activity with IC50 value of 3.2 μM. The results demonstrated that the benzylamines
group exhibited significant effect on the AChE inhibitory activity, generally, the
methoxy group at the 2-position of benzylamine showed good inhibitory activity, and
the substituted groups possessing a N-ethyl group showed better AChE inhibitory
activity than that with a N-methyl group, which was consistent with the previously
reported.21 On the other hand, we also investigated the effects of the side chain length

on inhibitory ability of AChE, the data revealed that the inhibitory activity increased
with methylene linker extended.
Table 1.
Inhibition of AChE and BuChE activity, oxygen radical absorbance capacity (ORAC, Trolox
equivalents) and inhibition of Aβ1-42 self-aggregation by target compounds, ferulic acid,
memoquin and curcumin.
Comp.
AChEa
BuChEb (%) ORACc
Self-induced Aβ1-42 aggregation (%)
IC50 (μM)
Inhibitiond
39.1 ±0.12
33.3±0.07
30.8 ±0.06
35.2±0.17
31.6 ±0.14
33.8±0.08
32.5 ±0.03
38.3±0.18
31.2 ±0.11
37.4±0.04
36.6 ±0.04
Disaggregation e
34.7±0.07
31.4±0.01
25.1±0.05
15.9±0.01
29.6±0.04
16.5±0.32
18.0±0.21
8.6±0.29
15.1±0.29
8.2±0.10
8.5±0.04
3.2 ±0.02
<5%
<5%
1.2±0.01
0.9±0.03
1.3±0.02
1.1±0.02
1.3±0.01
1.1±0.04
1.2±0.02
1.3±0.03
1.2±0.01
1.1±0.01
1.3±0.02
NTf
15a
15b
15c
15d
16a
16b
16c
16d
17a
17b
17c
17d
NTf
15.8%
31.4%
<5%
NTf
NTf
NTf
<5%
NTf
34.6%
<5%
NTf
NTf
<5%
NTf
17.2%
27.6%
36.2%
NTf
NTf
1.2±0.01 49.3±0.03 (50μM)
38.1±0.05 (25μM)
45.5 ±0.03
26.8±0.02 (10μM)
ferulic acid
>100
<5%
5.8±0. 01
NTf
1.1±0.02
NTf
28.3±0.07
72.7±0.11
56.2±0.03
NTf
NTf
memoquin 0.0067±0. 0001
curcumin
NTf
NTf
57.6±1.8
aAChE from electrophorus electrics. IC50 ± SD values represent the concentration of inhibitor
required to decrease enzyme activity by 50% and all experiments were performed in triplicate.
bInhibition of BuChE. The concentration of the tested inhibitor was 50 μM. cThe mean ± SD of the
3 independent experiments. Results are expressed as μM of Trolox equivalent/μM of tested
d
compound. Inhibition of self-induced Aβ1-42 aggregation, the thioflavin-T fluorescence method
was used, the mean ± SD of at least three independent experiments and the measurements were
carried out in the presence of 25 μM target compounds and reference compunds. eDisaggregation
of self-induced Aβ1-42 aggregation. The concentration of tested compounds and Aβ1-42 were 25 μM.
fNT = not tested.
To gain further insight into the mechanism for this class of ferulic acid-memoquin
hybrids on AChE, compound 17d, the most potent AChE inhibitor, was chosen for
further kinetic studies. Graphical analysis of the reciprocal Lineweaver-Burk plots
(Figure 2) showed both increasing slopes (decreased Vmax) and intercepts (higher Km)

at increasing concentration of the inhibitor. The results revealed that compound 17d
was a mixed-type inhibitor and could bind to both of catalytic site and the peripheral
site of AChE.
Figure 2. Steady state inhibition by compound 17d of the AChE hydrolysis of ACh. The plots
show mixed-type AChE inhibition for compound 17d.
The antioxidant activities of the target compounds were tested by following the
well-established ORAC-FL method (Oxygen Radicals Absorbance Capacity by
Fluorescence), a vitamin E analogue, Trolox was used as a standard (the activities
were expressed as Trolox equivalents).21 As shown in Table 1, all the target
compounds exhibited potent radical absorbance capacities, ORAC-FL values ranging
from 0.9 to 1.3 Trolox equivalents. The results revealed that the hydroxy group of the
ferulic acid derivatives contributed to the radical-scavenging ability, however, the
substituted groups showed no significant influence on structure activity relationship.
The compound 17d indicated ORAC-FL value was 1.2 Trolox equivalents.
Subsequently, to evaluate the effects of the target compounds against
self-mediated Aβ1−42 aggregation, we performed two individual studies: inhibitory
activity and disaggregation potency on self-induced Aβ1−42 aggregation. Thioflavin T
(ThT) fluorescence assay was used to evaluate the degree of Aβ1−42 aggregation.22
Curcumin, a known active natural product for inhibition of self-induced Aβ
aggregation, was used as reference compound.
For the inhibitory activity on self-induced Aβ1−42 aggregation, as shown in Table
1, all the target compounds exhibited moderate inhibitory activities, ranging from
30.8%-39.1% at 25 μM, and showed better inhibition than that of ferulic acid (18.3%),
but lower inhibitory potency than that of curcumin (56.2%) and memoquin (72.7%). It

was reasonable that the substituted groups might be benefical to inhibitory activity.
The data showed that the side chain substituted groups showed meaningless influence
on the inhibitory activity. The compound 17d, the most AChE inhibitor, inhibited a
dose-dependent inhibitory effect on self-induced Aβ1-42 aggregation (49.3% at 50 μM,
38.1% at 25 μM, 26.8% at 10 μM).
For the disaggregation effects on self-induced Aβ1−42 aggregation, compound 17d
could disaggregate Aβ fibrils (45.5% disaggregation at 25 μM) in Table 1. The above
results suggested that compound 17d could inhibit and disaggregate self-induced
Aβ1−42 aggregation.
To examine the cytotoxicity of the representative compound 17d, human neuronal
cell line SH-SY5Y cells were exposed to the test compound at 10 μM for 24 h and the
cell viability was tested by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium
(MTT) assays.21 As shown in Figure 3, 17d showed cell viability was (98.3±1.8)%
at 10 μM. The result showed that the target compound had therapeutic safety at 10 μM,
and encouraged further studies to elucidate the neuroprotective mechanisms of 17d.
Figure 3. The cytotoxicity of 17d (10 μM) on SH-SY5Y cells. ##P < 0.01 vs control;
The neuroprotective capacity of target compound 17d against oxidative stress
was assayed according to the reported protocol.23 After 100 μM H2O2 exposure, cell
viability, determined by MTT reduction, was markedly decreased to (47.6±7.3)% (p
< 0.01 vs control), suggesting high sensitivity to H2O2-induced injury. However,
compound 17d showed protective effect in a dose-dependent manner against
H2O2-induced PC12 cell injury (Figure 4). At concentration of 10.0 μM, compound

17d indicated significantly good neuroprotective effect and the cell viability was (88.3
±6.5)%. When the concentration was reduced to 1.0 μM, the cell viability decreased
to (68.6±3.8)%. It revealed that compound 17d could capture the hydroxyl radical,
generated by H2O2.
Figure 4. Protective effects of 17d on cell injury induced by hydrogen peroxide (100 μM) in PC12
cells. ##P < 0.01 vs control; *P < 0.05 vs H2O2 group and **P < 0.01 vs H2O2 group.
The ability to cross the blood-brain barrier (BBB) was crucial for CNS drugs. To
evaluate the possible BBB permeability of 17d, the parallel artificial membrane
permeation assay of the blood−brain barrier (PAMPA-BBB) was performed.24 We
compared the permeability of 11 commercial drugs with reported values to validate
the assay (see Supporting information, Table S1), a plot of the experimental data
versus the reported values produced a good linear correlation, Pe(exp) =
0.9163Pe(bibl.) − 0.2247 (R2 = 0.9558) (see Supporting information, Figure S1).
From this equation and considering the limit established by Di et al. for blood−brain
barrier permeation, we determined that compound with permeability above 3.44 ×
10−6 cm/s could cross the blood−brain barrier (see Supporting information, Table S2).
According to the measured permeability (Table 2), 17d could cross the BBB in vitro
and reach their biological targets located in the CNS. Therefore, compound 17d was
chosen for further study.
Table 2.
Permeability Pe (×10−6 cm/s) in the PAMPA-BBB assay of the selected compound 17d and their
predictive penetration in the CNS.
compounda
Pe (×10−6 cm/s)b
5.53 ± 0.05
prediction
CNS+
17d

a
Compound 17d was dissolved in DMSO at 5 mg/mL and diluted with PBS/EtOH (70:30). The
final concentration of compounds was 100 μg/mL.
b Values are expressed as the mean ± SD of three independent experiments.
On the basis of the knowledge that ferulic acid possesses a variety of bioactivities,
we have developed a novel series of ferulic acid-memoquin hybrids as multitarget
agents for the treatment of AD. Among the synthesized compounds, compound 17d
showed significant selective inhibition of AChE, inhibition and disaggregation of
Aβ1−42 aggregation, antioxidant activity and neuroprotective effect. Furthermore, 17d
could cross the blood-brain barrier (BBB) in vitro. These results showed that
compound 17d might be a promising multifunctional agent for the treatment of AD.
Notes
The authors declare no competing financial interest.
Acknowledgments
This study was financially supported by National Natural Science Foundation of
China (11404373) and National Natural Science Foundation of China (21502100).
Supplementary data
Experimental procedures for the synthesis and biological activities evaluation of
the studied compounds, Tables and Figures in vitro blood−brain barrier permeation
assay.

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Design, synthesis and evaluation of novel ferulic acid-memoquin hybrids as
potential multifunctional agents for the treatment of Alzheimer’s disease
Wanli Pana, Ke Hub, Ping Baic, Lintao Yua, Qinge Maa, Tao Lia, Xu Zhanga, Changzhong
Chena, Kelin Penga , Wenmin Liua, *, Zhipei Sanga, *
a College of Chemistry and Pharmaceutical Engineering, Nanyang Normal University,
Nanyang, 473061, China
b Nanyang City Center Hospital, Nanyang, 473061, China
c West China Hospital, Sichuan University, Chengdu, 610041, China
*