Bioorganic & Medicinal Chemistry Letters 25 (2015) 55765582

Contents lists available at ScienceDirect

Bioorganic & Medicinal Chemistry Letters

journal homepage: www.elsevier.com/locate/bmcl

Synthesis of donepezil-based multifunctional agents for the

treatment of Alzheimers disease
Kadir Ozden Yerdelen a,, Mehmet Koca a, Baris Anil b, Handan Sevindik c, Zeynep Kasap a, Zekai Halici d,
Kubra Turkaydin a, Gulsen Gunesacar a
a

Ataturk University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, 25240, Erzurum, Turkey
Ataturk University, Faculty of Pharmacy, Department of Organic Chemistry, 25240, Erzurum, Turkey
Ataturk University, Faculty of Pharmacy, Department of Pharmacognosy, 25240, Erzurum, Turkey
d
Ataturk University, Faculty of Medicine, Department of Pharmacology, 25240, Erzurum, Turkey
b
c

a r t i c l e

i n f o

Article history:
Received 5 September 2015
Revised 14 October 2015
Accepted 16 October 2015
Available online 20 October 2015
Keywords:
Donepezil
Amyloid beta
Alzheimer
AChE
BuChE

a b s t r a c t
Amyloid beta (Ab) and cholinesterase enzymes (AChE, BuChE) are important biological targets for the
effective treatment of Alzheimers disease. In this study, the aim was to synthesize new donepezil-like
secondary amide compounds that display a potent inhibition of cholinesterases and Ab with antioxidant
and metal chelation abilities. All test compounds showed activities against both ChEs and b142 inhibition.
The most encouraging compound, 20, is an AChE inhibitor with high anti-aggregation activity (55.3%).
Based on the results, compound 20 may be a promising structure in further research for new antiAlzheimers agents.
2015 Elsevier Ltd. All rights reserved.

Increasing incidence and mortality in the aging population

associated with Alzheimers disease (AD) has carried it to the group
of most common diseases in recent years, and requirements for the
development of new, effective treatments of AD increase day after
day. Pathophysiologic research has shown that AD is an abnormal
neurodegenerative disorder characterized by low levels of acetylcholine (ACh), increased oxidative stress, the level of metal ions,
and the overproduction and aggregation of b-amyloid (Ab).1,2
Currently, a definitive treatment for AD is unavailable, and the
most popular treatment strategies are primarily symptomatic.
The oldest and most popular strategy for current AD treatment is
based on the cholinergic hypothesis and specifically on acetylcholinesterase (AChE) inhibitionto improve cholinergic neurotransmission in the brain by increasing the levels of ACh.35 The
active sites of AChE consist of an anionic binding site, Trp84,
Glu199, and Phe330; an esteratic binding site that contains the catalytic triad Ser200, His440, and Glu327; an acyl binding site,
Phe288, and Phe299, which binds to the acetyl group of ACh. AChE
also has peripheral anionic sites (PAS), such as Trp279, Tyr70,
Tyr121, Asp72, Glu199 and Phe290.610 In addition, AChEs sister
enzyme, butyrylcholinesterase (BuChE), has been found to be
Corresponding author. Tel.: +90 442 2315220; fax: +90 442 2360962.
E-mail address: dadasozden@gmail.com (K.O. Yerdelen).
http://dx.doi.org/10.1016/j.bmcl.2015.10.051
0960-894X/ 2015 Elsevier Ltd. All rights reserved.

capable of compensating for missing AChE catalytic functions in

the synaptic cleft.11,12 This function has caused a rise in attention
regarding BuChE due to its ability to hydrolyze ACh and the other
esters.1315 The second main therapeutic strategy for AD is based
on preventing the aggregation of Ab. According to the amyloid
hypothesis, aggregation of amyloid peptide is considered to be
one of the critical stages of AD. Accumulation of Ab peptide in
neurons may induce biochemical events leading to neuronal dysfunctions.16 In addition, recent research has shown that oxidative
damage may increase the incidence of amyloid plaques in the
brains of AD patients.17 Another hypothesis called metal hypothesis indicates that high levels of metal ions (Fe2+, Cu2+, and Zn2+)
cause severe and fatal neurologic disorders. The accumulation of
metal ions is closely associated with abnormal clumps of Ab plaques, which is a hallmark of AD.1821 Several AChE inhibitors such
as donepezil, galantamine, and rivastigmine have been used for the
treatment of AD.22 Among these, donepezil interacts with catalytic
anionic sites (CAS) and PAS, in which the 5,6-dimethoxyindanone
cyclic moiety of donepezil binds to the PAS.23 Many studies have
demonstrated that donepezil analogues (I and II) are able to interact with central and peripheral binding sites of AChE and prevent
catalytic and noncatalytic actions of the enzyme with their highest
inhibitory activities (Fig. 1).24 In this research, we have synthesized
new, modified donepezil analogues bearing a secondary aromatic

K. O. Yerdelen et al. / Bioorg. Med. Chem. Lett. 25 (2015) 55765582

5577

Figure 1. Structures of some AChE inhibitors: donepezil and indanone-based donepezil analogues (94 and 95) reported as AChE inhibitors.

amide moiety and evaluated their biological activities, including

inhibitory effects on ChEs and Ab42 aggregation with their antioxidant and metal chelating abilities.
In our previous studies, we have also evaluated a series of tertiary amide derivatives bearing ortho-, meta-, and para-substituted
N-benzylaniline rings as potent ChE inhibitors. From those studies,
we have been able to describe that a carbonyl group of a tertiary
amide moiety can interact with the CAS of AChE. It was also determined to be a crucial structural part for cholinesterase, and especially AChE, inhibition. The study went on to observe that the
compounds, which have highly electronegative atoms on the phenyl ring, exhibited a considerable increase in AChE inhibition.2529
In this study, the 5,6-dimethoxy-indanone ring, which was
inherent in the chemical structure of donepezil, has been the main
consideration in the design of new AChE inhibitors in order to create a positive contribution on cholinesterase inhibition. To reduce
the cost of research and save time, in silico studies were used for
preliminary assessment before synthesizing the compounds
against AChE via the Sybyl X molecular docking program. For the
in silico study, various docking parameters (e.g., total score, polar
score, D_score, PMF_score) of the designed compounds were evaluated and molecular simulation studies were performed on a few
molecules of each. The results showed that the designed compounds are likely to interact with amino acid residues in the catalytic site of AChE. The docking scores are given on Table 3 in
Supplementary file.30
We synthesized some 5,6-dimethoxy-indanone-2-carboxamide
derivatives containing ortho-, meta-, and para-substituted secondary aromatic amines via the pathway outlined in Scheme 1.
Synthesis of the compounds was realized using well-established
methods and reaction details are given in Supplementary file.30
The microwave irradiation method was used for the final step of
the reaction under the following conditions: 300 W; 15 psi;
170 C; 10 min. All experimental and spectral data of the
target compounds are shown on Tables 2 and 4 in
Supplementary file.30
The AChE and BuChE inhibitory activities of the compounds
were examined by the method described by Ellman,31 using AChE
from an electric eel and BuChE from an equine serum. Donepezil
was used as the reference standard. As shown in Table 1, the compounds (122) clearly showed potent inhibitory activity against
AChE with IC50 values ranging from 0.08 to 0.92 lM concentrations. On the other hand, all synthesized compounds were found
significantly more effective inhibitors towards AChE than BuChE,

and with higher selectivity indexes (2.940.1). Among them, p-fluoro and o-fluoro analogue substitutes (compounds 6 and 20) displayed the highest inhibitory activities against AChE with IC50
values of 0.11 lM and 0.08 lM, respectively. The other potent
AChE inhibitors in the series, compounds 8 and 22 (para- and
ortho-bromo analogues), were found with IC50 values of 0.14 lM
and 0.12 lM, respectively. Comparison of the non-substituted
compound 1 and the other substituted compounds demonstrated
that the introduction of halogen, methyl, ethyl, methoxy, and
ethoxy groups at ortho-, meta-, and para-positions of the phenyl
ring increased anti-AChE activity 1.0911.5-fold.
During the evaluation of the effects of different substituent
positions on anti-AChE activity, it was observed that the orthomethyl-substituted compound 16 exhibited approximately twice
as much anti-AChE activity than the para- and meta-methyl-substituted compounds 2 and 9. It was observed that para-, meta-, and
ortho-ethyl substituted compounds have equivalent AChE inhibition activity. A similar situation was also found to be valid for
the AChE inhibition activities of the methoxy-, ethoxy-, and
chloro-substituted compounds at different positions (o-, m-, p-).
Fluoro- and bromo-substituted compounds (6, 20 and 8, 22) at
para- and ortho-positions exhibited at least twice as much potent
anti-AChE activity than m-substituted derivatives (13 and 15). As
shown in Table 1, the most potent compound, 20, had a high level
of AChE inhibitor selectivity (SI = 40.1). Moreover, other potent
compounds, like 7, 8, and 21, had high selectivity for AChE. These
results indicate that substitutions of the phenyl group often had
a positive effect on anti-AChE activity. Substitution of the halogen
group at any phenyl ring position seemed to have a crucial effect
on AChE inhibition. The cause of this contribution may be the high
electronegativity of halogen atoms. The IC50 values of target compounds revealed that they ranged from moderate to good when
used as BuChE inhibitors (2.107.10 lM). Compounds 9, 11, and
14 exhibited the best BuChE inhibition with IC50 values of 2.24,
2.10, and 2.24 lM, respectively (Table 1). The tendency for the
structureactivity relationship found in AChE inhibitory activity
was not found in BuChE inhibitory activity. When the activity
results are generally evaluated, it is clear that all the meta- and
para-substituted compounds offered more positive contribution
toward BuChE inhibition than ortho-substituted compounds.
Beside this, the meta-OCH3-substituted compound (11) was found
to be the most potent anti-BuChE inhibitor (IC50 = 2.10 lM) in the
series. The overall evaluation of these results is that no statistically
significant correlation was found between the physicochemical

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K. O. Yerdelen et al. / Bioorg. Med. Chem. Lett. 25 (2015) 55765582

Scheme 1. Synthesis of the compounds (122). Reagents and conditions: (a) oxalyl chloride, CH2Cl2, room temperature, 12 h; (b) AlCl3, CH2Cl2, 0 C, ice bath; (c) dimethyl
carbonate, NaH, 90 C (d) appropriate primary aniline, dioxane, microwave.

Table 1
Anticholinesterase activity, inhibition of self-induced Ab142 aggregation, DPPH free radical scavenging capacities IC50 values of the compounds (122)
Compound

R1

R2

IC50d (lM) SD

R3

a,e

1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
Donepezil
Curcumin
Trolox
a-Tocopherol
a
b
c
d
e
f

H
CH3
C2H5
OCH3
OC2H5
F
Cl
Br
H
H
H
H
H
H
H
H
H
H
H
H
H
H

H
H
H
H
H
H
H
H
CH3
C2H5
OCH3
OC2H5
F
Cl
Br
H
H
H
H
H
H
H

H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
CH3
C2H5
OCH3
OC2H5
F
Cl
Br

Selectivity for AChEc

Ab142 aggregation inhibitiond,e (%)

DPPH radical scavenging

activity IC50 (lg/ml) SD

3.4
3.2
4.6
5.5
4.5
24.1
8.8
26.1
2.9
4.4
3.9
5.0
9.1
4.8
7.4
8.5
7.3
6.9
8.6
40.1
23.7
28.3

14.3 1.9
26.8 2.2
32.1 1.8
34.5 2.5
40.8 0.6
45.4 1.2
38.2 1.7
47.6 0.8
19.1 2.9
27.4 3.3
30.2 3.9
28.3 2.3
38.7 2.7
37.4 3.4
31.9 2.5
40.3 1.6
21.8 3.8
25.6 1.5
38.1 2.9
55.3 0.9
40.4 1.1
52.8 0.4
NTf
42.3 2.6

61.28 0.81
67.82 1.60
76.15 2.43
49.47 1.93
48.16 1.12
54.96 2.22
56.76 0.73
72.14 2.00
55.83 1.21
64.11 2.03
38.94 1.39
44.89 1.75
58.11 2.30
76.32 1.67
58.88 1.42
43.74 1.25
55.00 0.93
45.76 1.12
63.67 2.01
75.68 1.78
65.92 0.72
65.44 2.14
NTf

b,e

AChE

BuChE

0.92 0.069
0.84 0.017
0.65 0.058
0.53 0.14
0.58 0.072
0.11 0.146
0.50 0.097
0.14 0.174
0.77 0.061
0.67 0.097
0.54 0.141
0.78 0.134
0.247 0.064
0.47 0.143
0.33 0.089
0.36 1.354
0.86 0.312
0.7 0.074
0.77 0.119
0.08 1.813
0.30 0.383
0.12 0.635
0.042 0.041

3.15 0.002
2.50 0.116
2.96 0.0459
2.90 0.127
2.61 0.04
2.65 0.093
4.40 0.066
3.66 0.012
2.24 0.39
2.98 0.03
2.10 0.015
3.87 0.042
2.25 0.15
2.24 0.0093
2.43 0.11
3.06 0.63
6.29 0.257
4.81 0.048
6.62 0.187
3.21 0.104
7.1 0.131
3.4 0.078
0.54 0.017

20.87 0.40
31.74 0.25

50% inhibitory concentration of AChE.

50% inhibitory concentration of BuChE.
Selectivity for AChE = IC50 (BuChE)/IC50 (AChE).
Inhibition of self-induced Ab142 aggregation of curcumin (25 lM) by tested inhibitors (25 lM).
Values are expressed as mean standard error of the mean of three independent experiments. Each performed in triplicate (SD = standard deviation).
NT = not tested.

properties of the synthesized compounds (Log P and molar refractivities) and their AChE and BuChE inhibition activities (Table 2).
According to the above activity results, the most potent AChE
(compound 20) and BuChE (compound 11) inhibitors were selected
for kinetic analysis to investigate their manner of inhibition. To
obtain deep insight into the active mechanisms of the most potent
cholinesterase inhibitors, compounds 20 and 11 were chosen for

further kinetic studies. A graphical presentation of the steady-state

inhibition data of both ChE compounds is shown in Figure 2.
Kinetic analysis of LineweaverBurk plots of compound 20s AChE
inhibitory activity showed that there was an increasing slope and
an increasing intercept at higher concentrations. This result indicates mixed-type inhibition mechanisms as the result of binding
to both AChE active sites (CAS and PAS). The kinetic study of

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K. O. Yerdelen et al. / Bioorg. Med. Chem. Lett. 25 (2015) 55765582

Table 2
Experimental, physicochemical properties and HRMS spectral data of the compounds (122)
H3CO

H3CO

HN

R1

O
R3

Compound

R1

R2

R3

Chemical formula

HR-MS
[M H]

1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22

H
CH3
C2H5
OCH3
OC2H5
F
Cl
Br
H
H
H
H
H
H
H
H
H
H
H
H
H
H

H
H
H
H
H
H
H
H
CH3
C2H5
OCH3
OC2H5
F
Cl
Br
H
H
H
H
H
H
H

H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
CH3
C2H5
OCH3
OC2H5
F
Cl
Br

C18H17NO4
C19H19NO4
C20H21NO4
C19H19NO5
C20H21NO5
C18H16FNO4
C18H16ClNO4
C18H16BrNO4
C19H19NO4
C20H21NO4
C19H19NO5
C20H21NO5
C18H16FNO4
C18H16ClNO4
C18H16BrNO4
C19H19NO4
C20H21NO4
C19H19NO5
C20H21NO5
C18H16FNO4
C18H16ClNO4
C18H16BrNO4

R2

+,a

312.1236
326.1392
340.1549
342.1341
356.3844
330.1142
346.0846
391.0242
326.1392
340.1549
342.1351
356.1490
330.1142
346.0801
391.0242
326.1380
340.1549
342.1351
356.1489
330.1140
346.0848
391.0242

Yield (%)

Mp

Log Pb

MRb

50
53
40
48
65
60
42
55
30
60
40
31
42
50
56
60
78
60
52
61
40
21

181183
167169
166168
185187
189191
205207
190192
186189
140142
162164
183185
159161
180182
164166
136138
166168
183185
178180
190192
165167
149152
178180

2.20
2.69
3.11
2.08
2.42
2.36
2.76
3.03
2.69
3.11
2.08
2.42
2.36
2.76
3.03
2.69
3.11
2.08
2.42
2.36
2.76
3.03

87.10
93.00
97.60
94.35
99.15
87.51
91.71
94.79
93.00
97.60
94.35
99.15
87.51
91.71
94.79
93.00
97.60
94.35
99.15
87.51
91.71
94.79

+,b

[M H]

312.1230
326.1379
340.1552
342.1354
356.1488
330.1142
346.0829
391.0271
326.1385
340.1543
342.1358
356.1486
330.1143
346.3829
391.0341
326.1380
340.1546
342.1354
356.1488
330.1141
346.0843
391.0348

Mp: melting point.

MR: molar refractivity.
a
Calculated by ChemDraw 2015.
b
Obtained by TOF-MS.

Figure 2. LineweaverBurk plots of inhibition kinetics of the compounds 11 and 20.

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K. O. Yerdelen et al. / Bioorg. Med. Chem. Lett. 25 (2015) 55765582

Figure 3. Inhibition of self-induced Ab142 aggregation by the test compounds and reference curcumin at concentration 25 lM.

Figure 4. Overlay of the docking pose of the compound 20 and donepezil at the
active site of AChE.

Figure 5. 3D representation of the binding mode of the most potent inhibitor 20 at

the active sites of AChE.

compound 11 on BuChE inhibitory activity showed lines crossing

the x-axis at the same point (unchanged Km) and a decreased Vmax
with increasing inhibitor concentrations. These results indicate
that donepezil-based secondary amide derivatives exhibit mixedtype and non-competitive inhibition mechanisms that are similar
to those seen in donepezil.
The inhibition of amyloid-beta (Ab142) self-induced aggregation by our indanone-2-carboxamide derivatives was studied
through a thioflavin T (ThT) fluorometric assay32 with curcumin.
The ThT assay is a well-known test for evaluating the inhibition
of Ab fibrillogenesis. ThT is used as a dye to visualize and quantify
the presence or fibrilization of misfolded protein aggregatesor
amyloidsboth in vitro and in vivo. Curcumin, a known active natural product that inhibits self-induced Ab42 aggregation, was used
as a reference compound.33,34 The effects on Ab142 peptide aggregation of the compounds and curcumin were summarized on
Table 1 and Figure 3 at a concentration of 25 lM. In the ThT assay,
results for Ab142 peptide self-aggregation inhibition indicated that
some compounds showed moderate to good inhibition ratios
(14.355.3%). The most potent AChE inhibitors (6, 8, 20, and 22)
exhibited good Ab142 inhibition potencies with respective inhibition ratios of 45.4%, 47.6%, 55.3% and 52.8%, all of which are higher
than the inhibition ratio of curcumin (42.3%).
The prevention of oxidative stress is an important aspect when
designing agents for AD treatment. With this understanding, we
evaluated the antioxidant abilities of our compounds by using
the DPPH free radical scavenger assay. Scavenging potencies to
the radicals was measured at a concentration of 1060 lg/mL
and compared with two reference compounds, Trolox (vitamin E
analogue) and a-tocopherol (shown on Table 1). The data showed
that the tested derivatives exhibited moderate antioxidative activity ranging from concentrations between 38.94 and 76.32 lg/mL.
Furthermore, compound 11 was found to be the most potent
antioxidant compound in the series. The activity results indicated
that the most potent cholinesterase and amyloid inhibitors was
also moderate antioxidant agents.
The chelation capacities of the most potent cholinesterase
inhibitors, 11 and 20, for metals such as Cu2+, Fe2+, and Zn2+ were
studied in DMSO solution using a UVvisible spectrophotometer
(190380 nm). When compounds 11 and 20 were mixed with an
equivalent molar of ZnSO4, a bathochromic shift was observed
after a 20 min incubation period. This spectral alteration appeared
to be a complex formation between the compounds and Zn2+. The
spectra of the Zn2+inhibitor 20 complex showed a bathochromic
shift from 317 nm to 325 nm with an increased absorption peak.

K. O. Yerdelen et al. / Bioorg. Med. Chem. Lett. 25 (2015) 55765582

5581

Figure 6. 3D representation of the binding mode of the most potent inhibitor 11 at the active sites of BuChE.

Also, the complex of compound 11 and Zn2+ exhibited a red shift

from 316 nm to 320 nm with a decrease in molar absorbance.
The changes in the absorption intensity and maximum wavelengths indicated that both inhibitor compounds could interact
with Zn2+ metal ions effectively. Results are shown in Figures 1
and 2 to UV absorption spectra of the complexes between the compounds (11, 20) and biometals are given in Supplementary file.30
Docking studies of the binding of the two most active compounds, derivatives 20 with AChE (PDB code: 1EVE) and 11 with
BuChE (PDB code: 1P0I), were carried out in order to investigate
the possible interacting mode of our synthetic inhibitors with
active site of related ChEs, by SYBYL X 2.0 docking program. The
docking results showed that compound 20 displayed multiple
binding
patterns
with
Torpedo
californica
(TcAChE)
(Figs. 4 and 5). In the 1EVE20 complex, all structural main moieties (5,6-dimethoxy-indanone, carboxamide and phenyl ring)
occupied the CAS and PAS of enzyme and dominated several
hydrogen bondings and pp stacking interaction with residues
Tyr130, Trp84, Glu199, Ser200, Gly117 and Ser122. Compound 20
is anchored at the bottom of CAS with many hydrogen bonding
interactions. For instance, compound 20 created two hydrogen
bonds in CAS: one of them is interaction NH group of amide moiety
with CO from Glu199 (2.11 ) and the other one is carbonyl group
of amide moiety with phenolic OH group of Tyr130 residue
(2.69 ). Also ligand 20 created pp stacking interaction with
indole moiety of Trp84 in CAS (distance 2.83.4 ). In catalytic site
of 1-EVE, fluorine atom at the ortho position on phenyl ring created
a hydrogen bond with OH from Ser200 (2.83 ). In oxyanion hole,
carbonyl group of ligand 20 is bridged to OH group of Ser122 via
hydrogen bonding. In the complex, 5,6-dimethoxy-indanone scaffold is stacked against Ser122 and Asp72, located at the PAS, The
OCH3 group in position 6 of the indanone ring is hydrogen bonded
to the OH group of Ser122 (2.61 ). The binding mode of compound
20 with both active sites of 1EVE shed light for its potent inhibitory
activity and mixed-type inhibition mechanism. The most potent
BuChE inhibitor, 11, showed hydrogen bonding interactions with
Thr120 and Asp70 residues of Human butyrylcholinesterase
enzyme (HuBuChE-1P0I) (Fig. 6). Hydrogen bond interaction
occurred between the C@O group of compound 11 and the OH
group of Thr120 (1.95 ) in CAS. The aromatic OCH3 group of the
ligand 11 occurred a hydrogen bond with NH group of Asp70
(2.19 ) in PAS of HuBuChE.

Twenty-two new donepezil-like secondary amide compounds

were designed and evaluated as novel multifunctional inhibitors
of ChE and Ab142 aggregation, antioxidant agents, and metal
chelation agents through molecular modelling studies. The final
indanone-2-carboxamide derivatives were synthesized through
single-step reactions between some primary anilines and 5,6dimethoxyindanone-2-carboxylic acid methyl ester by using
microwave irradiation for 10 min. Compound 20 (IC50 = 0.08 lM,
AChE) and the most potent antioxidative compound, 11
(IC50 = 2.10 lM, BuChE), were found to be the most potent inhibitors in the series. Compound 20 was potent in inhibiting
AChE activity, and it displayed the most selective inhibition
for AChE. Compound 20 also exhibited good amyloid inhibition
(55.3% at 25 lM) as well as moderate radical scavenging activity. Regarding inhibitory activity against AChE and the ability to
inhibit self-induced Ab142 aggregation, a significant correlation
has been found, indicating that potent AChE inhibitors are also
the most potent amyloid inhibitors. These similar results suggest that there may be an interdependent mechanism among
anti-AChE and Ab142 aggregation inhibition activities. Additionally, docking simulations showed that compound 20 could create many bonding interactions with both catalytic and
peripheral AChE binding sites, which supports its high inhibitory potency and mixed-type inhibition mechanism. Further
studies to synthesize indanone-based analogue compounds are
in progress.
Acknowledgements
This research work was supported by Ataturk University
Research Fund (Project No: 2014/167), Turkey. The fluorometric
measurement of Ab142 inhibition was performed at the Faculty
of Veterinary Medicine and Department of Biochemistry, University of Ataturk, Turkey, under the supervision of Assoc. Prof. Dr.
Mesut B. Halici.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2015.10.
051.

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References and notes

1. Hardy, J.; Bogdanovic, N.; Winblad, B.; Portelius, E.; Andreasen, N.; CedazoMinguez, A.; Zetterberg, H. J. Intern. Med. 2014, 275, 296.
2. Samadi, A.; Estrada, M.; Prez, C.; Rodrguez-Franco, M.; Iriepac, I.; Moraledac,
I.; Chioua, M.; Marco-Contelles, J. Eur. J. Med. Chem. 2012, 57, 296.
3. Akasofu, S.; Kimura, M.; Kosasa, I.; Sawada, K.; Ogura, H. Chem. Biol. Interact.
2008, 175, 222.
4. Dumas, J. A.; Newhouse, P. A. Pharmacol. Biochem. Behav. 2011, 99, 254.
5. Tai, H. C.; Serrano-Pozo, A.; Hashimoto, T.; Frosch, M. P.; Spires-Jones, T. L.;
Hyman, B. Am. J. Pathol. 2012, 181, 1426.
6. Castro, A.; Martinez, A. Mini-Rev. Med. Chem. 2001, 1, 267.
7. Giacobini, E. Neurochem. Res. 2003, 28, 515.
8. Harel, M.; Quinn, D. M.; Nair, H. K.; Silman, I.; Sussman, J. L. J. Am. Chem. Soc.
1996, 118, 2340.
9. Pang, Y. P.; Quiram, P.; Jelacic, T.; Hong, F.; Brimjoin, S. J. Biol. Chem. 1996, 271,
23646.
10. Zhou, X.; Wang, X. B.; Wang, T.; Kong, L. Y. Bioorg. Med. Chem. 2008, 16, 8011.
11. Li, B.; Stribley, J. A.; Ticu, A.; Xie, W.; Schopfer, L. M.; Hammond, P.; Brimijoin,
S.; Hinrichs, S. H.; Lockridge, O. J. Neurochem. 2000, 75, 1320.
12. Mesulam, M. M.; Guillozet, A.; Show, P.; Levey, A.; Duysen, E. G. M.; Lockridge,
O. Neuroscience 2002, 110, 627.
13. Darvesh, S.; Hopkins, D. A.; Geula, C. Nat. Rev. Neurosci. 2003, 4, 131.
14. Fernndez-Bachiller, M. I.; Prez, C.; Gonzlez-Muoz, G. C.; Conde, S.; Lpez,
M. G.; Villarroya, M.; Garca, A. G.; Rodrguez-Franco, M. I. J. Med. Chem. 2010,
53, 4927.
15. Galdeano, C.; Viayna, E.; Arroyo, P.; Bidon-Chanal, A.; Blas, J. R.; MuozTorrero, D.; Luque, F. J. Curr. Pharm. Des. 2010, 16, 2816.
16. Yankner, B. A.; Dawes, L. R.; Fisher, S.; Villa-Komaroff, L.; Oster-Granite, M. L.;
Neve, R. L. Science 1989, 245, 417.
17. He, Y.; Yao, P. F.; Chen, S. B.; Huang, Z. H.; Huang, S. L.; Tan, J. H.; Li, D.; Gu, L. Q.;
Huang, Z. S. S. Eur. J. Med. Chem. 2013, 63, 299.

18. Bush, A. I. J. Alzheimers Dis. 2008, 15, 223.

19. Dong, J.; Atwood, C. S.; Anderson, V. E.; Siedlak, S. L.; Smith, M. A.; Perry, G.;
Carey, P. R. Biochemistry 2003, 42, 2768.
20. Opazo, C.; Huang, X.; Cherny, R. A.; Moir, R. D.; Roher, A. E.; White, A. R.;
Cappai, R.; Masters, C. L.; Tanzi, R. E.; Inestrosa, N. C.; Bush, A. I. J. Biol. Chem.
2002, 277, 40302.
21. Yan, H.; Yao, P. F.; Chen, S. B.; Huang, Z. H.; Huang, S. L.; Tan, J. H.; Li, D.; Gu, L.
Q.; Huang, Z. S. Eur. J. Med. Chem. 2013, 63, 299.
22. Hansen, R. A.; Gartlehner, G.; Webb, A. P.; Morgan, L. C.; Moore, C. G.; Jonas, D.
E. Clin. Interv. Aging 2008, 3, 211.
23. Rizzo, S.; Bartolini, M.; Ceccarini, L.; Piazzi, L.; Gobbi, S.; Cavalli, A.; Recanatini,
M.; Andrisano, V.; Rampa, A. Bioorg. Med. Chem. 2010, 18, 49.
24. Sheng, R.; Lin, X.; Li, J.; Jiang, Y.; Shang, Z.; Hu, Y. Bioorg. Med. Chem. Lett. 2005,
15, 3834.
25. Koca, M.; Yerdelen, K. O.; Anil, B.; Kasap, Z. Chem. Pharm. Bull. 2015, 63, 210.
26. Yerdelen, K. O.; Gul, H. I. Med. Chem. Res. 2013, 22, 4920.
27. Yerdelen, K. O.; Koca, M.; Kasap, Z.; Anil, B. J. Enzyme Inhib. Med. Chem. 2015, 30,
671.
28. Y Yerdelen, K. O.; Tosun, E. Med. Chem. Res. 2015, 24, 588.
29. Kasap, Z.; Yerdelen, K. O.; Koca, M.; Anil, B. Lat. Am. J. Pharm. 2015, 34, 924.
30. For experimental details and in vitro activity assays, see Supplementary file.
31. Ellman, G. L.; Courtney, D.; Andies, V.; Featherstone, R. M. Biochem. Pharmacol.
1961, 7, 88.
32. Rosini, M.; Simoni, E.; Bartolini, M.; Cavalli, A.; Ceccarini, L.; Pascu, N.;
McClymont, D.; Tarozzi, A.; Bolognesi, M.; Minarini, A.; Tumiatti, V.; Andrisano,
V.; Mellor, I. R.; Melchiorre, C. J. Med. Chem. 2008, 51, 4381.
33. Endo, H.; Nikaido, Y.; Nakadate, M.; Ise, S.; Konno, H. Bioorg. Med. Chem. Lett.
2014, 24, 5621.
34. Prinz, M.; Parlar, S.; Bayraktar, G.; Alptzn, V.; Erciyas, E.; Fallarero, A.;
Karlsson, D.; Vuorela, P.; Burek, M.; Frster, C.; Turunc, E.; Armagan, G.; Yalcin,
A.; Schiller, C.; Leuner, K.; Krug, M.; Sotriffer, C. A.; Holzgrabe, U. Eur. J. Med.
Chem. 2013, 49, 603.