Synthesis and evaluation of selegiline derivatives as monoamine oxidase inhibitor, antioxidant and metal chelator against Alzheimer's disease

Article abstract of DOI:10.1016/j.bmc.2015.04.009

A series of compounds with monoamine oxidase inhibition and biometal chelation activities were designed, synthesised and evaluated as agents against Alzheimer's disease. The in vitro assay shows that most target compounds exhibit good MAO-B activities with submicromolar IC₅₀ values and antioxidant activity (1.49-5.67 ORAC-FL values). The selected compounds were used to determine the biometal chelating ability using UV-vis spectrometry and high-resolution mass spectrometry, which confirm that they can effectively interact with copper(II), iron(II) and zinc(II). The ThT fluorescence binding assay indicates that the synthetic compounds can inhibit Cu(II)-induced Aβ_1-42 aggregation. The parallel artificial membrane permeation assay shows that most target compounds can cross the BBB. Based on these results, compound 8a was selected as a potential multifunctional agent for the treatment of AD.

Full text of DOI:10.1016/j.bmc.2015.04.009

Bioorganic & Medicinal Chemistry xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Synthesis and evaluation of selegiline derivatives as monoamine
oxidase inhibitor, antioxidant and metal chelator against Alzheimer’s
disease
⇑
⇑
Shishun Xie, Jie Chen, Xiruo Li, Tao Su, Yali Wang, Zhiren Wang, Ling Huang , Xingshu Li
Institute of Drug Synthesis and Pharmaceutical Process, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of compounds with monoamine oxidase inhibition and biometal chelation activities were
designed, synthesised and evaluated as agents against Alzheimer’s disease. The in vitro assay shows that
most target compounds exhibit good MAO-B activities with submicromolar IC50 values and antioxidant
activity (1.49–5.67 ORAC-FL values). The selected compounds were used to determine the biometal
chelating ability using UV–vis spectrometry and high-resolution mass spectrometry, which confirm that
they can effectively interact with copper(II), iron(II) and zinc(II). The ThT fluorescence binding assay indi-
cates that the synthetic compounds can inhibit Cu(II)-induced Ab1–42 aggregation. The parallel artificial
membrane permeation assay shows that most target compounds can cross the BBB. Based on these
results, compound 8a was selected as a potential multifunctional agent for the treatment of AD.
Ó 2015 Elsevier Ltd. All rights reserved.
Received 19 January 2015
Revised 1 April 2015
Accepted 2 April 2015
Available online xxxx
Keywords:
Monoamine oxidase inhibitor
Metal chelator
Alzheimer’s disease
1. Introduction
5 fold in AD brains compared to those in age-matched controls.6
Zinc(II) and copper(II) are significantly enriched in plaque amyloid
Alzheimer’s disease (AD) is a fatal neurodegenerative disorder
that affects more than 24 million people worldwide, and there is
no effective treatment, although more than 100 years have passed
since its discovery.1 At present, the main clinical treatment strat-
egy for AD is the use of cholinesterase inhibitors such as donepezil,
rivastigmine, and galantamine.2 It is believed that these drugs
modestly improve the memory and cognitive function but do not
prevent progressive neurodegeneration because of the complexity
of AD pathogenesis. In the past decades, some hallmarks such as
low levels of acetylcholine, oxidative stress, b-amyloid (Ab) depos-
and are coordinated with histidine residues in senile plaque (SP)
cores, which was confirmed using Raman microscopy.7 Because
these biometal ions may be crucial participants in AD pathological
processes, the modulation of these biometals was proposed to be a
potential therapeutic strategy to treat this disease. Actually,
clioquinol and its analogue PBT2, an 8-OH quinoline derivative,
which exhibit rapid restoration of cognition in Alzheimer’s trans-
genic mice associated with decreased interstitial Ab,8 have been
studied in clinical trials.
Monoamine oxidases (MAOs) are flavin adenine dinucleotide
(FAD)-containing enzymes that are responsible for the oxidative
deamination of neurotransmitters.9 It is well known that high
expression levels of MAO-B in neuronal tissue can increase the
level of free radicals, which play a major role in the aetiology of
AD.10 Therefore, MAO inhibitors are considered potential candi-
dates for anti-Alzheimer drugs because of their capacity to inhibit
oxidative damage.11 Among the MAO inhibitors, selegiline, which
its,
s-protein aggregation, dyshomeostasis of biometals and
inflammation have been found to play important roles in the
pathogenesis of AD.3 Based on these discoveries, many different
approaches to treat AD have been developed. In particular, the
multi-target-directed ligand (MTDL) strategy, which incorporates
a sequential, multifactorial approach to this multifaceted disease,
has received much attention.4
Studies indicate that the dysregulation of brain metal-ion
homeostasis, particularly that of copper, iron and zinc, is an
important hallmark of AD.5 These metal levels increase from 3 to
is an irreversible and selective MAO-B inhibitor, acts as
a
neuroprotective agent in cellular and animal models of AD.12
In recent years, the multi-target-directed ligand (MTDL) treat-
ment strategy, which incorporates a sequential, multifactorial
approach to a multifaceted disease such as AD, has been developed
by many research groups.13 For example, ladostigil (TV3326), the
first anti-AD drug, targets cholinesterase, is a brain-selective
MAO-B inhibitor, is neuroprotective,14 and has been proven to be
⇑
Corresponding authors. Tel./fax: +86 20 3994 3051 (L.H.), +86 20 3994 3050
(X.L.).
E-mail addresses: huangl72@mail.sysu.edu.cn (L. Huang), lixsh@mail.sysu.edu.
cn (X. Li).
http://dx.doi.org/10.1016/j.bmc.2015.04.009
0968-0896/Ó 2015 Elsevier Ltd. All rights reserved.
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2
S. Xie et al. / Bioorg. Med. Chem. xxx (2015) xxx–xxx
safe and well tolerated in Phase I/IIa clinical trials and was taking
part in Phase IIb in 2011 by Yissum, Pontifax, and Clal
Biotechnology Industries. Previously, we reported the design,
synthesis, and evaluation of a new series of tacrine–selegiline
hybrids for the treatment of AD.15 In this Letter, we report the
study of the design, synthesis, and evaluation of a new series of
hybrids that involves fusing important pharmacophores of
selegiline and clioquinol in a new molecule.
0.21 lM. The substitutes at the R1 or R2 position seem to be unfa-
vourable for the inhibition activities. Compounds 8b and 8c, which
have methoxyl at the R1 or R2 position, have an IC50 value of more
than 1
chlorine and hydroxyl at the R2 position, have IC50 values of 0.31,
0.31 and 0.43 M. When the A ring is replaced with pyridyl, com-
pounds 7a and 7b also give good inhibition activities (7a:
IC50 = 0.31 M; 7b: IC50 = 0.52 M). The results in Table 1 indicate
that some of the target compounds also possess effective MAO-A
inhibition. In particular, 8d (IC50 = 1.02 M), 8f (IC50 = 0.70 M) and
8i (IC50 = 1.03 M) exhibit a good balance of inhibition for MAO-A
lM. Compounds 8d, 8f and 8i, which have methoxyl,
l
l
l
l
l
2. Results and discussion
2.1. Chemistry
l
and MAO-B. It is known that selective inhibitors for MAO-A have
been used as effective anti-depressants,18 and AD patients commonly
present depressive symptoms, which implies that the dual inhibition
of MAO-A and MAO-B can be beneficial to AD therapy.19
The synthetic route of the new selegiline derivatives is shown in
Scheme 1. First, the commercially available 4-nitrophenyl acetic
acid reacted with acetic anhydride and N-methylimidazole gave
4-nitrophenylacetone 2.16 2 was hydrogenated in the presence of
Pd/C, and the amino group was protected with di-tert-butyl dicar-
bonate to produce 3, which reacted with (R)-1-phenylethanamine
to provide chiral intermediate 4.17 Methylation and deprotection of
4 occurred in the presence of formaldehyde, H2 and Pd/C to
produce 5. Compound 5 reacted with propargylbromide in the
presence of potassium carbonate and subsequently with trifluo-
roacetic acid to produce 6. Finally, compound 6 was reacted with
2-pyridinecarboxaldehyde derivatives or 2-hydroxybenzaldehyde
derivatives to produce the target compounds 7 and 8.
2.3. Molecular modelling studies of MAO-B
To evaluate the binding modes of the selegiline derivatives with
MAO-B, docking simulation of compound 8a were carried out using
the CDOCKER program in the Discovery studio 2.1 software based
on the X-ray crystal structure of human MAO-B (PDB entry 2V60).
As shown in Figure 1, the Propargylamine group of selegiline moi-
ety is properly oriented to the flavin adenine dinucleotide (FAD)
cofactor adopting between Tyr394 (3.90 Å) and Tyr435 (5.51 Å)
form face-to-face cation–p stacking interactions in a ‘sandwich’
form. Besides, the benzyl group embedded into a hydrophobic
pocket delimited by Ile171, Cys172, Ile198, Ile199, Gln206, Tyr
326 and Phe343. Moreover, the OH atom of 8a forms a direct
hydrogen-bond contact with the backbone carbanyl group of
Pro102 (average OH distance of 2.20 Å).
2.2. In vitro inhibition studies of hMAO-A and hMAO-B
The inhibitory activity of all target compounds against MAOs
was determined with the recombinant human enzymes MAO-A
and MAO-B using clorgyline and pargyline as the reference com-
pounds (Table 1). As shown, most target compounds exhibit good
activity against MAO-B with IC50 in the submicromolar range.
Among them, compound 8a, which has no substitutes other than
hydroxyl on the A ring, gives the best result with an IC50 value of
2.4. Anti-oxidant activity in vitro
To evaluate the antioxidant activities of selegiline derivatives,
the oxygen radical absorbance capacity assay was performed using
Scheme 1. Synthesis of target compounds. Reagents and conditions: (a) acetic anhydride, N-methylimidazole; (b) Pd/C, H2, MeOH; (c) di-tert-butyl dicarbonate, Et3N, CH2Cl2;
(d) (i) (R)-1-phenylethanamine, Pt/C, H2; (ii) -(+)-tartaric acid, ethanol; (iii) NaOH, H2O; (e) HCHO, Pt/C, MeOH; (f) Pd/C, H2; (g) propargylbromide, K2CO3, MeCN, (h)
L
trifluoroacetic acid, CH2Cl2; (i) different 2-pyridinecarboxaldehyde derivatives, rt; (j) different 2-hydroxybenzaldehyde derivatives, rt.
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S. Xie et al. / Bioorg. Med. Chem. xxx (2015) xxx–xxx
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Table 1
Inhibition of MAOs and oxygen radical absorbance capacity (ORAC, Trolox equivalents) of 7a–7b, 8a–8i, clorgyline, pargyline and selegiline
H
N
H
N
N
H
N
N
N
O
HO
A
R3
N
N
7a
7b
8a-i
R1
SIb
R2
Compd
R
IC50
(l
M) SDa
ORACc
MAO-A IC50
MAO-B IC50
7a
7b
8a
8b
8c
8d
8e
8f
8g
8h
8i
Clorgyline
Pargyline
Selegiline
—
—
3.41 0.02
5.53 0.04
5.37 0.03
nt.
0.31 0.03
0.52 0.05
0.21 0.04
>1
11
1.49
1.78
4.20
2.44
4.35
3.81
4.52
4.44
2.26
2.10
5.67
nt.
10.6
25.6
—
—
3.3
—
2.2
—
—
2.4
—
—
R1 = R2 = R3 = H
R
R
R
R
R
1 = OCH3, R2 = R3 = H
2 = OCH3, R1 = R3 = H
3 = OCH3, R1 = R2 = H
3 = N(CH3)2, R1 = R2 = H
3 = Cl, R1 = R2 = H
nt.
>1
1.02 0.05
nt.
0.70 0.01
nt.
0.31 0.02
>1
0.31 0.06
>1
0.95 0.07
0.43 0.02
nt.
R3 = F, R1 = R2 = H
R
R
3 = NO2, R1 = R2 = H
3 = OH, R1 = R2 = H
nt.
1.03 0.06
0.0041
nt.
—
—
—
0.1880
0.0185 0.002
nt.
nt.
70.2 3.8
37945
a
b
c
Results are the mean of three independent experiments (n = 3) SD.
Selectivity ratio: IC50(MAO-A)/IC50(MAO-B).
The data are expressed as
l mol of Trolox equiv/l mol tested compound.
Figure 1. Docking pose of derivative 8a into human MAO-B (2V60) highlighting the protein residues that establish the main interactions with 8a. The FAD cofactor was
depicted using ball and stick representation.
fluorescein (ORAC-FL),20 and the vitamin E analogue Trolox was
used as a standard. The results in Table 1 indicate that all target
compounds exhibit excellent antioxidant capacity with ORAC-FL
values of 1.49–5.65 Trolox equivalents. Compound 8i, which fea-
tures two hydroxyls in the A ring, exhibits the best result (5.67
Trolox equivalents). Generally, compounds 8a–i exhibit better
activity (2.1–5.65 Trolox equivalents) than 7a–b (1.49–1.78
Trolox equivalents), which demonstrates that pyridyl is unfavour-
able for antioxidant capacity.
2.5. Metal-chelating properties of compound 8a
The metal-chelating ability of the target compounds with 8a as
an example was investigated using UV–vis spectrometry.21 The
results in Figure 2 show that 8a produces the maximum absorption
peaks at 236 and 276 nm. After CuSO4 was added to the solution of
8a, the maximum absorption at 276 nm shifted to 282 nm, and the
height of the peak at 236 nm obviously decreased, which demon-
strates the formation of an 8a–copper(II) complex. However, the
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S. Xie et al. / Bioorg. Med. Chem. xxx (2015) xxx–xxx
Figure 2. UV spectra of compound 8a (40 lM) alone and in the presence of 20 lM
CuSO4, FeSO4 or ZnCl2. All solutions were prepared using a HEPES buffer solution
(20 mM HEPES, 150 mM NaCl, pH 7.4).
specific absorbance at 236 nm and 276 nm slightly shifted when
FeSO4 or ZnCl2 was mixed with 8a, which suggests that 8a can
interact with iron(II) and zinc(II). To investigate the stoichiometry
of the 8aꢀCu(II) complex, high-resolution mass spectrometry was
performed (Fig. 3), and the peak of 675.6790, [2M+Cu]+ determi-
nes that the stoichiometry of the 8aꢀCu(II) complex is 2:1.
Figure 4. The inhibition of copper(II)-induced Ab1–42 aggregation by 7a, 8a, 8i and
CQ ([Ab1–42] = copper(II) = 25 M, [7a] = [8a] = [8i] = [CQ] = 50 M, 37 °C, 24 h).
Top: Scheme of the inhibition experiment. Bottom: Results of the ThT binding
assay. Statistical comparisons with control (Ab1–42 aggregation in the presence of
copper(II)) were performed by a one-way ANOVA followed by Dunnett’s multiple
comparison test using Graph Pad Prism 5.0 Software (level of significance ⁄⁄⁄p
<0.001).
l
l
2.6. Effects on Cu(II)-induced Ab1–42 aggregation using 8a, 8i,
and 7a
the brain penetration of the target compounds, the parallel artifi-
cial membrane permeation assay for the blood brain barrier
(PAMPA–BBB), which was described by Di et al.22 and successfully
applied by some of us to different classes of compounds. First, we
compared the permeability of 13 commercial drugs with reported
values to validate the assay. A plot of the experimental data
versus the reported values produced a good linear correlation: Pe
(exp.) = 1.4574Pe (bibil.) ꢀ 1.0773 (R2 = 0.9427). From this equation
and considering the limit established by Di et al. for blood–brain
barrier permeation, we found that molecules with a permeability
above 4.7 ꢁ 10ꢀ6 cm sꢀ1 would be able to cross the BBB by
passive permeation (CNS+). Pe values from 1.8 ꢁ 10ꢀ6 cm sꢀ1 to
4.7 ꢁ 10ꢀ6 cm sꢀ1 were classified as ‘CNS+/ꢀ’ (BBB permeation
uncertain). The results of the PAMPA–BBB assay of the tested
compounds are presented in Table 2, which indicated that 8a, 8d,
8e, 7a and 7b can cross the BBB, whereas the status of 8i is
uncertain.
To investigate the effects of the target compounds on metal-in-
duced Ab1–42 aggregation, we used the ThT fluorescence binding
assay to identify Cu(II)-induced Ab1–42 aggregation in the presence
of 8a, 8i and 7a with CQ as the reference.8 As shown in Figure 4, the
fluorescence of Ab1–42 treated with Cu(II) is 143% of that of Ab1–42
alone, which indicates that Ab1–42 aggregation is indeed acceler-
ated by Cu(II). In contrast, the fluorescence values of Ab1–42 treated
with Cu(II) and 8a, 8i, and 7a and CQ are obviously lower than that
of Ab1–42 alone (Ab1–42 alone: 100%; 8a: 69.10%; 8i: 40.37%; 7a:
63.09%; CQ: 68.25%), which suggests that our target compounds
can effectively inhibit the Cu(II)-induced Ab1–42 aggregation.
2.7. In vitro blood–brain barrier permeation assay
The ability to cross the blood–brain barrier (BBB) and reach
their therapeutic targets is important for CNS drugs. To evaluate
Figure 3. HRMS spectrum of 8aꢀCu(II) complex.
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S. Xie et al. / Bioorg. Med. Chem. xxx (2015) xxx–xxx
5
Table 2
mixture was stirred for 10 h, the organic phases were separated,
and the aqueous phase was extracted (EtOAc). The combined
organic layers were washed (brine), dried (Na2SO4), filtered, and
concentrated. The residue was purified using silica gel column
chromatography (PE/EA = 10) to produce compound 3 as a white
solid (75% yield). 1H NMR (400 MHz, CDCl3) d 7.32 (d, J = 8.4 Hz,
1H), 7.11 (d, J = 8.5 Hz, 1H), 6.59 (s, 1H), 3.62 (s, 1H), 2.12 (s, 1H),
1.50 (s, 4H).
Permeability (Pe ꢁ 10ꢀ6 cm sꢀ1) in the PAMPA-BBB assay for the selected compounds
and their predicted penetration into the CNS
Compda
Pe (ꢁ10ꢀ6 cm sꢀ1
)
Prediction
b
7a
7b
8a
8d
8e
8i
12.8 0.7
12.1 0.8
11.5 0.5
11.7 0.5
12.5 1.0
3.1 0.3
CNS+
CNS+
CNS+
CNS+
CNS+
CNS+/ꢀ
4.2.3. Synthesis procedure of tert-butyl(4-((R)-2-(((R)-1-
phenylethyl)amino)propyl)phenyl)carbamate (4)
a
Compounds were dissolved in DMSO at 5 mg/mL and diluted with PBS/EtOH
(70:30). The final concentration of compounds was 100 g/mL.
l
b
To a solution of 3 (3.0 mmol) and (R)-1-phenylethanamine
(3.0 mmol) in MeOH (10.0 mL), Pt/C (5% m/m) was added, and
the reaction mixture was charged with H2 atmosphere (20 bar).
After the solution was stirred at room temperature for 24 h, the
reaction mixture was filtered and concentrated. The residue was
purified using silica gel column chromatography to produce 4 as
a light yellow oil (90% yield). 1H NMR (400 MHz, CDCl3) d
7.37–7.25 (m, 4H), 7.19 (d, J = 8.4 Hz, 3H), 6.93 (d, J = 8.4 Hz, 2H),
6.37 (s, 1H), 3.64–3.69 (m, 1H), 2.97–3.02 (m, 1H), 2.85 (dd,
J = 13.1, 4.7 Hz, 1H), 2.30 (dd, J = 13.1, 9.3 Hz, 1H), 1.50 (s, 9H),
1.30 (d, J = 6.6 Hz, 3H), 0.87 (d, J = 6.6 Hz, 3H).
Values are expressed as the mean SD of three independent experiments.
3. Conclusion
In summary, we have developed a series of compounds by
merging the main pharmacophores of the MAO inhibitor selegiline
and biometal chelator clioquinol to treat Alzheimer’s disease. The
in vitro assays show that these compounds have both MAO-B inhi-
bition activities, antioxidant activity and biometal chelating ability,
which can effectively inhibit Cu(II)-induced Ab1–42 aggregation.
Among the compounds, compound 8a exhibits good inhibitory
4.2.4. Synthesis procedure of (R)-tert-butyl(4-(2-
potency toward MAO-B (IC50 = 0.21 lM) and good antioxidant
(methylamino)propyl)phenyl)carbamate (5)
activity (ORAC = 4.20). The parallel artificial membrane permeation
assay shows that most target compounds can cross the BBB. These
results indicate that compound 8a may be a good multifunctional
agent for the treatment of AD. Further studies based on these
results are in progress.
Pt (10% m/m) was slowly added to a mixture of compound 4
(5.0 mmol), formalin (3.0 mL) and methanol (15 mL), and the reac-
tion mixture was charged with H2 atmosphere. After the mixture
was stirred for 12 h, the catalyst was filtered away, and the filtrate
was evaporated in vacuum to produce a colourless oil. (f) To a solu-
tion of that oil (5.0 mmol) in methanol (10 mL), 10% Pd/C was
added, and the mixture was stirred in a hydrogen atmosphere
(1.5 MPa pressure) at 40 °C for 24 h. After the reaction was com-
pleted, the catalyst was filtered away, and the filtrate was evapo-
rated to produce 5 as a white oil (yield: 80%). 1H NMR (400 MHz,
CDCl3) d 7.41–7.20 (m, 2H), 7.11 (d, J = 8.4 Hz, 2H), 2.88–2.66 (m,
2H), 2.60 (dd, J = 13.2, 6.5 Hz, 1H), 2.41 (s, 3H), 1.51 (s, 9H), 1.07
(d, J = 6.2 Hz, 3H).
4. Experimental
4.1. Chemistry
The 1H NMR and 13C NMR spectra were collected on a Bruker
BioSpin GmbH spectrometer at 400 MHz with TMS as the internal
standard. The high-resolution mass spectra were obtained using a
Shimadzu LCMS-IT-TOF mass spectrometer. High-performance liq-
uid chromatography (HPLC), which was equipped with a TC-C18
4.2.5. Synthesis procedure of (R)-4-(2-(methyl(prop-2-yn-1-
yl)amino)propyl)aniline (6)
column (4.6 ꢁ 250 mm, 5
lm), was used to determine the purity
of the synthesised compounds.
(g) To a solution of 5 (3 mmol) and potassium carbonate
(4.5 mmol) in acetonitrile (20.0 mL), propargylbromide (80% in
toluene, 3 mmol) was slowly added. After the reaction mixture
was stirred in nitrogen atmosphere at room temperature for
12 h, the reaction mixture was filtered and concentrated to
produce a colourless oil (65% yield). (h) Trifluoroacetic acid was
slowly added to a solution of that oil (3 mmol) in dichloromethane
(15 mL) at 0 °C; then, the mixture was stirred at room temperature
for 8 h. After the solvent was evaporated in vacuum, the residue
was purified using silica gel column chromatography to produce
compound 6 as a colourless oil (90% yield). 1H NMR (400 MHz,
4.2. Synthesis procedure of intermediates 2-6
4.2.1. Synthesis procedure of 1-(4-nitrophenyl)propan-2-one (2)
In a stirred solution of 4-nitrophenyl acetic acid (0.05 mol,
1 equiv) in acetic anhydride (25 mL, 5 equiv), N-methylimidazole
(0.025 mol, 0.5 equiv) was added at room temperature. After stir-
ring for 6 h in nitrogen atmosphere, the reaction was quenched
by adding water (20 mL). The mixture was extracted (EtOAc),
washed (NaHCO3 and subsequently with H2O), dried (Na2SO4), fil-
tered and concentrated to give the product as a yellow solid (yield:
70%). 1H NMR (400 MHz, CDCl3): d 8.18 (d, J = 8.4 Hz, 2H), 7.35 (d,
J = 8.4 Hz, 2H), 3.84 (s, 2H), 2.23 (s, 3H).
CDCl3)
d 6.95 (d, J = 8.3 Hz, 2H), 6.67–6.49 (m, 2H), 3.41
(d, J = 1.6 Hz, 2H), 2.94–2.85 (m, 2H), 2.40 (s, 3H), 2.32–2.24
(m, 1H), 2.23 (s, 1H), 0.95 (d, J = 6.8 Hz, 3H).
4.2.2. Synthesis procedure of tert-butyl(4-(2-oxopropyl)
phenyl)carbamate (3)
4.3. General synthesis procedure of 7a–b and 8a–i
(b) To a solution of 2 (4.0 mmol) in MeOH (20.0 mL), Pd/C (5%
m/m) was added, and the reaction mixture was charged with H2
atmosphere. After the resulting solution was stirred at room tem-
perature for 4 h, the mixture was filtered and concentrated to pro-
duce a light yellow solid. (c) The yellow solid was dissolved in
25.0 mL of a THF and H2O mixture (1:1). After potassium carbonate
(4.0 mmol) was added to the mixture and stirred for 5 min, di-tert-
butyl dicarbonate (6.0 mmol) was added. After the reaction
To a solution of compound 6 (1 mmol) in ethanol (5 mL), alde-
hyde (1 mmol) was added, and the resulting mixture was stirred at
room temperature. After the substrates disappeared (monitored
using TLC), NaBH4 (3 mmol) was gradually added at 0 °C. After
the mixture was stirred for 1 h, water (10 mL) was added, and
the mixture was extracted using ethyl acetate. The organic phases
were evaporated in vacuum, and the residue was purified using sil-
ica gel column chromatography to produce the compounds.
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S. Xie et al. / Bioorg. Med. Chem. xxx (2015) xxx–xxx
4.3.1. (R)-N-((3-Methoxypyridin-2-yl)methyl)-4-(2-(methyl
(prop-2-yn-1-yl)amino)propyl)aniline (7a)
J = 8.3, 2.5 Hz, 1H), 4.34 (s, 2H), 3.78 (s, 3H), 3.41 (s, 2H), 3.03–
2.83 (m, 2H), 2.41 (s, 3H), 2.37–2.27 (m, 1H), 2.23 (t, J = 2.4 Hz,
1H), 0.96 (d, J = 6.7 Hz, 3H). 13C NMR (101 MHz, CDCl3) d 160.72,
158.01, 145.29, 132.68, 130.10, 129.21, 116.10, 115.23, 105.87,
102.23, 80.42, 72.50, 59.47, 55.31, 48.62, 43.15, 39.00, 37.47,
14.99. HRMS calcd for [MꢀH]ꢀ: 337.1922; found: 337.1926;
HPLC purity: 98.8%.
6-Methoxypyridine-2-carbaldehyde was treated with 7 accord-
ing to the general procedure to give the desired product 7a as an oil
(82% yield). IR: 3427, 3308, 2950, 2922, 1311, 1262, 794, 732 cmꢀ1
;
1H NMR (400 MHz, CDCl3) d 7.51 (dd, J = 8.1, 7.4 Hz, 1H), 6.99 (d,
J = 8.4 Hz, 2H), 6.89 (d, J = 7.3 Hz, 1H), 6.62 (dd, J = 8.6, 2.5 Hz,
3H), 4.33 (s, 2H), 3.95 (s, 3H), 3.41 (d, J = 1.6 Hz, 2H), 2.98–2.84
(m, 2H), 2.41 (s, 3H), 2.28 (dd, J = 12.6, 9.4 Hz, 1H), 2.23 (t,
J = 2.4 Hz, 1H), 0.96 (d, J = 6.7 Hz, 3H). 13C NMR (101 MHz, CDCl3)
d 163.84, 156.32, 146.32, 139.07, 130.01, 129.18, 114.06, 113.21,
108.75, 80.52, 72.43, 59.68, 53.32, 49.32, 43.13, 38.91, 37.52,
15.03. HRMS calcd for [M+H]+: 324.2070; found: 324.2069; HPLC
purity: 97.6%.
4.3.6. (R)-4-Methoxy-2-(((4-(2-(methyl(prop-2-yn-1-yl)
amino)propyl)phenyl)amino)methyl)phenol (8d)
2-Hydroxy-5-methoxybenzaldehyde was treated with 7 accord-
ing to the general procedure to give the desired product 8d as an
oil (73% yield). IR: 3411, 3288, 3228, 2952, 2930, 2121, 1267,
1201, 806, 736 cmꢀ1 1H NMR (400 MHz, CDCl3) d 7.09–6.98 (m,
;
2H), 6.78 (m, 5H), 4.34 (s, 2H), 3.76 (t, J = 1.7 Hz, 3H), 3.41 (s,
2H), 2.99–2.85 (m, 2H), 2.40 (d, J = 1.5 Hz, 3H), 2.31 (td, J = 11.0,
5.6 Hz, 1H), 2.24 (t, J = 2.1 Hz, 1H), 0.96 (d, J = 6.7 Hz, 3H). 13C
NMR (101 MHz, CDCl3) d 153.08, 150.58, 145.36, 132.40, 130.11,
123.90, 117.10, 115.82, 114.40, 113.93, 80.34, 72.60, 59.48, 55.81,
48.95, 43.14, 38.95, 37.48, 14.98. HRMS calcd for [MꢀH]ꢀ:
337.1922; found: 337.1919; HPLC purity: 96.2%.
4.3.2. (R)-4-(2-(Methyl(prop-2-yn-1-yl)amino)propyl)-N-
((3-methylpyridin-2-yl)methyl)aniline (7b)
6-Methyl-2-pyridinecarboxaldehyde was treated with 7 accord-
ing to the general procedure to give the desired product 7b as an
oil (76% yield). IR: 3392, 3297, 2961, 2924, 2100, 1316, 1259,
781, cmꢀ1 1H NMR (400 MHz, CDCl3) d 7.51 (t, J = 7.7 Hz, 1H),
;
7.13 (d, J = 7.7 Hz, 1H), 7.02 (d, J = 7.6 Hz, 1H), 6.98 (d, J = 8.4 Hz,
2H), 6.60 (d, J = 8.5 Hz, 2H), 4.39 (s, 2H), 3.41 (d, J = 1.9 Hz, 2H),
3.01–2.79 (m, 2H), 2.56 (s, 3H), 2.40 (s, 3H), 2.32–2.25 (m, 1H),
2.22 (t, J = 2.4 Hz, 1H), 0.95 (d, J = 6.7 Hz, 3H). 13C NMR (101 MHz,
CDCl3) d 158.01, 157.97, 146.25, 136.81, 129.99, 129.10, 121.54,
118.45, 113.11, 80.55, 72.38, 59.68, 49.65, 43.13, 38.92, 37.51,
24.43, 15.05. HRMS calcd for [M+H]+: 308.2121; found:
308.2115; HPLC purity: 99.4%.
4.3.7. (R)-4-(Dimethylamino)-2-(((4-(2-(methyl(prop-2-yn-1-yl)
amino)propyl)phenyl)amino)methyl)phenol (8e)
5-(Dimethylamino)-2-hydroxybenzaldehyde was treated with
7 according to the general procedure to give the desired product
8e as an oil (79% yield). IR: 3394, 3273, 3191, 2957, 2922, 2111,
1248, 1189, 807, 757 cmꢀ1 1H NMR (400 MHz, CDCl3) d 7.04 (d,
;
J = 8.4 Hz, 2H), 6.81 (d, J = 8.7 Hz, 1H), 6.77 (t, J = 5.5 Hz, 2H), 6.69
(d, J = 8.5 Hz, 1H), 6.63 (s, 1H), 4.34 (s, 2H), 3.42 (s, 2H), 3.00–
2.89 (m, 2H), 2.86 (s, 6H), 2.41 (s, 3H), 2.36–2.27 (m, 1H), 2.24 (t,
J = 2.4 Hz, 1H), 0.96 (d, J = 6.7 Hz, 3H). 13C NMR (101 MHz, CDCl3)
d 148.71, 145.59, 145.23, 132.18, 130.08, 123.57, 117.07, 115.72,
114.76, 114.55, 80.41, 72.55, 59.51, 49.23, 43.15, 41.96, 38.97,
37.49, 15.01. HRMS calcd for [MꢀH]ꢀ: 350.2238; found:
350.2242; HPLC purity: 97.6%.
4.3.3. (R)-2-(((4-(2-(Methyl(prop-2-yn-1-yl)amino)propyl)
phenyl)amino)methyl)phenol (8a)
2-Hydroxybenzaldehyde was treated with 7 according to the
general procedure to give the desired product 8a as a light yellow
oil (80% yield). IR: 3515, 3424, 3316, 2963, 2920, 2106, 1301, 1277,
1239, 758 cmꢀ1 1H NMR (400 MHz, CDCl3) d 7.25–7.18 (m, 1H),
;
7.18–7.12 (m, 1H), 7.05 (d, J = 8.4 Hz, 2H), 6.87 (m, 2H), 6.83–
6.72 (m, 2H), 4.40 (s, 2H), 3.42 (d, J = 1.4 Hz, 2H), 3.01–2.86 (m,
2H), 2.41 (s, 3H), 2.37–2.28 (m, 1H), 2.24 (s, 1H), 0.96 (d,
J = 6.7 Hz, 3H). 13C NMR (101 MHz, CDCl3) d 156.91, 145.25,
132.68, 130.12, 129.16, 128.64, 123.00, 119.96, 116.64, 116.02,
80.42, 72.49, 59.46, 49.08, 43.15, 39.01, 37.46, 15.00. HRMS calcd
for [MꢀH]ꢀ: 307.1816; found: 307.1816; purity: 96.8%.
4.3.8. (R)-4-Chloro-2-(((4-(2-(methyl(prop-2-yn-1-yl)amino)
propyl)phenyl)amino)methyl)phenol (8f)
5-Chloro-2-hydroxybenzaldehyde was treated with 7 according
to the general procedure to give the desired product 8f as an oil
(83% yield). IR: 3445, 3294, 2968, 2925, 2122, 1270, 1251, 814,
736 cmꢀ1 1H NMR (400 MHz, CDCl3) d 7.14 (dt, J = 7.3, 2.4 Hz,
;
2H), 7.05 (d, J = 8.4 Hz, 2H), 6.79 (d, J = 8.4 Hz, 1H), 6.75 (d,
J = 8.4 Hz, 2H), 4.35 (s, 2H), 3.41 (s, 2H), 2.99–2.86 (m, 2H), 2.40
(s, 3H), 2.37–2.28 (m, 1H), 2.24 (t, J = 2.4 Hz, 1H), 0.96 (d,
J = 6.6 Hz, 3H). 13C NMR (101 MHz, CDCl3) d 155.54, 144.94,
132.79, 130.18, 128.78, 128.21, 124.65, 124.46, 117.91, 116.02,
80.25, 72.69, 59.44, 48.65, 43.13, 38.92, 37.44, 14.93. HRMS calcd
for [MꢀH]ꢀ: 341.1426; found: 341.1434; HPLC purity: 98.5%.
4.3.4. (R)-2-Methoxy-6-(((4-(2-(methyl(prop-2-yn-1-yl)amino)
propyl)phenyl)amino)methyl)phenol (8b)
2-Hydroxy-3-methoxybenzaldehyde was treated with 7 accord-
ing to the general procedure to give the desired product 8b as an
oil (75% yield). IR: 3516, 3392, 3303, 2967, 2920, 2107, 1265,
;
1217, 1188, 735 cmꢀ1 1H NMR (400 MHz, CDCl3) d 6.99 (d,
J = 8.4 Hz, 2H), 6.89 (p, J = 4.0 Hz, 1H), 6.83–6.77 (m, 2H), 6.65 (d,
J = 8.5 Hz, 2H), 4.36 (s, 2H), 3.88 (s, 3H), 3.42 (d, J = 1.9 Hz, 2H),
2.98–2.83 (m, 2H), 2.41 (s, 3H), 2.28 (d, J = 3.2 Hz, 1H), 2.23 (t,
J = 2.4 Hz, 1H), 0.96 (d, J = 6.7 Hz, 3H). 13C NMR (101 MHz, CDCl3)
d 146.91, 146.25, 144.33, 129.98, 129.94, 124.81, 121.17, 119.54,
113.94, 110.08, 80.52, 72.46, 59.66, 56.04, 44.78, 43.13, 38.93,
37.52, 15.04. HRMS calcd for [M+H]+: 339.2067; found:
339.2082; HPLC purity: 96.5%.
4.3.9. (R)-4-Fluoro-2-(((4-(2-(methyl(prop-2-yn-1-yl)amino)
propyl)phenyl)amino)methyl)phenol (8g)
5-Fluoro-2-hydroxybenzaldehyde was treated with 7 according
to the general procedure to give the desired product 8g as an oil
(85%yield). IR: 3345, 3295, 3137, 2966, 2929, 2103, 1286, 1248,
819, 722 cmꢀ1 1H NMR (400 MHz, CDCl3) d 7.05 (d, J = 8.4 Hz,
;
2H), 6.94–6.83 (m, 2H), 6.83–6.78 (m, 1H), 6.76 (d, J = 8.5 Hz,
2H), 4.36 (d, J = 3.2 Hz, 2H), 3.41 (s, 2H), 2.99–2.85 (m, 2H), 2.40
(s, 3H), 2.37–2.27 (m, 1H), 2.23 (t, J = 2.4 Hz, 1H), 0.96 (d,
4.3.5. (R)-5-Methoxy-2-(((4-(2-(methyl(prop-2-yn-1-yl)amino)
propyl)phenyl)amino)methyl)phenol (8c)
J = 6.7 Hz, 3H). 13C NMR (101 MHz, CDCl3)
d 156.44 (d,
2-Hydroxy-4-methoxybenzaldehyde was treated with 7 accord-
ing to the general procedure to give the desired product 8c as an oil
(82%yield). IR: 3396, 3305, 3264, 2960, 2926, 2116, 1323, 1283,
J = 237.6 Hz), 152.83 (d, J = 2.1 Hz), 144.95, 132.91, 130.17,
124.02 (d, J = 6.7 Hz), 117.39 (d, J = 7.9 Hz), 116.02, 115.08 (d,
J = 59.59 Hz), 115.08 (d, J = 13.8 Hz), 80.38, 72.53, 59.44, 48.86,
43.15, 38.99, 37.46, 14.97. HRMS calcd for [M+H]+: 327.1867;
found: 327.1873; HPLC purity: 95.8%.
758, 712 cmꢀ1 1H NMR (400 MHz, CDCl3) d 7.04 (dd, J = 10.3,
;
8.4 Hz, 3H), 6.87–6.74 (m, 2H), 6.47 (d, J = 2.5 Hz, 1H), 6.43 (dd,
Please cite this article in press as: Xie, S.; et al. Bioorg. Med. Chem. (2015), http://dx.doi.org/10.1016/j.bmc.2015.04.009

S. Xie et al. / Bioorg. Med. Chem. xxx (2015) xxx–xxx
7
4.3.10. (R)-2-(((4-(2-(Methyl(prop-2-yn-1-yl)amino)propyl)
phenyl)amino)methyl)-4-nitrophenol (8h)
(2000
ꢀ80 °C. For the copper-induced Ab1–42 aggregation experiment,
the stock solution was diluted with 20 M HEPES (pH = 6.6),
150 M NaCl. Inhibition aggregation experiment: a mixture of
the peptide with or without copper and tested compound was
incubated at 37 °C for 24 h and subsequently diluted to a final vol-
lM), which was aliquoted into small samples and stored at
2-Hydroxy-5-nitrobenzaldehyde was treated with 7 according
to the general procedure to give the desired product 8h as an oil
(86% yield). IR: 3240, 3286, 2968, 2923, 2128, 1334, 1285 828,
l
l
752 cmꢀ1
;
1H NMR (400 MHz, CDCl3) d 8.16–8.03 (m, 2H), 7.05
(d, J = 8.4 Hz, 2H), 6.90–6.83 (m, 1H), 6.75 (d, J = 8.4 Hz, 2H), 4.47
(s, 2H), 3.48 (s, 2H), 2.98–2.85 (m, 2H), 2.40 (s, 3H), 2.37–2.27
(m, 1H), 2.23 (t, J = 2.4 Hz, 1H), 0.95 (d, J = 6.6 Hz, 3H). 13C NMR
ume of 200
contained thioflavin T (5
intensity was performed (kexc = 450 nm; kem = 485 nm), and values
at the plateau were averaged after subtracting the background flu-
orescence of thioflavin T solution.
l
L with 50 mM glycine–NaOH buffer (pH 8.0), which
lM). A 300-s time scan of fluorescence
(101 MHz, CDCl3)
d 163.60, 144.41, 139.20, 133.28, 130.26,
125.32, 124.60, 123.69, 116.90, 116.18, 80.24, 72.63, 59.38, 48.61,
43.12, 38.97, 37.40, 14.88. HRMS calcd for [MꢀH]ꢀ: 352.1667;
found: 352.1661; HPLC purity: 97.2%.
4.4.4. Oxygen radical absorbance capacity (ORAC-FL) assay
The fluorescein (FL) stock solution and the tested compound
4.3.11. (R)-2-(((4-(2-(Methyl(prop-2-yn-1-yl)amino)propyl)
phenyl)amino)methyl)benzene-1,4-diol (8i)
were diluted with phosphate buffer (75 mM, pH 7.4) to 0.117
and 20 M, respectively. The solution of ( )-6-hydroxy-2,5,7,8-te-
tramethylchroman-2-carboxylic acid (Trolox) was diluted with
lM
l
2,5-Dihydroxybenzaldehyde was treated with 7 according to
the general procedure to give the desired product 8i as an oil
(77% yield). IR: 3408, 3281, 2961, 2924, 2120, 1264, 1199, 811,
the same buffer to 100, 80, 60, 50, 40, 20, and 10 lM. The solution
of 2,20-azobis-(amidinopropane) dihydrochloride (AAPH) was pre-
pared before the experiment by dissolving 108.4 mg AAPH in
10 mL 75 mM phosphate buffer (pH 7.4) to 40 mM. The mixture
729 cmꢀ1 1H NMR (400 MHz, CDCl3) d 7.00 (d, J = 8.4 Hz, 2H),
;
6.72 (d, J = 8.4 Hz, 3H), 6.69–6.62 (m, 2H), 4.27 (s, 2H), 3.42 (s,
2H), 2.93 (tt, J = 10.7, 5.2 Hz, 2H), 2.41 (s, 3H), 2.31 (dd, J = 14.0,
10.7 Hz, 1H), 2.25 (t, J = 2.4 Hz, 1H), 0.96 (d, J = 6.4 Hz, 3H). 13C
NMR (101 MHz, CDCl3) d 150.04, 149.22, 145.43, 132.06, 130.10,
124.10, 117.19, 115.77, 115.63, 79.93, 72.99, 59.49, 48.57, 43.08,
38.85, 37.44, 14.79. HRMS calcd for [MꢀH]ꢀ: 323.1765; found:
323.1770; HPLC purity: 98.3%.
of the tested compound (20
centration) was pre-incubated for 10 min at 37 °C; then, 60
l
L) and FL (120
l
L; 70 nM, final con-
L of
l
the AAPH solution was added. The fluorescence was recorded every
minute for 120 min (kexc = 485 nm; kem = 520 nm). The fluores-
cence measurements were normalised to the curve of the blank
(without antioxidant). The ORAC-FL values were calculated as pre-
viously described.
4.4. Biological assays
4.4.5. Metal-chelating study
4.4.1. In vitro inhibition of monoamine oxidase
The chelating studies were performed using a UV–vis spec-
trophotometer. The absorption spectra of each compound, alone
or in the presence of CuSO4, FeSO4 or ZnCl2 for 30 min, were
recorded at room temperature. The stoichiometry of the complex
compound-Cu2+ was determined using high-resolution mass spec-
trometry. From separate solutions of the compound and CuSO4, the
solutions were obtained if the sum of the concentrations of both
species was constant in all samples but the proportions of both
components varied between 0% and 100%.
Recombinant hMAO-A and hMAO-B from Sigma–Aldrich were
adjusted to 12.5
compound, and 80
in a flat, black-bottomed 96-well microtest plate in the dark.
Amplex Red reagent (200 M), horseradish peroxidase (2 U/mL),
lg/mL and 75
lg/mL, respectively, of the test
lL of MAO was incubated for 15 min at 37 °C
l
and p-tyramine (2 mM) for hMAO-A or benzylamine (2 mM) for
hMAO-B were added to start the reaction. After 20 min of incuba-
tion at 37 °C, the assay was quantified in a multidetection micro-
plate fluorescence reader based on the generated fluorescence
(excitation, 545 nm; emission, 590 nm). The specific fluorescence
emission was calculated after subtracting the background activity,
which was determined from vials that contained all components
except the hMAO isoforms, which were replaced by a sodium
phosphate buffer solution.
4.4.6. In vitro blood–brain barrier permeation assay
The brain penetration of the compounds was evaluated using a
parallel artificial membrane permeation assay (PAMPA), which was
described by Di et al. Commercial drugs were purchased from
Sigma and Alfa Aesar. The porcine brain lipid (PBL) was obtained
from Avanti Polar Lipids. The donor microplate (PVDF membrane,
pore size 0.45 mm) and the acceptor microplate were obtained
from Millipore. The 96-well UV plate (COSTARÒ) was obtained
from Corning Incorporated. The acceptor 96-well microplate was
4.4.2. Docking study
The simulation system was built based on the structure
obtained from the Protein Data Bank (PDB: 2V60 for MAO-B). The
heteroatoms and water molecules were removed, and all hydrogen
atoms were subsequently added to the protein. Then force field
was assigned to the enzyme. The ligand binding site was defined
as 13 Å from the original ligand. Prior to the docking calculations,
the original ligand was removed. The 3D structures of compound
10 were generated and optimised with the Discovery Studio 2.1
package (Accelrys Inc., San Diego, CA).
The CDOCKER program of the Discovery Studio 2.1 software,
which allows full flexibility of ligands, was used to perform dock-
ing simulations. The docking and subsequent scoring were per-
formed using the default parameters of the CDOCKER program.
CDOCKER_INTERACTION_ENERGY is used like a score where a
lower value indicates a more favourable binding.
filled with 300
was impregnated with 4
The compounds were dissolved in DMSO at 5 mg mLꢀ1 and diluted
50-fold in PBS/EtOH (7:3) to obtain concentration of
100 mg mLꢀ1; then, 200
L was added to the donor wells. The
l
L of PBS/EtOH (7:3), and the filter membrane
l
L of PBL in dodecane (20 mg mLꢀ1).
a
l
acceptor filter plate was carefully put on the donor plate to form
a sandwich, which was left undisturbed for 10 h at 25 °C. After
incubation, the donor plate was carefully removed, and the con-
centrations of the compounds in the acceptor wells were deter-
mined using the UV plate reader (FlexstationÒ 3). Every sample
was analysed at five wavelengths, in four wells, and in at least
three independent runs, and the results are given as the
mean standard deviation. In each experiment, 13 quality control
standards with known BBB permeability were included to validate
the analysis set. A plot of experimental data versus bibliographic
4.4.3. ThT assay
Ab1–42 (Millipore, counter ion: NaOH) was dissolved in a solu-
tion of ammonium hydroxide (1%) to produce a stock solution
values gives a good linear correlation: Pe (exp.) = 1.4574Pe
(bibil.) ꢀ 1.0773 (R2 = 0.9427). Based on this equation and
Please cite this article in press as: Xie, S.; et al. Bioorg. Med. Chem. (2015), http://dx.doi.org/10.1016/j.bmc.2015.04.009

8
S. Xie et al. / Bioorg. Med. Chem. xxx (2015) xxx–xxx
10. (a) Song, M.-S.; Matveychuk, D.; MacKenzie, E. M.; Duchcherer, M.; Mousseau,
D. D.; Baker, G. B. Prog. Neuro-Psychoph. 2013, 44, 118; (b) Zheng, H.; Amit, T.;
Bar-Am, O.; Fridkin, M.; Youdim, M. B. H.; Mandel, S. A. J. Alzheimer’s Dis. 2012,
30(1), 1.
11. Kalgutkar, A. S.; Dalvie, D. K.; Castagnoli, N.; Taylor, T. J. Chem. Res. Toxicol.
2001, 14(9), 1139.
12. Riederer, P.; Danielczyk, W.; Grünblatt, E. Neurotoxicology 2004, 25, 271.
13. (a) Luo, Z.; Sheng, J.; Sun, Y.; Lu, C.; Yan, J.; Liu, A.; Luo, H.-B.; Huang, L.; Li, X. J.
Med. Chem. 2013, 56(22), 9089; (b) Luo, Z.; Liang, L.; Sheng, J.; Pang, Y.; Li, J.;
Huang, L.; Li, X. Bioorg. Med. Chem. 2014, 22(4), 1355; (c) Su, T.; Xie, S.; Wei, H.;
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considering the limit established by Di et al. for blood–brain barrier
permeation, we found that the compounds with permeability
above 4.7 ꢁ 10ꢀ6 cm sꢀ1 could cross the blood–brain barrier.
Acknowledgments
We thank the Natural Science Foundation of China (No.
21302235),
Guangdong
Natural
Science
Foundation
(2014A030313124) and the Ph.D. Programs Foundation of the
Ministry of Education of China (20120171120045) for financial
support of this study.
14. Youdim, M. B. H.; Amit, T.; Bar-Am, O.; Weinreb, O.; Yogev-Falach, M. Neurotox.
Res. 2006, 10(3/4), 181.
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16. Tran, K.-V.; Bickar, D. J. Org. Chem. 2006, 71(17), 6640.
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Please cite this article in press as: Xie, S.; et al. Bioorg. Med. Chem. (2015), http://dx.doi.org/10.1016/j.bmc.2015.04.009