Acetophenone derivatives: Novel and potent small molecule inhibitors of monoamine oxidase B

Article abstract of DOI:10.1039/c5md00357a

Two series of acetophenone derivatives have been designed, synthesized and evaluated for human monoamine oxidase A and B inhibitory activity in vitro. Most of the tested compounds acted preferentially on MAO-B with IC₅₀ values in the nanomolar range and weak or no inhibition of MAO-A. In particular, compounds 1j (IC₅₀ = 12.9 nM) and 2e (IC₅₀ = 11.7 nM) were the most potent MAO-B inhibitors being 2.76- and 2.99-fold more active than selegiline. In addition, the structure-activity relationships for MAO-B inhibition indicated that substituents at C3 and C4 of the acetophenone moiety, particularly with the halogen substituted benzyloxy, were more favorable for MAO-B inhibition. Molecular docking and kinetic studies have been carried out to explain the binding modes of MAO-B with the acetophenone derivatives. Furthermore, the representative compounds 1j and 2e showed low neurotoxicity in SH-SY5Y cells. It may be concluded that the acetophenone derivatives could be used to develop promising lead compounds for treating neurodegenerative diseases.

Full text of DOI:10.1039/c5md00357a

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Acetophenone derivatives: novel and potent small
molecule inhibitors of monoamine oxidase B†
Cite this: DOI: 10.1039/c5md00357a
*
Zhi-Min Wang, Xue-Mei Li, Wei Xu, Fan Li, Jin Wang, Ling-Yi Kong
*
and Xiao-Bing Wang
Two series of acetophenone derivatives have been designed, synthesized and evaluated for human mono-
amine oxidase A and B inhibitory activity in vitro. Most of the tested compounds acted preferentially on
MAO-B with IC50 values in the nanomolar range and weak or no inhibition of MAO-A. In particular, com-
pounds 1j (IC50 = 12.9 nM) and 2e (IC50 = 11.7 nM) were the most potent MAO-B inhibitors being 2.76- and
2.99-fold more active than selegiline. In addition, the structure–activity relationships for MAO-B inhibition
indicated that substituents at C3 and C4 of the acetophenone moiety, particularly with the halogen
substituted benzyloxy, were more favorable for MAO-B inhibition. Molecular docking and kinetic studies
have been carried out to explain the binding modes of MAO-B with the acetophenone derivatives. Further-
more, the representative compounds 1j and 2e showed low neurotoxicity in SH-SY5Y cells. It may be con-
cluded that the acetophenone derivatives could be used to develop promising lead compounds for treating
neurodegenerative diseases.
Received 20th August 2015,
Accepted 5th October 2015
DOI: 10.1039/c5md00357a
www.rsc.org/medchemcomm
single hydrophobic cavity. On the contrary, the active site of
MAO-B consists of two distinct cavities: one is the so-called
Introduction
Monoamine oxidase (MAO, EC 1.4.3.4) is a flavoenzyme that
plays an essential role in the regulation and metabolism of
amine neurotransmitters in the peripheral tissues and central
nervous system (CNS).1,2 Two isoforms of MAOs have been
identified in mammals and named MAO-A and MAO-B, which
were recognized on account of differences in immunological
properties, inhibitor specificity, amino acid sequences, sub-
strate preference and tissue distribution.3–5 MAO-A displays
higher affinity for the substrates norepinephrine and seroto-
nin (5-HT) than MAO-B and is inhibited by low concentra-
tions of clorgyline and preferentially metabolizes epinephrine,
5-hydroxytryptamine (5-HT) and norepinephrine (NE), whereas
MAO-B exhibits higher affinity toward benzylamine and phen-
ylethylamine (PEA) and is potently inhibited by selegiline and
rasagiline. Both enzymes can metabolize tryptamine, dopa-
mine (DA) and tyramine.6–9
“entrance cavity”, which is located towards the outside of the
protein, and another larger cavity called “substrate cavity” is
connected to the flavin adenine dinucleotide cofactor (FAD).
There are narrow pockets in these cavities of both isoen-
zymes, and the Tyr 326 and Ile 199 residues in MAO-B act as
a bottleneck and thus form a gate, which separates the region
as two cavities.11,12
Since the main role of the MAOs in the CNS is to termi-
nate the actions of neurotransmitter amines, they are consid-
ered attractive drug targets for the treatment of psychiatric
and neurological disorders. Selective inhibitors of MAO-A are
effective in the therapy of depression, while selective MAO-B
inhibitors have been applied alone or in combination to treat
Parkinson's and Alzheimer's diseases.13,14 Thus, the develop-
ment of specific MAO-B inhibitors could lead to clinically
useful neurological disorder therapeutic drugs.
Recent studies on crystal structures of the two MAO iso-
forms provide information about the pharmacophoric
requirements and the selective interactions, which are useful
to design potent and selective inhibitors.10 MAO-A has a
To search for novel MAO-B inhibitors, a variety of
benzyloxy substituted molecules have been developed as
promising scaffolds with inhibitory activities in the nano-
molar range (Fig. 1).15–25 These MAO-B inhibitors are related
to natural compounds such as coumarins, indoles,
chromones, chromanones, a-tetralone and phthalide ana-
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. E-mail: cpu_lykong@126.com, xbwang@cpu.edu.cn;
Fax: +86 25 8327 1405; Tel: +86 25 8327 1405
logues. In
a recent study, Petzer and colleagues have
disclosed that substituted 2-acetylphenols were promising
leads for the design of MAO-B inhibitors.24 Because the struc-
tural features of these MAO-B inhibitors with benzyloxy sub-
stituents are substantially similar, we explored the probability
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
c5md00357a
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Fig. 1 Structures of some known MAO inhibitors.
that the simplified acetophenones may also have potential
MAO-B inhibitory properties (Fig. 2). In order to obtain the
small molecule MAO-B inhibitors, our work was focused on
modifying the molecular structure of the potent MAO-B
inhibitors by introducing different benzyloxy substituents at
C3 and C4 of the acetophenone ring. To further examine the
structure–activity relationships (SAR) against MAO-B, differ-
ent substitutions (F, Cl, Br, CH3, NO2 and CF3) were
introduced to the benzyloxy ring, and the properties on MAO-
A and MAO-B inhibition were examined.
Results and discussion
Chemistry
The acetophenone derivatives (1a–1u and 2a–2m) were effi-
ciently synthesized using the pathway shown in Scheme 1.
Fig. 2 Design strategy for the novel series of acetophenone derivatives as MAO-B inhibitors.
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The corresponding IC50 values and MAO-B selectivity
ratios are shown in Table 1. Based on the screening data, it
could be seen that most of the tested compounds were selec-
tive inhibitors toward MAO-B with IC50 values in the nano-
molar range. MAO-A inhibition was very weak, and no appar-
ent structure–activity relationship existed. Among the two
series of synthesized compounds, 1j and 2e were the most
potent inhibitors against MAO-B (1j, IC50 = 12.9 nM, SI >
7752; 2e, IC50 = 11.7 nM, SI = 3393), being about 623-fold and
687-fold more active than iproniazid.
Scheme 1 Syntheses of acetophenone derivatives 1a–1u and 2a–2m.
Reagents and conditions: (a) K2CO3, CH3CN, reflux, 8 h.
Initially, to introduce benzyloxy substitution at C4 and C3
of 4-hydroxyacetophenone (1) and 3-hydroxyacetophenone (2),
respectively, compounds 1a and 2a were synthesized. As
shown in Table 1, the 4-benzyloxy acetophenone 1a exhibited
an IC50 value of 110 nM for MAO-B which was more active
than the 3-benzyloxy acetophenone 2a (IC50 = 1.95 μM for
MAO-B). From this result, it might be concluded that the
benzyloxy substitution at C4 of acetophenone was more suit-
able for volume of the substrate/inhibitor binding pockets
than that of 3-benzyloxy acetophenone. Then, we thought of
introducing substituents with varying positions and
electronic properties to benzyloxy substitution to study the
possible effects on MAO-B inhibition potency. It is notewor-
thy that the benzyloxy acetophenones substituted at the meta
and para positions were more potent than the corresponding
ortho position (1e, 1h, 1n and 1q) and unsubstituted (1a)
derivatives. Compounds 1h–1p and 1t–1u are both bearing
halogens (electron-withdrawing groups) which exhibited rela-
tively large enhancement of MAO-B inhibition. However, 1b–1d
substituted with methyl (electron-donating group) showed a
slight decrease in MAO-B inhibition. Furthermore, interest-
ingly, compounds with trifluoromethyl substitution (1q–1s)
of the benzyloxy phenyl ring were more potent for MAO-B
inhibition than those with nitrile substitution (1e–1g).
Moreover, to introduce benzyloxy substituents to the
3-position of acetophenone to study the possible effects on
MAO inhibition, compounds 2a–2m were synthesized. Com-
pared to compounds 2b–2g (halogen substitution), the same
behaviors were observed for the apparent increase in MAO-B
inhibition. Additionally, methyl- and nitrile-substituted
benzyloxy acetophenones (2h–2i and 2l–2m) were associated
with a slight decrease in MAO-B inhibition potency.
Overall, these results demonstrate that substitution with a
wide variety of benzyloxy side chains at C4 and C3 of
acetophenone led to structures with potent MAO-B inhibition
activity. In contrast, these derivatives were relatively weak
MAO-A inhibitors. No clear SAR trend can be obtained from
the data, but it seems that compounds (1f, 1n–1p, 2d–2e and
2m) bearing nitrile and chloro substituents showed a slight
increase in MAO-A inhibitory activities. All these results indi-
cated that the simplified benzyloxy acetophenones were
potent and selective MAO-B inhibitors.
The commercially available starting materials 4-hydroxy-
acetophenone (1) and 3-hydroxyacetophenone (2) were reacted
with appropriate amounts of benzyl bromide in the presence
of K2CO3 to give the target compounds in good yields. All com-
pounds were purified by column chromatography. The struc-
tures of the compounds were verified by 1H NMR, 13C NMR
and mass spectrometry as cited in the experimental section.
Inhibition of MAO activity
The MAO inhibitory activities of compounds 1a–1u and
2a–2m were explored by measuring the effects on the produc-
tion of hydrogen peroxide from p-tyramine, according to the
reported Amplex Red MAO assay,26 with iproniazid as a refer-
ence. Human MAO-A and MAO-B were purchased from
Sigma-Aldrich. Briefly, 0.1 mL of sodium phosphate buffer
(0.05 mM, pH 7.4) containing the test drugs at various con-
centrations and adequate amounts of recombinant MAO-A or
MAO-B required and adjusted to obtain, under our experi-
mental conditions, the same reaction velocity, i.e., to oxidize
(in the control group) the same concentration of substrate,
165 pmol of p-tyramine per min (MAO-A: 1.1 μg protein;
specific activity: 150 nmol of p-tyramine oxidized to
p-hydroxyphenylacetaldehyde per min per mg of protein;
MAO-B: 7.5 μg protein; specific activity: 22 nmol of
p-tyramine transformed per min per mg of protein), were
incubated for 15 min at 37 °C in a flat-black-bottom 96-well
microtest plate placed in a dark fluorimeter chamber. After
this incubation period, the reaction was started by adding
200 μM (final concentration) Amplex Red reagent, 1 U per
mL of horseradish peroxidase, and 1 mM p-tyramine. The
production of H2O2, and consequently, of resorufin, was
quantified at 37 °C using a SpectraMax Paradigm (Molecular
Devices, Sunnyvale, CA) multi-mode detection platform
reader based on the fluorescence generated (excitation, 545
nm; emission, 590 nm). The specific fluorescence emission
was calculated after subtraction of the background activity.
The background activity was determined from wells
containing all components except the MAO isoforms, which
were replaced by a sodium phosphate buffer solution (0.05
mM, pH 7.4). The percent inhibition was calculated by the
following expression: (1 − IFi/IFc) × 100% in which IFi and
IFc are the fluorescence intensities obtained for MAOs in the
presence and absence of inhibitors after subtracting the
respective background.
Reversibility of MAO-B inhibition
MAO-B inhibitors could be classified as irreversible or revers-
ible because of the different interactions between the
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Table 1 MAO inhibitory activities of the synthesized compounds
Compounds
R
MAO-A inhibitiona (%)
MAO-B IC50b (nM)
Selectivity indexc
1
2
—
—
9.74
7.18
15.4%a
11.2%
—
—
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
1o
1p
1q
1r
1s
1t
1u
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
H-
8.19
42.9
32.3
5.96
110
77.1 3.4
86.3 6.0
102
284 30
104
96.5 4.6
56.9 1.3
83.1 2.4
12.9 0.8
27.3 1.6
67.9 3.2
84.1 5.8
311 25
21.5 1.6
63.2 3.1
183 16
58.2 1.7
77.8 7.2
214 12
85.6 4.9
1.95 0.17 μM
193 11
86.4 3.7
34.2 1.6
11.7 0.4
96.3 6.7
16.5 1.5
893 32
140
21.2 0.7
43.2 1.8
114 10
7
>909
>1297
>1159
>980
>352
493
>1036
>1757
>1203
>7752
>3663
1153
>1189
288
3874
1481
385
>1718
>1285
>467
>1168
>51.3
>518
>1157
1368
3393
>1038
2952
>112
>714
>4717
>2315
>877
1179
2-CH3-
3-CH3-
4-CH3-
2-NO2-
3-NO2-
4-NO2-
2-F-
5
34
51.3 2.9 μM
33.8
47.1
48.4
43.5
45.7
78.3 4.7 μM
44.3
89.6 9.3 μM
83.3 7.9 μM
93.6 6.4 μM
70.5 3.3 μM
48.9
26.4
48.3
23.2
31.0
31
49.6
46.8 3.9 μM
39.7 2.1 μM
49.1
48.7 1.8 μM
31.1
23.0
46.7
27.2
17.8
88.3 7.4 μM
81.5 6.9 μM
7.31 1.07 nM
6.18 0.15 μM
7
3-F-
4-F-
2, 4-F-
3, 4-F-
3, 4, 5-F-
2-Cl-
3-Cl-
4-Cl-
2-CF3-
3-CF3-
4-CF3-
3-Br-
4-Br-
H-
3-F-
4-F-
3-Cl-
4-Cl-
3-Br-
4-Br-
3-CH3-
4-CH3-
3-CF3-
4-CF3-
3-NO2-
4-NO2-
—
8
2l
2m
Selegiline
Clorgyline
Iproniazid
75.4 4.9
35.6 2.1
71.5 8.3 μM
8.04 0.46 μM
2289
<0.0001
0.77
—
—
a
b
c
The test concentration is 100 μM. IC50: 50% inhibitory concentration (means SEM of three experiments). Selectivity index = IC50 (MAO-
A)/IC50 (MAO-B).
inhibitors and the enzyme. As we know, irreversible MAO-B
inhibitors may display pharmacological side effects and
safety issues. For example, the side effects of selegiline,
which is induced by its amphetamine metabolites, are the
major drawbacks.27 Compared to irreversible MAO-B inhibi-
tors, the enzyme activity of reversible MAO-B inhibitors can
be recovered when the inhibitors are metabolized. Moreover,
the enzyme activity will decrease when the substrate concen-
tration increases. For these reasons, discovering novel revers-
ible MAO-B inhibitors may be valuable.
To evaluate whether the benzyloxy-substituted acetophen-
one derivatives were reversible or irreversible MAO-B inhibi-
tors, the time dependencies of inhibition were evaluated.28
Compounds 1j and 2e were selected as representative inhibi-
tors since they displayed the most potent MAO-B inhibitory
activities. Pargyline, a known irreversible MAO-B inhibitor,
was used as a reference compound. For a reversible inhibitor,
the MAO-B activity would almost be same, when the enzyme
is pre-incubated with a reversible inhibitor over different
time periods. In contrast, when the enzyme is pre-incubated
with an irreversible inhibitor (pargyline) over different time
periods, the MAO-B activity would show a time-dependent
reduction. Compounds 1j and 2e were pre-incubated with
MAO-B over different time periods (0–60 min) at a concentra-
tion of about two fold IC50. As shown in Fig. 3, we could
observe a slight increase in catalytic activities when 1j and 2e
were pre-incubated with MAO-B, and the results demon-
strated that 1j and 2e were not time-dependent MAO-B inhib-
itors. In contrast, treatment of MAO-B with pargyline led to a
time-dependent reduction in enzyme activity. These experi-
ments clearly indicated that the acetophenone derivatives
were reversible MAO-B inhibitors.
Kinetic study of MAO-B inhibition
Compounds 1j and 2e were also used to further investigate
the mode of MAO-B inhibition. The type of MAO-B inhibition
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hydrogen atoms were subsequently added to the proteins.
According to the inhibition results, compounds 1j and 2e
were selected as typical ligands. Compounds 1j and 2e were
drawn and then protonated using the protonate 3D protocol,
and energy was minimized using the MMFF94x force field in
MOE. When the enzymes and compounds were ready for the
docking study, 1j and 2e were docked into the active site of
the protein by the “Triangle Matcher” method. The Dock
scoring in MOE software was performed using the ASE scor-
ing function and force field was selected as the refinement
method. The best 10 poses of molecules were retained and
scored. After docking, the geometry of the resulting complex
was studied using MOE's pose viewer utility.
The 3D and 2D binding pictures are illustrated in Fig. 5.
As shown in Fig. 5A and B, compound 1j is located in
the well-known binding pocket of MAO-B,11 with the
F-substituted benzyl positioned at the bottom of the sub-
strate cavity. There was a π–π interaction formed between the
benzyloxy ring of the ligand (1j) and Tyr 398. In addition, the
acetophenone ring occupied the entrance cavity, which was a
hydrophobic subpocket existing only in the MAO-B isoform
and consisted of Leu 171, Ile 199, Tyr 326, Ile 316, Phe 99,
Pro 104 and Phe 168. Surprisingly, different interactions
between the ligand (2e) and MAO-B were observed in
Fig. 5C and D. A hydrogen bond formed between the car-
bonyl oxygen of the ligand and Tyr 435-OH, and the
acetophenone moiety occupied the substrate cavity. However,
no direct interaction between the ligands (1j and 2e) and the
MAO-A (PDB code 2Z5X) was observed in Fig. S1A–D (ESI†).
Fig. 3 The time-dependent inhibition of MAO-B by compounds 1j and
2e and pargyline. All compounds were pre-incubated for various
periods of time (0–60 min) with MAO-B at concentrations equal to
two-fold the IC50 values for the inhibition of the enzyme. After dilution
to concentrations equal to the IC50, the inhibitory rates were recorded.
was determined by Michaelis–Menten kinetic experiments.29
The catalytic rates were measured at five different p-tyramine
concentrations (50–500 μM), and each plot was constructed
at four different concentrations of 1j (0, 6, 12 and 25 nM)
and 2e (0, 5, 10 and 20 nM). The overlaid reciprocal
Lineweaver–Burk plots (Fig. 4) showed that the plots for dif-
ferent concentrations of 1j and 2e were linear and intersected
at the y-axis. This pattern indicated that 1j and 2e were com-
petitive MAO-B inhibitors, and these results further proved
that the acetophenone derivatives were reversible MAO-B
inhibitors.
Prediction of BBB penetration of the compounds
With the aim of developing CNS drugs, the ability of com-
pounds to cross the blood–brain barrier (BBB) plays an
important role. So in the drug discovery process, BBB perme-
ability properties should be determined as early as possible.33
To cross the BBB, molecules should meet the limiting terms
of Lipinski's rules:34 molecular weight (MW) less than 500,
the number of hydrogen bond donor atoms (HBD) less than
5, the number of hydrogen bond acceptor atoms (HBA) less
than 10, the calculated logarithm of the octanol–water
Molecular modeling study
In order to explain the binding modes of compounds 1j and
2e, the molecular docking study was performed using soft-
ware package MOE 2008.10.30 The X-ray crystal structures of
the hMAO-A (PDB 2Z5X) and hMAO-B (PDB 2V61) were
applied to build the starting model, which were obtained
from the Protein Data Bank (www.rcsb.org).31,32 Heteroatoms
and water molecules in the PDB files were removed, and all
Fig. 4 Kinetic study on the mechanism of MAO-B inhibition by compounds 1j (A) and 2e (B). The overlaid Lineweaver–Burk reciprocal plots of
MAO-B initial velocity at increasing substrate concentration (50–500 μM) in the absence of an inhibitor and in the presence of 1j (A) and 2e (B) are
shown. The lines were derived from a weighted least-squares analysis of the data points.
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Fig. 5 (A) 3D docking model of compound 1j with MAO-B. Atom colors: yellow—carbon atoms of 1j, gray—carbon atoms of residues of MAO-B,
dark blue—halogen atoms, red—oxygen atoms. The dashed lines represent the interactions between the protein and the ligand. (B) 2D schematic
diagram of the docking model of compound 1j with MAO-B. (C) 3D docking model of compound 2e with MAO-B. (D) 2D schematic diagram of the
docking model of compound 2e with MAO-B. The figure was prepared using the ligand interaction application in MOE. (For interpretation of the
references to color in this figure legend, the reader is referred to the web version of this article.)
partition coefficient (Clog P) less than 5, and the small polar
surface area less than 90 Å.2 The log BB is calculated using
the following equation: log BB = 0.0148 × PSA + 0.152 ×
Clog P + 0.130.22 Calculated log BB (Tables 2 and S1 ESI†)
for potential applications in the brain and defined by the
restrictive terms of Lipinski's rules, and all compounds
satisfied the possible brain penetration and drug-like
properties.
compounds 1j and 2e might be used to develop promising
drug candidates for the therapy of neurodegenerative
diseases.
Conclusions
In this work, two series of benzyloxy-substituted acetophen-
one derivatives were designed, synthesized and evaluated for
MAO inhibitory activity in vitro. It was observed that most of
the studied compounds were remarkably reversible, competi-
tive and selective MAO-B inhibitors with nanomolar inhibi-
tory potency. In particular, compounds 1j and 2e were the
most potent MAO-B inhibitors. The MAO inhibition data
indicated that substitutions at the C3 and C4 positions of the
acetophenone moiety, particularly with the halogen
substituted benzyloxy, were more favorable for MAO-B inhibi-
tion. Molecular docking analysis of compounds 1j and 2e
suggested that the potent MAO-B inhibition and high selec-
tivity might be ascribed to the π–π and hydrogen bond
Cell toxicity
Based on the results above, compounds 1j and 2e as the most
potent and selective inhibitors against MAO-B were selected
to further investigate the potential toxicity effect on SH-SY5Y
cells.35 After incubating the cells with compounds 1j and 2e
for 48 h, the cell viability was determined by the 3-(4,5-
dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) assay. As
shown in Fig. 6, the results revealed that compounds 1j and
2e at 3–50 μM did not have neurotoxicity. This suggested that
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Table 2 Physical properties of some representative compounds
Compounds
MWa
Clog Pa
HBAa
HBDa
PASa
Log BBa
1a
1d
1g
1j
1k
1l
1m
1p
1s
1u
2a
2c
2e
2g
2i
2k
2m
Rules
226.27
240.3
3.569
4.068
3.312
3.712
3.855
3.785
3.858
4.282
4.452
4.432
3.569
3.712
4.282
4.432
4.068
4.452
3.312
≤5.0
2
2
4
3
4
4
5
3
5
3
2
3
3
3
2
5
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
≤5
26.3
26.3
78.11
26.3
26.3
26.3
26.3
26.3
26.3
26.3
26.3
26.3
26.3
26.3
26.3
26.3
78.11
≤90
0.292248
0.368096
−0.513604
0.313984
0.33572
271.27
244.26
262.25
262.25
280.24
260.72
294.27
305.17
226.27
244.26
260.72
305.17
240.3
0.32508
0.336176
0.400624
0.426464
0.423424
0.292248
0.313984
0.400624
0.423424
0.368096
0.426464
−0.513604
≥−1.0
294.27
271.27
≤450
4
≤10
a
MW: molecular weight; Clog P: calculated logarithm of the octanol–water partition coefficient; HBA: hydrogen-bond acceptor atoms; HBD:
hydrogen-bond donor atoms; PSA: polar surface area; log BB = 0.0148 × PSA + 0.152 × Clog P + 0.130.
interactions and the larger set of residues interacting with
MAO-B, respectively. Finally, due to the possible BBB perme-
ability and low neurotoxicity in SH-SY5Y cells, these com-
pounds could be used to develop promising drug candidates
for the therapy of neurodegenerative diseases.
using a Bruker ACF-500 spectrometer at 25 °C and referenced
to TMS. Chemical shifts are reported in ppm (δ) using the
residual solvent line as internal standard. Mass spectra were
obtained using an MS Agilent 1100 Series LC/MSD Trap mass
spectrometer (ESI-MS) and a Mariner ESI-TOF spectrometer
(HRESI-MS), respectively.
Experimental
General
General procedure for the preparation of acetophenone
derivatives (1a–1u)36,37
All common reagents and solvents were obtained from com-
mercial suppliers and used without further purification. The
reaction progress was monitored using analytical thin layer
chromatography (TLC) on precoated silica gel GF254 plates
(Qingdao Haiyang Chemical Plant, Qingdao, China), and the
spots were detected under UV light (254 nm). Column chro-
matography was performed on silica gel (90–150 μm; Qing-
dao Marine Chemical Inc.) Melting point was measured
using an XT-4 micromelting point instrument and
uncorrected. 1H NMR and 13C NMR spectra were measured
1-(4-Hydroxyphenyl)ethanone (1.0 mmol) was suspended in
acetonitrile (20 mL) containing K2CO3 (2.0 mmol). The reac-
tion was treated with appropriately substituted arylalkyl bro-
mide (1.2 mmol) and heated under reflux for 8 h. The reac-
tion progress was monitored using silica gel TLC with
petroleum ether/ethyl acetate as the mobile phase. Upon
completion, the acetonitrile was evaporated in vacuo and the
mixture was then poured into water, which was extracted
with 3 × 100 mL of EtOAc, washed with brine, dried over
anhydrous Na2SO4 and purified by chromatography (PE/EA)
on silica gel.
1-(4-(Benzyloxy)phenyl)ethanone (1a)
Yield 92%, white solid, m.p. 92–94 °C; 1H NMR (500 MHz,
DMSO) δ 7.95 (d, J = 8.8 Hz, 2H), 7.48 (d, J = 7.2 Hz, 2H), 7.42
(t, J = 7.4 Hz, 2H), 7.37 (d, J = 7.2 Hz, 1H), 7.14 (d, J = 8.8 Hz,
2H), 5.23 (s, 2H), 2.53 (s, 3H); 13C NMR (126 MHz, DMSO) δ
196.71, 162.67, 137.01, 130.93, 130.62, 130.62, 128.96, 128.96,
128.46, 128.21, 128.21, 115.16, 115.16, 70.02, 26.84. ESI-MS
m/z: 226.9 [M + H]+; HRMS (ESI) m/z 227.1066 [M + H]+ (calcd
for 227.1067, C15H15O2).
1-(4-((2-Methylbenzyl)oxy)phenyl)ethanone (1b)
Yield 90%, white solid, m.p. 97–99 °C; 1H NMR (500 MHz,
DMSO) δ 7.96 (d, J = 8.8 Hz, 2H), 7.44 (d, J = 7.4 Hz, 1H),
Fig. 6 The cell viability of compounds 1j and 2e in SH-SY5Y cells at
3.125–50 μM.
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7.32–7.19 (m, 3H), 7.16 (d, J = 8.8 Hz, 2H), 5.21 (s, 2H), 2.54
(s, 3H), 2.35 (s, 3H); 13C NMR (126 MHz, DMSO) δ 196.72,
162.80, 137.14, 134.90, 130.94, 130.94, 130.69, 130.65, 129.07,
128.71, 126.30, 115.10, 115.10, 68.78, 26.85, 18.92. ESI-MS m/
z: 240.9 [M + H]+; HRMS (ESI) m/z 241.1225 [M + H]+ (calcd
for 241.1223, C16H17O2).
HRMS (ESI) m/z 272.0918 [M + H]+ (calcd for 272.0917,
C15H14NO4).
1-(4-((2-Fluorobenzyl)oxy)phenyl)ethanone (1h)
Yield 87%, white solid, m.p. 87–88 °C; 1H NMR (500 MHz,
DMSO) δ 7.96 (d, J = 8.8 Hz, 2H), 7.59 (t, J = 7.5 Hz, 1H), 7.46
(td, J = 7.4, 1.6 Hz, 1H), 7.36–7.22 (m, 2H), 7.16 (d, J = 8.8 Hz,
2H), 5.27 (s, 2H), 2.54 (s, 3H); 13C NMR (126 MHz, DMSO) δ
196.74, 162.47, 131.25, 131.22, 131.11, 131.05, 130.96, 130.80,
125.07, 125.04, 116.01, 115.85, 115.06, 60.21, 26.87. ESI-MS
m/z: 244.9 [M + H]+; HRMS (ESI) m/z 245.0973 [M + H]+ (calcd
for 245.0974, C15H14FO2).
1-(4-((3-Methylbenzyl)oxy)phenyl)ethanone (1c)
Yield 85%, white solid, m.p. 70–72 °C; 1H NMR (500 MHz,
DMSO) δ 7.95 (d, J = 8.8 Hz, 2H), 7.34–7.24 (m, 3H), 7.17 (d, J
= 7.2 Hz, 1H), 7.13 (d, J = 8.8 Hz, 2H), 5.18 (s, 2H), 2.53 (s,
3H), 2.34 (s, 3H); 13C NMR (126 MHz, DMSO) δ 196.71,
162.72, 138.16, 136.92, 130.93, 130.93, 130.60, 129.10, 128.87,
128.76, 125.30, 115.13, 115.13, 70.06, 26.84, 21.44. ESI-MS m/
z: 240.9 [M + H]+; HRMS (ESI) m/z 241.1222 [M + H]+ (calcd
for 241.1223, C16H17O2).
1-(4-((3-Fluorobenzyl)oxy)phenyl)ethanone (1i)
Yield 83%, white solid, m.p. 82–83 °C; 1H NMR (500 MHz,
DMSO) δ 7.96 (d, J = 8.8 Hz, 2H), 7.47 (dd, J = 14.1, 8.0 Hz,
1H), 7.32 (dd, J = 8.0, 4.5 Hz, 2H), 7.19 (td, J = 8.7, 2.1 Hz,
1H), 7.14 (d, J = 8.8 Hz, 2H), 5.26 (s, 2H), 2.53 (s, 3H); 13C
NMR (126 MHz, DMSO) δ 196.72, 162.42, 139.99, 139.93,
131.04, 130.98, 130.94, 130.78, 124.03, 124.01, 115.28, 115.17,
114.84, 69.13, 26.84. ESI-MS m/z: 244.9 [M + H]+; HRMS (ESI)
m/z 245.0971 [M + H]+ (calcd for 245.0972, C15H14FO2).
1-(4-((4-Methylbenzyl)oxy)phenyl)ethanone (1d)
1
Yield 88%, white solid, m.p. 100–102 °C; H NMR (500 MHz,
DMSO) δ 7.94 (d, J = 8.7 Hz, 2H), 7.36 (d, J = 7.8 Hz, 2H), 7.22
(d, J = 7.7 Hz, 2H), 7.12 (d, J = 8.7 Hz, 2H), 5.17 (s, 2H), 2.53
(s, 3H), 2.33 (s, 3H); 13C NMR (126 MHz, DMSO) δ 196.68,
162.69, 137.74, 133.95, 130.89, 130.89, 130.53, 129.50, 129.50,
128.30, 128.30, 115.15, 115.15, 69.92, 26.83, 21.23. ESI-MS m/
z: 240.9 [M + H]+; HRMS (ESI) m/z 241.1224 [M + H]+ (calcd
for 241.1223, C16H17O2).
1-(4-((4-Fluorobenzyl)oxy)phenyl)ethanone (1j)
Yield 83%, white solid, m.p. 75–77 °C; 1H NMR (500 MHz,
DMSO) δ 7.95 (d, J = 8.8 Hz, 2H), 7.54 (dd, J = 8.4, 5.7 Hz,
2H), 7.25 (t, J = 8.8 Hz, 2H), 7.13 (d, J = 8.8 Hz, 2H), 5.21 (s,
2H), 2.53 (s, 3H); 13C NMR (126 MHz, DMSO) δ 196.72,
162.56, 161.39, 133.26, 130.93, 130.93, 130.68, 130.54, 130.48,
115.87, 115.70, 115.15, 115.15, 69.29, 26.84. ESI-MS m/z: 244.9
[M + H]+; HRMS (ESI) m/z 245.0970 [M + H]+ (calcd for
245.0972, C15H14FO2).
1-(4-((2-Nitrobenzyl)oxy)phenyl)ethanone (1e)
1
Yield 90%, white solid, m.p. 120–122 °C; H NMR (500 MHz,
DMSO) δ 8.16 (d, J = 8.0 Hz, 1H), 7.96 (d, J = 8.9 Hz, 2H),
7.87–7.78 (m, 2H), 7.66 (ddd, J = 8.5, 5.5, 3.5 Hz, 1H), 7.15 (d,
J = 8.9 Hz, 2H), 5.59 (s, 2H), 2.54 (s, 3H); 13C NMR (126 MHz,
DMSO) δ 196.74, 162.13, 148.04, 134.49, 132.33, 131.03,
131.00, 131.00, 129.83, 129.80, 125.35, 115.12, 115.12, 67.10,
26.88. ESI-MS m/z: 271.9 [M + H]+; HRMS (ESI) m/z 272.0919
[M + H]+ (calcd for 272.0917, C15H14NO4).
1-(4-((2,4-Difluorobenzyl)oxy)phenyl)ethanone (1k)
Yield 87%, white solid, m.p. 66–68 °C; 1H NMR (500 MHz,
DMSO) δ 7.96 (d, J = 8.8 Hz, 2H), 7.66 (dd, J = 15.3, 8.5 Hz,
1H), 7.33 (td, J = 10.4, 2.2 Hz, 1H), 7.22–7.09 (m, 3H), 5.23 (s,
2H), 2.54 (s, 3H); 13C NMR (126 MHz, DMSO) δ 196.73,
163.87, 162.38, 160.24, 132.71, 130.94, 130.86, 115.06, 115.06,
112.18, 104.77, 104.57, 104.36, 63.92, 26.84. ESI-MS m/z: 262.9
[M + H]+; HRMS (ESI) m/z 263.0880 [M + H]+ (calcd for
263.0878, C15H13F2O2).
1-(4-((3-Nitrobenzyl)oxy)phenyl)ethanone (1f)
1
Yield 91%, white solid, m.p. 106–108 °C; H NMR (500 MHz,
DMSO) δ 8.35 (s, 1H), 8.23 (d, J = 8.1 Hz, 1H), 7.96 (t, J = 8.7
Hz, 3H), 7.74 (t, J = 7.9 Hz, 1H), 7.17 (d, J = 8.8 Hz, 2H), 5.40
(s, 2H), 2.54 (s, 3H); 13C NMR (126 MHz, DMSO) δ 196.73,
162.22, 148.39, 139.42, 134.55, 130.98, 130.98, 130.90, 130.60,
123.33, 122.55, 115.19, 115.19, 68.69, 26.86. ESI-MS m/z: 271.9
[M + H]+; HRMS (ESI) m/z 272.0919 [M + H]+ (calcd for
272.0916, C15H14NO4).
1-(4-((3,4-Difluorobenzyl)oxy)phenyl)ethanone (1l)
Yield 85%, white solid, m.p. 61–63 °C; 1H NMR (500 MHz,
DMSO) δ 7.96 (d, J = 8.8 Hz, 2H), 7.57 (dd, J = 14.2, 5.2 Hz,
1H), 7.52–7.42 (m, 1H), 7.35 (dd, J = 7.0, 5.3 Hz, 1H), 7.13 (d,
J = 8.8 Hz, 2H), 5.21 (s, 2H), 2.53 (s, 3H); 13C NMR (126 MHz,
DMSO) δ 196.71, 162.33, 134.80, 130.93, 130.93, 130.81,
125.08, 118.11, 117.98, 117.40, 117.26, 115.15, 115.15, 68.68,
26.82. ESI-MS m/z: 262.9 [M + H]+; HRMS (ESI) m/z 263.0877
[M + H]+ (calcd for 263.0878, C15H13F2O2).
1-(4-((4-Nitrobenzyl)oxy)phenyl)ethanone (1g)
1
Yield 85%, white solid, m.p. 125–127 °C; H NMR (500 MHz,
DMSO) δ 8.28 (d, J = 8.6 Hz, 2H), 7.96 (d, J = 8.8 Hz, 2H), 7.75
(d, J = 8.5 Hz, 2H), 7.16 (d, J = 8.8 Hz, 2H), 5.41 (s, 2H), 2.54
(s, 3H); 13C NMR (126 MHz, DMSO) δ 196.74, 162.20, 147.64,
144.89, 130.98, 130.98, 130.95, 128.78, 128.78, 124.11, 124.11,
115.20, 115.20, 68.79, 26.86. ESI-MS m/z: 271.9 [M + H]+;
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1-(4-((3,4,5-Trifluorobenzyl)oxy)phenyl)ethanone (1m)
115.15, 115.15, 69.09, 26.84. ESI-MS m/z: 294.9 [M + H]+; HRMS
(ESI) m/z 295.0941 [M + H]+ (calcd for 295.0940, C16H14F3O2).
Yield 90%, white solid, m.p. 80–82 °C; 1H NMR (500 MHz,
DMSO) δ 7.96 (d, J = 8.9 Hz, 2H), 7.53–7.39 (m, 2H), 7.14 (d, J
= 8.9 Hz, 2H), 5.21 (s, 2H), 2.54 (s, 3H); 13C NMR (126 MHz,
DMSO) δ 196.73, 162.10, 151.71, 139.51, 134.05, 130.95,
130.95, 115.17, 115.17, 112.81, 112.77, 112.68, 112.64, 68.27,
26.84. ESI-MS m/z: 280.9 [M + H]+; HRMS (ESI) m/z 281.0786
[M + H]+ (calcd for 281.0784, C15H12F3O2).
1-(4-((4-(Trifluoromethyl)benzyl)oxy)phenyl)ethanone (1s)
Yield 91%, white solid, m.p. 77–79 °C; 1H NMR (500 MHz,
DMSO) δ 7.96 (d, J = 8.7 Hz, 2H), 7.78 (d, J = 8.1 Hz, 2H), 7.70
(d, J = 8.0 Hz, 2H), 7.15 (d, J = 8.7 Hz, 2H), 5.35 (s, 2H), 2.53
(s, 3H); 13C NMR (126 MHz, DMSO) δ 196.71, 162.34, 141.89,
130.96, 130.96, 130.85, 129.13, 128.87, 128.51, 128.51, 125.82
(q, J = 125.2 Hz), 123.60, 115.17, 115.17, 69.08, 26.81. ESI-MS
m/z: 294.9 [M + H]+; HRMS (ESI) m/z 295.0938 [M + H]+ (calcd
for 295.0940, C16H14F3O2).
1-(4-((2-Chlorobenzyl)oxy)phenyl)ethanone (1n)
Yield 83%, white solid, m.p. 94–96 °C; 1H NMR (500 MHz,
DMSO) δ 7.97 (d, J = 8.7 Hz, 2H), 7.67–7.60 (m, 1H), 7.55 (dd,
J = 8.0, 5.9 Hz, 1H), 7.48–7.37 (m, 2H), 7.16 (d, J = 8.8 Hz,
2H), 5.28 (s, 2H), 2.54 (d, J = 5.0 Hz, 3H); 13C NMR (126 MHz,
DMSO) δ 196.74, 162.47, 134.29, 133.24, 130.99, 130.99,
130.86, 130.74, 130.55, 129.95, 127.90, 115.08, 115.08, 67.68,
26.87. ESI-MS m/z: 260.9 [M + H]+; HRMS (ESI) m/z 261.0676
[M + H]+ (calcd for 261.0677, C15H14ClO2).
1-(4-((3-Bromobenzyl)oxy)phenyl)ethanone (1t)
Yield 84%, white solid, m.p. 81–83 °C; 1H NMR (500 MHz,
DMSO) δ 7.96 (d, J = 8.8 Hz, 2H), 7.70 (s, 1H), 7.56 (d, J = 8.0
Hz, 1H), 7.49 (d, J = 7.7 Hz, 1H), 7.39 (t, J = 7.8 Hz, 1H), 7.14
(d, J = 8.8 Hz, 2H), 5.25 (s, 2H), 2.54 (s, 3H); 13C NMR (126
MHz, DMSO) δ 196.74, 162.39, 139.86, 131.30, 131.18, 130.96,
130.96, 130.78, 130.74, 127.10, 122.22, 115.17, 115.17, 68.99,
26.86. ESI-MS m/z: 306.9 [M + H]+; HRMS (ESI) m/z 305.0174
[M + H]+ (calcd for 305.0172, C15H14BrO2).
1-(4-((3-Chlorobenzyl)oxy)phenyl)ethanone (1o)
Yield 89%, white solid, m.p. 79–81 °C; 1H NMR (500 MHz,
DMSO) δ 7.96 (d, J = 8.8 Hz, 2H), 7.55 (s, 1H), 7.49–7.39 (m,
3H), 7.14 (d, J = 8.8 Hz, 2H), 5.25 (s, 2H), 2.53 (s, 3H); 13C
NMR (126 MHz, DMSO) δ 196.73, 162.39, 139.61, 133.67,
130.95, 130.95, 130.89, 130.78, 128.39, 127.84, 126.69, 115.16,
115.16, 69.05, 26.85. ESI-MS m/z: 260.9 [M + H]+; HRMS (ESI)
m/z 261.0679 [M + H]+ (calcd for 261.0677, C15H14ClO2).
1-(4-((4-Bromobenzyl)oxy)phenyl)ethanone (1u)
1
Yield 90%, white solid, m.p. 101–103 °C; H NMR (500 MHz,
DMSO) δ 7.95 (d, J = 8.9 Hz, 2H), 7.62 (d, J = 8.3 Hz, 2H), 7.45
(d, J = 8.3 Hz, 2H), 7.13 (d, J = 8.8 Hz, 2H), 5.22 (s, 2H), 2.53
(s, 3H); 13C NMR (126 MHz, DMSO) δ 196.71, 162.43, 136.49,
131.89, 131.89, 130.93, 130.93, 130.72, 130.30, 130.30, 121.59,
115.17, 115.17, 69.17, 26.86. ESI-MS m/z: 306.9 [M + H]+; HRMS
(ESI) m/z 305.0171 [M + H]+ (calcd for 305.0172, C15H14BrO2).
1-(4-((4-Chlorobenzyl)oxy)phenyl)ethanone (1p)
Yield 92%, white solid, m.p. 88–89 °C; 1H NMR (500 MHz,
DMSO) δ 7.95 (d, J = 8.8 Hz, 2H), 7.50 (q, J = 8.5 Hz, 4H), 7.13
(d, J = 8.8 Hz, 2H), 5.23 (s, 2H), 2.53 (s, 3H); 13C NMR (126
MHz, DMSO) δ 196.72, 162.46, 136.08, 133.09, 130.94, 130.94,
130.73, 130.02, 130.02, 128.98, 128.98, 115.17, 115.17, 69.16,
26.85. ESI-MS m/z: 260.9 [M + H]+; HRMS (ESI) m/z 261.0678
[M + H]+ (calcd for 261.0677, C15H14ClO2).
General procedure for the preparation of acetophenone
derivatives (2a–2m)38
1-(3-Hydroxyphenyl)ethanone (1.0 mmol) was suspended in
acetonitrile (20 mL) containing K2CO3 (2.0 mmol). The reac-
tion was treated with appropriately substituted arylalkyl bro-
mide (1.2 mmol) and heated under reflux for 8 h. The reac-
tion progress was monitored using silica gel TLC with
petroleum ether/ethyl acetate as the mobile phase. Upon
completion, the acetonitrile was evaporated in vacuo, and the
mixture was then poured into water, which was extracted
with 3 × 100 mL of EtOAc, washed with brine, dried over
anhydrous Na2SO4 and purified by chromatography (PE/EA)
on silica gel.
1-(4-((2-(Trifluoromethyl)benzyl)oxy)phenyl)ethanone (1q)
Yield 94%, white solid, m.p. 68–70 °C; 1H NMR (500 MHz,
DMSO) δ 7.97 (d, J = 8.9 Hz, 2H), 7.86–7.71 (m, 3H), 7.62 (t, J
= 7.6 Hz, 1H), 7.14 (d, J = 8.9 Hz, 2H), 5.35 (s, 2H), 2.54 (s,
3H); 13C NMR (126 MHz, DMSO) δ 192.11, 159.32, 133.15,
131.74, 129.61, 129.53, 129.53, 129.48, 128.02, 125.48 (q, J =
125.2 Hz), 125.13, 124.13, 114.31, 114.31, 68.60, 30.32. ESI-
MS m/z: 294.9 [M + H]+; HRMS (ESI) m/z 295.0939 [M + H]+
(calcd for 295.0940, C16H14F3O2).
1-(3-(Benzyloxy)phenyl)ethanone (2a)
Yield 95%, colorless oil; 1H NMR (500 MHz, DMSO) δ 7.57
(dd, J = 11.3, 4.9 Hz, 2H), 7.52–7.39 (m, 5H), 7.36 (t, J = 7.3 Hz,
1H), 7.31 (dd, J = 8.2, 1.8 Hz, 1H), 5.20 (s, 2H), 2.59 (s, 3H);
13C NMR (126 MHz, DMSO) δ 198.13, 159.02, 138.81, 137.30,
130.36, 128.93, 128.93, 128.37, 128.18, 128.18, 121.41, 120.39,
114.29, 69.98, 27.28. ESI-MS m/z: 226.8 [M + H]+; HRMS (ESI)
m/z 227.1068 [M + H]+ (calcd for 227.1067, C15H15O2).
1-(4-((3-(Trifluoromethyl)benzyl)oxy)phenyl)ethanone (1r)
Yield 94%, white solid, m.p. 82–84 °C; 1H NMR (500 MHz,
DMSO) δ 7.97 (d, J = 8.8 Hz, 2H), 7.86 (s, 1H), 7.80 (d, J = 7.6
Hz, 1H), 7.73 (d, J = 7.8 Hz, 1H), 7.67 (t, J = 7.7 Hz, 1H), 7.16
(d, J = 8.8 Hz, 2H), 5.34 (s, 2H), 2.54 (s, 3H); 13C NMR (126
MHz, DMSO) δ 196.72, 162.38, 138.57, 132.17, 130.96, 130.96,
130.83, 130.10, 125.18, 125.15, 124.59, 124.56 (q, J = 125.2 Hz),
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1-(3-((3-Fluorobenzyl)oxy)phenyl)ethanone (2b)
69.16, 27.29. ESI-MS m/z: 306.9 [M + H]+; HRMS (ESI) m/z
326.9990 [M + Na]+ (calcd for 326.9991, C15H13BrNaO2).
Yield 95%, colorless oil; 1H NMR (500 MHz, DMSO) δ 7.62–
7.54 (m, 2H), 7.47 (dd, J = 15.4, 7.8 Hz, 2H), 7.36–7.28 (m,
3H), 7.18 (td, J = 8.8, 2.3 Hz, 1H), 5.23 (s, 2H), 2.59 (s, 3H);
13C NMR (126 MHz, DMSO) δ 198.11, 158.80, 140.30, 140.24,
138.83, 131.00, 130.94, 130.40, 123.99, 123.97, 121.59, 120.39,
114.28, 69.11, 27.28. ESI-MS m/z: 244.8 [M + H]+; HRMS (ESI)
m/z 245.0970 [M + H]+ (calcd for 245.0972, C15H14FO2).
1-(3-((3-Methylbenzyl)oxy)phenyl)ethanone (2h)
1
Yield 92%, light yellow oil; H NMR (500 MHz, DMSO) δ 7.58
(d, J = 7.6 Hz, 1H), 7.55 (d, J = 2.2 Hz, 1H), 7.47 (t, J = 7.9 Hz,
1H), 7.35–7.24 (m, 4H), 7.17 (d, J = 6.9 Hz, 1H), 5.15 (s, 2H),
2.59 (s, 3H), 2.34 (s, 3H); 13C NMR (126 MHz, DMSO) δ
198.14, 159.06, 138.81, 138.11, 137.21, 130.35, 129.01, 128.83,
128.75, 125.28, 121.36, 120.34, 114.30, 70.02, 27.28, 21.46.
ESI-MS m/z: 240.9 [M + H]+; HRMS (ESI) m/z 241.1221 [M +
H]+ (calcd for 241.1223, C16H17O2).
1-(3-((4-Fluorobenzyl)oxy)phenyl)ethanone (2c)
1
Yield 87%, light yellow oil; H NMR (500 MHz, DMSO) δ 7.59
(d, J = 7.7 Hz, 1H), 7.54 (dd, J = 7.3, 4.7 Hz, 3H), 7.47 (t, J =
7.9 Hz, 1H), 7.31 (dd, J = 8.1, 2.2 Hz, 1H), 7.25 (t, J = 8.9 Hz,
2H), 5.18 (s, 2H), 2.59 (s, 3H); 13C NMR (126 MHz, DMSO) δ
198.13, 158.91, 138.82, 133.54, 133.52, 130.47, 130.40, 130.37,
121.47, 120.40, 115.83, 115.66, 114.28, 69.26, 27.28. ESI-MS
m/z: 244.8 [M + H]+; HRMS (ESI) m/z 245.0974 [M + H]+ (calcd
for 245.0972, C15H14FO2).
1-(3-((4-Methylbenzyl)oxy)phenyl)ethanone (2i)
Yield 88%, light yellow oil; 1H NMR (500 MHz, DMSO) δ
7.57 (d, J = 7.7 Hz, 1H), 7.54 (d, J = 2.2 Hz, 1H), 7.46 (t, J =
7.9 Hz, 1H), 7.37 (d, J = 7.9 Hz, 2H), 7.32–7.26 (m, 1H), 7.22
(d, J = 7.8 Hz, 2H), 5.15 (s, 2H), 2.58 (s, 3H), 2.33 (s, 3H);
13C NMR (126 MHz, DMSO)
δ 198.14, 159.03, 138.79,
1-(3-((3-Chlorobenzyl)oxy)phenyl)ethanone (2d)
137.63, 134.25, 130.33, 129.48, 129.48, 128.27, 128.27,
121.33, 120.39, 114.31, 69.88, 27.28, 21.24. ESI-MS m/z:
240.9 [M + H]+; HRMS (ESI) m/z 241.1222 [M + H]+ (calcd
for 241.12223, C16H17O2).
1
Yield 81%, light yellow oil; H NMR (500 MHz, DMSO) δ 7.59
(d, J = 7.7 Hz, 1H), 7.56 (s, 2H), 7.52–7.39 (m, 4H), 7.32 (dd, J
= 8.2, 2.4 Hz, 1H), 5.22 (s, 2H), 2.59 (s, 3H); 13C NMR (126
MHz, DMSO) δ 198.11, 158.78, 139.91, 138.84, 133.65, 130.86,
130.41, 128.29, 127.80, 126.65, 121.61, 120.38, 114.29, 69.04,
27.29. ESI-MS m/z: 260.9 [M + H]+; HRMS (ESI) m/z 261.0678
[M + H]+ (calcd for 261.0677, C15H14ClO2).
1-(3-((3-Trifluoromethyl)oxy)phenyl)ethanone (2j)
1
Yield 83%, light yellow oil; H NMR (500 MHz, DMSO) δ 7.87
(s, 1H), 7.81 (d, J = 7.5 Hz, 1H), 7.73 (d, J = 7.7 Hz, 1H), 7.67
(t, J = 7.7 Hz, 1H), 7.59 (dd, J = 9.4, 4.8 Hz, 2H), 7.49 (t, J =
7.9 Hz, 1H), 7.34 (dd, J = 8.1, 2.3 Hz, 1H), 5.32 (s, 2H), 2.59
(s, 3H); 13C NMR (126 MHz, DMSO) δ 198.10, 158.77, 138.87,
132.14, 132.14, 130.43, 130.43, 130.07, 125.46, (q, J = 125.2
Hz), 121.67, 121.67, 120.41, 120.41, 114.29, 69.10, 27.27. ESI-
MS m/z: 294.9 [M + H]+; HRMS (ESI) m/z 317.0759 [M + Na]+
(calcd for 317.0760, C16H13F3NaO2).
1-(3-((4-Chlorobenzyl)oxy)phenyl)ethanone (2e)
1
Yield 82%, light yellow oil; H NMR (500 MHz, DMSO) δ 7.59
(d, J = 7.7 Hz, 1H), 7.55 (d, J = 2.0 Hz, 1H), 7.54–7.43 (m, 5H),
7.30 (dd, J = 8.0, 2.2 Hz, 1H), 5.20 (s, 2H), 2.59 (s, 3H); 13C
NMR (126 MHz, DMSO) δ 198.11, 158.83, 138.83, 136.37,
132.98, 130.39, 129.97, 129.97, 128.95, 128.95, 121.55, 120.41,
114.28, 69.13, 27.29. ESI-MS m/z: 260.9 [M + H]+; HRMS (ESI)
m/z 261.0676 [M + H]+ (calcd for 261.0677, C15H14ClO2).
1-(3-((4-Trifluoromethyl)oxy)phenyl)ethanone (2k)
1
Yield 88%, light yellow oil; H NMR (500 MHz, DMSO) δ 7.79
1-(3-((3-Bromobenzyl)oxy)phenyl)ethanone (2f)
(d, J = 8.1 Hz, 2H), 7.72 (d, J = 8.1 Hz, 2H), 7.60 (d, J = 7.7 Hz,
1H), 7.57 (d, J = 1.9 Hz, 1H), 7.48 (t, J = 7.9 Hz, 1H), 7.33 (dd,
J = 8.1, 2.2 Hz, 1H), 5.33 (s, 2H), 2.59 (s, 3H); 13C NMR (126
MHz, DMSO) δ 198.08, 158.74, 142.21, 138.86, 130.44, 129.03,
128.78, 128.50, 128.50, 125.81 (q, J = 125.2 Hz), 123.63,
121.70, 120.39, 114.25, 69.07, 27.27. ESI-MS m/z: 294.9 [M +
H]+; HRMS (ESI) m/z 317.0762 [M + Na]+ (calcd for 317.0760,
C16H13F3NaO2).
1
Yield 87%, light yellow oil; H NMR (500 MHz, DMSO) δ 7.71
(s, 1H), 7.59 (d, J = 7.7 Hz, 1H), 7.58–7.53 (m, 2H), 7.49 (dd, J
= 15.9, 7.8 Hz, 2H), 7.39 (t, J = 7.8 Hz, 1H), 7.32 (dd, J = 8.1,
2.3 Hz, 1H), 5.22 (s, 2H), 2.59 (s, 3H); 13C NMR (126 MHz,
DMSO) δ 198.11, 158.78, 140.16, 138.84, 131.20, 131.15,
130.70, 130.42, 127.06, 122.20, 121.61, 120.38, 114.30, 68.99,
27.29. ESI-MS m/z: 306.9 [M + H]+; HRMS (ESI) m/z 326.9994
[M + Na]+ (calcd for 326.9991, C15H13BrNaO2).
1-(3-((3-Nitrobenzyl)oxy)phenyl)ethanone (2l)
1-(3-((4-Bromobenzyl)oxy)phenyl)ethanone (2g)
1
Yield 93%, light yellow solid, m.p. 121–123 °C; H NMR (500
1
Yield 90%, light yellow oil; H NMR (500 MHz, DMSO) δ 7.60
MHz, DMSO) δ 8.36 (s, 1H), 8.23 (d, J = 8.1 Hz, 1H), 7.96 (d, J
= 7.6 Hz, 1H), 7.74 (t, J = 7.9 Hz, 1H), 7.60 (dd, J = 9.4, 4.8
Hz, 2H), 7.49 (t, J = 7.9 Hz, 1H), 7.35 (dd, J = 8.1, 2.4 Hz, 1H),
5.37 (s, 2H), 2.60 (s, 3H); 13C NMR (126 MHz, DMSO) δ
198.10, 158.65, 148.41, 139.73, 138.88, 134.53, 130.58, 130.48,
(dd, J = 14.3, 8.0 Hz, 3H), 7.54 (s, 1H), 7.51–7.40 (m, 3H), 7.30
(dd, J = 8.2, 1.9 Hz, 1H), 5.19 (s, 2H), 2.59 (s, 3H); 13C NMR
(126 MHz, DMSO) δ 198.10, 158.81, 138.83, 136.80, 131.87,
131.87, 130.39, 130.27, 130.27, 121.56, 121.49, 120.41, 114.28,
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123.26, 122.50, 121.78, 120.43, 114.29, 68.70, 27.30. ESI-MS
m/z: 271.9 [M + H]+; HRMS (ESI) m/z 294.0739 [M + Na]+
(calcd for 294.0737, C15H14NNaO4).
11 C. L. De, M. Li, C. Binda, A. Lustig, D. E. Edmondson and A.
Mattevi, Proc. Natl. Acad. Sci. U. S. A., 2005, 102, 12684–12689.
12 C. Binda, P. Newton-Vinson, F. Hubálek, D. E. Edmondson
and A. Mattevi, Nat. Struct. Biol., 2002, 9, 22–26.
13 A. Bolasco, S. Carradori and R. Fioravanti, Expert Opin. Ther.
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14 M. B. H. Youdim and Y. S. Bakhle, Br. J. Pharmacol.,
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1-(3-((4-Nitrobenzyl)oxy)phenyl)ethanone (2m)
1
Yield 81%, light yellow solid, m.p. 116–117 °C; H NMR (500
MHz, DMSO) δ 8.29 (d, J = 8.6 Hz, 2H), 7.77 (d, J = 8.6 Hz,
2H), 7.61 (d, J = 7.7 Hz, 1H), 7.58 (s, 1H), 7.49 (t, J = 7.9 Hz,
1H), 7.34 (dd, J = 8.1, 2.1 Hz, 1H), 5.39 (s, 2H), 2.59 (s, 3H);
13C NMR (126 MHz, DMSO) δ 198.08, 158.62, 147.59, 145.22,
138.88, 130.48, 128.75, 128.75, 124.10, 124.10, 121.82, 120.42,
114.25, 68.79, 27.29. ESI-MS m/z: 271.9 [M + H]+; HRMS (ESI)
m/z 294.0738 [M + Na]+ (calcd for 294.0737, C15H14NNaO4).
17 C. Gnerre, M. Catto, F. Leonetti, P. Weber, P. A. Carrupt, C.
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19 L. J. Legoabe, A. Petzer and J. P. Petzer, Bioorg. Chem.,
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20 W. Y. Wu, J. J. Hou, H. L. Long, W. Z. Yang, J. Liang and
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21 S. Belinda, J. B. Jacobus and J. P. Petzer, Bioorg. Med. Chem.
Lett., 2013, 23, 1269–1273.
Abbreviations
MAO Monoamine oxidase
FAD Flavin adenine dinucleotide
CNS Central nervous system
5-HT 5-Hydroxytryptamine
NE
DA
SI
Norepinephrine
Dopamine
Selectivity index
22 M. Letitia, J. P. Petzer and P. Anél, Bioorg. Med. Chem. Lett.,
2013, 23, 5498–5502.
BBB Blood–brain barrier
23 L. J. Legoabe, A. Petzer and J. P. Petzer, Bioorg. Med. Chem.
Lett., 2014, 24, 2758–2763.
MTT Methyl thiazolyl tetrazolium
24 L. J. Legoabe, A. Petzer and J. P. Petzer, Bioorg. Med. Chem.
Lett., 2012, 22, 5480–5484.
25 G. Esteban, J. Allan, A. Samadi, A. Mattevi, M. Unzeta, J.
Marco-Contelles, C. Binda and R. R. Ramsay, Biochim.
Biophys. Acta, 1844, 2014, 1104–1110.
Acknowledgements
The research work was financially supported by the Project of
the National Natural Sciences Foundation of China (81573313).
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