Synthesis and evaluation of 6-methylcoumarin derivatives as potent and selective monoamine oxidase B inhibitors

Article abstract of DOI:10.1039/c4md00437j

A new series of 6-methyl-3-phenylcoumarins (3a-c and 5a-o) and 6-methyl-3-heteroarylcoumarins (5p-s) have been designed, synthesized and evaluated as monoamine oxidase inhibitors. The results demonstrated that a large proportion of the synthesized compounds selectively inhibited monoamine oxidase B with IC₅₀ values in the sub-micromolar range. Among them, compound 5n (IC₅₀ = 0.0601 μM) exhibited the most potent inhibitory activity and the highest selectivity for monoamine oxidase B (SI > 1664-fold). In addition, the possible binding model of the active compound 5n was measured by docking it into the active site of the hMAO-B complex structure. The results showed that compound 5n interacted with the well-known binding pocket of MAO-B, and a π-π interaction was found between the phenyl ring at position 3 of the coumarin and the phenyl ring of Tyr 326. Consequently, we supplied useful information about the interaction between the enzyme and inhibitor, and developed the 6-methyl-3-phenylcoumarin scaffold as an agent for multifaceted brain disorders. This journal is

Full text of DOI:10.1039/c4md00437j

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CONCISE ARTICLE
Synthesis and evaluation of 6-methylcoumarin
derivatives as potent and selective monoamine
oxidase B inhibitors†
Cite this: DOI: 10.1039/c4md00437j
*
*
Jin-Shuai Lan,‡ Long-Fei Pan,‡ Sai-Sai Xie, Xiao-Bing Wang and Ling-Yi Kong
A new series of 6-methyl-3-phenylcoumarins (3a–c and 5a–o) and 6-methyl-3-heteroarylcoumarins (5p–s)
have been designed, synthesized and evaluated as monoamine oxidase inhibitors. The results
demonstrated that a large proportion of the synthesized compounds selectively inhibited monoamine
oxidase B with IC50 values in the sub-micromolar range. Among them, compound 5n (IC50 = 0.0601 μM)
exhibited the most potent inhibitory activity and the highest selectivity for monoamine oxidase B (SI >
1664-fold). In addition, the possible binding model of the active compound 5n was measured by docking it
into the active site of the hMAO-B complex structure. The results showed that compound 5n interacted
with the well-known binding pocket of MAO-B, and a π–π interaction was found between the phenyl ring
at position 3 of the coumarin and the phenyl ring of Tyr 326. Consequently, we supplied useful information
about the interaction between the enzyme and inhibitor, and developed the 6-methyl-3-phenylcoumarin
scaffold as an agent for multifaceted brain disorders.
Received 29th September 2014,
Accepted 12th December 2014
DOI: 10.1039/c4md00437j
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are used to treat several neurodegenerative disorders such as
Alzheimer's disease and Parkinson's disease,10 whereas inhib-
Introduction
Monoamine oxidase (MAO) is an important enzyme containing
flavin adenine dinucleotide (FAD) that regulates and metabolises
most monoamine neurotransmitters, such as norepinephrine
(NE), dopamine (DA), and 5-hydroxy-tryptamine (5-HT). MAO can
modulate the concentrations of monoamine neurotransmitters
in peripheral and central tissues.1 MAO has two functional isozy-
mic forms, namely MAO-A and MAO-B, which are differentiated
by differences in their amino acid sequences, immunological
properties, tissue distribution, inhibitor specificity, and substrate
preference.2–6 MAO-A is present in catecholaminergic neurons,
while MAO-B is located predominantly in serotonergic glia and
neurons.7 Both enzymes can deaminate tyramine, DA and trypt-
amine by oxidation. However, MAO-A tends to metabolize epi-
nephrine, 5-HT and NE, and is selectively inhibited by clorgyline.
MAO-B preferentially deaminates β-phenethylamine and
benzylamine, and is selectively inhibited by rasagiline and
selegiline.8,9 The MAOs have been used as drug targets for numer-
ous decades and inhibitors of these enzymes are used primarily
to treat neuropsychiatric syndromes. Selective MAO-B inhibitors
itors of MAO-A have been revealed to be effective antidepres-
sants.11 Based on these aspects, there is an intensive requirement
for novel MAO inhibitors.
The crystal structures of the two MAO isoforms were
described by Binda et al., providing information about their
pharmacophoric requirements and selective interactions to
design potent and selective inhibitors.12 The active site of
monoamine oxidase is a lipophilic cage, largely filled with aro-
matic amino acids, surrounding the isoalloxazine moiety of the
FAD cofactor. The diverse structure and shape of this active site
in MAO-A and MAO-B results in the different affinities or selec-
tivities for inhibitors and substrates.13
Coumarins are a wide family of compounds of both syn-
thetic and natural origins. Due to their versatile synthetic
methodologies and structural variability, they play a signifi-
cant role not only in medicinal chemistry but also in organic
chemistry.14,15 Recently, coumarins or coumarin analogues
have been utilized for the design of activity-based probes for
MAO enzymes,16–18 and differently substituted coumarins
have been synthesized or isolated from natural sources and
evaluated for their potential as MAO inhibitors (structures
A–H in Fig. 1), showing selective inhibitory activities for
either MAO-A or MAO-B isoforms in the micromolar to
picomolar ranges.19–28
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
Discoveries reveal that expression levels of MAO in neuro-
nal tissue increase 4-fold with age, leading to an increase in
the production of hydrogen peroxide and metabolism of
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
c4md00437j
‡ These authors contributed equally to this work.
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Fig. 1 Structures of known coumarin-based MAO inhibitors.
dopamine, which causes oxidative stress and might occur in
neurodegenerative diseases.29 Therefore, MAO-B inhibitors
could be used to treat some neurodegenerative diseases. For
example, it has been stated that neuronal cells are protected
from oxidative stress by selegiline in patients suffering from
neurodegenerative diseases.30 Therefore, the search for novel,
efficient and selective MAO-B inhibitors has significantly
intensified over the past few years.
Recent studies of structure–activity relationships show
that MAO-B inhibitory activity is modulated by substitution
at position 3 of the coumarin nucleus.21–23 Among the differ-
ent inhibitors that exist, 6-methyl-3-phenylcoumarin deriva-
tives have been deeply studied,24–27 and all of the studied
6-methyl-3-phenylcoumarins show very high MAO-B selectiv-
ity. In particular, 6-methyl-3-IJ3-methoxyphenyl)coumarin was
found to be the best MAO-B inhibitor (IC50 = 0.80 nM).28 On
the basis of previous studies, the methoxy group was
substituted with other groups to gain more selective and
potent MAO-B inhibitors.27 Some coumarin derivatives
substituted at the 3-position with different heterocyclic rings
were also synthesized.28 On account of these, we designed,
synthesized and tested some new 6-methyl-coumarin deriva-
tives as selective MAO-B inhibitors.
in 76–85% yields, and these compounds were treated with
dimethylamine hydrochloride in the presence of potassium
carbonate to give the key compounds 5d–f in 75–89% yields.
The treatment of 4a–c and acyl chlorides/benzyl bromides
with potassium carbonate in acetonitrile afforded com-
pounds 5g–o.
By condensation of the appropriately substituted acetic acids
and 5-methylsalicylaldehyde with N, N′-dicyclohexylcarbodiimide
(DCC) as a dehydrating agent, the 3-heteroarylcoumarin deriv-
atives 5p–s were synthesized via the classical Perkin reaction
in moderate yields (Scheme 2).
Inhibition of hMAO
With iproniazid as a reference, the hMAO inhibitory activities
were explored by using the Amplex Red MAO assay, according
to the reported procedure.32 The corresponding IC50 values
and selectivity ratios for MAO-B are shown in Table 1. Based
on the screening data, it can be seen that most of the tested
compounds selectively inhibit MAO-B with IC50 values in
the sub-micromolar range. Inhibition towards MAO-A was
very weak and the structure–activity relationship was not
apparent. Among the synthesized compounds, 5n was the
most potent and was a highly selective inhibitor against
MAO-B (IC50 = 0.0601 μM), being about 130-fold more active
than iproniazid.
Results and discussion
Chemistry
To introduce groups with different properties to the
3-hydroxyphenyl ring of the coumarin moiety, compounds
3b, 5a–i, 5k and 5n were synthesized. Among 5a–c, with the
number of methylenes in the substituent on the 3-hydroxyphenyl
The coumarin derivatives were synthesized according to
Schemes 1 and 2. The general reaction conditions and the
compound characterization are described in the experimental
section.
The synthetic routes for the 6-methyl-3-phenylcoumarins
derivatives are presented (Scheme 1). The commercially
available 5-methylsalicylaldehyde was reacted with ortho-
hydroxylated benzaldehydes 2a–c in the presence of triethyl-
amine and acetic anhydride to provide compounds 3a–c.31
Hydrolysis of 3a–c with 10% HCl/EtOH afforded phenolic
products 4a–c. Compound 4b was reacted with different α,ω-
dibromoalkanes in acetonitrile to produce compounds 5a–c
ring varying from two to four, compound 5a with
2-carbon spacer gave the best inhibition for MAO-B (IC50
a
=
2.45 μM). Extending the chain length resulted in an apparent
decrease in MAO-B inhibition, and a similar trend was
observed for 5d–f. On the other hand, 5d (IC50 = 0.2180 μM)
was a better inhibitor for MAO-B than 5a (IC50 = 2.45 μM),
and 5e gave better results than 5b. All of these results
revealed that the length of the alkyl chain could affect the
MAO-B inhibitory activity, and the inhibitory capacity was
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Scheme 1 Synthesis of 6-methyl-3-phenylcoumarin derivatives. Reagents and conditions: (i) triethylamine, acetic anhydride, 120 °C, 8 h; (ii) 10%
HCl/MeOH, 80 °C, 5–12 h; (iii) α,ω-dibromoalkanes, K2CO3, acetonitrile, 40 °C, 4 h; (iv) dimethylamine hydrochloride, K2CO3, acetonitrile, reflux,
8 h; (v) acyl chlorides, K2CO3, acetonitrile, r.t., 5 h; (vi) benzyl bromide or 3-fluorobenzyl bromide, K2CO3, acetonitrile, r.t., 4 h.
increased by introducing amino group side chains. Com-
pounds 3b and 5g–i were obtained by treating 4b with differ-
ent acyl chlorides. Among them, compounds 3b, 5h and 5i
had MAO-B inhibitory activities in the sub-micromolar range,
with 5h (IC50 = 0.3052 μM) being the best. Compound 5k was
designed with the aim to explore the differences when the
carboxyl group was deleted. Compared with 5i (IC50 = 0.6511 μM),
the inhibitory activity of 5k (IC50 = 0.2010 μM) toward
MAO-B was increased. On the basis of these results, com-
pounds 5j and 5l–o were synthesized to explore the structure–
activity relationship. 5j and 5l were ortho and para
substituted on the hydroxyphenyl ring with a benzyl group,
and compounds 5m–o were produced by introducing
3-fluorobenzyl into 4a–c. It is worth noting that compounds
5m–o bearing a fluorine group exhibited slightly better inhibi-
tory activities against MAO-B in comparation with 5j–l,
which revealed that an electron-withdrawing group seems to
be crucial in MAO-B inhibitory activity. In addition, the activ-
ity data of the synthesized compounds pointed out that it
seems to be unfavorable, in terms of the MAO inhibitory
activity, to introduce substituents at the ortho-position of the
3-phenyl ring. For example, compounds 3a, 5j and 5m
showed decreased inhibitory activities compared with com-
pounds bearing substituents at the meta- or para-positions.
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Scheme 2 Synthesis of 6-methyl-3-phenylcoumarin derivatives. Reagents and conditions: (vii) DCC, DMSO, 110 °C, 24–48 h.
It is notable that the replacement of the 3-phenyl group with
heterocyclic groups in the same position resulted in com-
pounds 5p–s, which all showed a reduction in anti-MAO
potency.
Molecular modeling studies
In order to carry out a detailed study of the MAO-B binding
modes, molecular docking studies were performed. The crys-
tallographic structure of MAO-B (PDB code 2V61) from the
Protein Data Bank was used to dock the derivatives under
study.33 According to the inhibition results, compound 5n
was selected as a typical ligand. The 2D and 3D pictures of
binding are illustrated in Fig. 2A and B. As shown in Fig. 2,
compound 5n interacted with the well-known binding pocket
of the isoenzyme,34 with the methyl substituent at C6
pointing towards the FAD cofactor, Tyr 188 and Tyr 435. The
coumarin ring was at the bottom of the substrate cavity,
interacting with Tyr 398 and Cys 172. There was a π–π inter-
action between the phenyl ring at position 3 of the coumarin
and the phenyl ring of Tyr 326, with length of 3.23 Å. Finally,
the substituted benzyl group occupied the entrance cavity, a
hydrophobic subpocket existing only in the MAO-B isoform
and is composed of Leu 164, Ile 199, Tyr 326, Leu 164, Trp
119, Leu 167 and Phe 168. This might be one reason for the
MAO-B selectivity of our compounds.
Table 1 MAO inhibitory activities of the synthesized compounds
IC50 (μM)a
Selectivity
Compounds
MAO-A
MAO-B
indexb
3a
3b
3c
Nc
N
N
0.9384 0.0089
0.7141 0.0194
0.4013 0.0120
2.45 0.12
>106.6
>140.0
>249.1
8.47
5a
20.75 0.83
5b
5c
19.46 0.76
40.58 1.23
3.67 0.14
10.71 0.37
5.30
3.79
5d
5e
5f
N
0.2180 0.0101
0.9046 0.0178
1.13 0.04
>458.7
38.57
23.65
34.89 1.41
26.73 0.97
5g
5h
5i
5j
5k
N
N
4.43 0.16
>22.57
>327.7
24.22
>390.0
>497.6
>947.0
>394.9
>1663.9
>572.1
2.16
0.3052 0.0045
0.6511 0.0203
0.2564 0.0082
0.2010 0.0120
0.1056 0.0044
0.2532 0.0056
0.0601 0.0024
0.1748 0.0031
3.76 0.14
2.58 0.13
6.49 0.31
5.67 0.28
7.82 0.41
15.77 0.45
N
N
N
N
N
N
8.09 0.18
6.67 0.09
55.47 1.80
43.93 1.76
6.58 0.69
5l
5m
5n
5o
5p
5q
5r
Cell toxicity
Based on the screening results above, compound 5n, the
most potent and a highly selective inhibitor against MAO-B,
was selected to further examine the potential toxicity effect
on the normal cell line HUVEC, neural cell line PC12 and
neural cell line SH-SY5Y.35 After incubating the cells with
compound 5n for 48 h, the cell viability was determined
using the 3-IJ4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium
(MTT) assay. As shown in the Fig. 3, compound 5n at
2.5–20 μM did not exhibit neurotoxicity. This suggests that
2.59
8.55
7.75
0.84
5s
Iproniazid
a
IC50
:
50% inhibitory concentration (mean
SEM of three
b
experiments).
Selectivity index = IC50 (MAO-A)/IC50 (MAO-B).
c
Inactive at 100 μM (highest concentration tested); at higher
concentrations the compounds precipitate.
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Fig. 2 Molecular docking of the compound 5n into the ligand binding model site of MAO-B was performed on the binding model based on the
MAO-B complex structure (2V61. pdb). The 2D picture of binding is depicted in part A. The 3D picture of binding is depicted in part B.
and selective hMAO-B inhibitors. In particular, compound 5n
was the best MAO-B inhibitor (IC50 = 0.0601 μM, SI >
1663.9). Both the type and position of the substituents
attached to the 3-phenyl group played an important role in
the MAO inhibitory activity. It is likely that meta and para
substituents were the most positive positions for the MAO-B
inhibitory activity. Due to their potent and selective MAO-B
inhibitory activities, these compounds could be used to
develop promising drug candidates for the treatment of
neurodegenerative diseases.
Fig. 3 The toxicity effect of 5n on the normal cell line HUVEC, neural
cell line PC12 and neural cell line SH-SY5Y.
Experimental
General
compound 5n might be used to develop promising drug can-
All common reagents and solvents were obtained from com-
didates for the treatment of neurodegenerative diseases.
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
Conclusions
In conclusion, a new series of 6-methylcoumarins were
designed, synthesized and evaluated for their MAO inhibitory
activity in vitro. Compared with the reference compound ipro-
niazid, most of the studied compounds were highly potent
the spots were detected under UV light (254 nm). Column
chromatography was performed on silica gel (90–150 μm;
Qingdao Marine Chemical Inc.) The purity of all compounds
used for biological evaluation was confirmed to be higher than
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95% through analytical HPLC, performed with an Agilent
1200 HPLC System. Melting points were measured on an
XT-4 micromelting point instrument and are uncorrected. 1H NMR
and 13C NMR spectra were measured on 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 the internal standard. Mass spectra were obtained on a
MS Agilent 1100 Series LC/MSD Trap mass spectrometer
(ESI-MS) and a Mariner ESI-TOF spectrometer (HRESI-MS).
General procedure for the preparation of 3a–c. Triethyl-
3-IJ3-IJ2-Bromoethoxy)phenyl)-6-methyl-2H-chromen-2-one (5a).
Yield 88%, yellow solid; H NMR (500 MHz, DMSO-d6) δ 8.25
1
(s, 1H, CHCH), 7.59 (br s, 1H, Ar–H), 7.47 (dd, J = 8.5,
2.0 Hz, 1H, Ar–H), 7.41 (t, J = 8.0 Hz, 1H, Ar–H), 7.38–7.33
(m, 3H, Ar–H), 7.06–7.04 (m, 1H, Ar–H), 4.40 (t, J = 5.5 Hz, 2H,
OCH2), 3.86 (t, J = 5.5 Hz, 2H, BrCH2), 2.41 (s, 3H, Ar–CH3);
13C NMR (125 MHz, DMSO-d6) δ 160.19, 158.22, 151.65,
141.26, 136.63, 134.29, 133.16, 129.89, 128.78, 126.88, 121.86,
119.68, 116.12, 115.50, 115.28, 68.39, 31.87, 20.78; m.p. 124–
126 °C; HRMS (ESI) m/z 381.0098 [M + Na]+ (calcd 381.0097,
C18H15BrNaO3).
amine (4 mL) was added to
a solution of 5-methyl-
salicylaldehyde (1, 10 mmol) and substituted phenyl acetic
acid (2a–c, 10 mmol) in acetic anhydride (6 mL). The mixture
was heated to 120 °C and stirred for 8 h. After cooling, it was
poured into ice water, stirred, and stored for 4 h. The precipi-
tated yellowish solid was filtered, washed with water, dried,
and recrystallized from ethyl acetate to give the target com-
pound (3a–c).
3-IJ3-IJ3-Bromopropoxy)phenyl)-6-methyl-2H-chromen-2-one (5b).
Yield 83%, red solid; 1H NMR (500 MHz, DMSO-d6) δ 8.24
(s, 1H, CHCH), 7.59 (br s, 1H, Ar–H), 7.47 (dd, J = 8.5,
2.0 Hz, 1H, Ar–H), 7.43–7.30 (m, 4H, Ar–H), 7.07–7.02 (m, 1H,
Ar–H), 4.16 (t, J = 6.0 Hz, 2H, OCH2), 3.72 (t, J = 6.5 Hz, 2H,
BrCH2), 2.41 (s, 3H, Ar–CH3), 2.33–2.27 (m, 2H, alkyl chains-H);
13C NMR (125 MHz, DMSO-d6) δ 160.20, 158.64, 151.64, 141.20,
134.28, 133.14, 129.84, 129.75, 128.77, 126.97, 121.54, 121.20,
119.68, 116.12, 115.37, 115.13, 65.93, 65.24, 57.84, 32.66,
32.38, 31.70, 20.78; m.p. 82–84 °C; HRMS (ESI) m/z 395.0254
[M + Na]+ (calcd 395.0253, C19H17BrNaO3).
3-IJ2-Acetoxyphenyl)-6-methylcoumarin (3a). Yield 60%, red
1
solid; H NMR (500 MHz, DMSO-d6) δ 8.02 (s, 1H, CHCH),
7.60 (br s, 1H, Ar–H), 7.55–7.47 (m, 3H, Ar–H), 7.41–7.36 (m,
2H, Ar–H), 7.31–7.27 (m, 1H, Ar–H), 2.40 (s, 3H, Ar–CH3),
2.12 (s, 3H, COCH3); 13C NMR (125 MHz, DMSO-d6) δ 168.89,
159.53, 151.91, 148.74, 143.08, 134.44, 133.41, 131.59, 130.17,
128.78, 128.52, 126.26, 124.87, 123.48, 119.20, 116.33, 21.14,
20.74. MS (ESI) m/z 295.1 [M + H]+; m.p. 112–115 °C; HRMS
(ESI) m/z 295.0963 [M + H]+ (calcd 295.0965, C18H15O4).
3-IJ3-Acetoxyphenyl)-6-methylcoumarin (3b). Yield 85%,
colorless solid; 1H NMR (500 MHz, DMSO-d6) δ 8.27 (s, 1H,
CHCH), 7.65 (d, J = 8.0 Hz, 1H, Ar–H), 7.59 (br s, 1H,
Ar–H), 7.56–7.51 (m, 2H, Ar–H), 7.48 (dd, J = 8.4, 2.0 Hz, 1H,
Ar–H), 7.37 (d, J = 8.5 Hz, 1H, Ar–H), 7.22 (dd, J = 8.0, 1.5 Hz,
1H, Ar–H), 2.41 (s, 3H, Ar–CH3), 2.32 (s, 3H, COCH3);
13C NMR (125 MHz, DMSO-d6) δ 168.96, 158.83, 152.91,
147.32, 143.51, 133.69, 133.46, 131.86, 130.17, 128.78, 128.61,
126.35, 124.78, 123.37, 119.16, 116.54, 21.26, 20.35. MS (ESI)
m/z 295.2 [M + H]+; m.p. 138–141 °C; HRMS (ESI) m/z
295.0966 [M + H]+ (calcd 295.0965, C18H15O4).
3-IJ4-Acetoxyphenyl)-6-methylcoumarin (3c). Yield 78%, colorless
solid; 1H NMR (500 MHz, DMSO) δ 8.23 (s, 1H, CHCH),
7.79 (d, J = 8.5 Hz, 2H, Ar–H), 7.58 (br s, 1H, Ar–H), 7.49–7.45
(m, 1H, Ar–H), 7.36 (d, J = 8.5 Hz, 1H, Ar–H), 7.25 (d, J =
9.0 Hz, 2H, Ar–H), 2.41 (s, 3H, Ar–CH3), 2.32 (s, 3H, COCH3);
13C NMR (125 MHz, DMSO-d6) δ 169.61, 160.32, 151.65, 151.15,
141.03, 134.33, 133.13, 132.74, 130.19, 128.73, 128.73, 126.52,
122.14, 122.14, 119.71, 116.15, 21.35, 20.77; MS (ESI) m/z
295.2 [M + H]+; m.p. 171–174 °C; HRMS (ESI) m/z 295.0967
[M + H]+ (calcd 295.0965, C18H15O4).
3-IJ3-IJ4-Bromobutoxy)phenyl)-6-methyl-2H-chromen-2-one (5c).
1
Yield 72%, yellow solid; H NMR (500 MHz, DMSO-d6) δ 8.24
(s, 1H, CHCH), 7.59 (s, 1H, Ar–H), 7.47 (dd, J = 8.4,
1.8 Hz, 1H, Ar–H), 7.38 (dd, J = 17.2, 8.5 Hz, 2H, Ar–H),
7.33–7.30 (m, 2H, Ar–H), 7.04–7.01 (m, 1H, Ar–H), 4.08 (t, J =
6.3 Hz, 2H, OCH2), 3.65 (t, J = 6.7 Hz, 2H, BrCH2), 2.41
(s, 3H, Ar–CH3), 2.02 (m, 2H, alkyl chains-H), 1.92–1.86
(m, 2H, alkyl chains-H); 13C NMR (125 MHz, DMSO-d6)
δ 160.20, 158.84, 151.64, 141.17, 136.51, 134.28, 133.13,
129.77, 128.76, 127.03, 121.34, 119.68, 116.12, 115.35, 115.07,
67.23, 35.28, 29.62, 27.91, 20.78; MS (ESI) m/z 387.1 [M + H]+;
m.p. 124–126 °C; HRMS (ESI) m/z 387.0589 [M + H]+ (calcd
387.0590, C20H20BrO3).
General procedure for the preparation of compounds
5d–f. To a stirred mixture of 5a–c (0.5 mmol) and K2CO3
(0.14 g, 1 mmol) in acetonitrile (10 mL), dimethylamine
hydrochloride (0.5 mmol) was added and the mixture was
refluxed for 8 h. After cooling to room temperature, the mix-
ture was filtered and the filtrate was evaporated under vacuum.
The obtained residue was purified by silica gel chromatography
with petroleum ether–acetone as the eluent to give the target
compound (5d–f).
3-IJ3-IJ2-IJDimethylamino)ethoxy)phenyl)-6-methyl-2H-chromen-2-
one (5d). Yield 84%, yellow solid; 1H NMR (500 MHz,
DMSO-d6) δ 8.24 (s, 1H, CHCH), 7.59 (br s, 1H, Ar–H), 7.47
(dd, J = 8.5, 2.0 Hz, 1H, Ar–H), 7.41–7.34 (m, 2H, Ar–H), 7.33–
7.30 (m, 2H, Ar–H), 7.02 (dd, J = 8.5, 2.0 Hz, 1H, Ar–H),
4.12 (t, J = 6.0 Hz, 2H, OCH2), 2.67 (t, J = 6.0 Hz, 2H, NCH2),
2.41 (s, 3H, Ar–CH3), 2.25 (s, 6H, NCH3); 13C NMR (125 MHz,
DMSO-d6) δ 160.19, 158.79, 151.63, 141.16, 136.50, 134.26,
133.12, 129.77, 128.76, 127.01, 121.31, 119.69, 116.11, 115.32,
115.06, 66.42, 58.19, 46.03, 20.78; MS (ESI) m/z 324.2 [M + H]+;
m.p. 93–95 °C; HRMS (ESI) m/z 324.1595 [M + H]+ (calcd
324.1594, C20H22NO3).
General procedure for the preparation of compounds
5a–c. To a stirred mixture of 4c (5 mmol) and K2CO3 (1.4 g,
10 mmol) in acetonitrile (15 mL), α,ω-dibromoalkane
(25 mmol) was added. After stirring for 4 h at 40 °C, the mix-
ture was filtered and the filtrate was evaporated under
reduced pressure. The obtained residue was purified by silica
gel chromatography with petroleum ether–ethyl acetate as
the eluent to give the target compound (5a–c).
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3-IJ3-IJ3-IJDimethylamino)propoxy)phenyl)-6-methyl-2H-chromen-2-
one (5e). Yield 82%, yellow solid; 1H NMR (500 MHz,
DMSO-d6) δ 8.24 (s, 1H, CHCH), 7.59 (br s, 1H, Ar–H),
7.47 (dd, J = 8.5, 2.0 Hz, 1H, Ar–H), 7.40–7.35 (m, 2H,
Ar–H), 7.30 (dd, J = 4.5, 2.0 Hz, 2H, Ar–H), 7.01 (dd, J = 8.5,
2.0 Hz, 1H, Ar–H), 4.07 (t, J = 6.4 Hz, 2H, OCH2), 2.42–2.38
(m, 5H, Ar–CH3, NCH2), 2.17 (s, 6H, NCH3), 1.92–1.86
(m, 2H, alkyl chains-H); 13C NMR (125 MHz, DMSO-d6)
δ 160.21, 158.95, 151.64, 141.14, 136.50, 134.26, 133.11,
129.77, 128.77, 127.05, 121.23, 119.70, 116.11, 115.27, 115.09,
66.42, 56.19, 45.69, 27.43, 20.78; m.p. 93–95 °C; HRMS (ESI)
m/z 338.1753 [M + H]+ (calcd 338.1751, C21H24NO3).
3-IJ3-IJ4-IJDimethylamino)butoxy)phenyl)-6-methyl-2H-chromen-2-
one (5f). Yield 73%, colorless solid; 1H NMR (500 MHz,
DMSO-d6) δ 8.23 (s, 1H, CHCH), 7.59 (s, 1H, Ar–H), 7.47
(dd, J = 8.4, 1.6 Hz, 1H, Ar–H), 7.40–7.34 (m, 2H, Ar–H), 7.32–
7.29 (m, 2H, Ar–H), 7.01 (dd, J = 8.2, 1.6 Hz, 1H, Ar–H), 4.05
(t, J = 6.5 Hz, 2H, OCH2), 2.41 (s, 3H, Ar–CH3), 2.27 (t, J =
7.2 Hz, 2H, NCH2), 2.15 (s, 6H, NCH3), 1.80–1.72 (m, 2H,
alkyl chains-H), 1.61–1.55 (m, 2H, alkyl chains-H); 13C NMR
(125 MHz, DMSO-d6) δ 160.18, 158.94, 151.61, 141.11, 136.48,
134.25, 133.10, 129.74, 128.75, 127.04, 121.19, 119.68, 116.09,
115.31, 115.06, 67.95, 59.19, 45.61, 27.07, 24.05, 20.77; MS
(ESI) m/z 352.3 [M + H]+; m.p. >250 °C; HRMS (ESI) m/z
352.1909 [M + H]+ (calcd 352.1907, C22H26NO3).
General procedure for the preparation of compounds 5g–i.
To a stirred mixture of 4b (0.5 mmol) and K2CO3 (0.14 g,
1 mmol) in acetonitrile (10 mL), acyl chloride (1 mmol) was
added. After stirring at room temperature for 5 h, the mixture
was filtered and the filtrate was evaporated under vacuum.
The obtained residue was purified by silica gel chromatogra-
phy with petroleum ether–acetone as the eluent to give the
target compound (5g–i).
3-IJ6-Methyl-2-oxo-2H-chromen-3-yl)phenyl dimethylcarbamate
(5g). Yield 79%, colorless solid; 1H NMR (500 MHz,
DMSO-d6) δ 8.27 (s, 1H, CHCH), 7.62–7.60 (m, 2H, Ar–H),
7.54–7.45 (m, 3H, Ar–H), 7.37 (d, J = 8.5 Hz, 1H, Ar–H),
7.20 (dd, J = 8.0, 2.0 Hz, 1H, Ar–H), 3.10 (s, 3H, NCH3),
2.95 (s, 3H, NCH3), 2.41 (s, 3H, Ar–CH3); 13C NMR
3-IJ6-Methyl-2-oxo-2H-chromen-3-yl)phenyl benzoate (5i).
Yield 86%, yellow solid; H NMR (500 MHz, DMSO-d6) δ 8.32
1
(s, 1H, CHCH), 8.20–8.18 (m, 2H, Ar–H), 7.79–7.60 (m, 7H,
Ar–H), 7.48 (dd, J = 8.5, 2.0 Hz, 1H, Ar–H), 7.39 (m, 2H,
Ar–H), 2.41 (s, 3H, Ar–CH3); 13C NMR (125 MHz, DMSO-d6) δ
159.86, 156.52, 151.78, 142.41, 137.57, 134.25, 132.93, 131.27,
130.50, 128.80, 128.47, 128.13, 127.64, 126.89, 126.33, 125.18,
121.08, 119.40, 116.22, 113.39, 70.19, 20.74; MS (ESI) m/z
357.2 [M + H]+; m.p. 140–142 °C; HRMS (ESI) m/z 379.0942
[M + Na]+ (calcd 379.0941, C23H16NaO4).
General procedure for the preparation of compounds 5j–o.
To a stirred mixture of 4a–c (0.5 mmol) and K2CO3 (0.14 g,
1 mmol) in acetonitrile (10 mL), benzyl bromide or 3-fluorobenzyl
bromide (1 mmol) was added. After stirring for 4 h at room
temperature, the mixture was filtered and the filtrate was
evaporated under vacuum. The obtained residue was purified
by silica gel chromatography with petroleum ether–EtOAc as
the eluent to give the target compound (5j–o).
3-IJ2-IJBenzyloxy)phenyl)-6-methyl-2H-chromen-2-one (5j). Yield
82%, red solid; 1H NMR (500 MHz, DMSO-d6) δ 8.15 (s, 1H,
CHCH), 7.71 (d, J = 8.8 Hz, 2H, Ar–H), 7.56 (s, 1H, Ar–H),
7.50 (d, J = 7.3 Hz, 2H, Ar–H), 7.43 (t, J = 7.5 Hz, 3H, Ar–H),
7.36 (m, 2H, Ar–H), 7.13 (d, J = 8.8 Hz, 2H, Ar–H), 5.20 (s, 2H,
OCH2), 2.40 (s, 3H, Ar–CH3); 13C NMR (125 MHz, DMSO-d6)
δ 160.44, 159.14, 151.41, 139.61, 137.45, 134.20, 132.69,
130.29, 128.93, 128.50, 128.33, 128.12, 127.66, 126.81, 119.86,
116.04, 115.09, 69.79, 20.78; MS (ESI) m/z 343.2 [M + H]+;
m.p. 108–111 °C; HRMS (ESI) m/z 365.1149 [M + Na]+ (calcd
365.1148, C23H18NaO3).
3-IJ3-IJBenzyloxy)phenyl)-6-methyl-2H-chromen-2-one (5k). Yield
85%, yellow solid; 1H NMR (500 MHz, DMSO-d6) δ 8.24
(s, 1H, CHCH), 7.59 (br s, 1H, Ar–H), 7.50–7.34 (m, 10H,
Ar–H), 7.10 (dd, J = 8.0, 2.5 Hz, 1H, Ar–H), 5.18 (s, 2H,
OCH2), 2.41 (s, 3H, Ar–CH3); 13C NMR (125 MHz, DMSO-d6)
δ 160.18, 158.69, 151.64, 141.20, 137.51, 136.55, 134.29,
133.16, 129.80, 128.94, 128.76, 128.35, 128.22, 126.96, 121.58,
119.67, 116.13, 115.75, 115.32, 69.90, 20.78; MS (ESI) m/z
343.2 [M + H]+; HRMS (ESI) m/z 365.1149 [M + Na]+ (calcd
365.1148, C23H18NaO3).
(125 MHz, DMSO-d6)
136.30, 134.32, 133.27, 129.51, 128.83, 126.24, 125.70,
122.64, 122.32, 119.63, 116.14, 36.62, 20.78; m.p. 166–168 °C;
HRMS (ESI) m/z 346.1052 [M
δ
160.12, 154.45, 151.68, 141.41,
3-IJ4-IJBenzyloxy)phenyl)-6-methyl-2H-chromen-2-one (5l). Yield
90%, yellow solid; 1H NMR (500 MHz, DMSO-d6) δ 8.15
(s, 1H, CHCH), 7.71 (d, J = 8.8 Hz, 2H, Ar–H), 7.56 (s, 1H,
Ar–H), 7.50 (d, J = 7.3 Hz, 2H, Ar–H), 7.43 (t, J = 7.5 Hz, 3H,
Ar–H), 7.36 (dd, J = 12.9, 7.8 Hz, 2H, Ar–H), 7.13 (d, J =
8.8 Hz, 2H, Ar–H), 5.20 (s, 2H, OCH2), 2.40 (s, 3H, Ar–CH3);
13C NMR (125 MHz, DMSO-d6) δ 160.44, 159.14, 151.41,
139.61, 137.45, 134.20, 132.69, 130.29, 128.93, 128.50, 128.33,
128.12, 127.66, 126.81, 119.86, 116.04, 115.09, 69.79, 20.78;
MS (ESI) m/z 343.2 [M + H]+; m.p. 169–172 °C; HRMS (ESI)
m/z 365.1149 [M + Na]+ (calcd 365.1148, C23H18NaO3).
3-IJ2-IJ(3-Fluorobenzyl)oxy)phenyl)-6-methyl-2H-chromen-2-one
(5m). Yield 87%, red solid; 1H NMR (500 MHz, DMSO-d6)
δ 7.96 (s, 1H, CHCH), 7.52–7.30 (m, 8H, Ar–H), 7.25–7.12
(m, 3H, Ar–H), 5.19 (s, 2H, OCH2), 2.37 (s, 3H, Ar–CH3);
13C NMR (125 MHz, DMSO-d6) δ 161.45, 159.83, 159.49,
156.29, 151.76, 142.46, 134.25, 132.95, 131.37, 130.55, 128.44,
+
Na]+ (calcd 346.1050,
C19H17NNaO4).
3-IJ6-Methyl-2-oxo-2H-chromen-3-yl)phenyl-4-methylbenzenesulfonate
(5h). Yield 81%, yellow solid; 1H NMR (500 MHz, DMSO-d6)
δ 8.18 (s, 1H, CHCH), 7.81 (d, J = 8.5 Hz, 2H, Ar–H), 7.71
(d, J = 8.0 Hz, 1H, Ar–H), 7.58 (br s, 1H, Ar–H), 7.53–7.48
(m, 5H, Ar–H), 7.37 (d, J = 8.5 Hz, 1H, Ar–H), 7.08–7.06
(m, 1H, Ar–H), 2.45 (s, 3H, Ar–CH3), 2.41 (s, 3H, Ar–CH3);
13C NMR (125 MHz, DMSO-d6) δ 159.95, 151.75, 149.38,
146.34, 141.80, 137.01, 134.42, 133.52, 132.04, 130.77, 130.32,
128.89, 128.73, 127.88, 125.57, 122.54, 122.40, 119.47, 116.20,
21.66, 20.76; MS (ESI) m/z 407.2 [M + H]+; m.p. 140–143 °C;
HRMS (ESI) m/z 429.0768 [M
C23H18NaO5S).
+
Na]+ (calcd 429.0767,
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126.03, 125.30, 124.90, 124.87, 121.42, 119.36, 116.23, 115.82,
115.65, 113.64, 64.54, 20.74; MS (ESI) m/z 361.0 [M + H]+;
m.p. 99–102 °C; HRMS (ESI) m/z 383.1052 [M + H]+ (calcd
383.1054, C23H17FNaO3).
8.34 (s, 1H, Ar–H), 8.17–8.13 (m, 1H, Ar–H), 7.59 (br s,
1H, Ar–H), 7.54–7.48 (m, 2H, Ar–H), 7.38 (d, J = 8.5 Hz, 1H,
Ar–H), 2.41 (s, 3H, Ar–CH3); 13C NMR (125 MHz, DMSO-d6) δ
160.23, 151.84, 149.80, 149.48, 141.84, 136.50, 134.46, 133.50,
131.17, 128.86, 124.57, 123.65, 119.57, 116.28, 20.76; MS (ESI)
m/z 238.1 [M + H]+; m.p. 167–170 °C; HRMS (ESI) m/z
238.0864 [M + H]+ (calcd 238.0863, C15H12NO2).
6-Methyl-3-IJnaphthalen-1-yl)-2H-chromen-2-one (5r). Yield
67%, yellow solid; 1H NMR (500 MHz, DMSO-d6) δ 8.14 (s,
1H, CHCH), 8.03 (t, J = 7.0 Hz, 2H, Ar–H), 7.79 (d, J =
8.5 Hz, 1H, Ar–H), 7.59 (m, 4H, Ar–H), 7.54–7.50 (m, 2H, Ar–H),
7.43 (d, J = 8.4 Hz, 1H, Ar–H), 2.42 (s, 3H, Ar–CH3); 13C NMR
3-IJ3-IJ(3-Fluorobenzyl)oxy)phenyl)-6-methyl-2H-chromen-2-one
1
(5n). Yield 89%, yellow solid; H NMR (500 MHz, DMSO-d6) δ
8.25 (s, 1H, CHCH), 7.62 (t, J = 7.6 Hz, 2H, Ar–H), 7.46 (dd,
J = 7.8, 5.6 Hz, 2H, Ar–H), 7.42 (dd, J = 8.9, 7.0 Hz, 2H, Ar–H),
7.36 (d, J = 8.2 Hz, 2H, Ar–H), 7.28 (dd, J = 15.5, 8.1 Hz, 2H,
Ar–H), 7.13 (dd, J = 8.0, 2.1 Hz, 1H, Ar–H), 5.22 (s, 2H,
OCH2), 2.41 (s, 3H, Ar–CH3); 13C NMR (125 MHz, DMSO-d6) δ
161.89, 160.17, 159.93, 158.52, 151.65, 141.24, 136.61, 134.29,
133.16, 129.84, 128.76, 126.91, 125.04, 125.02, 121.80, 119.67,
116.12, 115.97, 115.80, 115.62, 115.26, 64.19, 64.16, 20.77. MS
(ESI) m/z 361.0 [M + H]+; m.p. 96–98 °C; HRMS (ESI) m/z
383.1052 [M + H]+ (calcd 383.1054, C23H17FNaO3).
(125 MHz, DMSO-d6)
δ 160.61, 152.19, 143.63, 134.33,
133.21, 131.74, 129.32, 128.73, 128.16, 127.78, 126.87,
126.54, 125.92, 125.87, 119.51, 116.37, 20.76; MS (ESI) m/z
287.2 [M + H]+; m.p. 131–135 °C; HRMS (ESI) m/z 287.1065
[M + H]+ (calcd 287.1067, C20H15O2).
3-IJ4-IJ(3-Fluorobenzyl)oxy)phenyl)-6-methyl-2H-chromen-2-one
1
(5o). Yield 82%, yellow solid; H NMR (500 MHz, DMSO-d6) δ
3-IJ1H-Indol-3-yl)-6-methyl-2H-chromen-2-one (5s). Yield 69%,
yellow solid; 1H NMR (500 MHz, DMSO-d6) δ 11.59 (s, 1H,
NH), 8.32 (s, 1H, CHCH), 8.13 (d, J = 2.6 Hz, 1H, Ar–H),
8.04 (d, J = 7.8 Hz, 1H, Ar–H), 7.69 (s, 1H, Ar–H), 7.50 (d, J =
7.9 Hz, 1H, Ar–H), 7.36 (d, J = 8.4 Hz, 1H, Ar–H), 7.32 (d, J =
8.4 Hz, 1H, Ar–H), 7.19 (m, 2H, Ar–H), 2.39 (s, 3H, Ar–CH3);
13C NMR (125 MHz, DMSO-d6) δ 160.36, 150.18, 136.90,
134.80, 134.05, 131.50, 128.51, 128.14, 125.62, 122.69, 122.36,
120.61, 120.29, 120.19, 115.87, 112.63, 108.86, 20.86; m.p.
216–219 °C; HRMS (ESI) m/z 298.0840 [M + Na]+ (calcd
298.0838, C18H13NNaO2).
8.16 (s, 1H, CHCH), 7.73 (d, J = 8.8 Hz, 2H, Ar–H), 7.60
(dd, J = 16.5, 8.9 Hz, 2H, Ar–H), 7.48–7.43 (m, 2H, Ar–H), 7.35
(d, J = 8.4 Hz, 1H, Ar–H), 7.31–7.26 (m, 2H, Ar–H), 7.15 (d, J =
8.8 Hz, 2H, Ar–H), 5.23 (s, 2H, OCH2), 2.40 (s, 3H, Ar–CH3);
13C NMR (125 MHz, DMSO-d6) δ 160.43, 158.97, 151.42,
139.69, 134.20, 132.71, 131.15, 130.93, 130.34, 128.52, 127.92,
126.78, 125.04, 119.85, 116.05, 115.97, 115.80, 115.00, 64.14,
20.78. MS (ESI) m/z 361.0 [M + H]+; m.p. 147–140 °C; HRMS
(ESI) m/z 383.1052 [M + H]+ (calcd 383.1054, C23H17FNaO3).
General procedure for the preparation of compounds
5p–s. A solution of 5-methylsalicylaldehyde (1, 8 mmol),
substituted acetic acid (2d–g, 10 mmol) and DCC (12 mmol)
in dimethylsulfoxide (DMSO, 10 mL) was heated at 110 °C for
24–48 h. On completion of the reaction, cold water (100 mL)
and acetic acid (15 mL) were added. The reaction mixture
was stirred at room temperature for 4 h and extracted with
diethyl ether. The precipitated dicyclohexylurea was filtered
off. The filtrate was extracted with 5% aqueous NaHCO3
(200 mL). The organic phase was stirred for 1 h with 5%
aqueous sodium metabisulfite in order to remove the
unreacted hydroxybenzaldehyde. The organic phase was
washed with water, dried IJNa2SO4) and the solvent removed
under reduced pressure. The obtained residue was purified
by silica gel chromatography with petroleum ether–EtOAc as
the eluent to give the target compound (5p–s).
Abbreviations
MAO Monoamine oxidase
FAD Flavin adenine dinucleotide
5-HT 5-Hydroxytryptamine
NE
DA
SI
Norepinephrine
Dopamine
Selectivity index
Acknowledgements
We acknowledge financial support from the Program for
Changjiang Scholars and Innovative Research Team in Uni-
versity (IRT1193), a project founded by the Priority Academic
Program Development of Jiangsu Higher Education Institu-
tions (PAPD).
6-Methyl-3-IJthiophen-2-yl)-2H-chromen-2-one (5p). Yield 58%,
yellow solid; 1H NMR (500 MHz, DMSO-d6) δ 8.54 (s, 1H,
CHCH), 7.89 (d, J = 4.0 Hz, 1H, Ar–H), 7.72 (d, J = 5.0 Hz, 1H,
Ar–H), 7.59 (s, 1H, Ar–H), 7.45 (dd, J = 8.5, 1.5 Hz, 1H, Ar–H),
7.37 (d, J = 8.4 Hz, 1H, Ar–H), 7.23–7.21 (m, 1H, Ar–H), 2.41
(s, 3H, Ar–CH3); 13C NMR (125 MHz, DMSO-d6) δ 159.60,
150.85, 136.67, 135.89, 134.58, 132.94, 129.23, 128.50, 127.85,
127.12, 120.99, 119.54, 116.19, 20.80; MS (ESI) m/z 243.1 [M + H]+;
m.p. 177–180 °C; HRMS (ESI) m/z 265.0925 [M + Na]+ (calcd
265.0924, C14H10NaO2S).
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