Synthesis and evaluation of small molecules bearing a benzyloxy substituent as novel and potent monoamine oxidase inhibitors

Article abstract of DOI:10.1039/c6md00586a

A new series of small molecules bearing a benzyloxy substituent have been designed, synthesized and evaluated for hMAO inhibitory activity in vitro. Most of the compounds were potent and selective MAO-B inhibitors, and were weak inhibitors of MAO-A. In particular, compounds 9e (IC₅₀ = 0.35 μM) and 10e (IC₅₀ = 0.19 μM) were the most potent MAO-B inhibitors, and exhibited the highest selectivity for MAO-B (9e, SI > 285.7-fold and 10e, SI = 146.8-fold). In addition, the structure-activity relationships for MAO-B inhibition indicated that electron-withdrawing groups in the open small molecules were more suitable for MAO-B inhibition, and substitutions at the benzyloxy of the open small molecules, particularly with the halogen substituted benzyloxy, were more favorable for MAO-B inhibition. Molecular docking studies have been done to explain the potent MAO-B inhibition of the open small molecules. Furthermore, the representative compounds 9e and 10e showed low neurotoxicity in SH-SY5Y cells in vitro. So the small molecules bearing the benzyloxy substituent could be used to develop promising drug candidates for the therapy of neurodegenerative diseases.

Full text of DOI:10.1039/c6md00586a

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Page 1 of 31
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DOI: 10.1039/C6MD00586A
Synthesis and evaluation of small molecules bearing a benzyloxy substituent as
novel and potent Monoamine Oxidase inhibitors†
JinꢀShuai Lan1#, Tong Zhang2#, Yun Liu1, Yong Zhang1, Jianꢀwei Hou1, SaiꢀSai Xie3,
Jing Yang1, Yue Ding1*, Zhenꢀzhen Cai4*
1 Experiment Center of Teaching & Learning, Shanghai University of Traditional
Chinese Medicine, Shanghai 201203, China;
2 School of Pharmacy, Shanghai University of Traditional Chinese Medicine,
Shanghai 201203, China;
3 National Pharmaceutical Engineering Center for Solid Preparation in Chinese
Herbal Medicine, Jiangxi University of Traditional Chinese Medicine, Nanchang
330006, China;
4 Experiment Center for Science and Technology, Shanghai University of Traditional
Chinese Medicine, Shanghai 201203, China.
* Corresponding author.
* Eꢀmail: zhangtongshutcm@hotmail.com (TZ); dingyueꢀ2001@hotmail.com (YD)
# These authors contributed equally to this work.
†The authors declare no competing interests.
1

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Abstract
A new series of small molecules bearing the benzyloxy substituent have been
designed, synthesized and evaluated for hMAO inhibitory activity in vitro. Most of
compounds were potent and selective MAOꢀB inhibitors, and were weak inhibition on
MAOꢀA. In particular, compounds 9e (IC50 = 0.35 ꢁM) and 10e (IC50 = 0.19 ꢁM)
were the most potent MAOꢀB inhibitors, and exhibited the highest selectivity for
MAOꢀB (9e, SI > 285.7ꢀfold and 10e, SI = 146.8ꢀfold). In addition, the structureꢀ
activity relationships for MAOꢀB inhibition indicated that electronꢀwithdrawing
groups in the open small molecules were more suitable for MAOꢀB inhibition, and
substitutions at the benzyloxy of the open small molecules, particularly with the
halogen substituted benzyloxy, were more favorable for MAOꢀB inhibition.
Molecular docking studies have been done to explain the potent MAOꢀB inhibition of
the open small molecules. Furthermore, the representative compounds 9e and 10e
showed low neurotoxicity in SHꢀSY5Y cells in vitro. So the small molecules bearing
the benzyloxy substituent could be used to develop promising drug candidates for the
therapy of neurodegenerative diseases.
Keywords
Monoamine Oxidase; benzyloxy substituent; neurodegenerative diseases; Molecular
docking.
Abbreviations
2

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MAO, Monoamine oxidase; CNS, central nervous system; 5ꢀHT, 5ꢀhydroxyꢀ
tryptamine; NE, norepinephrine; DA, dopamine; FAD, flavin adenine dinucleotide; SI,
selectivity index; BBB, bloodꢀbrain barrier; MTT, methyl thiazolyl tetrazolium.
Introduction
Monoamine oxidase (EC 1.4.3.4; MAO), located in the peripheral tissues and
central nervous system (CNS), is a FADꢀcontaining enzyme, which binds tightly to
the outer mitochondrial membrane of glial, neuronal and other cells. MAOs could
regulate and metabolize biogenic amines by oxidative deamination, such as serotonin,
dopamine (DA) and epinephrine.1
On account of differences in inhibitor specificity, immunological properties,
substrate preference, amino acid sequences and tissue distribution, mammals contain
two distinctive MAO enzymes, namely MAOꢀA and MAOꢀB.2ꢀ6 The MAOꢀA
preferentially metabolizes epinephrine, norepinephrine, and serotonin, and is
selectively inhibited by clorgyline. Whereas the MAOꢀB is selectively inhibited by
selegiline or rasagiline, and specifically deaminates βꢀphenethylamine.7ꢀ8 With an
increasing number of studies in Xꢀray crystal structures of the two MAOs,
information about the pharmacophoric requirements and the selective interactions is
useful to design potent and selective MAO inhibitors. The active sites of hMAOs are
supposed to be the key structural differences because of the different shapes and
volume of the inhibitors/substrate binding pockets. The active site of hMAOꢀA is a
single hydrophobic cavity, while hMAOꢀB has two distinct cavities: one is the
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soꢀcalled “substrate cavity”, which is connected to the flavine adenine dinucleotide
cofactor (FAD) and the other smaller cavity called “entrance cavity” is located
towards the outside of the protein. These cavities of MAOs have narrow pockets, but
in hMAOꢀB the Tyr326 and Ile199 residues act as a bottleneck and thus form a gate,
which separates the region as two cavities.9ꢀ10
Since the MAOs could terminate the actions of neurotransmitter amines in the CNS,
they are regarded as attractive targets to treat psychiatric and neurological disorders.
Selective MAOꢀA inhibitors are effective in the therapy of depression,11 while
selective MAOꢀB inhibitors have been applied alone or in combination to treat
Alzheimer's and Parkinson's diseases.12 Thus the specific MAO inhibitors are
developed for the treatment of neurological disorder.
Heteroꢀbenzofused derivatives bearing a benzyloxy substituent, for novel MAOꢀB
inhibitors, have been selected as promising scaffolds with potent inhibition.13ꢀ20 These
MAOꢀB inhibitors are related to natural compounds, such as coumarins, indoles,
chromones, and chromanones analogues (Fig. 1. compounds 1ꢀ4).13ꢀ16 Interestingly,
we find that some smaller molecules also exhibit potent MAOꢀB inhibitory activity,
when the heterocycle of heteroꢀbenzofused derivatives is opened (Fig. 1. compounds
5ꢀ8).17ꢀ20 Because these MAOꢀB inhibitors with benzyloxy substituents are
substantially similar, we suppose that the simplified substituents on the benzene ring
(A) may also have potential MAOꢀB inhibitory properties, and the different small
substituents may affect the MAOꢀB inhibitory activity. To obtain the smaller MAOꢀB
inhibitors with novel structure, we modify the molecular structure by introducing
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different substituents (Br, CHO, and OCH3) at metaꢀposition of the benzene ring (A)
(Fig. 2). To further examine the structure–activity relationships (SAR) against MAO,
different substitutions (F, Br and CH3) were introduced to the benzyloxy ring, and the
properties on MAO inhibition were examined.
Results and Discussion
Chemistry
The target compounds (9a–g, 10a–g and 11a–g) were efficiently synthesized as
shown in Scheme 1. The commercially available 3ꢀbromophenol (9),
3ꢀHydroxybenzaldehyde (10) and 3ꢀmethoxyphenol (11) were reacted with the
appropriate benzyl bromides in the presence of K2CO3 to give the target compounds
in good yields (85ꢀ97%).
Inhibition of hMAO activity
For compounds 9a–g, 10a–g and 11a–g, the MAO inhibitory activities were tested
with iproniazid as a reference.21 The corresponding IC50 values with MAO and the
selectivity ratios (IC50 of MAOꢀA/IC50 of MAOꢀB) were shown in Table 1. It could
be seen that most of the tested compounds (except compound 11a-g) were selective
MAOꢀB inhibitors with IC50 values in the low micromole range. Among the
synthesized compounds, compound 9e (IC50 = 0.35 ꢁM, SI > 285.7) and compound
10d (IC50 = 0.19 ꢁM, SI = 206.3) were the most potent and selective inhibitors against
MAOꢀB, being about 23.5ꢀfold more and 43.4ꢀfold more active than iproniazid.
Initially, introducing benzyloxy groups to compounds 9, 10 and 11, compounds 9a,
10a and 11a were synthesized. As shown in Table 1, compound 11a,
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OCH3ꢀsubstitution at metaꢀposition of the benzene ring (A), exhibited an IC50 value of
15.8 ꢁM for MAOꢀB which was less active than Brꢀsubstituted compound 9a (IC50 =
2.73 ꢁM) and CHOꢀsubstituted compound 10a (IC50 = 1.96 ꢁM). From this result, it
might be concluded that the electronꢀwithdrawing groups at metaꢀposition of the
benzene ring (A) was more suitable for MAOꢀB inhibition.
Then, we thought of introducing substituents with varying positions and electronic
properties to benzyloxy substitution to study the possible effects on MAOꢀB
inhibition potency. It was noteworthy that the substituted at the paraꢀpositions
(compounds 9c, 9e and 9g) were more potent than the corresponding metaꢀposition
(compounds 9b, 9d and 9f). Compared to compound 9a, compounds 9b-e bearing
electronꢀwithdrawing groups exhibited large enhancement in MAOꢀB inhibition.
However, compounds 9f and 9g with an electronꢀdonating group showed a slight
increase in MAOꢀB inhibition. For example, compound 9e (IC50 = 0.35 ꢁM for
MAOꢀB) possessing an electronꢀwithdrawing substituent Br was about 8ꢀfold more
active than compound 9a, while compound 9f (IC50 = 1.98 ꢁM for MAOꢀB)
substituted with CH3, increased the MAOꢀB inhibition potency of compound 9a by
1.4ꢀfold. Furthermore, among compounds 9b-g, compounds with paraꢀsubstitution of
the benzyloxy phenyl ring were more portent for MAOꢀB inhibition than
metaꢀsubstitution.
Moreover, introducing different substituents to benzyloxy of compound 10a to
study the possible effects on MAO inhibition, compounds 10b–g were synthesized.
Interestingly, the substituted at the para positions were more potent than the
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corresponding metaꢀposition, which was consistent with the compounds 9b–g.
Additionally, compared to compound 10a, compounds 10f and 10g with an
electronꢀdonating group showed a slight decrease in MAOꢀB inhibition.
Overall, these results demonstrated that substitution with a wide variety of
benzyloxy side chains of small molecules led to structures with potent MAOꢀB
inhibition. While MAOꢀA inhibition was very weak and no apparent SARs existed.
Reversibility of hMAO-B inhibition
As we know, MAOꢀB inhibitors could be classified as irreversible and reversible.
To examine whether the small molecules bearing a benzyloxy substituent were
reversible or irreversible MAOꢀB inhibitors, the time dependencies of inhibition was
evaluated.14 Compounds 9e and 10e were selected as representative inhibitors since
they displayed the most potent MAOꢀB inhibitory activity. For a reversible inhibitor,
the MAOꢀB activity would be almost the same, when the enzyme was preincubated
with a reversible inhibitor over different time periods. In contrast, for an irreversible
inhibitor the MAOꢀB activity would show a timeꢀdependent reduction. Compounds 9e
and 10e were preincubated with MAOꢀB over different time periods (0ꢀ60 min) at a
concentration of twofold IC50. As shown in Fig. 3, we could observe that MAOꢀB
activities were almost the same (Compound 9e: 44.8% at 0 min, 44.9% at 15 min,
48.6% at 30 min and 49.2% at 60 min; Compound 10e: 46.4% at 0 min, 45.8% at 15
min, 49.9% at 30 min and 49.5% at 60 min), and the result demonstrated that
compounds 9e and 10e were not timeꢀdependent inhibitors of MAOꢀB. So these
experiments clearly indicated that the small molecules bearing a benzyloxy
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substituent were reversible MAOꢀB inhibitors.
Kinetic study of hMAO-B inhibition
Compound 9e was also used to further investigate the mode of MAOꢀB inhibition.
The type of MAOꢀB inhibition was determined by MichaelisꢀMenten kinetic
experiments.22 The catalytic rates were measured at five different pꢀtyramine
concentrations (50ꢀ500 ꢁM), and each plot was constructed at four different
concentrations of compound 10e (0, 0.095, 0.19 and 0.38 ꢁM). The overlaid
reciprocal LineweaverꢀBurk plots (Fig. 4) showed that the plots for different
concentrations of compound 9e were linear and intersected at the yꢀaxis. This pattern
indicated that compound 9e was a competitive MAOꢀB inhibitor, and these results
further proved that the small molecules bearing a benzyloxy substituent were
reversible MAOꢀB inhibitors.
Molecular modeling studies
In order to explain the difference in MAOꢀB inhibiton, we have carried out a
structureꢀbased molecular modeling study using hMAOs cocrystals deposited into the
PDB. Crystallographic structures of MAOꢀB (PDB code 2V61) was used to dock the
derivatives under study.17 And molecular docking study was performed using software
package MOE 2008.10.23 According to the inhibition results, compounds 9e, 10e and
11e with different small substituents (Br, CHO, and OCH3) at metaꢀposition of the
benzene ring (A) was selected as a typical ligand. The 3D and 2D pictures of binding
were illustrated in Fig. 5. As shown in Fig. 5A and 5B, compound 9e located in the
wellꢀknown binding pocket of MAOꢀB,24 with the Brꢀsubstituted benzene ring (A)
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interacting with Tyr 398 via an aromatic πꢀπ stacking interactions at bottom of the
substrate cavity; The Brꢀsubstituted benzyl group occupied the entrance cavity via a
πꢀπinteraction with Tyr 326. From Fig. 5C and 5D, compound 10e, with the
CHOꢀsubstituted benzene ring (A), not only had an aromatic πꢀπ stacking interactions
with Tyr 398, but also had a hydrogen bond interaction with Tyr 188 at bottom of the
substrate cavity; The Brꢀsubstituted benzyl group occupied the entrance cavity which
was a hydrophobic subpocket existing only in the MAOꢀB isoform and constituted by
Leu 171, Ile 316, Tyr 326, Ile 199, Phe 99, Pro 104 and Phe 168. However, no
interaction between the ligands 11e with the OCH3ꢀsubstituted benzene ring (A) and
the MAOꢀB was observed in Fig. 5E and 5F. So these results might explain why the
MAOꢀB inhibitory activities of compounds 9e and 10e were more potent than that of
compound 11e, and the reason could be ascribed to the different interaction between
compounds and the MAOꢀB. Moreover, the modelling studies between compound 10e
and
standard
compound
7ꢀ((3ꢀchlorobenzyl)oxy)ꢀ4ꢀ((methylamino)methyl)
ꢀcoumarin(Claudia Binda, J Med Chem. 2007, 50, 5848ꢀ5852.) were compared in
supporting information.
Cells toxicity
Based on the screening results above, compounds 9e and 10e as the most potent
inhibitors against MAOꢀB were selected to further examine the potential toxicity
effect on the SHꢀSY5Y cells.25 After incubating the cells with compound 9e or 10e for
48 h, the cell viability was determined by the 3ꢀ(4,5ꢀdimethylthiazolꢀ2ꢀ
yl)ꢀ2,5ꢀdiphenyltetrazolium (MTT) assay. As shown in the Fig. 6, the result revealed
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that compounds 9e and 10e at 3ꢀ50 ꢁМ did not have neurotoxicity. This suggested that
compounds 9e and 10e might be used to develop promising drug candidates for the
therapy of neurodegenerative diseases.
Prediction of BBB penetration of compounds 9a-g, 10a-g and 11a-g
High pharmacological activity and low toxicological effects are not enough for a
compound to become a drug candidate. Molecules should meet the limiting terms of
Lipinski’s rules: molecular weight (MW) less than 500, the number of hydrogen bond
acceptor atoms (HBA) less than 10, the number of hydrogen bond donor atoms (HBD)
less than 5, the calculated logarithm of the octanolꢀwater partition coefficient (Clog P)
less than 5, and the small polar surface area less than 90 Å2. With the aim of
developing the CNS drugs, the ability of compounds to cross the bloodꢀbrain barrier
(BBB) is very important.26 The log BB is calculated as the following equation: log BB
= 0.0148 × PSA + 0.152 × Clog P + 0.139.27 Calculated log BB for potential
applications in brains and defined by the restrictive terms of Lipinski’s rules, as
shown in Table 2, compounds 9a-g, 10a-g and 11a-g satisfied possible brain
penetration and drugꢀlike standards.
Conclusions
In conclusion, we have synthesized a series of small molecules bearing the
benzyloxy substituent and evaluated their MAO inhibitory activity and toxicity in
vitro. The results showed that most of the studied compounds were remarkably
competitive and reversible MAOꢀB inhibitors rather than of MAOꢀA. The SAR of
synthesized compounds showed the electronꢀwithdrawing groups at metaꢀposition of
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the benzene ring (A) were more suitable for MAOꢀB inhibition; halogen substituents
on the benzyloxy ring further increased MAOꢀB inhibition. So different electronꢀ
withdrawing groups will be introduced at different position of the benzene ring (A)
and the MAOꢀB inhibition will be tested, which is on further study. Moreover,
molecular docking studies of the 9e and 10e suggested that the potent MAOꢀB
inhibition might be ascribed to the πꢀπ stacking/cation–π interactions and the larger set
of residues interacting with MAOꢀB. Due to the possible BBB permeability and low
neurotoxicity in SHꢀSY5Y cells in vitro, these compounds could be used to develop
promising drug candidates for the therapy of neurodegenerative diseases.
Experimental Section
Materials and Methods
All chemicals (reagent grade) used were purchased from Sino pharm Chemical
Reagent Co., Ltd. (China). Reaction progress was monitored using analytical thin
layer chromatography (TLC) on precoated silica gel GF254 (Qingdao Haiyang
Chemical Plant, QingꢀDao, China) plates and the spots were detected under UV light
(254 nm). 1H NMR and 13C NMR spectra were measured on a BRUKER AVANCE III
spectrometer at 25°C and referenced to TMS. Chemical shifts are reported in ppm (δ)
using the residual solvent line as internal standard. Splitting patterns are designed as s,
singlet; d, doublet; t, triplet; m, multiplet. The purity of all compounds was confirmed
to be higher than 95% through analytical HPLC performed with Agilent 1200 HPLC
System, photodiode array detector (DAD), 55% (v/v) of CH3OH gradient, flow rate:
1.0 mL /min. Mass spectra were obtained on a MS Agilent 1100 Series LC/MSD Trap
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mass spectrometer (ESIꢀMS).
General Procedure for the Preparation of compounds 9a–g, 10a–g and 11a–g.
Compounds 9, 10 or 11 (1.85 mmol) was suspended in acetonitrile (15 mL)
containing K2CO3 (3.70 mmol). The reaction was treated with an appropriately
substituted arylalkyl bromide (2.04 mmol) and heated under reflux for 12 h. The
reaction progress was monitored using silica gel TLC with hexanes/EtOAc as mobile
phase. Upon completion, the acetonitrile was evaporated in vacuo and the mixture
was then poured into water, which was extracted with 3 × 200 mL of EtOAc, washed
with brine, dried over anhydrous Na2SO4 and purified by chromatography (hexanes
/EtOAc) on silica gel.
1-(benzyloxy)-3-bromobenzene (9a)
1
Yield 89%; light yellow oil; ESI/MS m/z: 264.1 [M+H]+; HꢀNMR (400 MHz,
CDCl3): δ 7.45–7.38 (m, 4H), 7.37–7.31 (m, 1H), 7.18–7.07 (m, 3H), 6.95ꢀ6.87 (m, J
= 8.0, 2.4, 1.2 Hz, 1H), 5.05 (s, 2H). 13CꢀNMR (100 MHz, CDCl3): δ 159.57, 136.42,
130.59, 128.68, 128.18, 127.51, 124.10, 122.84, 118.22, 113.86, 70.24.
1-bromo-3-((3-fluorobenzyl)oxy)benzene (9b)
Yield 92%; light yellow oil; ESI/MS m/z: 282.1 [M+H]+; 1H NMR (400 MHz, CDCl3)
δ 7.36ꢀ7.25 (m, 1H), 7.20 –7.09 (m, 5H), 7.03ꢀ6.95 (m, 1H), 6.89ꢀ6.81 (m, 1H), 5.04
(s, 2H). 13CꢀNMR (100 MHz, CDCl3) δ 162.93(d, 1JCF= 287.43 Hz), 159.24, 139.01(d,
3
3JCF = 8.27 Hz), 130.64, 130.22(d, JCF = 8.48 Hz), 124.35, 122.88, 122.71, 118.21,
115.01 (d, 2JCF = 21.68 Hz), 114.23 (d, 2JCF = 22.25 Hz), 113.80, 69.37.
1-bromo-3-((4-fluorobenzyl)oxy)benzene (9c)
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Yield 93%; light yellow oil; ESI/MS m/z: 282.1 [M+H]+; 1H NMR (400 MHz,
CDCl3) δ 7.43–7.35 (m, 2H), 7.18–7.03 (m, 5H), 6.89ꢀ6.79 (m, 1H), 5.00 (s, 2H).
1
13CꢀNMR (100 MHz, CDCl3) δ 162.62(d, JCF= 245.43 Hz), 159.37, 132.18, 132.15,
3
2
130.62, 129.38(d, JCF = 8.36 Hz), 124.24, 122.87, 118.19, 115.59, 115.59(d, JCF
=
21.59 Hz), 113.83, 69.56.
1-bromo-3-((3-bromobenzyl)oxy)benzene(9d)
Yield 89%; light yellow oil; ESI/MS m/z: 343.0 [M+H]+; 1H NMR (400 MHz, CDCl3)
δ 7.58 (s, 1H), 7.47 (d, J = 7.9 Hz, 1H), 7.34 (d, J = 7.7 Hz, 1H), 7.29 – 7.23 (m, 1H),
7.18 – 7.08 (m, 3H), 6.89ꢀ6.80 (m, 1H), 5.01 (s, 2H). 13CꢀNMR (100 MHz, CDCl3) δ
159.22, 138.73, 131.23, 130.66, 130.35, 130.22, 125.84, 124.39, 122.90, 122.76,
118.21, 113.76, 69.28.
1-bromo-3-((4-bromobenzyl)oxy)benzene (9e)
1
Yield 90%; light yellow oil; ESI/MS m/z: 343.1 [M+H]+; H NMR (400 MHz,
DMSOꢀd6) δ 7.59 (d, J = 8.2 Hz, 2H), 7.40 (d, J = 8.2 Hz, 2H), 7.28 –7.20 (m, 2H),
7.14 (d, J = 7.9 Hz, 1H), 7.02ꢀ6.95 (m, 1H), 5.11 (s, 2H). 13C NMR (101 MHz,
DMSOꢀd6) δ 159.58, 136.55, 131.86, 131.86, 131.69, 130.30, 130.30, 124.23, 122.57,
121.55, 118.16, 114.80, 69.16.
1-bromo-3-((3-methylbenzyl)oxy)benzene (9f)
Yield 87%; light yellow oil; ESI/MS m/z: 278.2 [M+H]+; 1H NMR (400 MHz, CDCl3)
δ 7.29 (t, J = 7.5 Hz, 1H), 7.25–7.20 (m, 2H), 7.18 – 7.08 (m, 4H), 6.91ꢀ6.86 (m, 1H),
5.00 (d, J = 6.0 Hz, 2H), 2.38 (s, 3H). 13CꢀNMR (100 MHz, CDCl3) δ 159.63, 138.39,
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136.31, 130.57, 128.95, 128.57, 128.27, 124.63, 124.04, 122.83, 118.21, 113.83,
70.31, 21.43.
1-bromo-3-((4-methylbenzyl)oxy)benzene (9g)
Yield 86%; light yellow oil; ESI/MS m/z: 278.2 [M+H]+; 1H NMR (400 MHz, CDCl3)
δ 7.31 (d, J = 8.0 Hz, 2H), 7.21 (d, J = 7.8 Hz, 2H), 7.17–7.05 (m, 3H), 6.90ꢀ6.83 (m,
1H), 5.00 (s, 2H), 2.37 (s, 3H). 13CꢀNMR (100 MHz, CDCl3) δ 159.64, 138.00,
133.36, 130.55, 129.35, 129.35, 127.66, 127.66, 123.99, 122.81, 118.21, 113.87,
70.18, 21.22.
3ꢀ(benzyloxy)benzaldehyde (10a)
Yield 88%; light yellow oil; ESI/MS m/z: 213.2 [M+H]+; 1H NMR (400 MHz, CDCl3)
δ 9.98 (s, 1H), 7.50 – 7.32 (m, 8H), 7.26ꢀ6.17 (m, 1H), 5.13 (s, 2H). 13CꢀNMR (100
MHz, CDCl3) δ 192.07, 159.35, 137.86, 136.33, 130.13, 128.70, 128.70, 128.22,
127.55, 127.55, 123.69, 122.21, 113.32, 70.26.
3-((3-fluorobenzyl)oxy)benzaldehyde (10b)
Yield 93%; light yellow oil; ESI/MS m/z: 231.2 [M+H]+; 1H NMR (400 MHz,
CDCl3) δ 9.98 (s, 1H), 7.52–7.44 (m, 3H), 7.36ꢀ7.24 (m, 1H), 7.27–7.14 (m, 3H), 7.03
(td, J = 8.3, 2.4 Hz, 1H), 5.12 (s, 2H). 13CꢀNMR (100 MHz, CDCl3) δ 191.97,
1
3
163.02(d, JCF= 245.48 Hz), 159.05, 138.93 (d, JCF = 7.83 Hz), 137.89, 130.30,
2
2
130.22, 123.99, 122.79, 122.17, 115.06(d, JCF = 21.32 Hz), 114.27(d, JCF = 22.14
Hz), 113.14, 69.38.
3-((4-fluorobenzyl)oxy)benzaldehyde (10c)
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Yield 90%; light yellow oil; ESI/MS m/z: 231.2 [M+H]+; 1H NMR (400 MHz, CDCl3)
δ 9.98 (s, 1H), 7.50–7.45 (m, 3H), 7.45 – 7.39 (m, 2H), 7.27–7.22 (m, 1H), 7.12–7.06
(m, 2H), 5.08 (s, 2H). 13CꢀNMR (100 MHz, CDCl3) δ 192.02, 162.64(d, 1JCF= 245.58
3
Hz), 159.17, 137.87, 132.08, 130.18, 129.43, 129.43(d, JCF = 8.27 Hz), 123.92,
122.22, 115.62, 115.62(d, 2JCF = 21.84 Hz), 113.11, 69.57.
3-((3-bromobenzyl)oxy)benzaldehyde (10d)
Yield 90%; light yellow oil; ESI/MS m/z: 292.1 [M+H]+; 1H NMR (400 MHz, CDCl3)
δ 9.95 (s, 1H), 7.59 (s, 1H), 7.49–7.45 (m, 2H), 7.45–7.42 (m, 2H), 7.34 (d, J = 7.7
Hz, 1H), 7.25–7.20 (m, 2H), 5.06 (s, 2H). 13CꢀNMR (100 MHz, CDCl3) δ 191.95,
159.03, 138.65, 137.90, 131.28, 130.39, 130.24, 130.24, 125.90, 124.01, 122.79,
122.14, 113.15, 69.29.
3-((4-bromobenzyl)oxy)benzaldehyde (10e)
1
Yield 91%; light yellow oil; ESI/MS m/z: 292.1 [M+H]+; H NMR (400 MHz,
DMSOꢀd6) δ 9.98 (s, 1H), 7.61 (s, 1H), 7.50–7.47 (m, 2H), 7.45–7.41 (m, 2H), 7.35
(d, J = 7.7 Hz, 1H), 7.26–7.21 (m, 2H), 5.21 (s, 2H). 13C NMR (100 MHz, DMSOꢀd6)
δ 193.35, 159.09, 139.97, 138.15, 131.25, 131.17, 130.94, 130.72, 130.27, 127.09,
123.43, 122.15, 114.38, 68.95.
3-((3-methylbenzyl)oxy)benzaldehyde (10f)
Yield 89%; light yellow oil; ESI/MS m/z: 227.2 [M+H]+; 1H NMR (400 MHz,
CDCl3) δ 9.98 (s, 1H), 7.51–7.45 (m, 3H), 7.30–7.22 (m, 4H), 7.16 (d, J = 7.3 Hz,
1H), 5.09 (s, 2H), 2.39 (s, 3H). 13CꢀNMR (100 MHz, CDCl3) δ 192.10, 159.41,
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138.43, 137.86, 136.23, 130.12, 129.00, 128.60, 128.32, 124.68, 123.62, 122.18,
113.36, 70.33, 21.43.
3-((4-methylbenzyl)oxy)benzaldehyde (10g)
Yield 91%; light yellow oil; ESI/MS m/z: 227.1 [M+H]+; 1H NMR (400 MHz,
CDCl3) δ 9.97 (s, 1H), 7.51–7.43 (m, 3H), 7.34 (d, J = 8.0 Hz, 2H), 7.27–7.19 (m,
3H), 5.09 (s, 2H), 2.37 (s, 3H). 13CꢀNMR (100 MHz, CDCl3) δ 192.10, 159.41,
138.05, 137.84, 133.29, 130.10, 130.10, 129.38, 129.38, 127.71, 123.57, 122.23,
113.37, 70.21, 21.22.
1-(benzyloxy)-3-methoxybenzene (11a)
Yield 91%; light yellow oil; ESI/MS m/z: 215.2 [M+H]+; 1H NMR (400 MHz, CDCl3)
δ 7.60 (s, 1H), 7.46 (d, J = 7.9 Hz, 1H), 7.35 (d, J = 7.7 Hz, 1H), 7.29 –7.16 (m, 3H),
6.56ꢀ6.43 (m, 3H), 5.02 (s, 2H), 3.80 (s, 3H). 13CꢀNMR (100 MHz, CDCl3) δ 160.91,
159.75, 139.36, 131.03, 130.38, 130.15, 130.00, 125.88, 122.70, 106.90, 106.87,
101.44, 69.13, 55.31.
1-fluoro-3-((3-methoxyphenoxy)methyl)benzene (11b)
Yield 93%; light yellow oil; ESI/MS m/z: 233.2 [M+H]+; 1H NMR (400 MHz, CDCl3)
δ 7.60 (s, 1H), 7.46 (d, J = 7.9 Hz, 1H), 7.35 (d, J = 7.7 Hz, 1H), 7.29–7.16 (m, 2H),
6.56ꢀ6.41 (m, 3H), 5.02 (s, 2H), 3.80 (s, 3H). 13CꢀNMR (100 MHz, CDCl3) δ
1
3
163.02(d, JCF= 245.35 Hz), 160.91, 159.78, 139.65(d, JCF= 8.27 Hz), 130.13 (d,
3JCF= 8.24 Hz), 129.99, 122.76, 114.80(d, 2JCF= 21.33 Hz), 114.26(d, 2JCF= 22.26 Hz),
106.93, 106.81, 101.44, 69.21, 55.30.
1-((4-fluorobenzyl)oxy)-3-methoxybenzene (11c)
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Yield 91%; light yellow oil; ESI/MS m/z: 233.2 [M+H]+; 1H NMR (400 MHz, CDCl3)
δ 7.45–7.36 (m, 2H), 7.23–7.16 (m, 1H), 7.12–7.02 (m, 2H), 6.60–6.50 (m, 3H), 5.01
1
(s, 2H), 3.79 (s, 3H). 13CꢀNMR (100 MHz, CDCl3) δ 162.54(d, JCF= 245.19 Hz),
3
160.89, 159.89, 132.73, 129.96, 129.38, 129.38(d, JCF= 8.95 Hz), 115.50, 115.50(d,
3JCF= 22.11 Hz), 106.94, 106.71, 101.43, 69.37, 55.29.
1-bromo-3-((3-methoxyphenoxy)methyl)benzene (11d)
Yield 90%; light yellow oil; ESI/MS m/z: 294.1 [M+H]+; 1H NMR (400 MHz, CDCl3)
δ 7.45 (m, 2H), 7.42 –7.37 (m, 2H), 7.20 (t, J = 8.1 Hz, 1H), 6.62–6.51 (m, 3H), 5.06
(s, 2H), 3.80 (s, 3H). 13CꢀNMR (100 MHz, CDCl3) δ 160.88, 160.10, 137.01, 129.93,
128.62, 128.62, 128.00, 127.55, 127.55, 106.99, 106.64, 101.43, 70.08, 55.30.
1-((4-bromobenzyl)oxy)-3-methoxybenzene (11e)
Yield 94%; light yellow oil; ESI/MS m/z: 294.1 [M+H]+; 1H NMR (400 MHz, CDCl3)
δ 7.58 (d, J = 8.3 Hz, 2H), 7.40 (d, J = 8.3 Hz, 2H), 7.18 (t, J = 8.1 Hz, 1H), 6.60–
6.54 (m, 2H), 6.53 (dd, J = 8.2, 2.1 Hz, 1H), 5.07 (s, 2H), 3.72 (s, 3H). 13C NMR (100
MHz, DMSOꢀd6) δ 160.97, 159.83, 137.07, 131.81, 131.81, 130.46, 130.22, 130.22,
121.35, 107.46, 107.04, 101.60, 68.84, 55.56.
1-methoxy-3-((3-methylbenzyl)oxy)benzene (11f)
Yield 91%; light yellow oil; ESI/MS m/z: 229.2 [M+H]+; 1H NMR (400 MHz, CDCl3)
δ 7.36–7.13 (m, 5H), 6.59ꢀ6.47 (m, 3H), 5.04 (s, 2H), 3.82 (s, 3H), 2.41 (s, 3H). 13C
NMR (100 MHz, CDCl3) δ 160.87, 160.16, 138.30, 136.89, 129.90, 128.77, 128.51,
128.31, 124.67, 106.95, 106.60, 101.40, 70.14, 55.29, 21.43.
1-methoxy-3-((4-methylbenzyl)oxy)benzene (11g)
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Yield 91%; light yellow oil; ESI/MS m/z: 229.3 [M+H]+; 1H NMR (400 MHz, CDCl3)
δ 7.36 (d, J = 8.0 Hz, 2H), 7.22 (t, J = 8.2 Hz, 3H), 6.67 – 6.52 (m, 3H), 5.04 (s, 2H),
3.82 (s, 3H), 2.40 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 160.85, 160.16, 137.76,
133.94, 129.88, 129.28, 129.28, 129.28, 129.28, 106.98, 106.55, 101.40, 69.99, 55.28,
21.21.
Acknowledgments
This work was supported by the programs of the National Natural Science
Foundation of China [Grant No.81274200, 81403175]; Youth Talent Sail Plan from
Shanghai Committee of Science and Technology [Grant No. 14YF1411300]; Project
from Shanghai Municipal Commission of Health and Family planning [Grant No.
20134Y053] and Research Fund for the Docoral Program of Shanghai [Grant No.
13401900301].
Conflicts of Interest
The authors declare no conflict of interest.
References
1. Tipton, K. Cell. Biochem. Funct. 1986, 4, 79ꢀ87.
2. Bach, A.; Lan, N. C.; Johnson, D. L.; Abell, C. W.; Bembenek, M. E.; Kwan,
S.ꢀW.; Seeburg, P. H.; Shih, J. C. Proc. Natl. Acad. Sci. USA. 1988, 85, 4934ꢀ4938.
3. Wouters, J. Curr. Med. Chem. 1998, 5, 137ꢀ162.
4. Grimsby, J.; Lan, N. C.; Neve, R.; Chen, K.; Shih, J. C. J. Neurochem. 1990, 55,
1166ꢀ1169.
5. Kalgutkar, A. S.; Castagnoli, N.; Testa, B. Med. Res. Rev. 1995, 15, 325ꢀ388.
18

Page 19 of 31
MedChemComm
View Article Online
DOI: 10.1039/C6MD00586A
6. Geha, R. M.; Rebrin, I.; Chen, K.; Shih, J. C. J. Biol. Chem. 2001, 276,
9877ꢀ9882.
7. Ma, J.; Yoshimura, M.; Yamashita, E.; Nakagawa, A.; Ito, A.; Tsukihara, T. J. Mol.
Biol. 2004, 338,103ꢀ114.
8. Weyler, W.; Hsu, Y.ꢀP. P.; Breakafield, X. O. Pharmacol. Ther. 1990, 47, 391ꢀ417.
9. Binda, C.; Li, M.; Hubálek, F.; Restelli, N.; Edmondson, D. E.; Mattevi, A. Proc.
Natl. Acad. Sci. U.S.A. 2003, 100, 9750ꢀ9755.
10. Ma, J.; Yoshimura, M.; Yamashita, E.; Nakagawa, A.; Ito, A.; Tsukihara, T. J. Mol.
Biol. 2004, 338, 103ꢀ114.
11. Chen, J. J.; D. Swope, M.; Dashtipour, K. Clin. Ther. 2007, 29, 1825ꢀ1849.
12. Pacher, P.; Kecskemeti, V. Curr. Med. Chem. 2004, 11, 925ꢀ943.
13. Gnerre C.; Catto M.; Leonetti F.; Weber, P.; Carrupt, P.ꢀA.; Altomare, C.; Carotti,
A.; Testa, B. J. Med. Chem. 2000, 43, 4747ꢀ4758.
14. Legoabe, L. J.; Petzer, A.; Petzer, J. P. Bioorg Chem. 2012, 45, 1ꢀ11.
15. Lan, JS.; Xie, SS.; Huang, M.; Hu, YJ.; Kong LY.; Wang XB. Med. Chem.
Commun. 2015, 6, 1293ꢀ1302.
16. Perez, V.; Unzeta, M. Neurochem Int. 2003, 42, 221ꢀ229.
17. Binda, C.; Wang, J.; Pisani, L.; Caccia, C.; Carotti, A.; Salvati, P.; Edmondson,
DE.; Mattevi, A. J Med Chem. 2007, 50, 5848ꢀ5852.
18. ManleyꢀKing, CI.; Bergh, JJ.; Petzer, JP. Bioorg Chem. 2012, 40,114ꢀ124.
19. Legoabe, LJ.; Petzer, A.; Petzer, JP. Bioorg Med Chem Lett. 2012, 22,
5480ꢀ5484.
19

MedChemComm
Page 20 of 31
View Article Online
DOI: 10.1039/C6MD00586A
20. Wang, ZM.; Li, XM.; Xu, W.; Li, F.; Wang, J.; Kong, LY.; Wang XB. Med. Chem.
Commun. 2015, 6, 2146ꢀ2157.
21. Santana, L.; GonzálezꢀDíaz, H.; Quezada, E. a.; Uriarte, E.; Yáñez, M.; Vina, D.;
Orallo, F. J. Med. Chem. 2008, 51, 6740ꢀ6751.
22. Tzvetkov, N. T.; Hinz, S.; Küppers, P.; Gastreich, M.; Müller, C. E. J Med Chem.
2014, 15, 6679ꢀ6703.
23. Muzammil, S.; Armstrong, A.; Kang, L.; Jakalian, A.; Bonneau, P.; Schmelmer,
V.; Amzel, L.; Freire, E. J Virol. 2007, 81, 5144ꢀ5154.
24. Binda, C.; Hubalek, F.; Li, M.; Herzig, Y.; Sterling, J.; Edmondson, D. E.;
Mattevi, A. J. Med. Chem. 2004, 47, 1767ꢀ1774.
25. Lu, C.; Zhou, Q.; Yan, J.; Du, Z.; Huang, L.; Li, X. Eur. J. Med. Chem. 2013, 62,
745ꢀ753.
26. Pardridge, W. M. Alzheimers Dement. 2009, 5, 427ꢀ432.
27. Brayamer, J. J.; DeToma, A. S.; Choi, J.ꢀS.; Ko, K. S.; Lim, M. H. Int J
Alzheimers Dis. 2011, 2011, 623051ꢀ623059.
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Scheme 1 Syntheses of target compounds 9a–g, 10a–g and 11a–g. Reagents and
conditions: (a) K2CO3, CH3CN, reflux, 12 h.
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Table 1.
hMAO inhibitory activities of the synthesized compounds.
Compounds
R
MAOꢀA
MAOꢀB
Selectivity
Indexc
inhibition (%)a
IC50 (ꢁM)b
ꢀ
23
2.73 ± 0.08
1.06 ± 0.18
0.58 ± 0.12
0.76 ± 0.03
0.35 ± 0.06
1.98 ± 0.09
1.53 ± 0.06
1.96 ± 0.11
1.21 ± 0.08
0.93 ± 0.05
0.53 ± 0.04
0.19 ± 0.07
2.91 ± 0.08
2.53 ± 0.16
15.8 ± 0.23
12.3 ± 0.79
15.6 ± 0.28
19.3 ± 0.51
8.63 ± 0.24
10.9 ± 0.17
14.6 ± 0.35
8.24 ± 0.18
>36.6
>94.3
>172.4
>131.6
>285.7
>50.5
>65.4
23.3
9a
9b
3ꢀF
37
4ꢀF
31
9c
3ꢀBr
4ꢀBr
3ꢀCH3
4ꢀCH3
ꢀ
27
9d
30
9e
43
9f
24
9g
45.6 ± 0.87 ꢁMb
10a
10b
10c
10d
10e
10f
3ꢀF
64.2 ± 0.59 ꢁM
53.1
4ꢀF
42.5 ± 1.06 ꢁM
45.7
3ꢀBr
4ꢀBr
3ꢀCH3
4ꢀCH3
ꢀ
28.2 ± 0.85 ꢁM
53.2
27.9 ± 0.49 ꢁM
146.8
17.7
51.6 ± 0.53 ꢁM
64.8 ± 0.73 ꢁM
25.6
10g
11a
11b
11c
11d
11e
11f
25
>6.3
3ꢀF
19
>8.1
4ꢀF
22
>6.4
3ꢀBr
4ꢀBr
3ꢀCH3
4ꢀCH3
ꢀ
22
>5.2
25
>11.6
>9.2
23
26
>6.8
11g
Iproniazid
6.78 ± 0.35 ꢁM
0.82
a) Test concentration is 100 ꢁM.
b) IC50: 50% inhibitory concentration (means ± SEM of three experiments).
c) Selectivity Index = IC50 (MAOꢀA)/IC50 (MAOꢀB).
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Table 2
Physical properties of compounds 9a-g, 10a-g and 11a-g.
Compounds
9a
MW a
261.99
279.99
279.99
339.91
339.91
276.02
276.02
212.08
230.07
230.07
289.99
289.99
226.10
226.10
214.10
232.09
232.09
292.01
292.01
228.12
228.12
≤450
Clog P a
4.832
4.975
4.975
5.695
5.695
5.311
5.311
3.546
3.690
3.690
4.410
4.410
4.046
4.046
3.918
4.061
4.061
4.781
4.781
4.417
4.417
≤5.0
HBA a
HBD a
PAS a
9.23
Log BB a
1.010
1.031
1.031
1.141
1.141
0.953
0.953
1.067
1.089
1.089
1.199
1.199
1.143
1.143
0.878
1.029
1.029
1.139
1.139
1.084
1.084
≥ꢀ1.0
1
1
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
≤5
9.23
9b
1
9.23
9c
1
9.23
9d
1
9.23
9e
1
9.23
9f
1
9.23
9g
2
26.30
26.30
26.30
26.30
26.30
26.30
26.30
18.46
18.46
18.46
18.46
18.46
18.46
18.46
≤90
10a
10b
10c
10d
10e
10f
2
2
2
2
2
2
10g
11a
11b
11c
11d
11e
11f
2
2
2
2
2
2
2
11g
Rules
≤10
a MW: molecular weight; C log P: calculated logarithm of the octanolꢀwater partition
coefficient; HBA: hydrogenꢀbond acceptor atoms; HBD: hydrogenꢀbond donor atoms;
PSA: polar surface area; log BB = 0.0148 × PAS + 0.152 × Clog P + 0.139.
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Figure 1. Structures of known MAO inhibitors bearing a benzyloxy substituent.
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Figure 2. Design strategy for the novel series of heterocycleꢀopened derivatives as
MAOꢀB inhibitors.
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Figure 3. The timeꢀdependent inhibition of hMAOꢀB by compounds 9e and 10e.
Compound was preincubated for various periods of time (0ꢀ60 min) with hMAOꢀB at
concentrations equal to twofold the IC50 values for the inhibition of the enzyme.
After dilution to concentrations equal to the IC50, the inhibitory rates were recorded.
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Figure 4. Kinetic study on the mechanism of hMAOꢀB inhibition by compound 10e.
Overlaid LineweaverꢀBurk reciprocal plots of MAOꢀB initial velocity at increasing
substrate concentration (50–500 ꢁM) in the absence of inhibitor and in the presence of
10e are shown. Lines were derived from a weighted leastꢀsquares analysis of the data
points.
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Figure 5. (A) 3D docking model of compound 9e with hMAOꢀB. Atom colors:
yellowꢀcarbon atoms of compound 9e, grayꢀcarbon atoms of residues of hMAOꢀB,
dark blueꢀnitrogen atoms, redꢀoxygen atoms. The dashed lines represent the
interactions between the protein and the ligand. (B) 2D schematic diagram of docking
model of compound 9e with hMAOꢀB. (C) 3D docking model of compound 10e with
hMAOꢀB. (D) 2D schematic diagram of docking model of compound 10e with
hMAOꢀB. (E) 3D docking model of compound 11e with hMAOꢀB. (F) 2D schematic
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diagram of docking model of compound 11e with hMAOꢀB. The figure was prepared
using the ligand interactions 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.)
29