Design, synthesis and biological evaluation of lazabemide derivatives as inhibitors of monoamine oxidase

Article abstract of DOI:10.1016/j.bmc.2018.08.024

In the studied a series novel of lazabemide derivatives were designed, synthesized and evaluated as inhibitors of monoamine oxidase (MAO-A or MAO-B). These compounds used lazabemide as the lead compound, and the chemistry structures were modified by used the bioisostere and modification of compound with alkyl principle. The two types of inhibitors (inhibition of MAO-A and inhibition of MAO-B) were screened by inhibition activity of MAO. In vitro experiments showed that compounds 3a, 3d and 3f had intensity inhibition the biological activity of MAO-A, while compounds 3i and 3m had intensity inhibition the biological activity of MAO-B. It could be seen from the data of inhibition activity experiments in vitro, that the compound 3d was IC₅₀ = 3.12 ± 0.05 μmol/mL of MAO-A and compound 3m was IC₅₀ = 5.04 ± 0.06 μmol/mL. In vivo inhibition activity experiments were conducted to evaluate the inhibitory activity of compounds 3a, 3d, 3f, 3i and 3m by detecting the contents of 5-HT, NE, DA and activity of MAO-A and MAO-B in plasma and brain tissue. In vivo inhibition activity evaluation results showed that the compounds 3a, 3d, 3f, 3i and 3m had increased the contents of 5-HT, NE and DA in plasma and brain tissues. Meanwhile, the determination results activity of MAO in plasma and brain tissue showed that the compounds 3a, 3d, and 3f had a significant inhibitory effect on the activity of MAO-A, while the compounds 3i and 3m showed inhibitory effect on the activity of MAO-B. This study provided a new inhibitors for inhibiting of MAO activity.

Full text of DOI:10.1016/j.bmc.2018.08.024

Accepted Manuscript
Design, synthesis and biological evaluation of lazabemide derivatives as inhib-
itors of monoamine oxidase
Shiyang Zhou, Guangying Chen, Gangliang Huang
PII:
S0968-0896(18)31216-1
https://doi.org/10.1016/j.bmc.2018.08.024
BMC 14511
DOI:
Reference:
Bioorganic & Medicinal Chemistry
To appear in:
Received Date:
Revised Date:
Accepted Date:
3 July 2018
8 August 2018
17 August 2018
Please cite this article as: Zhou, S., Chen, G., Huang, G., Design, synthesis and biological evaluation of lazabemide
derivatives as inhibitors of monoamine oxidase, Bioorganic & Medicinal Chemistry (2018), doi: https://doi.org/
10.1016/j.bmc.2018.08.024
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Design, synthesis and biological evaluation of lazabemide derivatives as
inhibitors of monoamine oxidase
Shiyang Zhoua, b, Guangying Chena, b, Gangliang Huangc*
a. College of Chemistry and Chemical Engineerin, Hainan Normal University, Hainan
571158, China;
b. Key Laboratory of Tropical Medicinal Plant Chemistry of Ministry of Education, Hainan
Normal University, Hainan 571158, China;
c. College of Chemistry, Chongqing Normal University, Chongqing 401331, China
E-mail: huangdoctor226@163.com
Abstract: In the studied a series novel of lazabemide derivatives were designed, synthesized and
evaluated as inhibitors of monoamine oxidase (MAO-A or MAO-B). These compounds used
lazabemide as the lead compound, and the chemistry structures were modified by used the
bioisostere and modification of compound with alkyl principle. The two types of inhibitors
(inhibition of MAO-A and inhibition of MAO-B) were screened by inhibition activity of MAO. In
vitro experiments showed that compounds 3a, 3d and 3f had intensity inhibition the biological
activity of MAO-A, while compounds 3i and 3m had intensity inhibition the biological activity of
MAO-B. It could be seen from the data of inhibition activity experiments in vitro, that the
compound 3d was IC50=3.12±0.05 μmol/mL of MAO-A and compound 3m was IC50=5.04±0.06
μmol/mL. In vivo inhibition activity experiments were conducted to evaluate the inhibitory
activity of compounds 3a, 3d, 3f, 3i and 3m by detecting the contents of 5-HT, NE, DA and
activity of MAO-A and MAO-B in plasma and brain tissue. In vivo inhibition activity evaluation
results showed that the compounds 3a, 3d, 3f, 3i and 3m had increased the contents of 5-HT, NE
and DA in plasma and brain tissues. Meanwhile, the determination results activity of MAO in
plasma and brain tissue showed that the compounds 3a, 3d, and 3f had a significant inhibitory
effect on the activity of MAO-A, while the compounds 3i and 3m showed inhibitory effect on the
activity of MAO-B. This study provided a new inhibitors for inhibiting of MAO activity.
Keyword: monoamine oxidase; inhibitors; design; synthesis, biological activities
1. Introduction
Monoamine oxidase (MAO) can be catalyst human and other biological in vivo monoamine
neural metabolism (oxidative deamination reaction) inactivation of enzyme, the full name of
1

monoamine-oxidoreductase, sometimes also called flavin amine oxidase1-3. According to the
classification by the Enzyme Commission (EC) of the international society of biochemistry, MAO
was EC1.4.3.4. MAO was first discovered in the liver in 1928 by Mary lias Christian Hare and
was named tyramine oxidase4. MAO was a familial catalytic oxidase, in vivo distribution was
widespread, mainly distributed in liver, kidney, brain, stomach and intestinal mucosa organisations
such as the outer surface of mitochondria, and taken flavin adenine dinucleotide as coenzyme.
Another group exists in the connective tissue of organisms, and taken pyridoxal phosphate as
coenzyme5-7. MAO was a binding enzyme, and containing of Cu2+, Fe2+ and phospholipid. And
effects on primary amine and methylation of secondary and tertiary amine, the main catalytic
deamination of monoamines (R-CH2NH2). The corresponding aldehydes, hydrogen peroxide and
ammonia were produced. The aldehydes could be further metabolized into acids or alcohols in
vivo. Based on the combination of substrate selectivity and inhibitors of different sensitivity, MAO
was divided into two subtypes of type A and type B (MAO-A and MAO-B). They were composed
of 527 and 520 amino acid residues, with 72.6% of the amino acid sequence was the same, and the
homology was extremely high9,10. Studies on the MAO gene level have found that both MAO-A
and MAO-B genes were located on the X chromosome, which it can be seen that these two
subtypes of MAO were likely to come from the same ancestral gene11. But there have some
different, MAO-A protein has a monopartite cavity of 550 angstroms, and MAO-B has a bipartite
cavity of 290 angstroms. The protein structures of MAO-A12 and MAO-B13 were shown in Fig.1
and Fig.2. The MAO-A polarity was based on aromatic amines, such as 5-hydroxytryptamine
(5-HT) and norepinephrine (NE), which were mainly distributed in the gastrointestinal tract, liver,
kidney and lungs around the body. And it was mainly distributed in the brain in the adrenergic
neurons. The MAO-B polarity was based on non-aromatic amines, such as phenethylhydrazine.
The mainly exists in peripheral platelets, and was mainly distributed in 5-HT neurons and glial
cells in the brain. Three major neurological diseases including Depression (DEP), Parkinson's
disease (PD) and Alzheimer's disease (AD), and DEP of the highest risk, about 3-5% of all the
world's adult population, particularly in the elderly rates can be 7-10%14,15. According to current
pathogenesis studies, DEP was associated with activity of MAO-A, while PD and AD were
associated with activity of MAO-B.
2

Fig.1.The protein structure of MAO-A12.
Fig.2.The protein structures of MAO-B13.
Monoamine oxidase inhibitors (MAOIs) were mainly hydrazine and non-hydrazine
compounds, which have the function of inhibiting MAO bioactivity and showed anti-depression
effect16. MAOIs could be inhibition of 5-HT, NE and DA, thus reducing the brain oxidative
deamination metabolism of 5-HT and NE, and neurotransmitter receptors in the brain areas
content of 5-HT or NE concentration, and raise the level of prompting synaptic neurotransmitter
metabolism to antidepressant effect. MAOIs found that it was an accident. During the treatment of
tuberculosis, patients with tuberculosis were found to be taking isoniazid unexpectedly17-19. There
was the phenomenon that not consistent with physical signs, and the mood was obviously
improved20-23. The studies found that isoniazid strongly inhibits MAO activity, and after the
phenethylhydrazine inhibitors were synthesized24-26. Depending on the selectivity, MAOIs could
be divided into non-selective MAOIs, MAO-A inhibitors and MAO-B inhibitors. At present,
MAOIs mainly have toloxatone, moclobemide, lazabemide, rasagiline and safinamide27-31
.
They have the advantages of selectivity and effect, therefore, it was commonly used in clinical
treatment or improvement of DEP, PD and AD patients. In recent years, although many new
inhibitors have been reported to inhibition the biological activity of MAO, most of them remain at
the stage of in vitro activity screening, and few of them are actually marketed32. These MAOIs
have the same amide group,which have been listed in the sales, such as moclobemide, lazabemide,
safinamide, isoniazid and isocarboxazid (Fig. 3). Isoniazid and isocarboxazid were the early for
hydrazinecontaining drugs in clinic.It could be seen from the existing MAOIs structure that
compounds with amide groups were likely to have the inhibition to MAO33. In this paper, a series
3

of novel lazabemide derivatives with amide groups were designed by used the bioisostere and
modification of compound with alkyl principle. From the structure-activity relationship (SAR), the
newly designed compounds have similar chemical structure to lazabemide and may be inhibition
the biological activity of MAO-A or MAO-B (Fig. 4). This series novel of lazabemide analogues
or derivatives used 4-chlorobenzoic acid (1a) or 5-chloropyridine-2-carboxylic (1b) as the starting
material, and the target compounds was synthesized by acyl chloride reaction and amidation
reaction (Scheme 1). Biological activity experiments result showed that the series of compounds
had good inhibition and selective effects on MAO-A or MAO-B.
Fig.3.The amide groups of MAOIs.
4

Fig.4. Design of of lazabemide derivatives.
2. Results and discussion
2.1. Chemistry
The lazabemide had on effect inhibition of MAO-B. In this research, we used lazabemide as
the lead compound, and used bioisostere and modification of compound with alkyl principle (Fig.
4) to modified lazabemide (the lead compound). Thus a series of novel monoamine oxidase
inhibitors (MAOIs) were designed. The moclobemide, lazabemide, safinamide, isoniazid and
Isocarboxazid were MAO inhibitors (inhibition of MAO-A or MAO-B). From their chemical
structure (Fig.3), we could be found they have the same amide group. This means that compounds
with amide groups be likely to inhibition of MAO-A or MAO-B. Form Fig.4, the target
compounds have the same spatial structure and amide group for lazabemide. According to the
structure-activity relationship(SAR) of drugs, these compounds were likely to have inhibition
biological activity of MAO-A or MAO-B. In the chemistry structural modification of lazabemide,
5

the amide group, hexatomic ring and alkyl chain (basic framework) was retained. In modification
of hexatomic ring, the benzene ring was added, the two atoms in the ring we chose carbon and
nitrogen atom. In modification of alkyl chain, the length and substituents of alkyl chains were
modified. The designed of alkyl chains chemistry structural 1, 2 and 3 carbons were chose, and the
substituent R in the alkyl chains increased -OH, -Br and -NH2. In modification of alkyl chain and
substituent R, the mainly purpose was to change the physical and chemical properties (logP and
pKa) of target compounds, so as to change the inhibition activity of target compounds. In the
synthesis of target compounds, we chose a simple and general synthetic route (Scheme 1). The
1
13
synthesized target compounds were analyzed by H NMR, C NMR, MS and elemental analysis.
In synthesis section, the compounds 2a-2b were synthesised by general method of acyl chloride
reaction, and the 4-chlorobenzoic acid (1a) or 5-chloropyridine-2-carboxylic (1b) as the starting
material, with CH2Cl2 as solvent, DFM as catalyst, SOCl2 as chloride reagent in the refluxing for 8
hours to complete reaction. The synthesis of compounds 3a-3i and 3j-3q by general method of
amidation reaction, with CH2Cl2 as solvent, reaction temperature control in the 0-10 ℃. The crude
target products were recrystallised with toluene, filtered, and dried in vacuum to give pure product.
The synthesis of the target compounds superiority was a simple operation, safety, general, the
target compounds high total yield, and the total yield of the target compounds 3a-3i and 3j-3q
were 92.1%-98.6% and 92.8%-99.3% .
Scheme 1. The synthesis of lazabemide derivatives.
2.2. Monoamine oxidase inhibition studies
6

2.2.1. The inhibitory activity to MAO in vitro
The lazarabine was a compound containing amide group, and selective and reversible
inhibition biological activity of MAO-B in the brain and peripheral organs. The drug was used to
treat Parkinson's disease (PD) in clinical. This research used the lazarabine as a lead compounds,
and the lazarabine derivatives were designed and synthesized. The a series of target compounds,
we studying the inhibition activity of MAO-A or MAO-B in vitro. The drugs biological activity
was related to the physical and chemical properties of their compounds, therefore, this research
involved the logP and pKa of all target compounds (Table.1). In Table.1, we could be found the
target compounds belong fat-soluble and digested and absorbed in the gut. In vitro experiment, the
two types of inhibitors (inhibition of MAO-A and inhibition of MAO-B) were screened by
inhibition activity of MAO (Table.1). In the experiment in vitro, MAO-A and MAO-B were used
as the inhibition biological activity targets, and the inhibition activity was measured by half
maximal inhibitory concentration (IC50). In vitro experiment moclobemide (inhibitory MAO-A)
and rasagilin (inhibitory MOA-B) were used as the positive reference substance and DMSO was
used as the blank control. Form the Table.1, we could be found compounds 3a, 3d and 3f had
intensity inhibition the biological activity of MAO-A, while compounds 3i and 3m had inhibition
the biological activity of MAO-B. It could be seen from the data of inhibition activity experiments
in vitro, that the compound 3d was IC50=3.12±0.05 μmol/mL of MAO-A and compound 3m was
IC50=5.04±0.06 μmol/mL.
Table 1 In vitro IC50 values of test compounds 3a-3q for inhibition activity of MAO-A and
MAO-B.
IC50±SD（μmol/mL）
Compounds
X
n
R
log P
pKa
MAO-A
MAO-B
C
C
C
C
C
C
C
C
C
1
1
1
2
2
2
3
3
3
-OH
-Br
1.51
2.39
1.13
1.25
2.59
0.89
1.34
2.68
0.97
12.7
17.3
8.1
3a
3b
3c
3d
3e
3f
7.49±0.10
40.55±2.67
18.70±0.45
3.12±0.05
26.78±1.06
5.04±0.13
15.80±0.34
78.06±3.76
24.50±1.70
1435.43±15.93
1370.43±13.65
1569.65±17.21
685.05±4.61
894.65±6.76
1396.50±15.03
1509.56±17.23
1873.23±20.13
1609.44±18.90
-NH2
-OH
-Br
14.2
20.2
9.3
-NH2
-OH
-Br
14.9
21.1
9.8
3g
3h
3i
-NH2
7

N
N
N
N
N
N
N
N
1
1
1
2
2
3
3
3
-OH
-Br
0.59
1.48
0.23
0.35
1.67
0.45
1.78
0.06
12.8
16.8
7.8
3j
986.56±6.93
569.65±6.46
707.83±6.51
586,86±4.67
790.34±5.98
1201.76±12.23
1304.98±13.41
1054.96±9.23
6.30±0.12
12.78±0.34
60.69±1.90
34.79±1.09
5.04±0.06
24.79±0.56
20.58±0.56
109.67±4.10
35.87±1.35
783.31±3.28
10.36±0.21
***
3k
-NH2
-OH
-Br
3l
14.0
19.8
14.5
20.5
9.5
3m
3n
3o
-OH
-Br
3p
-NH2
3q
moclobemide
rasagilin
DMSO(control)
401.32±3.11
***
2.2.1. The inhibitory activity to MAO in vivo
In vivo biological activity experiments were conducted on the basis of in vitro biological
activity screened, and it was further studied the pharmacology and toxicology of drugs in vivo.
Through the in vivo biological activity experiment, the target compound will be prepared for the
clinical experiment. The this research was used lazarabine as a lead compound, and the acute
toxicity test (oral) of lazarabine, the results showed that LD50 was 1000-2000 mg.kg-1, it belong
low toxic compound. In vivo experiments, the research changes of monoamine contents (5-HT, NE
and DA), and activity of monoamine oxidase (MAO-A and MAO-B) in plasma and brain tissue,
when after administration of compounds 3a, 3d, 3f, 3i and 3m (Table 2, Fig.5 and Fig.6) . In
Table 2, the compounds 3a, 3d and 3f had increase the 5-HT and DA contents in brain tissue and
plasma. And compounds 3i and 3m had increase the NE contents in brain tissue and plasma. In
Fig.5 and Fig.6, test activity of MAO-A or MAO-B in plasma and brain tissue. The result showed
that the compounds 3a, 3d and 3f had significantly inhibition of MAO-A, especially compound 3d,
and compounds 3i and 3m had significantly inhibition activity of MAO-B, especially compound
3m. In toxicology, we studied the acute toxicity of these target compounds in vivo (Table 3). In
Table 3, we could be found these target compounds (3a, 3d, 3f, 3i and 3m) belong low acute
toxicity, and oral dose LD50≥ 2800 mg.kg-1.
Table 2 In vivo content of test compounds 3a-3q for 5-HT, NE and DA.
Content (ng/mg)
Compounds
brain tissue
5-HT
plasma
5-HT
NE
DA
NE
DA
8

0.545±0.006 2.641±0.211 0.832±0.231 123.2±10.6 436.9±21.8 231.1±11.5
3a
0.753±0.013 3.732±0.126 1.511±0.163 214.8±6.3
0.613±0.032 3.135±0.218 1.214±0.326 150.4±8.6
0.469±0.115 4.118±0.118 0.667±0.114 100.6±5.8
0.515±0.154 4.988±0.125 0.768±0.164 116.4±9.5
0.211±0.032 1.438±0.054 0.459±0.078 67.4±5.9
452.7±10.3 379.4±10.8
440.4±9.6 307.5±9.6
3d
3f
569.2±10.6 201.3±8.9
628.3±10.9 211.6±11.2
200.8±13.2 121.3±10.1
3j
3m
DMSO
30
25
20
15
10
5
MAO-A
MAO-B
0
3a
3d
3f
3j
3m
DMSO
Fig.5 In vivo activity of MAO test for compounds in plasma.
35
30
25
20
15
10
5
MAO-A
MAO-B
0
3a
3d
3f
3j
3m
DMSO
Fig.6 In vivo activity of MAO test for compounds in brain tissue.
9

Table 3 In vivo LD50 of test compounds.
Compounds Structures
LD50±SD（mg.kg-1）
3004.5±3.0
3087.2±3.4
2808.6±2.8
2996.4±2.9
3056.2 ±3.1
3a
3d
3f
3j
3m
3. Conclusion
We report a series novel of compounds that inhibition biological activity of MAO (A/B). In
this research lazabemide derivatives were designed, synthesized and evaluated as inhibitors of
MAO. These compounds used lazabemide as the lead compound, and the chemistry structures
were modified by used the bioisostere and modification of compound with alkyl principle. In vitro
experiments result showed that compounds 3a, 3d and 3f had intensity inhibition the biological
activity of MAO-A, while compounds 3i and 3m had inhibition the biological activity of MAO-B.
It could be seen from the data of inhibition activity experiments in vitro, that the compound 3d
was IC50=3.12±0.05 μmol/mL of MAO-A and compound 3m was IC50=5.04±0.06 μmol/mL. In
vivo inhibition activity experiments were conducted to evaluate the inhibitory activity of
compounds 3a, 3d, 3f, 3i and 3m by detecting the contents of 5-HT, NE and DA, and activity of
MAO-A and MAO-B in plasma and brain tissue. In vivo inhibition activity evaluation results
showed that compounds 3a, 3d, 3f, 3i and 3m had increased the content of 5-HT, NE and DA in
plasma and brain tissues.Meanwhile, the determination results activity of MAO in plasma and
10

brain tissue showed that compounds 3a, 3d, and 3f had a significant inhibitory effect on the
activity of MAO-A, while compound 3i and 3m showed inhibitory effect on the activity of
MAO-B. The acute toxicity experiment showed that their compounds belong to low toxicity.
4. Experimental section
4.1. Chemistry section
4.1.1. A general method for synthesis of compounds 2a to 2b
The 4-chlorobenzoic acid (1a, 15.65 g, 0.10 mol) was put into 500mL round bottom flask,
then 200 mL methylene chloride as solvent and 10 drops of N, N’-dimethyl formamide (DMF)
used as catalyst for the reaction were added. The flask was placed in the ice water bath (≤10 ℃),
and a magnetic mixer was used to stir until the reaction liquid became clarified. The thionyl
chloride (11.25 mL, 0.15 mol) was constantly dropped into the flask under stirring, and the drop
speed rate and reaction temperature were controlled (≤10 ℃and ≥20 min). After the reactants were
added, the reaction lasted 8 h under refluxing. The methylene chloride and excessive thionyl
chloride were removed under vacuum. The mixture was dried to get the crude product of
4-chlorobenzoyl chloride (2a). The crude product was atmospheric distillation, collect the product
of 221 ℃, and give pure product of 4-chlorobenzoyl chloride (2a) as a colorless transparent liquid.
The general method was used to synthesis crude 5-chloropyridine-2-carbonyl chloride (2b) , the
crude product was recrystallised with hexane, filtered, and dried in vacuum to give pure product of
5-chloropyridine-2-carbonyl chloride (2b) as a white crystal.
4.1.2. A general method for synthesis of compounds 3a to 3s
The 4-chlorobenzoyl chloride (2a, 17.50 g, 0.10 mol) was put into 500mL round bottom flask,
then 200 mL methylene chloride as solvent for the reaction were added. The flask was placed in
the ice water bath (0-10℃）, and a magnetic mixer was used to stir until the reaction liquid became
clarified. The aminomethanol (9.75 mL, 0.20 mol) was constantly dropped into the flask under
stirring, and the drop speed rate and reaction temperature were controlled (0-10 ℃ and ≥30 min).
After the reactants were added, the reaction lasted 24 h under standing. The methylene chloride
was removed under vacuum. The mixture was dried to get the crude product of
4-chloro-N-(hydroxymethyl) benzamide (3a). The crude product was recrystallised with toluene,
filtered, and dried in vacuum to give pure product of 4-chloro-N-(hydroxymethyl) benzamide (3a)
11

as a white crystal. The general method was used to synthesis compound 3b to3s.
1
4-chloro-N-(hydroxymethyl) benzamide (3a): white crystal, yield 97.3%, m.p.105-107 ℃; H
NMR（300MHz, DMSO）δ: 4.29 (1H, t, J = 4.9 Hz, -OH), 5.44 (2H, d, J = 4.9 Hz, -CH2- ), 7.50
13
(2H, m, J=7.0 Hz, Ph-H), 7.74 (2H, m, J=7.0 Hz, Ph-H); C NMR （75MHz, DMSO）δ: 59.3,
+
128.9, 130.6, 133.6, 136.8, 168.8; HR-ESI-MS m/z: calcd for C8H8ClNO2｛［ M+H］｝ 185.6071,
found 185.0246; Anal.calcd for C8H8ClNO2: C, 51.77; H, 4.34; Cl, 19.10; N, 7.55; O, 17.24;
found: C, 51.78; H, 4.33; Cl, 19.11; N, 7.55; O, 17.23%.
4-chloro-N-(bromomethyl) benzamide (3b): white crystal, yield 96.5%, m.p.144-146 ℃; 1H NMR
（300MHz, DMSO）δ: 5.21 (2H, s, -CH2- ), 7.50 (2H, m, J=7.0 Hz, Ph-H), 7.92 (2H, m, J=7.0 Hz,
Ph-H); 13C NMR（75MHz, DMSO）δ: 46.6, 127.2, 128.9, 133.6, 136.8, 168.6; HR-ESI-MS m/z:
+
calcd for C8H7BrClNO ｛［M+H］ ｝ 248.5041, found 247.0405; Anal.calcd for C8H7BrClNO:
C, 38.67; H, 2.84; Br, 32.15; Cl, 14.27; N, 5.64; O, 6.44; found: C, 38.66; H, 2.85; Br, 32.14; Cl,
14.28; N, 5.65; O, 6.43%.
1
4-chloro-N-(aminomethyl) benzamide (3c): white crystal, yield 98.6%, m.p.101-103 ℃; H NMR
（300MHz, DMSO δ: 3.38 (2H, t, J = 4.1 Hz, -CH2-), 7.50 (2H, m, J=7.0 Hz, Ph-H), 7.83 (2H, m,
J=7.0 Hz, Ph-H); 13C NMR（75MHz, DMSO）δ: 53.0, 127.4, 128.9, 133.6, 136.8, 169.4;
+
HR-ESI-MS m/z: calcd for C8H9ClN2O｛［ M+H］｝ 184.6232, found 184.0404; Anal.calcd for
C8H9ClN2O: C, 52.05; H, 4.91; Cl, 19.20; N, 15.17; O, 8.67; found: C, 52.06; H, 4.90; Cl, 19.21;
N, 15.15; O, 8.68%.
1
4-chloro-N-(2-hydroxyethyl) benzamide (3d): white crystal, yield 96.8%, m.p.110-112 ℃; H
NMR（300MHz, DMSO δ: 4.56 (2H, s, -CH2-), 7.50 (2H, m, J=7.0 Hz, Ph-H), 7.74 (2H, m, J=7.0
Hz, Ph-H); 13C NMR（75MHz, DMSO）δ: 42.8, 61.4, 126.5, 128.9, 133.6, 136.8, 167.7;
+
HR-ESI-MS m/z: calcd for C9H10ClNO2 ｛［ M+H］ ｝ 199.6343, found 199.0402; Anal.calcd for
C9H10ClNO2 : C, 54.15; H, 5.05; Cl, 17.76; N, 7.02; O, 16.03; found: C, 54.16; H, 5.04; Cl, 17.76;
N, 7.01; O, 16.04%.
4-chloro-N-(2-bromoethyl) benzamide (3e): white crystal, yield 94.8%, m.p.151-153 ℃; 1H NMR
（300MHz, DMSO）δ: 3.70 (2H, t, J = 4.4 Hz, -CH2- ), 3.87 (2H, t, J = 4.4 Hz, -CH2- ), 7.50 (2H,
m, J=7.0 Hz, Ph-H), 7.83 (2H, m, J=7.0 Hz, Ph-H); 13C NMR（75MHz，DMSO）δ: 35.5, 43.4,
+
126.9, 128.9, 133.6, 136.8, 168.4; HR-ESI-MS m/z: calcd for C9H9BrClNO｛［ M+H］｝262.5311,
found 260.9553; Anal.calcd for C9H9BrClNO: C, 41.18; H, 3.46; Br, 30.44; Cl, 13.50; N, 5.34; O,
12

6.09; found: C, 41.19; H, 3.45; Br, 30.45; Cl, 13.51; N, 5.33; O, 6.08%.
1
4-chloro-N-(2-aminoethyl) benzamide (3f): white crystal, yield 96.8%, m.p.114-116 ℃; H NMR
（300MHz, DMSO）δ: 3.26 (2H, t, J = 4.9 Hz, -CH2-),3.94 (2H, t, J = 4.9 Hz, -CH2-) 7.50 (2H, m,
J=7.0 Hz, Ph-H), 7.83(2H, m, J=7.0 Hz, Ph-H); 13C NMR（75MHz, DMSO）δ: 37.9, 48.1, 127.2,
+
128.9, 133.6, 136.8, 168.4; HR-ESI-MS m/z: calcd for C9H11ClN2O｛［ M+H］｝198.6503, found
198.0561; Anal.calcd for C9H11ClN2O: C, 54.42; H, 5.58; Cl, 17.85; N, 14.10; O, 8.05; found: C,
54.41; H, 5.58; Cl, 17.84; N, 14.11; O, 8.06%.
1
4-chloro-N-(3-hydroxypropyl) benzamide (3g): white crystal, yield 94.9%, m.p.126-128℃; H
NMR（300MHz, DMSO）δ: 1.72 (2H, m, J = 5.2 Hz, -CH2-),3.41 (2H, q, J = 5.0 Hz, -CH2-), 4.47
( 2H, t, J = 5.3 Hz, -CH2-), 4.72 (1H, t, J = 5.0 Hz, -OH),7.50 (2H, m, J=7.0 Hz, Ph-H), 7.83 (2H,
m, J=7.0 Hz, Ph-H); 13C NMR（75MHz, DMSO）δ: 31.8, 37.4, 59.9, 126.5, 128.8, 133.6, 136.8,
168.6; HR-ESI-MS m/z: calcd for C10H12ClNO2 ｛［M+H］+｝ 213.6613, found 213.0554;
Anal.calcd for C10H12ClNO2: C, 56.22; H, 5.66; Cl, 16.59; N, 6.56; O, 14.98; found: C, 56.21; H,
5.67; Cl, 16.58; N, 6.56; O, 14.99%.
1
4-chloro-N-(3-bromopropyl) benzamide (3h): white crystal, yield 92.1%, m.p.176-178 ℃; H
NMR（300MHz, DMSO）δ:2.09 (2H, t, J = 7.8 Hz, -CH2- ), 3.28 ( 2H, t, J = 7.8 Hz, -CH2-), 3.48
(2H, t, J = 7.8 Hz, -CH2-), 7.50 (2H, m, J=7.0 Hz, Ph-H), 7.83 (2H, m, J=7.0 Hz, Ph-H); 13C NMR
（75MHz, DMSO）δ: 30.8, 32.5, 40.8, 126.2, 128.7, 133.6, 136.8, 168.6; HR-ESI-MS m/z: calcd
for C10H11BrClNO｛［M+H］+｝ 276.5582, found 275.1713; Anal.calcd for C10H11BrClNO: C,
43.43; H, 4.01; Br, 28.89; Cl, 12.82; N, 5.06; O, 5.79; found: C, 43.44; H, 4.02; Br, 28.88; Cl,
12.83; N, 5.07; O, 5.78%.
4-chloro-N-(3-aminopropyl) benzamide (3i): white crystal, yield 94.5%, m.p.130-132 ℃; 1H NMR
（300MHz, DMSO）δ: 2.20 (2H, t, J = 7.7 Hz, -CH2-), 2.63 (2H, t, J = 7.7 Hz, -CH2-), 3.48 (2H, t,
J = 7.7 Hz, -CH2-), 7.50 (2H, m, J=7.0 Hz, Ph-H), 7.83 (2H, m, J=7.0 Hz, Ph-H); 13C NMR
（75MHz, DMSO）δ: 28.9, 37.1, 38.6, 127.6, 128.9, 133.6, 136.8, 168.6; HR-ESI-MS m/z: calcd
+
for C10H13ClN2O｛［ M+H］｝212.6772, found 212.0713; Anal.calcd for C10H13ClN2O: C, 56.48;
H, 6.16; Cl, 16.67; N, 13.17; O, 7.52; found: C, 56.49; H, 6.17; Cl, 16.65; N, 13.16; O, 7.53%.
5-chloropyridine-N-(hydroxymethyl)-2-carbonylamide (3j): white crystal, yield 98.3%, m.p.100-
1
102 ℃; H NMR（300MHz, DMSO）δ: 4.67 (1H, t, J = 4.9 Hz, -OH), 5.18 (2H, d, J = 5.1 Hz,
-CH2-), 8.04 (1H, dd, J = 8.1, 1.3 Hz, Py-H), 8.12 (1H, d, J = 8.0 Hz, Py-H), 8.86 (1H, d, J = 1.3
13

Hz, Py-H); 13C NMR（75MHz, DMSO）δ: 69.3, 126.4, 127.7, 132.9, 148.8, 150.8, 164.4;
+
HR-ESI-MS m/z: calcd for C7H7ClN2O2 ｛［ M+H］ ｝ 186.5952, found 186.0197; Anal.calcd for
C7H7ClN2O2 : C, 45.06; H, 3.78; Cl, 19.00; N, 15.01; O, 17.15; found: C, 45.07; H, 3.77; Cl, 19.02;
N, 15.00; O, 17.14%.
4-chloropyridine-N-(bromomethyl)-2-carbonylamide (3k): white crystal, yield 95.6%, m.p.130-
132 ℃; 1H NMR（300MHz, DMSO）δ: 4.97 (2H, s, -CH2-), 8.04 (1H, dd, J = 8.1, 1.3 Hz, Py-H),
8.14 (1H, d, J = 8.0 Hz, Py-H), 8.87 (1H, d, J = 1.3 Hz, Py-H); 13C NMR（75MHz, DMSO）δ: 44.2,
126.4, 127.7, 132.9, 148.8, 150.8, 164.0; HR-ESI-MS m/z: calcd for C7H6BrClN2O ｛［M+H］+｝
249.4922, found 247.9350; Anal.calcd for C7H6BrClN2O : C, 33.70; H, 2.42; Br, 32.03; Cl, 14.21;
N, 11.23; O, 6.41; found: C, 33.69; H, 2.44; Br, 32.03; Cl, 14.22; N, 11.24; O, 6.40%.
5-chloropyridine-N-(aminomethyl)-2-carbonylamide (3l): white crystal, yield 99.3%, m.p.98-100
℃; 1H NMR（300MHz, DMSO）δ: 4.32 (2H, s, -CH2-), 8.01 (1H, dd, J = 8.1, 1.3 Hz, Py-H), 8.11
(1H, d, J = 8.0 Hz, Py-H), 8.84 (1H, d, J = 1.3 Hz, Py-H); 13C NMR（75MHz, DMSO）δ: 53.0,
126.4, 127.7, 132.9, 148.8, 150.8, 164.9; HR-ESI-MS m/z: calcd for C7H8ClN3O ｛［M+H］+｝
185.6112, found 185.0357; Anal.calcd for C7H8ClN3O : C, 45.30; H, 4.34; Cl, 19.10; N, 22.64; O,
8.62; found: C, 45.29; H, 4.32; Cl, 19.11; N, 22.65; O, 8.63%.
5-chloropyridine-N-(2-hydroxyethyl)-2-carbonylamide (3m): white crystal, yield 96.5%, m.p.118-
120 ℃; 1H NMR（300MHz, DMSO）δ: 3.39(2H, t, J = 4.0 Hz, -CH2-), 3.54(2H, dt, J = 5.1, 4.1 Hz,
-CH2-), 4.86(1H, t, J = 6.1 Hz,-OH), 8.04 (1H, dd, J = 8.0, 1.2 Hz, Py-H), 8.10 (1H, d, J = 8.1 Hz,
Py-H), 8.70 (1H, d, J = 1.3 Hz, Py-H); 13C NMR（75MHz, DMSO）δ: 42.1, 60.1, 123.7, 134.3,
+
138.0, 147.4, 148.9, 163.4; HR-ESI-MS m/z: calcd for C8H9ClN2O2｛［ M+H］｝200.6221, found
200.0355; Anal.calcd for C8H9ClN2O2 : C, 47.90; H, 4.52; Cl, 17.67; N, 13.96; O, 15.95; found: C,
47.91; H, 4.53; Cl, 17.65; N, 13.97; O, 15.94%.
5-chloropyridine-N-(2-bromoethyl))-2-carbonylamide (3n): white crystal, yield 94.1%, m.p.170-
171 ℃; 1H NMR（300MHz, DMSO）δ: 3.15 (2H, t, J = 4.4 Hz, -CH2-), 3.80 (2H, t, J = 4.4 Hz,
-CH2-), 7.74 (1H, dd, J = 8.1, 1.3 Hz, Py-H), 7.79 (1H, d, J = 7.9 Hz, Py-H), 8.40 (1H, d, J = 1.2
13
Hz, Py-H); C NMR（75MHz, DMSO）δ: 33.6, 43.4, 126.4, 127.7, 132.9, 148.8, 150.8, 165.1;
+
HR-ESI-MS m/z: calcd for C8H8BrClN2O｛［ M+H］｝ 263.5192, found 261.9507; Anal.calcd for
C8H8BrClN2O: C, 36.46; H, 3.06; Br, 30.32; Cl, 13.45; N, 10.63; O, 6.07; found: C, 36.47; H, 3.05;
Br, 30.33; Cl, 13.44; N, 10.64; O, 6.06%.
14

6-chloropyridine-N-(3-hydroxypropyl)-2-carbonylamide (3o): white crystal, yield 93.1%, m.p.132
-134 ℃; 1H NMR（300MHz, DMSO）δ: 1.68 (2H, p, J = 4.9 Hz, -CH2-), 3.41 (2H, q, J = 4.7 Hz,
-CH2-), 3.61 (2H, t, J = 5.0 Hz, -CH2-), 4.33(1H, t, J = 5.0 Hz,-OH), 8.03 (1H, dd, J = 8.0, 1.2 Hz,
Py-H), 8.12 (1H, d, J = 8.0 Hz, Py-H), 8.86 (1H, d, J = 1.3 Hz, Py-H); 13C NMR（75MHz,
DMSO）δ: 32.0, 37.8, 59.9, 126.4, 127.7, 132.9, 148.8, 150.8, 164.0; HR-ESI-MS m/z: calcd for
+
C9H11ClN2O2｛［ M+H］｝ 214.6491, found 214.0507; Anal.calcd for C9H11ClN2O2: C, 50.36; H,
5.17; Cl, 16.52; N, 13.05; O, 14.91; found: C, 50.37; H, 5.17; Cl, 16.53; N, 13.04; O, 14.90%.
5-chloropyridine-N-(3-bromopropyl))-2-carbonylamide (3p): white crystal, yield 92.8%, m.p.170-
171 ℃; 1H NMR（300MHz, DMSO）δ: 2.05 (2H, tt, J = 7.8, 5.1 Hz, -CH2-), 3.24 (2H, t, J = 5.1 Hz,
-CH2-), 3.47 ( 2H, t, J = 7.9 Hz, -CH2-), 8.00 (1H, dd, J = 7.9, 1.2 Hz, Py-H), 8.10 (1H, d, J = 8.0
Hz, Py-H), 8.86 (1H, d, J = 1.2 Hz, Py-H); 13C NMR（75MHz, DMSO）δ: 30.8, 32.5, 40.8, 126.4,
127.7,132.9, 148.8, 150.8, 164.0; HR-ESI-MS m/z: calcd for C9H10BrClN2O ｛［M+H］+｝
277.5461, found 275.9663; Anal.calcd for C9H10BrClN2O: C, 38.95; H, 3.63; Br, 28.79; Cl, 12.77;
N, 10.09; O, 5.76; found: C, 38.94; H, 3.65; Br, 28.78; Cl, 12.77; N, 10.08; O, 5.77%.
5-chloropyridine-N-(3-aminopropyl)-2-carbonylamide (3q): white crystal, yield 95.1%, m.p.133-
135 ℃; 1H NMR（300MHz, DMSO）δ: 2.16 (2H, p, J = 5.1 Hz, -CH2-), 2.63 (2H, t, J = 5.1 Hz,
-CH2-), 3.24 (2H, t, J = 5.1 Hz, -CH2-), 7.95 (1H, dd, J = 8.0, 1.2 Hz, Py-H), 8.07 (1H, d, J = 8.0
Hz, Py-H), 8.79 (1H, d, J = 1.1 Hz, Py-H); 13C NMR（75MHz, DMSO）δ: 28.9, 37.2, 38.1, 126.4,
+
127.7, 132.9, 148.8, 150.8, 164.6; HR-ESI-MS m/z: calcd for C9H12ClN3O｛［ M+H］｝213.6653,
found 213.0668; Anal.calcd for C9H12ClN3O: C, 50.59; H, 5.66; Cl, 16.59; N, 19.67; O, 7.49;
found: C, 50.58; H, 5.67; Cl, 16.58; N, 19.68; O, 7.48%.
4.2. Biological section
4.2.1. Screening of biological activity of compounds in vitro
4.2.1.1. Preparation of MAO in vitro
According to the literature6, with mature male rat, broken its marrow to death on the super
net work quickly remove the liver, with 0.9% saline wash liver 3 times, with dry absorbent paper,
in the in -80 ℃refrigerator frozen preservation, and later using.
Used electronic analytical balance said in 5 g frozen after liver tissue, add 1200 mL of 0.3
mol/L sucrose solution, slurry, and low temperature (0-5 ℃) at high speed refrigerated centrifuge
in liver tissue in 25 r/s centrifugal about 600 s. Take that to 150 r/s centrifugal supernatant fluid of
15

1800 s, and precipitation suspension in the 5 mL of 0.3 mol/L sucrose solution, and then placed in
60 mL of 1.2 mol/L sucrose solution, and with 160 r/s centrifugal about 2400 s. Take the
precipitation with a tendency for 100 mmol/L potassium phosphate buffer solution (pH7.9)
washing, and the precipitation was suspended by 50 mL of 100 mmol/L potassium phosphate
buffer to obtain MAO. Partial shipments into 1 mL each EP tube, and into the frozen storage in a
freezer -80℃, and later using.
4.2.1.2. In vitro screening of MAO inhibitors
(a) Inhibition of MAO-A
The 5-HT was used as a reaction substrate to inhibit MAO-A biological activity. The
tendency for 75 μL of 100 mmol/L potassium phosphate buffer solution (pH7.9), 25 μL different
concentrations for compounds, and 50 μL MAO, and under the condition of 37℃and 5% CO2
incubation of 1200 s. In addition, the 5-HT of 100 μL was added, so that the final concentration of
MAO was 0.40 mg/mL and 5-HT was 5 mmol/L, and allowed to continue to react after 3600 s.The
add 200 μL of 10% perchloric acid solution, and the reaction product 2-(5-hydroxyindole)
acetaldehyde was extracted with 5 mL ethyl acetate, and its absorbance A value was determined at
wavelength of 280 nm.
(b) Inhibition of MAO-B
The benzylamine was used as a reaction substrate to inhibit MAO-A biological activity. The
tendency for 75 μL of 100 mmol/L potassium phosphate buffer solution (pH7.9), 25 μL different
concentrations for compounds, and 50 μL MAO, and under the condition of 37 ℃and 5% CO2
incubation of 1200 s. In addition, the benzylamine of 100 μL was added, so that the final
concentration of MAO was 0.15 mg/mL and benzylamine was 2 mmol/L, and allowed to continue
to react after 3600 s. The add 200 μL of 10% perchloric acid solution, and the reaction product
benzaldehyde was extracted with 5 mL cyclohexane, and its absorbance A value was determined at
wavelength of 240 nm. Moclobemide and Rasagilin were used as the positive reference substance
and DMSO was used as the blank control.
4.2.2. Biological activity of compounds inhibition MAO in vivo
The 20 adult rats (half male and half female ) were taken, and were given oral doses of 20
mg.kg-1.d-1 for one week. All the rats were put to death with their heads cut off, the rats were
dissected on the ultra-clean working table and 100 mg of brain tissue was taken out. Added 1 mL
16

for 10% perchloric acid solution, homogenate at low temperature, and centrifuge at high speed
300 r/s at low temperature for 1200 s. Take the supernatant, and into the frozen storage in a freezer
-80℃, and later using. At the same time, the 1 mL plasma was taken out, and 10% perchloric acid
solution of the same volume was added, and violent vibration for 60 s. And then centrifuged at
high speed 300 r/s at low temperature for 1200 s. Take the supernatant, and into the frozen storage
in a freezer -80 ℃, and later using. The 20 μL spare liquid was taken out, and the contents of 5-HT,
NE and DA were measured by High Performance Liquid Chromatography (HPLC, internal
standard method). Moclobemide and Rasagilin were used as the positive reference substance and
DMSO was used as the blank control.
Acknowledgements
The Project is sponsored by the Scientific Research Foundation for the Returned Overseas
Chinese Scholars, State Education Ministry (No. 2015-1098). The work was also supported by
Chongqing Key Research Project of Basic Science
&
Frontier Technology (No.
cstc2017jcyjBX0012), Foundation Project of Chongqing Normal University (No. 14XYY020),
Chongqing General Research Program of Basic Research and Frontier Technology (No.
cstc2015jcyjA10054), and Chongqing Normal University Postgraduate's Research and Innovation
Project (No. YKC17004), China.
References
1. Penelope T, Peter G, Katharine A. Monoamine oxidase inhibitory activity in tobacco particulate
matter: Are harman and norharman the only physiologically relevant inhibitors. Neuro
Toxicol. 2017; 59: 22-26.
2. Kalgutar A, Dalvie D, Castagnoli N, et al. Interactionsof nitrogen-containing xenobiotics with
monoamine oxidase (MAO) isozymes A and B: SAR studies on MAO substrates and
inhibitors. Chem Res Toxico. 2001; 14: 1139-1162.
3. Makoto N, Wakako M. Monoamine oxidase inhibitors as neuroprotective agents in
agedependent neurodegenerative disorders. Curr Pharm Des. 2010; 16 : 2799-2817.
4. Here M. Tyramine oxidase: A new enzyme system in liver. Biochem J. 1928; 22 : 968-979.
17

5. Gabriel O, Jernej S, Robert V, et al. MavriMultiscale simulation of monoamine oxidase
catalyzed decomposition of phenylethylamine analogs. Eur J Pharmacol.2017; 817: 46-50.
6. Anzelle D, Brian H, Anél P, et al. The monoamine oxidase inhibition properties of selected
structural analogues of methylene blue. Toxicol App Pharm.2017; 325: 1-8.
7. Grimsby J, Chen K, Wang L, et al. Human monoamineoxidase A and B genes exhibit identical
exonintron organization. P Natl A Sci. 1991; 88: 3637-3641.
8. Luigi D, Min L, Claudia B, et al. Three-dimensional structure of human monoamine oxidase A
(MAO A): Relation to the structures of rat MAO A and human MAO B. P Natl A Sci USA.
2005; 102 : 12684-12689.
9. Binda C, Newton V, Hubalek F, et al. Structure of Human Monoamine Oxidase B, a Drug
Target for the Treatment of Neurological Disorders. Nat Struct Biol. 2001; 9: 22-26.
10. Wang C, Ellen B, Astrid B, et al. Monoamine oxidases in development. Cell Mol Life Sci.
2013; 70: 599-630.
11. Olanow C, Rascol O, Hauser R, et al. A double-blind, delayed-start trial of rasagiline in
Parkinson ’s disease. New Engl J Med. 2009; 361: 1268-1278.
12. Luigi D, Min L, Claudia B, et al.Three-dimensional structure of human monoamine oxidase A
(MAO A): Relation to the structures of rat MAO A and human MAO B.P Natl A Sci
USA.2005; 102:12684-12689.
13. Binda C,Newton V P,Hubalek F,et al.Structure of Human Monoamine Oxidase B, a Drug
Target for the Treatment of Neurological Disorders. Nat Struct Biol.2001; 9: 22-26.
14. Karen R, Michael R, Bruce A. et al.Recommended cognitive outcomes in preclinical
Alzheimer's disease: Consensus statement from the European Prevention of Alzheimer's
Dementia project. Alzheimers Dement. 2017; 13: 186-195.
15. Olanow C, Stern M, Sethi K. The scientific and clinical basis for the treatment of Parkinson
disease. Neurology. 2009; 72: 1136.
16. Konradi C, Kornhuber J, Sofic E, et al. Variatioos of monoamines and their metabolites in the
human brain putamen. Brain Res. 1992; 579: 285-290.
17. Geha R, Rebrin I, Chen K, et al. Effects of carboxyl -terminal truncations on the activity and
solubility of human monoamine oxidase B. Biol Chem. 2001; 276 : 29499-29506.
18. Mai A, Artico M, Esposito M, et al. 3-(H-Pyrrol-1-yl)-2-oxazolidinones as reversible, highly
18

potent, and selective inhibitors ofmonoamine oxidase type A. J Med Chem. 2002; 45:
1180-1183.
19. Seham Y, Sherine N, Adnan A, et al. Synthesis of 3-benzyl-2 -substituted quinoxalines as
novel monoamine oxidase A inhibitors. Bioorg Med Chem Lett. 2006; 16: 1753-1756.
21. Cecilia M, Peder S, Clas S. A novel series of 6-substituted 3-(pyrrolidin-1-ylmethyl)
chromen-2-ones as selective monoamine oxidase (MAO) A inhibitors. Eur J Med Chem.
2014; 73: 177-186.
20. Wang Y, Sun Y, Guo Y, et al. Dual functional cholinesterase and MAO inhibitors for the
treatment of Alzheimer's disease: synthesis,pharmacological analysis and molecular modeling
of homoisoflavon-oid derivatives. J Enzym Inhib Med Chem. 2016; 31: 89-97.
21. Youdim M, Bakhle Y. Monoamine oxidase isoforms and inhibitors in Parkinson’s disease and
depressive illness. Brit J Pharmacol. 2006; 147: 5287-5296.
22. Naoi M, Wakako M. Monoamine oxidase inhibitors as neuroprotective agents in
age-dependent neuro-degenerative disorders. Curr Pharm Des. 2010; 16: 2799-2817.
23. Heikkila R, Manzino L, Cabbat F, et al. Protection against the dopaminergic neurotoxicity of
1-methyl-4-phenyl-1, 2, 5, 6-tetrahydropyridine by monoamine oxidase inhibitors. Nature.
1984; 311: 467-469.
24. Valentin K, Leonard K. The need for new approaches in CNS drug discovery: Why drugs
have failed, and what can be done to improve outcomes. Neuropharmacology. 2017; 120:
11-19.
25. Henchcliffe C, Schumacher H, Burgut F. Recent advances in Parkinson' s disease therapy: use
of monoamine oxidase inhibitors. Exp Rev Neur. 2005; 5: 811-821.
26. Guay D. Rasagiline (TVP-1012): a new selective monoamine oxidase inhibitor for Parkinson’s
disease. Ame J Geriatr Pharmac. 2006; 4: 330-346.
27. Blandini F. Neuroprotective compounds and innovative therapeutic strategies for Parkinson's
disease:experimental and clinical studies. Clin Trials. 2009; 1: 1-15.
28. Robottom B. Efficacy, safety, and patient preference of monoamine oxidase B inhibitors in the
treatment of Parkinson's disease. Pat Prer Adh. 2011; 5: 57-64.
29. Bar A, Weinreb O, Amit T, et al. The neuroprotective mechanism of 1-(R)-aminoindan，the
major metabolite of the anti-parkinsonian drug rasagiline. J Neurochem. 2010; 112:
19

1131-1137.
30. Nikolay T, Hans S, Liudmil A. Tautomerism of N-(3, 4-dichlorophenyl)-1H-indazole-5-
carboxamide-A new selective, highly potent and reversible MAO-B inhibitor. J Mol Struct.
2017; 1149 : 273-281.
31. Francesco L, Carmelida C, Leonardo P, et a1. Solid-phase synthesis and insights into structure
activity relationships of safinamide analogues as potent and selective inhibitors of type B
monoamine oxidase. J Med Chem. 2007; 50: 4909-4916.
32. Moussa B, Youdim, A. Rasagiline [N-propargyl-1R (+)-Amin-oindan], a selective and potent
inhibitor of mitochondrial monoamine oxidase. Brit J Pharmacol. 2001; 132: 500-506.
33. Chachignon H, Scalacci N, Petricci E, et al. Synthesis of 1, 2, 3-substituted pyrroles from
propargyl-amines via a one-pot tandem enyne cross metathesis-cyclization reaction. Org
Chem. 2015; 80: 5287-5295.
Graphical abstract
20

21