Discovery of novel 2,3-dihydro-1H-inden-1-amine derivatives as selective monoamine oxidase B inhibitors

Article abstract of DOI:10.1016/j.bmcl.2019.02.030

Inhibition of MAO-B has been an effective strategy for the treatment of Parkinson's disease. To find more potent and selective MAO-B inhibitors with novel chemical scaffold, we designed and synthesized a series of new 2,3-dihydro-1H-inden-1-amine derivatives on basis of our previous study. Furthermore, the corresponding structure-activity relationship (SAR) of these compounds is detailedly discussed. Compounds L4 (IC₅₀ = 0.11 μM), L8 (IC₅₀ = 0.18 μM), L16 (IC₅₀ = 0.27 μM) and L17 (IC₅₀ = 0.48 μM) showed similar MAO-B inhibitory activity as Selegiline. Moreover, L4, L16 and L17 also exhibited comparable selectivity with Selegiline, indicating that L4, L16 and L17 could be promising selective MAO-B inhibitors for further study.

Full text of DOI:10.1016/j.bmcl.2019.02.030

Bioorganic&MedicinalChemistryLettersxxx(xxxx)xxx–xxx
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery of novel 2,3-dihydro-1H-inden-1-amine derivatives as selective
monoamine oxidase B inhibitors
Shiyu Lia, Xiao Lva, Kai Cheng, Yongbing Tian, Xufeng Huang, Haiyan Kong, Yajun Duan,
Jihong Han, Chenzhong Liao⁎, Zhouling Xie⁎
School of Food and Biological Engineering, Hefei University of Technology, Hefei, Anhui 230009, PR China
A R T I C L E I N F O
A B S T R A C T
Keywords:
Inhibition of MAO-B has been an effective strategy for the treatment of Parkinson’s disease. To find more potent
and selective MAO-B inhibitors with novel chemical scaffold, we designed and synthesized a series of new 2,3-
dihydro-1H-inden-1-amine derivatives on basis of our previous study. Furthermore, the corresponding structure-
activity relationship (SAR) of these compounds is detailedly discussed. Compounds L4 (IC50 = 0.11 μM), L8
(IC50 = 0.18 μM), L16 (IC50 = 0.27 μM) and L17 (IC50 = 0.48 μM) showed similar MAO-B inhibitory activity as
Selegiline. Moreover, L4, L16 and L17 also exhibited comparable selectivity with Selegiline, indicating that L4,
L16 and L17 could be promising selective MAO-B inhibitors for further study.
Monoamine oxidase B
Selectivity
2,3-Dihydro-1H-inden-1-amine
Structure activity relationship
Monoamine oxidases (MAOs) are flavin adenine dinucleotide (FAD)-
containing enzymes that catalyze the oxidative deamination of dietary
amines and monoamine neurotransmitters. They are divided into two
different isoforms, MAO-A and MAO-B on the basis of their gene and
tissue distribution.1–3 In addition, MAO-A and MAO-B are specificity for
their corresponding substrates, respectively. MAO-A prefer to the oxi-
dative deamination of serotonin (5-HT), adrenaline (A), and nora-
drenaline (NA); while MAO-B catalyzes β-phenethylamine and benzy-
lamine.4,5 Due to the function of MAOs is associated with the levels of
several neurotransmitters mainly in the central nervous system (CNS),
inhibition of MAOs has been an attracted strategy for the discovery of
new drugs targeting brain disorders. MAO-A inhibitors are mainly used
in the treatment of depression6,7; whereas MAO-B inhibitors are mainly
used for Parkinson’s disease and Alzhenimer’s disease.8,9 In addition,
MAO-B inhibitors also show potential neuroprotective effects in the
treatment of other neurodegenerative diseases.10
MAO-B inhibitors have been identified with high potency and good
selectivity in recent years, most of them were finally discontinued in
clinical phase. Thus, identifying more novel MAO-B inhibitors with
effective scaffolds and high selectivity over MAO-A isoform is im-
portant, and we have tried our endeavors in this field.16–19
In our previous work,16 we have employed a strategy of fragment
based drug discovery (FBDD) by growing hydrophobic moieties from
the 4-position of Rasagiline to hope the fragments could occupy the
entrance cavity as 2-BFI, a fragment located in the entrance cavity that
is distinct from the substrate-binding cavity (PDB ID: 2FXQ). Several
compounds with high affinity and selectivity against MAO-B were
yielded in accordance with this way. In this study, we further did SAR
study of this series of compounds, in which the linking atom in the 4-
position of Rasagiline is oxygen. In addition, this linking atom was
changed to nitrogen and sulphur atoms (Fig. 2) to explore more che-
mical space for the purpose of discovering more selective and potent
MAO-B inhibitors. On the basis of this design strategy, we synthesized
compounds L1–L20 and tested their MAO-A/B inhibitory activity as
well as discussing SAR and selectivity.
MAO-A and MAO-B are highly homologous proteins with 70% se-
quence identity.11 Up to now, several MAO-A and MAO-B inhibitors
have been developed into markets. Clorgyline and Moclobemide
(Fig. 1) are selective, irreversible and reversible MAO-A inhibitors, re-
spectively.12,13 Selegiline, Rasagiline and Safinamide are selective ir-
reversible and reversible MAO-B inhibitors, respectively.14 For MAO-B
inhibitors, Selegiline, Rasagiline showed dissatisfactory selectivity for
MAO-A, leading to serious adverse effects including tyramine-induced
hypertensive crisis (cheese reaction).15 Moreover, despite many new
The synthesis of target compounds L1–L9 was shown as Scheme 1.
L1–L6 were synthesized from 4-hydroxy-2,3-dihydro-1H-inden-1-one
(1) which was nitrified to intermediate 2. Compound 2 was further
reduced to compound 3. Compounds b1–b6 were obtained by reacting
with various substituted benzyl bromide derivatives, which were fur-
ther reacted with mono-propargylamine, leading to L1–L6.
⁎ Corresponding authors.
E-mail addresses: czliao@hfut.edu.cn (C. Liao), zhoulingxie@hfut.edu.cn (Z. Xie).
a These authors contributed to this work equally.
https://doi.org/10.1016/j.bmcl.2019.02.030
Received 29 November 2018; Received in revised form 26 February 2019; Accepted 26 February 2019
0960-894X/©2019ElsevierLtd.Allrightsreserved.
Pleasecitethisarticleas:ShiyuLi,etal.,Bioorganic&MedicinalChemistryLetters,https://doi.org/10.1016/j.bmcl.2019.02.030

S. Li, et al.
Bioorganic&MedicinalChemistryLettersxxx(xxxx)xxx–xxx
mono-propargylamine. In addition, compound L18 was synthesized
from 4-hydroxy-2,3-dihydro-1H-inden-1-one (5) by reacting with 2-
(naphthalen-1-yl) ethan-1-ol.
All synthesized compounds were evaluated against hMAO-B and
hMAO-A as shown in Table 1. We chose approved drug Selegiline and
Clorgiline as the MAO-B positive control and the MAO-A positive con-
trol, respectively. In our assay, Selegiline received IC50 values of
0.06 μM and 54.3 μM, and Clorgiline received IC50 values of 20.3 μM
and 0.04 μM against MAO-B and MAO-A respectively. Regarding our
compounds in this work, the MAO-B inhibitory activity of L2
(IC50 = 1.86 μM) was improved compared with compound L19
(IC50 = 2.7 μM), indicating that the replacement of O atom by N atom is
favorable for MAO-B inhibition. Additionally, changing the para-posi-
tion F atom at L2 to meta-position at L3 (IC50 = 0.98 μM) further en-
hanced the potency. However, without substituent on the phenyl ring,
the MAO-B inhibitory activity of L1 (IC50 > 20 μM) is drastically de-
creased. Replacement of F substituent by -Br or -Me group led to
compounds L4–L6 which showed improved potency. These results
above suggesting that a substituent on the phenyl ring is advantage to
the enhancement of MAO-B inhibitory activities. In addition, electron
donating group (-Me) is superior to electron withdrawing group (-F)
and weak electron withdrawing group (-Br) is most suitable. Among N
linked compounds, L4 was most potent with an IC50 value of 0.11 μM,
which was 20-fold more potent than L19 and comparable with Selegi-
line (IC50 = 0.06 μM). Moreover, the MAO-B inhibitory activity was
also increased by changing of the O atom by S in compound L7
(IC50 = 0.24 μM) and L8 (IC50 = 0.18 μM). However, conversion of
halogen to tertiary butyl group in L9 (IC50 > 20 μM) decreased the
potency, suggesting the halogen substituent is favorable. In addition,
electron withdrawing group (-F) is more suitable than electron donating
group (tert-butyl) in S linked derivatives.
Fig. 1. The chemical structures of approved MAO-A and MAO-B inhibitors.
Fig. 2. Design strategy of novel selective MAO-B inhibitors by changing the
linking atom of oxygen to sulphur and nitrogen atoms.
Intermediates b7–b9 were synthesized from 4-bromo-2,3-dihydro-1H-
inden-1-one (4) by reacting with several benzyl mercaptan derivatives.
b7–b9 further reacted with mono-propargylamine, affording final
compounds L7–L9. As shown in Scheme 2, compounds L10–L20 were
synthesized as previous reported methods.16 Firstly, intermediates 6
and 7 were synthesized by reacting with arylethanol derivatives, which
were further conversed to b10-b17 by nitro reduction and acylation.
Compounds L10–L17 were obtained from b10-b17 by reacting with
L20 (IC50 = 0.36 μM) is also a potent MAO-B inhibitor. Introduction
of Cl atom to the phenyl ring of L20 provided L15 (IC50 > 20 μM) with
much lower potency. Optimizing the substituent on the benzamide or
changing the Cl atom by F atom, the inhibitory activities of them (L11-
L14, IC50 > 5 μM) still maintained reduced potency. We hypothesized
that the Cl atom resulted in conformational change of the benzamide
group in L11-L14, reducing the affinity for MAO-B. Interestingly,
Scheme 1. Reagents and conditions: i) KNO3, H2SO4, 0 °C to rt, 3 h; ii) Pd/C (10% wt), methanol, H2, rt, 6 h; iii) bromine derivatives, potassium carbonate, acetonitrile
e, 85 °C, 4 h; iv) benzyl mercaptan derivatives, Pd2(dba)3, xantphos, cesium carbonate, 1,4-dioxane, 100 °C, 12 h; v) mono-propargylamine, acetic acid, STAB,
CH2Cl2, rt, 18 h.
Scheme 2. Reagents and conditions: i) phenylethanol derivatives, Ph3P, DBAD, THF, 30 °C, 12 h; ii) Zn, methanol, saturated NH4Cl water, rt, 3 h; iii) acyl chloride,
Et3N, CH2Cl2, 0 °C to rt, 2 h; iv) mono-propargylamine, acetic acid, STAB, CH2Cl2, rt, 12 h.
2

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Table 1
Inhibitory activities of 2,3-dihydro-1H-inden-1-amine derivatives L1-L20 against hMAO-B and hMAO-A.
Compd
L1
X
R
IC50 for hMAO-B (μM)a
> 20
IC50 for hMAO-A (μM)b
SIc
–
d
NH
–
L2
L3
L4
NH
NH
NH
1.86
0.98
0.11
0.10
0.05
0.01
94.3
8.4
857
172
L5
L6
L7
NH
NH
S
0.71
0.25
0.24
0.04
0.02
0.01
43.1
4.2
< 0.1
L8
L9
S
S
0.18
0.03
0.23
–
0.02
1.2
–
> 20
L10
L11
O
O
0.59
0.03
85.2
–
8.5
144
–
> 20
L12
L13
L14
L15
O
O
O
O
> 20
> 20
5.1
–
–
–
–
0.40
> 20
–
–
L16
L17
O
O
0.27
0.48
0.02
0.04
252.2
436.5
20.4
934
909
40.3
L18
O
1.9
0.015
L19
L20
O
O
2.7
0.20
0.03
0.36
Selegiline
Clorgiline
0.06
20.3
0.005
2.2
54.3
0.04
5.1
0.002
905
< 0.002
a,b
Each IC50 is the mean
SEM from three experiments. Standard error of the IC50 was generally < 10%.
c
Selectivity Index = IC50(hMAO-A)/IC50(hMAO-B).
Not determined.
d
3

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introducing a Cl atom to the C-6 of phenyl ring at L20 significantly
decrease the MAO-B potency unless reducing the big substituents at the
tail as small groups like –Me, -CH2OH, -CH2OOCCH3. Among all target
compounds, L4, L8, L16 and L17 were identified with similar MAO-B
inhibitory activity as Selegiline. L4, L16 and L17 also showed com-
parable selectivity with Selegiline. In the next work, we will make a
chiral separation for compounds L4, L16 and L17 to explore their
corresponding potency and selectivity, finally obtaining more effective
and selective MAO-B inhibitors. Additionally, more S linked derivatives
will be studied for the development of selective MAO-A inhibitors.
Acknowledgments
Fig. 3. Putative binding modes of L4 (A, purple ball and stick mode) and L8 (B,
green ball and stick mode) shown as purple ball and stick mode. 2-BFI is pre-
sented as yellow mode.
This work was supported by National Natural Science Foundation of
China (81803352 and 21672050); and the Fundamental Research
Funds for the Central Universities (JZ2018HGBZ0167 and
JZ2018HGTA0225).
replacement of the phenyl ring at the tail by a small group (–Me) led to
L10 (IC50 = 0.59 μM) with enhanced MAO-B inhibitory activity. On the
basis of L10, we introduced small groups –OH or acetoxy to substitute
methyl group, obtaining L16 (IC50 = 0.27 μM) and L17
(IC50 = 0.48 μM) which both were more potent than L10. Compound
L18 (IC50 > 20 μM), with a naphthalene group replacing the benza-
mide fragment displayed reduced potency. Among this series of com-
pounds, L16 was the most potent.
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://
doi.org/10.1016/j.bmcl.2019.02.030.
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MAO-A inhibitory activity of L8 (IC50 = 0.23 μM) was as potent as its
MAO-B inhibitory activity. the MAO-A inhibitory activity of L7
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