Novel deoxyvasicinone and tetrahydro-beta-carboline hybrids as inhibitors of acetylcholinesterase and amyloid beta aggregation

Article abstract of DOI:10.1016/j.bmcl.2020.127659

A novel series of deoxyvasicinone-tetrahydro-beta-carboline hybrids were synthesized and evaluated as acetylcholinesterase (AChE) and β-amyloid peptide (Aβ) aggregation inhibitors for the treatment of Alzheimer's disease. The results revealed that the der

Full text of DOI:10.1016/j.bmcl.2020.127659

Bioorg. Med. Chem. Lett. 30 (2020) 127659
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Novel deoxyvasicinone and tetrahydro-beta-carboline hybrids as inhibitors
of acetylcholinesterase and amyloid beta aggregation
,
c
,
,*
Hongtao Dua *, Xinyu Jianga, Meng Maa, Huili Xua, Shuang Liua, Fang Mab
a College of Life Science, Xinyang Normal University, Xinyang 464000, China
b School of Geographic Sciences, Xinyang Normal University, Xinyang 464000, China
c College of Science, Northwest A&F University, Yangling 712100, Shaanxi Province, China
A R T I C L E I N F O
A B S T R A C T
Keywords:
A novel series of deoxyvasicinone-tetrahydro-beta-carboline hybrids were synthesized and evaluated as acetyl-
cholinesterase (AChE) and β-amyloid peptide (Aβ) aggregation inhibitors for the treatment of Alzheimer’s dis-
ease. The results revealed that the derivatives had multifunctional profiles, including AChE inhibition, Aβ1-42
aggregation inhibition, and neuroprotective properties. Inspiringly, hybrids 8b and 8d displayed excellent
Deoxyvasicinone
Tetrahydro-β-carboline
Acetylcholinesterase
β-Amyloid peptide
Alzheimer’s disease
inhibitory activities against hAChE (IC50 = 0.93 and 1.08 nM, respectively) and Aβ1ꢀ 42 self-aggregation (IC50
=
19.71 and 2.05
μ
M, respectively). In addition, 8b and 8d showed low cytotoxicity and good neuroprotective
activity against Aβ1ꢀ 42-induced damage in SH-SY5Y cells.
Alzheimer’s disease (AD) is progressive, fatal, and the most common
neurodegenerative disease. Alzheimer’s Disease International (ADI) es-
timates that more than 50 million people suffered from AD in 2019, a
figure set to increase to 152 million by 2050.1 The causes of AD are not
yet fully understood, but some factors, including neuron loss, Aβ de-
progressive deposition of Aβ plays a crucial role in AD pathogenesis,
which can cause neuronal death and eventually dementia. Therefore,
many series of compounds have been developed as inhibitors of AChE
and Aβ aggregation in recent years.13–15
Natural products are important sources of novel lead compounds
with bioactive properties.16 Deoxyvasicinone (A) and β-carboline (B)
alkaloids (Fig. 1) are the main active ingredients of Peganum harmala,
which possesses many biological activities, including antitumor, anti-
bacterial, and anti-inflammatory activities.17 Recently, deoxyvasicinone
and its derivatives have been researched as cholinesterase inhibitors
(Fig. 1).18–21 For instance, derivatives C and D show potent inhibitory
activity against AChE with IC50 values of 50 and 23 nM, respec-
tively.22,23 Moreover, there is growing evidence that β-carboline de-
rivatives demonstrate potential inhibitory activities against
cholinesterase, monoamine oxidase, and Aβ aggregation.24–26 For
example, derivative E displays an excellent ability to inhibit cholines-
terase (IC50, 21.6 nM for AChE, and 39.8 nM for butyrylcholinesterase
posits, τ-aggregation, neuroinflammation, and oxidative stress, have
been suggested to play significant roles in AD.2–6 Currently, drugs for the
treatment of AD include four acetylcholinesterase inhibitors (tacrine,
donepezil, rivastigmine and galantamine) and one N-methyl-D-aspartate
(NMDA) receptor antagonist (memantine). Unfortunately, these drugs
can only improve symptoms but not cure the disease. Furthermore, side
effects, including nausea, vomiting, and liver damage, have been re-
ported after the use of these drugs.7 Thus, it is necessary to develop more
effective drugs for the treatment of AD.
Due to the complexity of AD and the interconnections of various
factors in its progression, the development of multitarget-directed li-
gands (MTDLs) with two or more disease targets has attracted much
attention as a therapeutic method for the treatment of AD.8,9 Among the
diverse factors of AD, both the low levels of ACh and the deposition of Aβ
play vital roles in AD pathogenesis.10,11 AChE is a key enzyme in the
hydrolysis of acetylcholine. Thus, acetylcholinesterase inhibitors
(AChEIs) could increase the amount of ACh in AD patients. Furthermore,
some researchers have identified that the peripheral anionic site (PAS)
of AChE contributes to accelerating senile Aβ deposition.12 The
(BuChE)), good inhibition of Aβ aggregation (65.8% at 20 μM) and good
antioxidant activity (1.57 Trolox equivalents).27 In addition, Qu et al
reported that a novel series of bivalent β-carboline derivatives (F)
showed good potency for BuChE inhibition, Aβ1-42 disaggregation and
neuroprotection.25 Thus, β-carboline is regarded as a useful framework
for AD drug design. Additionally, a literature study reported that two
naturally occurring dimers (G) of deoxyvasicinone and β-carboline
* Corresponding authors at: College of Life Science, Xinyang Normal University, Xinyang 464000, China (H. Du).
E-mail addresses: htdu@xynu.edu.cn (H. Du), mafang_1984@126.com (F. Ma).
https://doi.org/10.1016/j.bmcl.2020.127659
Received 13 May 2020; Received in revised form 30 September 2020; Accepted 27 October 2020
Available online 31 October 2020
0960-894X/© 2020 Elsevier Ltd. All rights reserved.

H. Du et al.
Bioorganic & Medicinal Chemistry Letters 30 (2020) 127659
O
N
O
N
O
N
O
Cl
N
N
O
N
N
N
N
H
Deoxyvasicinone (A)
(D)
(C)
COOCH3
X
N
O
NH
n
N
O
n
O
N
NH
N
N
O
N
R1
4
N
H
R1
H
N
NH
H3COOC
(F)
N
N
H
N
H
NH
beta-carboline (B)
(E)
(G)
Fig. 1. The structures of deoxyvasicinone, β-carboline and their derivatives discussed in the text.
O
N
NH
N
N
H
O
HN
N
binding CAS and PAS sites
inhibition 1-42 aggregation
N
O
N
n
X
X: NH or , n = 1-5
O
N
N
O
O
Cl
N
NH
4
N
H
NH
N
N
H
H
N
Fig. 2. Design strategy for the new hybrids of deoxyvasicinone and tetrahydro-β-carboline.
display inhibitory activity against AChE.28
were prepared via the Claisen-Schmidt condensation reaction between 2
and 4-hydroxybenzaldehyde/4-nitrobenzaldehyde in the presence of
acetic acid and sodium acetate. Then, the reduction of compound 4 was
carried out with sodium sulfide/nonahydrate sodium hydroxide to yield
intermediate 5. The condensation of intermediates 3 and 5 with
different linear bromo-acids and EDCI in dry dichloromethane gave in-
termediates 6 and 7. Their further amination with tetrahydro-β-carbo-
line produced target compounds 8a-8e and 9a-9e. These
deoxyvasicinone- tetrahydro-beta-carboline hybrids were characterized
by NMR and HRMS (see supplementary material).
Inspired by the above studies, we assumed that the rational combi-
nation of deoxyvasicinone and β-carboline may enhance inhibitory ac-
tivity against AChE. Therefore, in this work, we designed, synthesized
and evaluated a novel series of deoxyvasicinone-tetrahydro-beta-carbo-
line hybrids as multifunctional agents for the treatment of AD (Fig. 2).
These new hybrids could bind simultaneously to the catalytic active site
(CAS) and peripheral anionic site (PAS) of AChE and show inhibitory
activity against Aβ
aggregation. Additionally, two potential com-
pounds were invest1igꢀ a42ted for their cytotoxicity and protective capacity
for Aβ1ꢀ 42-induced SH-SY5Y cell death. Furthermore, molecular dock-
ing studies were performed to research binding modes in the active site.
The detailed synthetic route for the target compounds is outlined in
Scheme 1. Deoxyvasicinone (2) was produced from 2-aminobenzoic acid
(1) according to a previously described method.21 Intermediates 3 and 4
The inhibitory properties of the target compounds against hAChE
(from human erythrocytes) and hBuChE (from human serum) were
evaluated using Ellman’s method,29 with tacrine and donepezil as pos-
itive controls. The IC50 values and selectivity indices for AChE over
BuChE are given in Table 1. The tested target compounds were potent
2

H. Du et al.
Bioorganic & Medicinal Chemistry Letters 30 (2020) 127659
O
O
N
O
N
N
COOH
NH2
(ii)
(ii)
N
N
(i)
N
R
1
NH2
2
3
4
R=OH; R=NO2
5
O
O
N
O
N
N
HN
N
N
(iv)
(v)
O
O
N
N
n
Br
R
R
n
R
6a-7e
3
5
R=OH; R=NH2
8a-9e
9a
R=NH, n=1
R=NH, n=2
R=NH, n=3
R=NH, n=4
R=NH, n=5
7a
7b
7c
7d
7e
8a
R=NH, n=1
R=NH, n=2
R=NH, n=3
R=NH, n=4
R=NH, n=5
R=O, n=1
R=O, n=2
R=O, n=3
R=O, n=4
R=O, n=5
6a
6b
6c
6d
6e
R=O, n=1
R=O, n=2
R=O, n=3
R=O, n=4
R=O, n=5
9b
9c
9d
9e
8b
8c
8d
8e
Scheme 1. Synthesis of deoxyvasicinone and tetrahydro-β-carboline hybrids. Reagents and conditions: (i) 2-pyrrolidinone, POCl3, dry toluene; (ii) PNBD or PHBA,
AcOH, AcONa, reflux; (iii) NaOH, Na2S9⋅H2O, EtOH, reflux; (iv) Different bromo-acids, EDCI, dry CH2Cl2, reflux; (v) Tetrahydro-β-carboline, K2CO3, EtOH, reflux.
respectively.
Table 1
To investigate the inhibitory potency of the derivatives on Aβ1ꢀ 42
Inhibition of hAChE, hBuChE and Aβ1-42 aggregation by the synthesized
self-aggregation, a thioflavin-T (ThT) fluorescence assay was carried
compounds.
Compound
out,30 and resveratrol and curcumin were used as controls. As shown in
IC50 (nM)a or
S.I.b
IC50
(
μ
M)a for Aβ1-
Table 1, 4 compounds (8b, 8d, 8e and 9e) displayed potent inhibition of
Aβ1ꢀ 42 aggregation that was similar to or greater than that of resveratrol
(IC50 = 12.43 nM) and curcumin (IC50 = 15.37 nM). In particular,
compound 8d exhibited the strongest inhibitory activity, which was 6-
fold better than that of resveratrol. Moreover, 8d also acts as a potent
hAChE inhibitor. Furthermore, it was interesting to observe that the
esterified derivatives 8a-8e have better hAChE and inhibitory activity
than the corresponding amidated hybrids 9a-9e.
inhibition % at 1
μ
M
42 or inhibition %
at 20
μM
hAChE
hBuChE
8a
8b
8c
8d
8e
9a
9b
9c
9d
9e
216.34
± 21.82
0.93 ±
0.12
238.31
± 18.28
69.18 ±
25.56
1.1
38.8%
74.4
2.7
19.71 ± 0.82
41.5%
16.54 ±
1.25
44.15 ±
2.47
To support the above experimental results, molecular docking sim-
ulations of compound 8d with hAChE (PDB code: 4EY7), BuChE (PDB:
4TPK) and Aβ1-42 (PDB code: 1IYT) were performed using the Surflex-
Dock program in Sybyl-X 2.0 software. The figures were prepared
using PyMOL and PoseView (Fig. 3).31,32 As shown in Fig. 3a-b, hybrid
8d could simultaneously bind to both the hAChE catalytic active site
(CAS) and the peripheral anionic site (PAS). The β-carboline moiety of
1.08 ±
0.26
422.28
± 29.52
507.07
± 32.29
596.15
± 48.15
725.95
± 60.58
215.14
± 10.83
32.75 ±
1.76
391.0
47.3
< 0.6
74.5
<0.2
0.3
2.05 ± 0.13
15.12 ± 0.75
37.5%
10.72 ±
0.81
21.6%
9.75 ±
0.59
31.6%
49.9%
21.2%
8d occupied the catalytic active site (CAS), forming
π–π stacking in-
teractions with Trp86 (4.4 Å). The benzene group was able to bind to the
98.3 ±
7.97
27.9%
PAS through π–π stacking interactions with Trp286 (3.6 Å) and Tyr341
153.25
± 13.58
29.7%
485.53
± 35.62
40.5%
3.2
18.3 ± 0.62
20.7%
(5.0 Å). Additionally, the long alkyl linker and the deoxyvasicinone
moiety formed hydrophobic interactions with Gly120, Gly121, Tyr337,
Phe338, Trp286, His287 and Tyr341, which could enhance the inter-
Deoxyvasicinone and
Tetrahydro-
β-carboline
–
action with hAChE. These results indicated that
π–π stacking in-
Tacrine
72.38 ±
5.39
n.d.c
n.d.c
n.d.c
n.d.c
n.d.c
n.d.c
teractions and hydrophobic interactions play important roles in the
binding of 8d with hAChE. It can be seen from Fig. 3c-3d that the
Donepezil
17.76 ±
1.26
β-carboline moiety interacts with the Trp82 residue of hBuChE via a π–π
Resveratrol
Curcumin
n.d.c
n.d.c
n.d.c
n.d.
n.d.
13.43 ± 0.85
16.25 ± 0.73
stacking interaction at a distance of 3.0 Å. Meanwhile, the amino group
of the β-carboline formed a hydrogen bond with His438 at a distance of
2.2 Å. Additionally, hybrid 8d showed hydrophobic interactions with
n.d.c
a
Values are expressed as mean ± SD of five independent experiments.
Selectivity index for AChE is defined as IC50 (hBuChE)/IC50 (hAChE).
n.d. Not determined.
Trp82, Ala328 and Tyr332. From Fig. 3e-f, a π–π stacking interaction
b
c
was found between the Phe20 residue of Aβ1ꢀ 42 and the benzene group
of the linker (4.3 Å). In addition, the carbonyl group of the linker formed
a hydrogen bond with Lys16 (2.0 Å). Moreover, hydrophobic in-
inhibitors of hAChE and hBuChE, with IC50 values <1 μM (except for
teractions between hybrid 8d and residues of Aβ
(His13, Lys16,
1ꢀ 42
compounds 9a and 9c). Most compounds showed selectivity for hAChE
over hBuChE (except for compounds 9a, and 9c). Importantly, com-
pounds 8b, 8c, 8d, 8e and 9b exhibited hAChE inhibitory activity that
Leu17, Phe20, Ala21 Val24 and Gly25) were found, which could
improve the Aβ1ꢀ 42 self-aggregation inhibitory activity.
In order to evaluate safety, two potential compounds (8b and 8d)
were selected to investigate toxicity in the human neuronal cell line SH-
SY5Y using the MTT assay.31 As depicted in Fig. 4, compound 8b did not
was greater than that of tacrine (IC50 = 72.38 nM) and donepezil (IC50
=
17.76 nM). Compounds 8b and 8d displayed excellent inhibitory po-
tential for hAChE, with IC50 values of 0.93 nM and 1.08 nM,
3

H. Du et al.
Bioorganic & Medicinal Chemistry Letters 30 (2020) 127659
Fig. 3. 3D docking model of compound 8d with (a) AChE (PDB: 4ey7), (c) BuChE (PDB: 4tpk) and (e) Aβ1-42 (PDB: 1iyt). Dashed blue lines represent hydrogen
bonds, and dashed red lines stand for interaction. 2D schematic diagram of docking model of compound 8d with (b) AChE, (d) AChE and (f) Aβ1-42. Dashed dark
lines represent hydrogen bonds, dashed green lines stand for interaction, and solid green lines stand for hydrophobic interaction.
π-π
π-π
display a significant effect on cell viability at a concentration of 0.1
after incubation for 48 h. Compound 8d did not show cytotoxicity at
concentrations of 0.1–1 M. When the concentrations increased to 10
μ
M
concentrations (0.1 μM, 1 μM, and 10 μM) for 48 h. The results (Fig. 4)
showed that the cell viability significantly decreased (52.8%, ***p <
0.001) when SH-SY5Y cells were cultivated with Aβ1-42. However, the
two compounds showed significant neuroprotection at concentrations
μ
μ
M, compounds 8b and 8d exhibited significant effects on SH-SY5Y cell
viability, but the cell viability was still above 76%. These results
demonstrated that compounds 8b and 8d exhibit very low toxicity to
SH-SY5Y cells in the range of tested concentrations.
between 1 μM and 10 μM. Compared with the Aβ1-42-treated group, the
most promising compound, 8d, induced marked cellular recovery at the
lowest concentration of 0.1
μ
M (#p < 0.05). The results demonstrated
To further explore the neuroprotective effects of 8b and 8d on Aβ1-42
-
that the two hybrids have neuroprotective activity against Aβ1-42-
induced damage, SH-SY5Y cells were exposed to 8b and 8d at different
induced neurotoxicity.
4

H. Du et al.
Bioorganic & Medicinal Chemistry Letters 30 (2020) 127659
3 Fish PV, Steadman D, Bayle ED, Whiting P. New approaches for the treatment of
Alzheimer’s disease. Bioorg Med Chem Lett. 2019;29:125–133. https://doi.org/
10.1016/j.bmcl.2018.11.034.
4 Sevigny J, Chiao P, Bussiere T, et al. The antibody aducanumab reduces A beta
plaques in Alzheimer’s disease. Nature. 2016;537:50–56. https://doi.org/10.1038/
nature19323.
5 Cheignon C, Tomas M, Bonnefont-Rousselot D, Faller P, Hureau C, Collin F. Oxidative
stress and the amyloid beta peptide in Alzheimer’s disease. Redox Biol. 2018;14:
450–464. https://doi.org/10.1016/j.redox.2017.10.014.
6 Fu W, Vukojevic V, Patel A, et al. Role of microglial amylin receptors in mediating
beta amyloid (Aβ)-induced inflammation. J Neuroinflammation. 2017;14. https://doi.
org/10.1186/s12974-017-0972-9.
7 Tan C-C, Yu J-T, Wang H-F, et al. Efficacy and safety of donepezil, galantamine,
rivastigmine, and memantine for the treatment of Alzheimer’s disease: a systematic
review and meta-analysis. J Alzhmer’s Dis. 2014;41:615–631. https://doi.org/
10.3233/JAD-132690.
8 Savelieff MG, Nam G, Kang J, Lee HJ, Lee M, Lim MH. Development of
multifunctional molecules as potential therapeutic candidates for Alzheimer’s
disease, Parkinson’s disease, and amyotrophic lateral sclerosis in the last decade.
Chem Rev. 2019;119:1221–1322. https://doi.org/10.1021/acs.chemrev.8b00138.
9 Sang Z, Wang K, Shi J, et al. The development of advanced structural framework as
multi-target-directed ligands for the treatment of Alzheimer’s disease. Eur J Med
Chem. 2020;192:112180. https://doi.org/10.1016/j.ejmech.2020.112180.
10 He L, Jiang Y, Green J, Blevins H, Zhang S. Development of bivalent compounds as
potential neuroprotectants for Alzheimer’s disease. Bioorg Med Chem Lett. 2019;29:
1957–1961. https://doi.org/10.1016/j.bmcl.2019.05.035.
Fig. 4. Neurotoxicity and neuroprotective effects of compounds 8a and 8d in
SH-SY5Y cells. Data are represented as mean ± SD of five independent exper-
iments. *p < 0.05, **p < 0.01 and ***p < 0.001 vs control group (untreated
cells); #p < 0.05, ##p < 0.01, ###p < 0.001 vs Aβ1-42-treated cells.
11 Kou X, Song L, Wang Y, et al. Design, synthesis and anti-Alzheimer’s disease activity
study of xanthone derivatives based on multi-target strategy. Bioorg Med Chem Lett.
2020;30:126927. https://doi.org/10.1016/j.bmcl.2019.126927.
12 Jiang N, Ding J, Liu J, et al. Novel chromanone-dithiocarbamate hybrids as
multifunctional AChE inhibitors with beta-amyloid anti-aggregation properties for
the treatment of Alzheimer’s disease. Bioorg Chem. 2019;89, 103207. https://doi.
org/10.1016/j.bioorg.2019.103027.
In this study, a series of novel deoxyvasicinone-tetrahydro-beta-car-
boline hybrids was designed, synthesized and evaluated as dual in-
hibitors for AChE and amyloid beta aggregation. The results showed that
13 Fu J, Bao F, Gu M, et al. Design, synthesis and evaluation of quinolinone derivatives
containing dithiocarbamate moiety as multifunctional AChE inhibitors for the
treatment of Alzheimer’s disease. J Enzyme Inhib Med Chem. 2020;35:118–128.
https://doi.org/10.1080/14756366.2019.1687460.
most compounds were potent inhibitors of hAChE and Aβ
self-
aggregation. Among them, 5 compounds had inhibitory1ꢀ a4c2tivity
against hAChE that was higher than that of the standard drugs tacrine
(IC50 = 72.38 nM) and donepezil (IC50 = 17.76 nM). In addition, four
compounds displayed potent inhibition of Aβ1ꢀ 42 aggregation that was
similar to or higher than that of resveratrol (IC50 = 12.43 nM) and
curcumin (IC50 = 15.37 nM). In particular, hybrids 8b and 8d showed
significant inhibition of hAChE (IC50 = 0.93 and 1.08 nM, respectively)
14 Pradhan K, Das G, Mondal P, Khan J, Barman S, Ghosh S. Genesis of neuroprotective
peptoid from a beta 30–34 inhibits a beta aggregation and AChE activity. Acs Chem
Neurosci. 2018;9:2929–2940. https://doi.org/10.1021/acschemneuro.8b00071.
15 Jalili-Baleh L, Nadri H, Moradi A, et al. New racemic annulated pyrazolo[1,2-b]
phthalazines as tacrine-like AChE inhibitors with potential use in Alzheimer’s
disease. Eur J Med Chem. 2017;139:280–289. https://doi.org/10.1016/j.
ejmech.2017.07.072.
and possessed strong Aβ
self-aggregation inhibitory activities.
Moreover, hybrids 8b and18ꢀ d42exhibited good neuroprotective activity
against Aβ1ꢀ 42-induced damage in SH-SY5Y cells and showed low
toxicity. Thus, compounds 8b and 8d should be considered potent drug
candidates for the treatment of AD and further investigation of their
mechanisms of action.
16 Silva T, Reis J, Teixeira J, Borges F. Alzheimer’s disease, enzyme targets and drug
discovery struggles: From natural products to drug prototypes. Ageing Res Rev. 2014;
15:116–145. https://doi.org/10.1016/j.arr.2014.03.008.
17 Niroumand MC, Farzaei MH, Amin G. Medicinal properties of Peganum harmala L. in
traditional Iranian medicine and modern phytotherapy: a review. J Tradit Chin Med.
2015;35:104–109. https://doi.org/10.1016/S0254-6272(15)30016-9.
18 Darras FH, Kling B, Heilmann J, Decker M. Neuroprotective tri- and tetracyclic BChE
inhibitors releasing reversible inhibitors upon carbamate transfer. ACS Med Chem
Lett. 2012;3:914–919. https://doi.org/10.1021/ml3001825.
19 Darras FH, Wehle S, Huang G, Sotriffer CA, Decker M. Amine substitution of
quinazolinones leads to selective nanomolar AChE inhibitors with ‘inverted’ binding
mode. Bioorg Med Chem. 2014;22:4867–4881. https://doi.org/10.1016/j.
bmc.2014.06.045.
Declaration of Competing Interest
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence
the work reported in this paper.
20 Ma F, Du H. Novel deoxyvasicinone derivatives as potent multitarget-directed
ligands for the treatment of Alzheimer’s disease: design, synthesis, and biological
evaluation. Eur J Med Chem. 2017;140:118–127. https://doi.org/10.1016/j.
ejmech.2017.09.008.
21 Du H, Liu X, Xie J, Ma F. Novel deoxyvasicinone–donepezil hybrids as potential
multitarget drug candidates for Alzheimer’s disease. ACS Chem Neurosci. 2019;10:
2397–2407. https://doi.org/10.1021/acschemneuro.8b00699.
Acknowledgments
22 Darras FH, Pockes S, Huang G, et al. Synthesis, biological evaluation, and
computational studies of tri- and tetracyclic nitrogen-bridgehead compounds as
potent dual-acting AChE inhibitors and h H 3 receptor antagonists. ACS Chem
Neurosci. 2014;5:225–242. https://doi.org/10.1021/cn4002126.
This work was financially supported by grants from the Program for
Natural Science Foundation of China [grant no. 21602178] and the
Nanhu Scholars Program for Young Scholars of XYNU. We thank Dr.
Qiuju Zhou (Analysis and Testing Center, Xinyang Normal University)
for help with the compound structure analyses.
23 Yan J-W, Li Y-P, Ye WJ, et al. Design, synthesis and evaluation of isaindigotone
derivatives as dual inhibitors for acetylcholinesterase and amyloid beta aggregation.
Bioorg Med Chem. 2012;20:2527–2534. https://doi.org/10.1016/j.bmc.2012.02.061.
24 Liao Q, Li Qi, Zhao Y, et al. Design, synthesis and biological evaluation of novel
carboline-cinnamic acid hybrids as multifunctional agents for treatment of
Alzheimer’s disease. Bioorg Chem. 2020;99:103844. https://doi.org/10.1016/j.
bioorg.2020.103844.
Appendix A. Supplementary data
Supplementary data (experimental procedures and spectroscopic
characterizations of the compounds) to this article can be found online
at https://doi.org/10.1016/j.bmcl.2020.127659.
25 Zhao Y, Ye F, Xu J, et al. Design, synthesis and evaluation of novel bivalent beta-
carboline derivatives as multifunctional agents for the treatment of Alzheimer’s
disease. Bioorg Med Chem. 2018;26:3812–3824. https://doi.org/10.1016/j.
bmc.2018.06.018.
26 Frost D, Meechoovet B, Wang T, et al. Beta-carboline compounds, including harmine,
inhibit DYRK1A and tau phosphorylation at multiple Alzheimer’s disease-related
sites. PLoS ONE. 2011;6, e19264. https://doi.org/10.1371/journal.pone.0019264.
27 Lan JS, Xie SS, Li SY, Pan LF, Wang XB, Kong LY. Design, synthesis and evaluation of
novel tacrine-(beta-carboline) hybrids as multifunctional agents for the treatment of
Alzheimer’s disease. Bioorg Med Chem. 2014;22:6089–6104. https://doi.org/
10.1016/j.bmc.2014.08.035.
References
1 Alzheimer’s Disease International. World Alzheimer Report 2019: Attitudes to
dementia, https://www.alz.co.uk/research/WorldAlzheimerReport2019.pdf.
2 Ittner LM, Goetz J. Amyloid-beta and tau - a toxic pas de deux in Alzheimer’s disease.
Nat Rev Neurosci. 2011;12:67–72. https://doi.org/10.1038/nrn2967.
5

H. Du et al.
Bioorganic & Medicinal Chemistry Letters 30 (2020) 127659
28 Zhao T, Ding KM, Zhang L, Cheng XM, Wang CH, Wang ZT. Acetylcholinesterase and
butyrylcholinesterase inhibitory activities of beta-carboline and quinoline alkaloids
derivatives from the plants of genus Peganum. J Chem-ny. 2013;32:1245–1251.
https://doi.org/10.1007/s12272-009-1910-x.
30 Bartolini M, Bertucci C, Bolognesi ML, Cavalli A, Melchiorre C, Andrisano V. Insight
into the kinetic of amyloid beta(1–42) peptide self-aggregation: elucidation of
inhibitors’ mechanism of action. ChemBioChem. 2007;8:2152–2161. https://doi.org/
10.1002/cbic.200700427.
29 Lee S, Zheng X, Krishnamoorthy J, et al. Rational design of a structural framework
with potential use to develop chemical reagents that target and modulate multiple
facets of Alzheimer’s disease. J Am Chem Soc. 2014;136:299–310. https://doi.org/
10.1021/ja409801p.
31 PyMOL 0.99rc6; DeLano Scientific LLC: Palo Alto, CA, USA, 2006. http://www.
pymol.org.
32 Stierand K, Maass PC, Rarey M. Molecular complexes at a glance: automated
generation of two-dimensional complex diagrams. Bioinformatics. 2006;22:
1710–1716. https://doi.org/10.1093/bioinformatics/btl150.
6