Novel BuChE-IDO1 inhibitors from sertaconazole: Virtual screening, chemical optimization and molecular modeling studies

Article abstract of DOI:10.1016/j.bmcl.2020.127756

In our effort towards the identification of novel BuChE-IDO1 dual-targeted inhibitor for the treatment of Alzheimer's disease (AD), sertaconazole was identified through a combination of structure-based virtual screening followed by MM-GBSA rescoring. Preliminary chemical optimization was performed to develop more potent and selective sertaconazole analogues. In consideration of the selectivity and the inhibitory activity against target proteins, compounds 5c and 5d were selected for the next study. Further modification of compound 5c led to the generation of compound 10g with notably improved selectivity towards BuChE versus AChE. The present study provided us with a good starting point to further design potent and selective BuChE-IDO1 inhibitors, which may benefit the treatment of late stage AD.

Full text of DOI:10.1016/j.bmcl.2020.127756

Bioorg. Med. Chem. Lett. 34 (2021) 127756
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Novel BuChE-IDO1 inhibitors from sertaconazole: Virtual screening,
chemical optimization and molecular modeling studies
,
You Zhoua *, Xin Lub, Chenxi Dub, Yijun Liub, Yifan Wanga, Kwon Ho Hongc, Yao Chend,
,
*
Haopeng Sunb
a College of Sericulture, Textile and Biomass Sciences, Southwest University, Chongqing 400715, China
b Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China
c Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis, MN 55414, USA
d School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China
A R T I C L E I N F O
A B S T R A C T
Keywords:
In our effort towards the identification of novel BuChE-IDO1 dual-targeted inhibitor for the treatment of Alz-
heimer’s disease (AD), sertaconazole was identified through a combination of structure-based virtual screening
followed by MM-GBSA rescoring. Preliminary chemical optimization was performed to develop more potent and
selective sertaconazole analogues. In consideration of the selectivity and the inhibitory activity against target
proteins, compounds 5c and 5d were selected for the next study. Further modification of compound 5c led to the
generation of compound 10g with notably improved selectivity towards BuChE versus AChE. The present study
provided us with a good starting point to further design potent and selective BuChE-IDO1 inhibitors, which may
benefit the treatment of late stage AD.
Alzheimer’s disease
Multifunctional agents
Butyrylcholinesterase (BuChE)
Indoleamine 2,3-dioxygenase 1 (IDO1)
Sertaconazole
Virtual screening
Docking
Alzheimer’s disease (AD) is a common cause for dementia, charac-
terized by impaired cognitive capacity beyond what could be considered
a consequence of normal aging. It affects the memory, thinking process,
learning ability and other cognitive functions.1 According to the World
Alzheimer Report 2019, there are currently>50 million people living
with AD worldwide. The population of AD will reach 152 million in
2050.2 AD imposes immense suffering on patients and their families and
has become one of the most severe public health issues worldwide.
Although the etiology of AD is not yet entirely known, a variety of
conditions are believed to be implicated in the development of AD such
as aggregation and accumulation of amyloid-β (Aβ), tau-protein aggre-
gation, oxidative stress, and low levels of neurotransmitter acetylcholine
(ACh).3–6 Currently approved AD treatments are based on the cholin-
ergic and anti-glutamatergic mechanisms. Unfortunately, they only
provide temporary and modest improvement in cognitive functions, but
cannot effectively reverse the neuronal injury and death caused by
AD.7,8 Thus, great efforts should be made to develop more effective
therapies to fight the upcoming AD epidemic.
an increasing interest in developing multi-target-directed ligands
(MTDLs) which simultaneously manipulate multiple targets for
improving both therapeutic safety and (or) efficacy. Many multifunc-
tional agents in this field have been reported recently, such as MTDLs
targeting glycogen synthase kinase 3β (GSK3β) and tau aggregation,
MTDLs targeting GSK3β and acetylcholinesterase (AChE), MTDLs tar-
geting AChE and serotonin transporter (SERT), and some of them have
already entered clinical trials.10
It is widely accepted that the cognitive and memory deteriorations
associated with AD are caused by
the decline of ACh.11 There are two types of cholinesterase enzymes,
AChE and butyrylcholinesterase (BuChE), responsible for the hydrolysis
of ACh in the brain. In a healthy brain, AChE is more active than BuChE
and has long been considered as a key target for the development of AD
therapeutics. However, as AD progresses, the AChE level in the brain
decreases progressively while BuChE level remains unchanged or even
increases up to 165% when compared to that of the normal brain.12,13
Hence, in progressed AD, BuChE plays an essential role as a compen-
sating enzyme. In addition, selective BuChE inhibition is able to restore
ACh levels in mice and improve the cognitive performance of mice
Due to the complexity nature of AD and the involvement of multiple
pathologic mechanisms in its progression, traditional drugs that only act
on a single target might not exhibit satisfactory efficacy.9 Thus, there is
treated
with
the
Aβ
peptide,
yet
without
peripheral
* Corresponding authors.
E-mail addresses: zhouy701005@swu.edu.cn (Y. Zhou), sunhaopeng@cpu.edu.cn (H. Sun).
https://doi.org/10.1016/j.bmcl.2020.127756
Received 27 September 2020; Received in revised form 14 November 2020; Accepted 16 December 2020
Available online 24 December 2020
0960-894X/© 2020 Elsevier Ltd. All rights reserved.

Y. Zhou et al.
Bioorganic & Medicinal Chemistry Letters 34 (2021) 127756
Neurotoxic metabolites, including quinolinic acid (QUIN) and 3-hydrox-
ykynurenine (3-HK), exhibit neurotoxicity through different mecha-
nisms and induce motor neurons death.26 Specially, elevated levels of
IDO1 and QUIN were found in the hippocampus of AD patients, and
were specifically co-localized with the well-known AD hallmarks, Aβ
deposits and tau.27–29 Recently, an IDO1 inhibitor, coptisine, was re-
ported to ameliorate cognitive impairment in AD mouse models by
preventing neuron loss and reducing amyloid plaque formation.30 Thus,
down-regulation of neurotoxic KP metabolites by effectively inhibiting
over-activated IDO1 will be a promising strategy for the treatment of
AD. Based on the roles of BuChE and IDO1 in AD progression, we hy-
pothesize that a compound with dual BuChE-IDO1 inhibitory activity is
expected to provide superior effects to fight AD, especially the pro-
gressed AD. In 2018, our group reported the first BuChE-IDO1 dual-
targeted inhibitor miconazole (Fig. 1) and its derivatives as potential
anti-AD agents31, which provides strong support to our hypothesis.
To identify novel BuChE-IDO1 inhibitors, here we report the dis-
covery of novel potent and non-toxic BuChE-IDO1 inhibitors through a
combination of computational studies, chemical modifications and
biological evaluations (Fig. 2). As shown in Fig. 2, reported IDO1
Fig. 1. The structure of miconazole.
(parasympathomimetic) adverse side effects, which are results of un-
desirable inhibition of peripheral cholinesterases.14–20 Moreover,
several evidence indicated that BuChE could promote the formation of
Aβ fibrils and BuChE inhibition could reduce the aggregation.21,22
Therefore, selectively inhibiting BuChE has become a promising strategy
for treating advanced AD.
In addition to the dysfunction of cholinergic system, neuro-
inflammation is believed to be another pathogenic mechanism for the
development and progression of AD.23 In the AD brain misfolded pro-
teins and damaged neurons provide obvious stimuli for inflammation.
Consequently, significantly higher levels of pro-inflammatory cytokines,
such as interleukin (IL)-1, IL-6, and tumor necrosis factor-α (TNF-α), as
well as activated microglia and astrocytes, have been observed in the
brain of AD patients.23,24 Recently, mounting evidences indicate that the
kynurenine pathway (KP) of tryptophan metabolism, may play a core
role in the pathology of AD induced by neuroinflammation.25 Indole-
amine 2,3-dioxygenase 1 (IDO1), which is the rate-limiting enzyme of
KP, is activated by pro-inflammatory cytokines and other molecules
consequently inducing the up-regulation of neurotoxic metabolites.
Fig. 3. Structures of purchased virtual hits.
Fig. 2. The discovery workflow of the hit compound. A 3-step molecular docking protocol comprised of high-throughput virtual screening (HTVS), standard pre-
cision (SP) docking, and extra-precision (XP) docking.
2

Y. Zhou et al.
Bioorganic & Medicinal Chemistry Letters 34 (2021) 127756
Scheme 1. Synthetic route of sertaconazole analogues 5a-5g. Reagents and conditions: (i) Br2, CHCl3, 0 ◦C then rt, 60 min; (ii) imidazole, K2CO3, THF, rt, 3 h ; (iii)
NaBH4, MeOH, 0 ◦C then reflux, 3 h; (iv) tetrabutylammonium bromide /toluene, 49% NaOH, substituted benzyl bromide, 85 ◦C, 30 min.
inhibitors (1,880) have been collected from Binding Database32 and
Table 1
PubChem Library33. The crystallographic structure of human BuChE
The inhibitory activities of AChE, BuChE and IDO1 by miconazole and 5a-5g.
(PDB ID: 5NN0)34 was used to perform a structure-based virtual screen.
Compound
AChE IC50
(μ
M)
BuChE IC50
(μM)
SIa
IDO1 IC50 (μM)
A hierarchical molecular docking protocol was performed using the
¨
Glide module of the Schrodinger Suite to narrow down the number of
5a
15.5 ± 0.3
44.6 ± 3.5
13.1 ± 0.8
4.3 ± 0.4
1.4 ± 0.1
17.6 ± 0.9
3.9 ± 0.5
0.09 ± 0.02
4.0 ± 0.1
31.9 ± 2.7
41.7 ± 2.8
4.3 ± 0.9
11
17.7 ± 0.4
screening compounds by gradually increase docking precisions.35 After
docking screening, 136 compounds were retained and subjected to the
subsequent binding free energy calculations using MM-GBSA method,
and the top 20% molecules (26) based on dG bind scores were
5b
2.5
3.4
47.8
22.6
0.6
0.3
0.6
136.1 ± 8.5
6.7 ± 0.9
5c
5d
22.3 ± 1.9
48.6 ± 2.8
63.6 ± 2.9
94.5 ± 5.9
2.9 ± 0.5
5e
90.4 ± 7.2
18.3 ± 1.9
11.9 ± 0.2
2.4 ± 0.2
5f
retained.36 The output was filtered for IDO1 IC50 value of < 10
μM, three
5g
Miconazole
compounds were identified. Finally, two available compounds (NLG919
and sertaconazole) were purchased from Topscience cooperation
(Fig. 3).
Data are shown as mean ± SEM of three experiments. SEM = standard error of
mean. a SI = AChE IC50/BuChE IC50
The purchased virtual hits were tested in vitro for their BuChE and
IDO1 inhibitory activities using the modified Ellman’s method37 and a
fluorimetric method,38 respectively (methods were provided in Sup-
plementary data). Interestingly, sertaconazole showed a potent dual
give intermediate 2. Subsequent nucleophilic substitution reaction of 2
with imidazole yielded intermediate 3, which was reduced to interme-
diate 4 in the presence of NaBH4. Finally, intermediate 4 was reacted
with various benzyl bromides in the presence of tetrabutylammonium
bromide in toluene, to obtain the target compounds 5a-5g.
inhibitory activity against both BuChE (IC50 = 7.4
3.8
μM) and IDO1 (IC50 =
μ
M). Sertaconazole was first approved by FDA as an antifungal
agent. As an approved drug with acceptable drug-like property, it offers
an attractive starting point for further development of new BuChE-IDO1
inhibitor against AD. To develop more potent and safe compounds,
chemical modifications on sertaconazole were performed. The 7-chloro-
3-substituted benzothiophene moiety of sertaconazole was selected for
subsequent modifications. As shown in Scheme 1, a set of seven com-
pounds (5a-5g) were designed and synthesized.
The inhibitory activities of sertaconazole analogues are shown in
Table 1. To study the selectivity profile of the compounds, target com-
pounds were first evaluated on AChE and BuChE. Results showed that
target compounds exhibited better inhibitory activity against BuChE, as
IC50 values ranging from 0.09 to 41.7
μ
M. Meanwhile, the target com-
pounds showed IC50 values on AChE ranging from 4.3 to 90.4
μM.
Among them, compounds 5d and 5e indicated much better BuChE
selectivity index (SI = 47.8 and 22.6, respectively) than reference
compound miconazole (SI = 0.6). Notably, compound 5d showed a
The synthetic route of sertaconazole analogues (Scheme 1) was
similar to our previously reported protocol.31 1-(2,4-dichlorophenyl)
ethan-1-one (1) was used as the starting material and reacted with Br2 to
3

Y. Zhou et al.
Bioorganic & Medicinal Chemistry Letters 34 (2021) 127756
Table 2
The inhibitory activities of AChE, BuChE and IDO1 by 10a-10j.
Compound
AChE IR
AChE IC50
BuChE IC50
M)
IDO1 IC50
M)
(%)a
(μ
M)
(
μ
(μ
10a
10b
10c
10d
10e
10f
10g
10h
10i
11.4
12.4
7.2
n.d.b
3.9 ± 0.6
5.7 ± 0.8
1.1 ± 0.4
7.9 ± 1.9
6.0 ± 1.4
11.3 ± 1.4
1.0 ± 0.3
6.2 ± 1.2
10.0 ± 2.4
15.1 ± 3.3
73.6 ± 13.0
133.1 ± 9.6
35.4 ± 6.1
87.0 ± 14.4
25.0 ± 3.5
59.6 ± 9.7
3.0 ± 0.4
n.d.
n.d.
17.8
19.9
47.4
5.0
n.d.
n.d.
58.7 ± 7.6
n.d.
22.1
21.0
25.5
n.d.
57.7 ± 10.8
49.3 ± 6.3
3.7 ± 1.0
n.d.
10j
n.d.
Data are shown as mean ± SEM of three experiments. SEM = standard error of
mean. a Inhibition ratio (IR) against AChE at 50
μ
M. b n.d., not determined.
compound 5b (IC50 = 136.1 μM) is much lower than compound 5c,
which might be due to weaker interactions between the smaller oxygen
atom and the surrounding amino acid residues. In addition, compound
5c showed better anti-IDO1 activity than compound 5a (IC50 = 17.7
μ
M), indicating that benzothiazole ring is better suited to IDO1 inhibi-
tory activity over the thiophene ring.
Among the synthesized compounds, compound 5c presented a
balanced potency to BuChE and IDO1 with IC50 values in micromolar
ranges. Meanwhile, it could selectively inhibit BuChE over AChE. In
addition, although the IDO1 inhibitory effect of compound 5d decreased
nearly 10-fold when compared with micocnazole, compound 5d showed
a nanomolar BuChE inhibitory activity and >45-fold selectivity towards
BuChE. Hence, compounds 5c and 5d were selected for further study. To
determine the potential cytotoxic effects of compounds 5c and 5d on
neuroblastoma cell line SH-SY5Y, their LD50 values were determined by
using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT)
Fig. 4. Inhibition of aggregation of Aβ1-42 by compounds 5c and 5d (10, 20, 50
μ
M) and resveratrol (50 μM). Data are shown as mean ± SEM of three exper-
iments. SEM = standard error of mean.
nanomolar BuChE inhibition (IC50 = 0.09 μM). When compared to other
compounds, compounds 5f and 5g with relatively smaller substituent
groups than other compounds exert lower BuChE inhibitory activities
and lower BuChE selectivities, demonstrating that both spatial and
electronic factors might play a vital role. It is speculated that fewer in-
teractions of compounds 5f and 5g with surrounding amino acid resi-
dues were formed. Interestingly, compounds 5d displayed superior
BuChE inhibitory activity than compound 5e. It was thought that the
change in the orientation of naphthyl group affected the interactions
between compound 5e and the surrounding amino acid residues in the
pocket.
assay39. Data indicated that both compound 5c (LD50 = 11.8
μM) and 5d
(LD50 = 9.8 μM) showed good safety on neuroblastoma cell line SH-
SY5Y. It is assumed that the accumulation and aggregation of Aβ de-
posits could be originated from soluble and nonfibrillary oligomeric
intermediates which are regarded as a key neurotoxicity inducer.40,41
Therefore, inhibition of aggregation and accumulation of Aβ peptide is
regarded as a strongly potential strategy targeting AD. In addition,
BuChE contributed to the formation of Aβ fibrils, and various Aβ com-
plexes would trigger neuroinflammation resulting in IDO1 up-regulation
and an imbalance in neurotoxic and neuroprotective KP intermediates.42
Based on these studies, it is believed that a single molecule with anti-Aβ
aggregation effect as well as IDO-BuChE inhibitory effect may lead to
Inhibitory activities of target compounds against IDO1 were also
evaluated using BuChE-IDO1 inhibitor miconazole as the reference
compound. Compared with miconazole (IC50 = 2.9 μM), most of target
compounds showed lower inhibitory activities against IDO1 except
compound 5c (IC50 = 6.7 M), indicating that modification in this po-
sition was detrimental. Notably, the IDO1 inhibitory activity of
μ
Scheme 2. Synthetic route of compounds 10a-10j. Reagents and conditions: (i) , Br2, CHCl3, 0 ◦C then rt, 60 min; (ii) imidazole, K2CO3, THF, rt, 3 h ; (iii) NaBH4,
MeOH, 0 ◦C then reflux, 3 h; (iv) tetrabutylammonium bromide /toluene, 49% NaOH, 2-(bromomethyl)benzo[d]thiazole, 85 ◦C, 30 min.
4

Y. Zhou et al.
Bioorganic & Medicinal Chemistry Letters 34 (2021) 127756
Fig. 5. Binding mode predictions for compounds 5c and 10g with BChE (PDB ID: 5NN0) (A and B) and IDO1 (PDB ID: 5EK3) (C and D). Compounds 5c and 10g are
shown in green ball-and-stick mode; key residues are shown in yellow tube mode; Heme ring is shown in grey thick tube mode. The green dashed lines represent
cation-
π stackings, the magenta dashed lines represent an ionic interaction, the yellow dashed lines represent hydrogen-bonding interactions, and the light blue
dashed lines represent
π-π and T-π stackings.
excellent anti-AD efficacy. In this work, compounds 5c and 5d were
evaluated for its in vitro ability to inhibit Aβ aggregation using the thi-
oflavin T (ThT) method.43 Resveratrol was used as a positive control. As
shown in Fig. 4, compounds 5c and 5d exhibited weak to moderate anti-
Aβ1-42 aggregation activity in a dose-dependent manner ranging from
substituted compound 10e (IC50 = 25.0 μM). Considering the impact of
the mono-substituents on the IDO1 IC50 value, we found 3-Br > 3-Cl > 4-
Br > 2-Cl > 4-F > 4-Cl. For di-substituted compounds, results indicated
that introduction of halogen with larger size could retain IDO1 inhibi-
tory activity.
the concentration of 10 to 50
and compound 5d (52.2 ± 0.1%) displayed similar anti-Aβ1-42 aggre-
gation activity with resveratrol (48.3 ± 1.6%) at 50 M.
μ
M. Notably, compound 5c (54.2 ± 1.4%)
According to the above-mentioned chemical optimization on com-
pound 5c, we obtained compound 10g which inhibited both BuChE and
IDO1 with IC50 values in low micromolar ranges while displayed highly
selective BuChE inhibitory activity. To obtain insights on the detailed
binding patterns of compounds 5c and 10g to target proteins, molecular
modeling studies using Glide were performed. The proposed binding
mode of compound 5c with the key residues in the cavity of BuChE was
μ
In this study, further chemical modification of compound 5c was
performed in order to obtain compounds with increased potency and/or
selectivity. The synthetic method of 10a-10j (Scheme 2) was similar to
that of 5a-5g. As shown in Table 2, all target compounds (10aꢀ 10j)
exhibited extremely weak to moderate AChE inhibitory activity, while
retained potent BuChE inhibitory activity. Result showed that simulta-
neous introduction of electron-withdrawing groups to meta- and para-
positions could apparently decrease the AChE inhibitory activity of
compounds (compounds 10c and 10g, AChE inhibition ratio < 10%
shown in Fig. 5A. The 2-benzothiazole group forms T-π stacking in-
teractions with Trp231 in the acyl-binding pocket and Phe329, respec-
tively. The imidazole ring occupies the choline-binding pocket and
forms a salt bridge with Glu197 located at the catalytic active site and
additionally forms cation-
π and π-π interactions with Trp82 in the
under 50
μM). All target compounds (10a ꢀ 10j) showed selectivity on
choline-binding pocket. The interactions with Trp231 and Trp82 were
considered vital in BuChE inhibition.44 The 2,4-dichlorophenyl group is
exposed to the solvent accessible area. As depicted in Fig 5B, compound
10g also forms the same U-shaped conformation for potent protein
bound as compound 5c, and shows the similarity in their interactions
with the key residues in the cavity of BuChE (Trp231, Trp82 and
Glu197). Specifically, the imidazole ring of compound 10g forms a
hydrogen bond with His438 located at the catalytic site in addition to
the salt bridge interaction with Glu197.
BuChE inhibition. Compared with compound 5c (SI = 3.4), compounds
10c and 10g showed significantly improved selectivity (SI > 50).
Inhibitory activities of 10a ꢀ 10j against IDO1 were also tested using
compound 5c as the reference compound. As shown in Table 2, two
synthesized compounds (10g and 10j) displayed comparable inhibitory
activity to compound 5c. The para-substituted compounds (10a, 10d,
10i) and ortho-chloro substituted compound 10f displayed weaker
inhibitory activity against IDO1 than compound 5c. For mono-
substituted compounds, meta-bromo substituted compound 10j (IC50
=
For IDO1, the crystallographic structure of IDO1 in complex with
3.7 M) showed better IDO1 inhibitory activity than meta-chloro
μ
NLG919 analogue (PDB ID: 5EK3)45 was used for molecular docking. As
5

Y. Zhou et al.
Bioorganic & Medicinal Chemistry Letters 34 (2021) 127756
ligands approach for ad treatment. Med Res Rev. 2013;33(1):139–189. https://doi.
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shown in Fig. 5C, the 2-benzothiazole group of compound 5c occupies
the pocket A which mainly consists of Tyr126, Val130, Phe163, Phe164,
Leu234. The 2,4-dicholorophenyl group of 5c is located with the
entrance of pocket B which mainly consists of Phe226, Phe227, Arg231,
Ile354. In addition, the imidazole group is exposed to the solvent
accessible area. The binding conformation of compound 10g with IDO1
is similar to that of compound 5c (Fig.5D). Based on the binding mode
predictions, introduction of suitable substituents on 2- benzothiazole
ring that can form additional interactions with the surrounding amino
acids and the heme iron are speculated to increase the binding affinity of
analogues to BuChE and IDO1.
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In conclusion, sertaconazole was identified as a novel BuChE-IDO1
dual-targeted inhibitor via structure-based virtual screening and MM-
GBSA rescoring. Preliminary chemical modifications have been per-
formed to improve the selectivity and inhibitory activity of sertacona-
zole. In consideration of the selectivity and the inhibitory activity
against target proteins, compounds 5c and 5d were selected for further
study. Both compounds showed dose-dependent anti-Aβ aggregation
activity and good safety on neuroblastoma cell line SH-SY5Y. Further
chemical optimization on compound 5c generated compound 10g
which inhibited both BuChE and IDO1 with IC50 values in low micro-
molar ranges while displayed highly selective BuChE inhibitory activity.
To obtain insights on the detailed binding patterns of compounds 5c and
10g to target proteins, molecular modeling studies were performed in
this study. In summary, the present study provided us with a good
starting point to further design potent and selective BuChE-IDO1 in-
hibitors, which may benefit the treatment of late stage AD.
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Declaration of Competing Interest
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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.
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Acknowledgments
This work was supported by Fundamental Research Funds for the
Central Universities under Grant No. XDJK2019C103; National Natural
Science Foundation of China [grant numbers 81803367, 81872728, and
81573281]; Basic Research and Frontier Exploration Project of
Chongqing [grant number cstc2018jcyjAX0715]; Venture & Innovation
Support Program for Chongqing Overseas Returnees.
27 Guillemin GJ, Brew BJ, Noonan CE, Takikawa O, Cullen KM. Indoleamine 2,3
dioxygenase and quinolinic acid immunoreactivity in Alzheimer’s disease
hippocampus. Neuropathol Appl Neurobio. 2005;31:395–404.
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Appendix A. Supplementary data
29 Bonda DJ, Mailankot M, Stone JG, Garrett MR, Staniszewska M, Castellani RJ,
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30 Yu D, Tao B-B, Yang Y-Y, Du L-S, Yang S-S, He X-J, Zhu Y-W, Yan J-K, Yang Q. The
IDO Inhibitor Coptisine Ameliorates Cognitive Impairment in a Mouse Model of
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