Synthesis and antiviral activity of a series of novel quinoline derivatives as anti-RSV or anti-IAV agents

Article abstract of DOI:10.1016/j.ejmech.2021.113208

We report herein the synthesis of a series of novel quinoline derivatives, based on the lead compound 1a, identified from a rRSV-mGFP high-throughput screening assay. Our results revealed that target compounds 1b, 1g-h, 1af and 1ah (IC₅₀ = 3.10–6.93 μM) had good in vitro activity against RSV, which were better than 1a and ribavirin. In addition, we found that compound 1g displayed the lower cytotoxicity (CC₅₀: 2490.33 μM) and the highest selective index (SI = 673.06), suggesting its promising potential as a candidate for further development. On the other hand, compounds 1a, 1m, 1v, 1ad-1af and 1ah-1ai (IC₅₀s: 1.87–14.28 μM) were more active against IAV than or comparable to ribavirin (IC₅₀: 15.36 ± 0.93 μM). Particularly, the most active compound 1ae (IC₅₀: 1.87 ± 0.58 μM) was found to be 8.2-fold more potent than the reference drug, which could inhibit the virus transcription and replication cycle at an early stage.

Full text of DOI:10.1016/j.ejmech.2021.113208

European Journal of Medicinal Chemistry 214 (2021) 113208
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Research paper
Synthesis and antiviral activity of a series of novel quinoline
derivatives as anti-RSV or anti-IAV agents
,
,
Minghua Wang a 1, Guoning Zhang a 1, Jianyuan Zhao a, Ningning Cheng b, Yujia Wang a,
Yuanhui Fu b, Yanpeng Zheng b, Juxian Wang a, Mei Zhu a, Shan Cen a **, Jinsheng He b
,
,
, ***
,
*
Yucheng Wang a
a Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China
b College of Life Sciences and Bioengineering, Beijing Jiaotong University, Beijing, 100044, China
a r t i c l e i n f o
a b s t r a c t
Article history:
We report herein the synthesis of a series of novel quinoline derivatives, based on the lead compound 1a,
identified from a rRSV-mGFP high-throughput screening assay. Our results revealed that target com-
Received 15 January 2020
Received in revised form
24 November 2020
Accepted 12 January 2021
Available online 27 January 2021
pounds 1b, 1g-h, 1af and 1ah (IC50 ¼ 3.10e6.93
better than 1a and ribavirin. In addition, we found that compound 1g displayed the lower cytotoxicity
(CC50: 2490.33
M) and the highest selective index (SI ¼ 673.06), suggesting its promising potential as a
candidate for further development. On the other hand, compounds 1a, 1m, 1v, 1ad-1af and 1ah-1ai
(IC50s: 1.87e14.28 M) were more active against IAV than or comparable to ribavirin (IC50
15.36 0.93 M). Particularly, the most active compound 1ae (IC50: 1.87 0.58 M) was found to be 8.2-
mM) had good in vitro activity against RSV, which were
m
m
:
Keywords:
Quinoline derivatives
Synthesis
m
m
fold more potent than the reference drug, which could inhibit the virus transcription and replication
cycle at an early stage.
Anti-RSV
© 2021 Elsevier Masson SAS. All rights reserved.
Anti-IAV
Structure-activity relationships
1. Introduction
approved for prophylaxis in high-risk infants in 1998. However,
palivizumab showed no efficacy in the treatment of established RSV
Over the course of human civilization and globalization, viral
infections have caused millions of human casualties worldwide,
and the prevention and treatment of viral diseases are a global
public health challenge [1]. Respiratory syncytial virus (RSV), a
negative sense single-stranded RNA virus in the paramyxoviridae
family [2], is a leading viral cause of hospitalization due to acute
lower respiratory infection especially in infants and young children
[3]. In addition, RSV can cause severe illness in the elderly people
and those adults with cardiopulmonary diseases or immunocom-
promised [4]. Currently available options (palivizumab and riba-
virin) for preventing and treating RSV are limited to select
populations in high-resource settings (Fig. 1). As a humanized
monoclonal antibody against RSV fusion protein, Palivizumab was
infection [5]. Ribavirin is the only approved antiviral therapy for
RSV infection. It is rarely used in clinic due to limited efficacy and
side effects [6]. Above all, safe and effective therapy for RSV infec-
tion is still a high unmet medical need.
As a linear, negative-sense, single-stranded RNA virus, influenza
virus belongs to the orthomyxoviridae family, which could also
cause acute respiratory infectious diseases and remains serious
public health problems worldwide [7]. It can be divided into four
classes, A, B, C and D. Influenza A viruses (IAV) possess high path-
ogenicity and are the main cause of annual epidemics and occa-
sional pandemics of respiratory diseases worldwide [8e10]. These
annual epidemics are estimated to result in approximately 3e5
million cases of severe illness, and about 290,000 to 650,000 res-
piratory deaths [11].
Currently, three classes of anti-influenza drugs have been
approved by the FDA, namely, M2 ion-channel blockers (amanta-
dine and rimantadine), neuraminidase inhibitors (oseltamivir,
zanamivir, peramivir and laninamivir octanoate) and cap-
dependent endonuclease (CEN) inhibitor (baloxavir marboxil,
BXM) (Fig.1) [12,13]. In addition, Favipiravir, which inhibits the RNA
dependent RNA polymerase of multiple RNA viruses, was approved
* Corresponding author.
** Corresponding author.
*** Corresponding author.
E-mail addresses: shancen@imb.pumc.edu.cn (S. Cen), jshhe@bjtu.edu.cn (J. He),
wangyucheng@imb.pumc.edu.cn (Y. Wang).
1
These authors made equal contributions to this work.
https://doi.org/10.1016/j.ejmech.2021.113208
0223-5234/© 2021 Elsevier Masson SAS. All rights reserved.

M. Wang, G. Zhang, J. Zhao et al.
European Journal of Medicinal Chemistry 214 (2021) 113208
Fig. 1. Timeline of approval of drugs against RSV and influenza virus. The x axis indicates the period from January 1930 to August 2019, and the y axis shows the total number of
approved drugs.
by Japan against influenza infection in 2014 (Fig. 1) [14]. However,
the M2 ion-channel inhibitors are no longer recommended for
treatment of influenza and NA inhibitors have several limitations in
clinical practice due to their severe drug resistance and side effects
[15e19]. Therefore, we are constantly required to develop new
antiviral agents with new scaffold and novel mechanism of action.
In previous work, leading compound 1a (Fig. 2) containing
quinoline scaffold, was identified as potent RSV inhibitors from a
rRSV-mGFP high-throughput screening assay. It exhibited consid-
[25] and human immunodeficiency virus [26]. Inspired by the
promising antiviral activity of quinoline scaffold, we intend to
synthesis new quinoline derivatives based on compound 1a and
evaluate their in vitro anti-RSV and IAV activities, which were ex-
pected to explore structure-activity relationships (SAR), and iden-
tify alternative candidate as antiviral agents.
2. Results and discussion
erable anti-RSV activity (IC50: 55.75
mM) and low toxicity (CC50:
2.1. Chemistry
539.5 M), which encouraged us to explore its preliminary
m
structure-activity relationship (SAR) study against RSV. As known
to all, heterocyclic scaffolds play a significant role in antiviral drugs,
aside from diverse pharmacological profiles, like pyrimidine-fused
heterocycles [20], diaminothiophene [21] and quinoline which
were reported as potential antiviral agents. Besides, quinoline de-
rivatives have also proved active against several viruses, such as
coronaviruses [22,23], respiratory syncytial virus [24], Zika virus
Quinoline derivatives 1ae1y described herein were mostly
prepared according to the procedure shown in Scheme 1. Starting
with 2,8-dihydroxylquinoline 2, chlorination with thionyl chloride
in dimethylformamide gives 2-chloroquinoline 3, which was fol-
lowed by substitution with pyrrolidine to afford the key interme-
diate 4. Nucleophilic substitution of intermediate 4 with ethyl
bromoacetate in the presence of potassium carbonate yielded the
Fig. 2. Quinolines originating from rRSV-mGFP high-throughput screening platform.
2

M. Wang, G. Zhang, J. Zhao et al.
European Journal of Medicinal Chemistry 214 (2021) 113208
Scheme 1. Synthesis of the target compounds 1a-1y.
corresponding compound 5, which was followed by hydrolysis gave
the sodium carboxylate 6. Finally, Amidation of sodium salt 6 with
different amines in the presence of O-Benzotriazole-N,N,N0,N0-tet-
ramethyl-uronium- hexafluorophosphate (HBTU) and N,N-
diisopropylethylamine (DIPEA) afforded the amides 1ae1v. Com-
pounds 1we1y with the alkyl linker were also synthesized from
alkyl bromide 7we7y, which can be easily prepared through the
nucleophilic substitution of 4 and dibromoalkane (Scheme 1).
The synthesis of quinoline derivatives 1aae1ai are shown in
Scheme 2. Commercially available benzylamine 8 were acylated
with bromoacetyl bromide 9 to afford the corresponding 2-bromo-
N-(substituted phenyl) acetamides 10, which underwent a coupling
reaction with 2-chloroquinoline 3 to generate the key intermediate
11. Condensation of 11 with available amines in the presence of
potassium carbonate to provide the target compounds 1aae1ai.
particular, compounds 1b, 1geh, 1af and 1ah (IC50 ¼ 3.10e6.93
mM)
were found to be 2.5e5.6-fold more potent than the reference
ribavirin.
Generally, for the benzyl part, compounds bearing a substituent
on the para-position of the benzyl generally showed higher activ-
ities than the corresponding ortho- or meta-substituent analogues
(1b vs 1c vs 1d, 1g vs 1h, 1j vs 1k) and the contribution of the para-
position substituent group to the activity was in this order:
methoxyl > F > CF3 > Cl > methylsulfonyl. When the benzyl was
converted into furan-2-ylmethyl (1q), cyclopropylmethy (1r) or
phenyl (1t), all compounds displayed potent activity, which were
found more potent than that of 1a, but less than that of ribavirin.
The introduction of ethyoxyl on the 2-position of benzyl and phenyl
did not bring about significant changes in activity (1a vs 1m, 1t vs
1u). Additionally, the influence of the acyl chain was investigated.
When it was replaced by the corresponding ether chain (1w,1x, and
1y), the increase of some activity was observed, indicating that its
carbonyl group was not necessary for the activity.
2.2. Anti-RSV activity
For the 2-position of quinoline ring part, the replacement of the
pyrrolidinyl group by the piperidyl (1 ab), morpholine (1ac), N-
methylpiperazinyl (1ad), and methylamino (1 ag) generally
enhanced the antivirus activities of the compounds. Whereas the
dimethylamino (1af) and the (S)-boc-3-amnio-pyrrolidinyl (1ah)
The target compounds 1ae1y and 1aae1ai were evaluated for
their anti-RSV activity in HEp-2 cells. The IC50 values of the quno-
line derivatives along with ribavirin for comparison were summa-
rized in
mM in Tables 1 and 2.
Surprisingly, all the target compounds (IC50 < 50
mM) were more
derivatives showed significantly increased IC50 values (3.10
mM,
active against the RSV than the lead compound 1a, with the
exception of 1c, 1f and 1p, which exhibited higher IC50 values of
4.57 M, respectively). The (3R)-configured 1ai showed a signifi-
m
cantly decreased anti-RSV activity (7.7-fold) compared to (3S)-
configured 1ah.
2919
mM,182
mM and 220
mM. Among the target compounds,1b,1d,
1geh, 1t, 1wex, 1aeeah exhibited potent activity (IC50 < 17
mM). In
Scheme 2. Synthesis of the target compounds 1aa-1ai.
3

M. Wang, G. Zhang, J. Zhao et al.
European Journal of Medicinal Chemistry 214 (2021) 113208
Table 1
Anti-RSV activity and cytotoxicity of the target compounds1ae1y.
Compds.
R1
R2
H
IC50
(
m
M)
CC50
(
m
M)
SI
1a
55.75 18.68
539.5 291.16
9.68
1b
H
4.41 3.05
2131.67 433.00
483.37
1c
H
H
2919.33 1622.62
16.48 5.26
443.6 2787.81
20.57 6.38
0.15
1.25
1d
1e
1f
H
H
H
ND
ND
NA
182.25 131.28
3.70 1.78
311.87 85.41
2490.33 984.34
1.71
1g
673.06
1h
1i
H
H
H
6.93 4.40
ND
74.31 61.13
ND
10.72
NA
1j
39.18 19.43
245.11 161.93
6.26
1k
1l
H
H
30.24 16.70
ND
72.96 60.00
ND
2.41
NA
1m
H
45.69 19.40
113.18 62.71
2.48
1n
1o
H
H
ND
ND
NA
27.76 21.39
326.8 151.21
11.77
1p
1q
H
H
220.90 6.28
22.89 5.19
1356 130.17
249.33 93.29
6.14
10.89
4

M. Wang, G. Zhang, J. Zhao et al.
European Journal of Medicinal Chemistry 214 (2021) 113208
Table 1 (continued)
Compds.
R1
R2
H
IC50
(
m
M)
CC50
(
m
M)
SI
1r
28.98 11.05
579.96 352.83
20.01
1s
1t
CH2CH2O
CH2CH2
H
ND
16.54 5.75
ND
NA
18.35
303.54 254.89
1u
1v
H
H
33.16 23.47
ND
1043.6 491.56
ND
31.47
NA
1w
1x
1y
5
e
e
e
e
e
e
e
e
e
e
14.07 7.24
11.60 4.35
31.33 13.78
16.41 8.47
17.33 0.06
551.60 698.69
691.17 409.95
173.02 144.56
826.03 67.48
3039.67 1336.69
39.20
59.58
5.52
50.34
175.40
ribavirin
ND, not detected; NA, not available.
inhibition of more than 70% towards IAV A/WSN/33 (H1N1) at a
concentration of 10 M (Fig. 3).
Table 2
m
Anti-RSV activity and cytotoxicity of the target compounds1aa-1ai.
According to the result of preliminary screening, the IC50 values
of the selected qunoline derivatives along with ribavirin for com-
parison were summarized in
mM in Table 3. The selected target
compounds had potent in vitro anti-IAV activity. Among them,
compounds 1a, 1m, 1v, 1ade1af and 1ahe1ai (IC50s:
1.87e14.28 mM) were more active than or comparable to ribavirin
(IC50: 15.36 0.93
(IC50: 1.87 0.58
m
M). In particular, the most active compound 1ae
mM) was found to be 8.2-fold more potent than
the reference drug. These compounds had a little correlation be-
tween anti-RSV activity and anti-IAV activity.
Compds.
R
IC50
ND
(m
M)
CC50
ND
(
mM)
SI
1aa
NA
As shown in Fig. 3 and Table 3, 1be1d, 1h, 1j, 1l and 1qe1r had
no activity against IAV. Surprisingly, the introduction of F, Cl
markedly reduced or even lost activity and replacing the benzyl
(1a) by furan-2-ylmethyl (1q) or cyclopropylmethy (1r) lead to the
loss of anti-IAV activity. Although a simple SAR was difficult to
explore, substitution on different position of the benzene ring was
crucial for their anti IAV effect. When a substitution group was
introduced into these molecules on the benzene ring, compounds
displayed decreased or equivalent antiviral effects. Compounds
with a 2-ethoxyl substitution on the benzene ring (1m) and
adamantly (1v) showed relatively higher activity than the corre-
sponding 1a.
1 ab
1ac
1ad
1ae
26.11 7.05
1740.33 493.19
66.65
1.28
36.05 16.96 46.22 24.95
19.27 3.02
16.92 9.79
263.83 144.64
13.69
1368.33 1166.85 80.87
Furthermore, we kept benzyl and investigated the effect of the
substitution groups at C-2 position on quinoline ring. N-benzyl-2-
(quinolin-8-yloxy)acetamides 1aae1ai generally exhibited in vitro
activity, which indicated that converting pyrrolidinyl to other
amine groups was permitted at the C-2 position. The activity
imparted to the quinoline ring by amino group was as follows: boc-
piperazinyl > boc-3-amnio-pyrrolidinyl > methyl piperazinyl >
1af
3.10 1.61
10.30 6.50
4.57 2.46
167.76 114.79
94.81 107.73
43.83 23.56
54.12
9.20
9.59
1 ag
1ah
dimethylamino
> diethylin > morpholine > methylamino >
piperidinyl, which suggested that simply increasing the hydrophi-
licity could improve the activity. The configuration of C0-3 on pyr-
rolidine ring had almost similar effect against IAV (1ah vs 1ai),
which was contrary to that against RSV. Among them, compound
1ai
35.29 11.26 58.56 25.72
20.66 11.40 528.20 151.77
1.66
11
ribavirin
Cl
25.57
1ae (IC50 ¼ 1.87 0.58
mM) demonstrated to be more potent than
17.33 0.06
3039.67 1336.69 175.40
the lead compound 1a.
ND, not detected; NA, not available.
2.3. Anti-IAV activity
2.4. Molecular docking studies of compound 1g against RSV
We also assessed the anti-IAV effect of these compounds and
found that the most potent compounds 1ae, 1ah and 1ai showed an
To further understand the molecular basis of the inhibitory
properties of quinoline derivatives against RSV, we docked the
5

M. Wang, G. Zhang, J. Zhao et al.
European Journal of Medicinal Chemistry 214 (2021) 113208
Fig. 3. Inhibition rate of the target compounds on IAV. The IAV inhibition rates were calculated by GraphPad Prism 7.
Table 3
2.5. Primary mechanism of compound 1ae against IAV
Anti-IAV activity and cytotoxicity of the selected compounds.
The most promising compound 1ae was selected as a repre-
sentative one for the primary mechanisms of action study against
the influenza virus. Firstly, to investigate the possible time-
dependent inhibitory effects on influenza replication, a time-of-
addition experiment for 1ae was carried out and the results were
shown in Fig. 5. When compound 1ae was added before viral
infection (from ꢀ1 to 0 h), no reduction in viral yield was observed.
However, 1ae displayed a significant inhibitory effect on influenza
virus when added after viral infection, particularly in the early stage
(from 2 to 6 h), suggesting that 1ae affects the early steps of the
replication cycle.
In order to further confirm the mode of action of these com-
pounds against influenza virus, we investigated the effect on IAV
RNA transcription and replication using an IAV mini-genome
replicon system. As shown in Fig. 6, compound 1ae significantly
inhibited the activity of luciferase in a dose-dependent manner
Compds.
IC50
(
m
M)
CC50
(
m
M)
SI
1a
1e
1m
1o
1v
13.34 0.43
42.31 3.75
7.46 0.09
36.05 2.30
11.46 1.13
50.66 6.33
32.42 2.86
9.87 0.25
1.87 0.58
14.25 2.81
5.11 0.39
4.99 0.44
15.36 0.93
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>7.50
>2.36
>13.40
>2.77
>8.73
>1.97
>3.08
>10.13
>53.47
>7.02
11.34
9.99
1w
1y
1ad
1ae
1af
1ah
1ai
57.97 3.00
49.87 1.02
>100
ribavirin
>6.51
most active compound 1g into the same 3-fold-symmetric cavity in
profusion RSV F-protein reported by Yun et al. [22], using CDOCKER
of discovery studio program. As shown in Fig. 4A, compound 1g
fitted perfectly into the RSV F-protein binding site. As shown in
Fig. 4B, we observed that quinoline ring and pyrrolidinyl could bind
with Phe488 and Phe140 by Pi-Pi stacked and Pi-alkyl interactions,
which picked more hydrophobic interaction with protein. 8-
substitued group could produce hydrogen-bonding interactions
with the residues Asp486, as well as Pi-Pi stacked interactions with
Phe488, which might account for the essential of phenyl for anti-
RSV activity and 15-fold potency increase compared to original
lead.
with IC50 values of 1.93
influenza virus replication subsystem was basically equivalent to
the IC50 value (1.87 0.58 M) of the anti-IAV activity, indicating
mM. The IC50 value of the compound on the
m
that these compounds may target viral RNA transcription and
replication.
3. Conclusions
In summary, the compound 1a, identified from a rRSV-mGFP
high-throughput screening assay, was selected as our lead com-
pound which displays considerable anti-RSV activity (IC50
:
Fig. 4. Docking model of compound 1g binding to a 3-fold symmetric cavity in prefusion RSV F glycoprotein. (A) Solid surface map of the interaction pocket with compound 1g.
Brown, blue, and white colored regions correspond to hydrophobicity. (B) 2D ligand-interaction diagram was generated in Discovery Studio 2018 software. Key bonds are indicated
by dashed lines between the atoms involved, and the colors of key bonds and residues are shown according to the interaction modes.
6

M. Wang, G. Zhang, J. Zhao et al.
European Journal of Medicinal Chemistry 214 (2021) 113208
Fig. 5. Time-of-addition of 1ae after infected with IAV. A549 cells were inoculated with influenza single-cycle A/WSN/33(H1N1) virus at a multiplicity of infection of 0.2 and
compound 1ae (5 M) was added. Viral yields were determined at 11 h post infection by measuring Gluc activity. In this experiment, DMSO was used as the negative control and
ribavirin (30 M) as the positive control.
m
m
4. Experimental section
4.1. Chemistry
Melting points were obtained from an X4 micromelting point
meter and the temperature was uncorrected. 1H NMR and 13C NMR
spectra were determined on an on a Bruker AVANCE III 400 MHz,
500 MHz or 600 MHz spectrometer (Bruker Inc) in DMSO‑d6,
CD3OD or CDCl3 using tetramethylsilane as an internal standard.
High resolution mass spectra were obtained on an Autospee
Ultima-TOF spectrometer. TLC was performed on silica gel plates
(Merck, ART5554 60 F254). Commercially available starting mate-
rials, reagents, and solvents were used without further purification.
4.1.1. The synthesis of 2-pyrrolidin-1-ylquinolin-8-ol 4
Fig. 6. Inhibition of compound 1ae on influenza viral vRNP. HEK239T cells were
transfected with pCAGGS expression plasmids encoding PB2、PB1、PA、NP、pol-LUC
and SV40-Relina in the absence or presence of compound 1ae at the indicated con-
centration. Effect of vRNA transcription was evaluated by measuring luciferase and
relina at 24h post-transfection.
To a suspension of 2,8-dihydroxyquinoline (2) (10.0 g, 62 mmol)
in 50 mL of anhydrous N,N-dimethylformamide (DMF) was added
thionyl chloride (17.8 mL, 248 mol) at ꢀ5 ꢁC and the reaction
mixture was heated at 50 ꢁC for 12 h. After cooling to room tem-
perature, the mixture was poured into ice water and extracted with
ethyl acetate (50 mL ꢂ 3). The combined extracts were washed with
water, saturated brine, dried over anhydrous Na2SO4, filtrated and
concentrated under reduced pressure to give crude product 2-
chloro-8-hydroxyquinoline (3) (7.5 g, 68% from 2) as white solid.
55.75
mM). A series of novel quinoline derivatives with diverse
substituents at C-2 and C-8 position were synthesized and evaluated
for their antiviral activity against RSV and IAV. The results revealed
1H NMR (400 MHz, CDCl3):
7.46 (t, J ¼ 7.0 Hz, 1H), 7.38 (t, J ¼ 7.0 Hz, 1H), 7.32 (d, J ¼ 8.0 Hz, 1H),
7.21 (d, J ¼ 7.0 Hz, 1H).
d
8.09 (d, J ¼ 8.0 Hz, 1H), 7.69 (brs, 1H),
that compounds 1b, 1geh, 1af and 1ah (IC50 ¼ 3.10e6.93
mM) had
good in vitro activity against RSV, which were better than 1a and
ribavirin. In addition, we found that compound 1g displayed the
To a solution of 3 (6.0 g, 33.4 mmol) and potassium carbonate
(9.2 g, 66.8 mmol) dissolved in DMF (30 mL) was added pyrrolidine
(4.7 g, 66.8 mmol) and stirred for 3 h at 110 ꢁC. After cooling to
room temperature, the mixture was poured into ice water (150 mL)
and extracted with ethyl acetate (80 mL ꢂ 3). The combined ex-
tracts were dried over anhydrous Na2SO4, filtrated and concen-
trated under reduced pressure. The residue was purified by column
chromatography (silica gel) eluting with petroleum ether and ethyl
acetate (10:1, v/v) to get the title compound 4 (6.6 g, 92% from 3) as
lower cytotoxicity (CC50: 2490.33 mM) and the highest selective in-
dex (SI ¼ 673.06), suggesting its promising potential as a candidate
for further development. Studies to determine the in vivo efficacy of
1g are currently underway. On the other hand, compounds 1a, 1m,
1v, 1ade1af and 1ahe1ai (IC50s: 1.87e14.28 mM) were more active
against IAV than or comparable to ribavirin (IC50: 15.36 0.93
mM).
In particular, the most active compound 1ae (IC50: 1.87 0.58
mM)
was found to be 8.2-fold more potent than the reference drug. In the
primary mechanism against IAV, compound 1ae could inhibit the
virus transcription and replication cycle at an early stage. This study
provided a foundation and an opportunity for the development of a
new antiviral agent.
white solid. 1H NMR (500 MHz, DMSO‑d6)
d 8.38 (s, 1H), 7.95 (d,
J ¼ 9.0 Hz, 1H), 7.14 (d, J ¼ 8.0 Hz, 1H), 7.01 (t, J ¼ 7.5 Hz, 1H), 6.92 (d,
J ¼ 7.5 Hz, 1H), 6.86 (d, J ¼ 9.0 Hz, 1H), 3.56 (t, J ¼ 6.0 Hz, 4H),
2.03e1.88 (m, 4H). LC-MS (ESI), m/z:215[MþH]þ, 237[MþNa]þ.
7

M. Wang, G. Zhang, J. Zhao et al.
European Journal of Medicinal Chemistry 214 (2021) 113208
4.1.2. General procedure for the synthesis of compounds 1ae1v
To a solution of 4 (3.0 g, 14.2 mmol) and potassium carbonate
(3.9 g, 24.4 mmol) dissolved in DMF (20 mL) was added ethyl
bromoacetate (3.6 g, 21.2 mmol) dropwise and stirred for 5 h at
65 ꢁC and then poured into water (100 mL), extracted with ethyl
acetate (80 mL ꢂ 3). The combined extracts were dried over
anhydrous Na2SO4, filtrated and concentrated under reduced
pressure. The residue was purified by column chromatography
(silica gel) eluting with petroleum ether and ethyl acetate (10:1, v/
v) to get compound 5 (4.2 g, 98% from 4) as yellow oil. 1H NMR
J ¼ 6.0 Hz, 1H), 7.97 (d, J ¼ 9.0 Hz, 1H), 7.38 (d, J ¼ 8.0 Hz, 1H),
7.29e7.25 (m, 2H), 7.09 (t, J ¼ 8.0 Hz, 1H), 7.06e7.01 (m, 1H), 6.97 (d,
J ¼ 8.0 Hz, 1H), 6.88 (d, J ¼ 10.0 Hz, 1H), 6.83 (d, J ¼ 9.0 Hz, 1H), 4.81
(s, 2H), 4.39 (t, J ¼ 6.0 Hz, 2H), 3.43e3.34 (m, 4H),1.91e1.80 (m, 4H).
13C NMR (151 MHz, DMSO‑d6)
d 169.46, 162.59, 155.10, 152.21,
142.32, 140.63, 137.59, 130.62, 123.94, 123.54, 122.49, 121.27, 116.29,
114.12, 111.50, 71.09, 46.82, 41.80, 25.36. LC-MS (ESI), m/z: 380
[MþH]þ. HRMS-ESI (m/z): Calcd. for C22H23FN3O2 (M þ H)þ:
380.1769; Found: 380.1762.
(500 MHz, DMSO‑d6)
d
7.96 (d, J ¼ 9.0 Hz, 1H), 7.32 (d, J ¼ 7.5 Hz,
4.1.2.4. N-(2-fluorobenzyl)-2-((2-(pyrrolidin-1-yl)quinolin-8-yl)oxy)
acetamide 1d. According to the general procedure, employing 6
and 2-fluorobenzylamine afforded compound 1d as a white solid,
1H), 7.10e6.93 (m, 2H), 6.85 (d, J ¼ 9.0 Hz, 1H), 5.03 (s, 2H), 4.15 (q,
J ¼ 7.0 Hz, 2H), 3.52 (d, J ¼ 6.0 Hz, 4H),1.97 (q, J ¼ 6.0 Hz, 4H),1.20 (t,
J ¼ 7.0 Hz, 3H). LC-MS (ESI), m/z:301[MþH]þ, 323[MþNa]þ.
To a solution of 5 (4.3g, 14.4 mmol) in alcohol (30 mL) was added
sodium hydroxide (1.2 g, 28.7 mmol) in 30 mL water at 0 ꢁC. The
reaction mixture was stirred for 3 h at room temperature. The
resulting solid was collected by filtration and washed successively
with methanol (10 mL), and dried in vacuo to give the title com-
pound 6 (3.2 g, 77%) as white solid. 1H NMR (500 MHz, CD3OD)
37% yield, mp: 136e137 ꢁC. 1H NMR (500 MHz, DMSO‑d6)
d 8.88 (t,
J ¼ 6.0 Hz, 1H), 7.98 (d, J ¼ 9.0 Hz, 1H), 7.38 (d, J ¼ 8.0 Hz, 1H),
7.33e7.27 (m,1H), 7.24 (d, J ¼ 8.0 Hz,1H), 7.12e7.05 (m, 4H), 6.84 (d,
J ¼ 9.0 Hz,1H), 4.80 (s, 2H), 4.42 (d, J ¼ 5.5 Hz, 2H), 3.41 (t, J ¼ 6.5 Hz,
4H), 1.93e1.86 (m, 4H). 13C NMR (151 MHz, DMSO‑d6)
d 169.37,
160.49, 155.10, 152.11, 140.59, 137.55, 129.88, 129.53, 125.77, 124.70,
123.88, 122.37, 121.23, 115.89, 115.52, 111.49, 70.79, 46.79, 36.21,
25.39. LC-MS (ESI), m/z: 380[MþH]þ. HRMS-ESI (m/z): Calcd. for
d
7.98 (d, J ¼ 9.0 Hz, 1H), 7.31 (d, J ¼ 7.5 Hz, 1H), 7.18 (t, J ¼ 7.5 Hz,
1H), 7.03 (d, J ¼ 7.5 Hz, 1H), 6.91 (d, J ¼ 9.0 Hz, 1H), 4.68 (s, 2H), 3.63
(t, J ¼ 6.0 Hz, 4H), 2.09 (m, 4H). LC-MS (ESI), m/z:273[MþH]þ.
A solution of compound 6 (96.2 mg, 0.32 mmol), O-Benzo-
C
22H23FN3O2 (M þ H)þ: 380.1769; Found: 380.1759.
4.1.2.5. N-(4-bromobenzyl)-2-((2-(pyrrolidin-1-yl)quinolin-8-yl)oxy)
acetamide 1e. According to the general procedure, employing 6 and
4-bromobenzylamine afforded compound 1e as a white solid, 34%
triazole-N,N,N0,N0-
tetramethyl-uronium-hexafluorophosphate
(HBTU) (136.5 mg, 0.36 mmol) in DMF (2 mL) was stirred at room
temperature under the atmosphere of nitrogen for 5 min. The
substituted amines (0.36 mmol) and N,N-diisopropylethylamine
(DIPEA) (0.36 mmol) was added to the mixture and stirred for
3 h at room temperature. The mixture was diluted with water and
extracted with ethyl acetate. The combined extracts were washed
by saturated brine, dried over Na2SO4. After filtration, the solvent
was removed under reduced pressure. The residue was purified by
column chromatography (silica gel) eluting with hexanes/EtOAc
(1:1, v/v) to give the target compounds 1ae1v as white or off-white
solids.
yield, mp: 163e165 ꢁC. 1H NMR (500 MHz, DMSO‑d6)
d 8.97 (t,
J ¼ 6.0 Hz, 1H), 7.98 (d, J ¼ 9.0 Hz, 1H), 7.41 (d, J ¼ 8.0 Hz, 2H), 7.38
(d, J ¼ 8.0 Hz, 1H), 7.25 (d, J ¼ 7.5 Hz, 1H), 7.12e7.02 (m, 3H), 6.83 (d,
J ¼ 9.0 Hz, 1H), 4.79 (s, 2H), 4.34 (d, J ¼ 6.0 Hz, 2H), 3.40e3.33 (m,
4H), 1.85e1.88 (m, 4H). 13C NMR (151 MHz, DMSO‑d6)
d 169.39,
155.07, 152.17, 140.62, 138.70, 137.56, 131.55, 129.85, 123.91, 122.47,
121.27, 120.39, 116.20, 111.50, 71.04, 46.80, 41.76, 25.37. LC-MS (ESI),
m/z: 440, 442[MþH]þ. HRMS-ESI (m/z): Calcd. for C22H23BrN3O2
(M þ H)þ: 440.0968; Found: 440.0975, 442.0954.
4.1.2.6. N-(2-bromobenzyl)-2-((2-(pyrrolidin-1-yl)quinolin-8-yl)oxy)
acetamide 1f. According to the general procedure, employing 6 and
2-bromobenzylamine afforded compound 1f as a white solid, 45%
4.1.2.1. N-benzyl-2-((2-(pyrrolidin-1-yl)quinolin-8-yl)oxy)acetamide
1a. According to the general procedure, employing 6 and benzyl-
amine afforded compound 1a as a white solid, 37% yield, mp:
yield, mp: 148e150 ꢁC. 1H NMR (500 MHz, DMSO‑d6)
d 8.95 (t,
151e152 ꢁC. 1H NMR (500 MHz, DMSO‑d6)
d
8.95 (t, J ¼ 6.0 Hz, 1H),
J ¼ 6.0 Hz,1H), 7.97 (d, J ¼ 9.0 Hz,1H), 7.55 (d, J ¼ 7.5 Hz,1H), 7.38 (d,
J ¼ 8.0 Hz, 1H), 7.29e7.21 (m, 2H), 7.19 (t, J ¼ 7.5 Hz, 1H), 7.16e7.06
(m, 2H), 6.82 (d, J ¼ 9.0 Hz, 1H), 4.83 (s, 2H), 4.40 (d, J ¼ 6.0 Hz, 2H),
3.38 (t, J ¼ 6.5 Hz, 4H), 1.90e1.83 (m, 4H). 13C NMR (151 MHz,
7.97 (d, J ¼ 9.0 Hz, 1H), 7.37 (d, J ¼ 8.0 Hz, 1H), 7.27e7.19 (m, 4H),
7.15e7.05 (m, 3H), 6.83 (d, J ¼ 9.0 Hz, 1H), 4.79 (s, 2H), 4.38 (d,
J ¼ 6.0 Hz, 2H), 3.36 (s, 4H), 1.85 (s, 4H). 13C NMR (151 MHz,
DMSO‑d6)
d
169.27, 155.12, 152.22, 140.62, 139.22, 137.54, 128.70,
DMSO‑d6) d 169.52, 155.09, 152.17, 140.66, 137.57, 137.55, 132.85,
127.54, 127.31, 123.89, 122.37, 121.25, 116.00, 111.52, 70.97, 46.80,
42.31, 25.37. LC-MS (ESI), m/z:362[MþH]þ, 384[MþNa]þ. HRMS-ESI
(m/z): Calcd. for C22H24N3O2 (M þ H)þ: 362.1863; Found: 362.1851.
129.50, 129.33, 128.07, 123.95, 122.84, 122.45, 121.27, 116.08, 111.51,
70.92, 46.82, 42.81,25.38. LC-MS (ESI), m/z: 440, 442[MþH]þ.
HRMS-ESI (m/z): Calcd. for C22H23BrN3O2 (M þ H)þ: 440.0968;
Found: 440.0980, 442.0945.
4.1.2.2. N-(4-fluorobenzyl)-2-((2-(pyrrolidin-1-yl)quinolin-8-yl)oxy)
acetamide 1b. According to the general procedure, employing 6
and 4-fluorobenzylamine afforded compound 1b as a white solid,
4.1.2.7. N-(4-methoxybenzyl)-2-((2-(pyrrolidin-1-yl)quinolin-8-yl)
oxy)acetamide 1g. According to the general procedure, employing 6
and 4-methoxybenzylamine afforded compound 1g as a white
solid, 39% yield, mp: 139e141 ꢁC. 1H NMR (500 MHz, DMSO‑d6)
38% yield, mp: 140e142 ꢁC. 1H NMR (500 MHz, DMSO‑d6)
d 8.93 (s,
1H), 7.97 (d, J ¼ 9.0 Hz,1H), 7.37 (d, J ¼ 8.0 Hz,1H), 7.24 (d, J ¼ 7.5 Hz,
1H), 7.18e7.13 (m, 2H), 7.12e7.02 (m, 3H), 6.83 (d, J ¼ 9.0 Hz, 1H),
4.78 (s, 2H), 4.35 (t, J ¼ 6.0 Hz, 2H), 3.37 (s, 4H),1.87 (s, 4H). 13C NMR
d
8.80 (t, J ¼ 6.0 Hz, 1H), 7.97 (d, J ¼ 9.0 Hz, 1H), 7.36 (d, J ¼ 8.0 Hz,
1H), 7.23 (d, J ¼ 8.0 Hz, 1H), 7.13e7.00 (m, 3H), 6.88e6.73 (m, 3H),
4.76 (s, 2H), 4.29 (d, J ¼ 6.0 Hz, 2H), 3.72 (s, 4H), 3.35 (s, 3H), 1.86 (s,
(151 MHz, DMSO‑d6) d 169.28, 155.09, 152.18, 140.61, 137.57, 135.46,
129.61, 123.90, 122.41, 121.25, 116.08, 115.49, 115.35, 111.49, 70.97,
46.80, 41.62, 25.37. LC-MS (ESI), m/z: 380[MþH]þ. HRMS-ESI (m/z):
Calcd. for C22H23FN3O2 (M þ H)þ: 380.1769; Found: 380.1773.
4H). 13C NMR (151 MHz, DMSO‑d6)
d 169.06, 158.72, 155.10, 152.16,
140.58, 137.51, 131.01, 128.99, 123.85, 122.30, 121.22, 115.77, 114.11,
111.51, 70.83, 55.53, 46.78, 41.86, 25.37. LC-MS (ESI), m/z: 392
[MþH]þ. HRMS-ESI (m/z): Calcd. for C23H26N3O3 (M þ H)þ:
392.1969; Found: 392.1954.
4.1.2.3. N-(3-fluorobenzyl)-2-((2-(pyrrolidin-1-yl)quinolin-8-yl)oxy)
acetamide 1c. According to the general procedure, employing 6 and
3-fluorobenzylamine afforded compound 1c as a white solid, 57%
4.1.2.8. N-(3-methoxybenzyl)-2-((2-(pyrrolidin-1-yl)quinolin-8-yl)
oxy)acetamide 1h. According to the general procedure, employing
yield, mp: 132e133 ꢁC. 1H NMR (500 MHz, DMSO‑d6)
d
9.05 (t,
8

M. Wang, G. Zhang, J. Zhao et al.
European Journal of Medicinal Chemistry 214 (2021) 113208
6 and 3-methoxybenzylamine afforded compound 1h as a white
solid, 56% yield, mp: 98e100 ꢁC. 1H NMR (500 MHz, DMSO‑d6)
4.1.2.13. N-(2-ethoxybenzyl)-2-((2-(pyrrolidin-1-yl)quinolin-8-yl)
oxy)acetamide 1m. According to the general procedure, employing
6 and 2-ethoxybenzylamine afforded compound 1m as a white
d
8.99 (t, J ¼ 6.0 Hz, 1H), 7.96 (d, J ¼ 9.0 Hz, 1H), 7.37 (d, J ¼ 8.0 Hz,
1H), 7.25 (d, J ¼ 7.5 Hz, 1H), 7.14 (t, J ¼ 8.0 Hz, 1H), 7.09 (t, J ¼ 7.5 Hz,
1H), 6.82 (d, J ¼ 9.0 Hz, 1H), 6.77 (dd, J ¼ 8.0, 3.0 Hz, 1H), 6.69 (d,
J ¼ 8.0 Hz, 1H), 6.65 (s, 1H), 4.80 (s, 2H), 4.35 (d, J ¼ 6.0 Hz, 2H), 3.62
(s, 3H), 3.37 (t, J ¼ 6.5 Hz, 4H), 1.87e1.85 (m, 4H). 13C NMR
solid, 31% yield, mp: 83e84 ꢁC. 1H NMR (500 MHz, DMSO‑d6)
d 8.68
(t, J ¼ 6.0 Hz,1H), 7.96 (d, J ¼ 9.0 Hz,1H), 7.37 (d, J ¼ 8.0 Hz,1H), 7.25
(d, J ¼ 8.0 Hz, 1H), 7.18 (t, J ¼ 7.0 Hz, 2H), 7.09 (t, J ¼ 8.0 Hz, 1H), 7.00
(d, J ¼ 7.5 Hz, 1H), 6.84 (d, J ¼ 8.0 Hz,1H), 6.82e6.76 (m, 2H), 4.78 (s,
2H), 4.32 (d, J ¼ 6.0 Hz, 2H), 3.82 (q, J ¼ 7.0 Hz, 2H), 3.35 (t,
J ¼ 6.5 Hz, 4H), 1.88e1.81 (m, 4H), 1.15 (t, J ¼ 7.0 Hz, 3H). 13C NMR
(151 MHz, DMSO‑d6) d 169.28, 159.71, 155.10, 152.26, 140.78, 140.63,
137.52, 129.73, 123.90, 122.40, 121.24, 119.74, 116.09, 113.06, 112.84,
111.51, 71.06, 55.31, 46.80, 42.31, 25.36. LC-MS (ESI), m/z: 392
[MþH]þ. HRMS-ESI (m/z): Calcd. for C23H26N3O3 (M þ H)þ:
392.1969; Found: 392.1955.
(151 MHz, DMSO‑d6) d 169.14, 156.51, 155.04, 152.23, 140.67, 137.44,
128.70, 128.43, 126.36, 123.86, 122.31, 121.19, 120.30, 115.83, 111.76,
111.48, 70.93, 63.52, 46.72, 38.03, 25.35,14.98. LC-MS (ESI), m/z:406
[MþH]þ. HRMS-ESI (m/z): Calcd. for C24H28N3O3 (M þ H)þ:
406.2125; Found: 406.2115.
4.1.2.9. N-(2-methoxybenzyl)-2-((2-(pyrrolidin-1-yl)quinolin-8-yl)
oxy)acetamide 1i. According to the general procedure, employing 6
and 2-methoxybenzylamine afforded compound 1i as a white solid,
4.1.2.14. N-(2-methylbenzyl)-2-((2-(pyrrolidin-1-yl)quinolin-8-yl)
oxy)acetamide 1n. According to the general procedure, employing
6 and 2-methylbenzylamine afforded compound 1n as a white
solid, 35% yield, mp: 125e126 ꢁC. 1H NMR (500 MHz, DMSO‑d6)
60% yield, mp: 103e105 ꢁC.1H NMR (500 MHz, DMSO‑d6)
d 8.70 (t,
J ¼ 6.0 Hz, 1H), 7.97 (d, J ¼ 9.0 Hz, 1H), 7.37 (d, J ¼ 8.0 Hz, 1H),
7.26e7.18 (m, 2H), 7.09 (t, J ¼ 8.0 Hz,1H), 7.03e6.98 (m, 1H), 6.89 (d,
J ¼ 8.0 Hz, 1H), 6.83e6.77 (m, 2H), 4.78 (s, 2H), 4.33 (d, J ¼ 6.0 Hz,
2H), 3.64 (s, 3H), 3.37 (t, J ¼ 6.5 Hz,4H), 1.86 (s, 4H). 13C NMR
d
8.72 (s, 1H), 7.95 (d, J ¼ 9.0 Hz, 1H), 7.36 (d, J ¼ 8.0 Hz, 1H), 7.26 (d,
J ¼ 7.5 Hz, 1H), 7.17e7.01 (m, 5H), 6.78 (d, J ¼ 9.0 Hz, 1H), 4.80 (s,
2H), 4.32 (s, 2H), 3.32 (s, 4H), 1.99 (s, 3H), 1.85 (s, 4H). 13C NMR
(151 MHz, DMSO‑d6)
d 169.21, 157.14, 155.10, 152.20, 140.62, 137.49,
128.72, 128.32, 126.35, 123.86, 122.27, 121.22, 120.45, 115.71, 111.50,
110.91, 70.81, 55.62, 46.75, 37.74, 25.38. LC-MS (ESI), m/z: 392
[MþH]þ. HRMS-ESI (m/z): Calcd. for C23H26N3O3 (M þ H)þ:
392.1969; Found: 392.1956.
(151 MHz, DMSO‑d6) d 168.99,155.04,152.09,140.62,137.43,136.50,
136.16, 130.36, 128.15, 127.48, 126.05, 122.28, 121.19, 115.64, 111.49,
70.71, 46.73, 40.74, 25.34, 18.75. LC-MS (ESI), m/z:406[MþH]þ.
HRMS-ESI (m/z): Calcd. for C23H26N3O2 (M þ H)þ: 376.2020; Found:
406.2016.
4.1.2.10. N-(4-chlorobenzyl)-2-((2-(pyrrolidin-1-yl)quinolin-8-yl)
oxy)acetamide 1j. According to the general procedure, employing 6
and 4-chlorobenzylamine benzylamine afforded compound 1j as a
white solid, 46% yield, mp: 151e153 ꢁC.1H NMR (500 MHz,
4.1.2.15. N-(4-(trifluoromethyl)benzyl)-2-((2-(pyrrolidin-1-yl)quino-
lin-8-yl)oxy)acet-amide 1o. According to the general procedure,
employing 6 and 4-trifluoromethylbenzylamine afforded com-
pound 1o as a white solid, 37% yield, mp: 176e178 ꢁC. 1H NMR
DMSO‑d6)
d
8.97 (s, 1H), 7.98 (d, J ¼ 9.0 Hz, 1H), 7.38 (d, J ¼ 8.0 Hz,
1H), 7.29e7.24 (m, 3H), 7.15e7.06 (m, 3H), 6.83 (d, J ¼ 9.0 Hz, 1H),
(500 MHz, DMSO‑d6)
d
9.12 (t, J ¼ 6.0 Hz,1H), 7.97 (d, J ¼ 9.0 Hz,1H),
4.79 (s, 2H), 4.35 (d, J ¼ 6.0 Hz, 2H), 3.36 (t, J ¼ 6.5 Hz, 4H),1.90e1.84
7.58 (d, J ¼ 8.0 Hz, 2H), 7.38 (d, J ¼ 8.0 Hz, 1H), 7.32 (d, J ¼ 8.0 Hz,
2H), 7.27 (d, J ¼ 8.0 Hz,1H), 7.10 (t, J ¼ 8.0 Hz,1H), 6.81 (d, J ¼ 9.0 Hz,
1H), 4.82 (s, 2H), 4.47 (d, J ¼ 6.0 Hz, 2H), 3.36 (t, J ¼ 6.5 Hz, 4H),
(m, 4H). 13C NMR (151 MHz, DMSO‑d6)
d 169.39, 155.08, 152.17,
140.62, 138.30, 137.57, 131.91, 129.49, 128.64, 123.91, 122.46, 121.27,
116.19, 111.50, 71.03, 46.80, 41.69, 25.36. LC-MS (ESI), m/z: 396
[MþH]þ. HRMS-ESI (m/z): Calcd. for C22H23ClN3O2 (M þ H)þ:
396.1474; Found: 396.1469, 398.1441.
1.87e1.82 (m, 4H).13C NMR (151 MHz, DMSO‑d6)
d 169.58, 155.06,
152.20,144.23,140.64,137.60,128.22,125.67,125.53,123.95,122.55,
121.30, 116.43, 111.47, 71.16, 46.79, 41.90, 25.32. LC-MS (ESI), m/
z:430[MþH]þ. HRMS-ESI (m/z): Calcd. for C23H23F3N3O2 (M þ H)þ:
430.1737; Found: 430.1721.
4.1.2.11. N-(3-chlorobenzyl)-2-((2-(pyrrolidin-1-yl)quinolin-8-yl)
oxy)acetamide 1k. According to the general procedure, employing
6 and 3-chlorobenzylamine afforded compound 1k as a white solid,
51% yield, mp: 107e109 ꢁC. 1H NMR (500 MHz, DMSO‑d6)
d 9.10 (t,
4.1.2.16. N-(4-(methylsulfonyl)benzyl)-2-((2-(pyrrolidin-1-yl)quino-
lin-8-yl)oxy)acet-amide 1p. According to the general procedure,
employing 6 and 4-methylsulphonylbenzyl- amine hydrochloride
afforded compound 1p as a white solid, 31% yield, mp: 189e191 ꢁC.
J ¼ 6.0 Hz, 1H), 7.97 (d, J ¼ 9.0 Hz, 1H), 7.38 (d, J ¼ 8.0 Hz, 1H),
7.28e7.23 (m, 3H), 7.15e7.05 (m, 3H), 6.83 (d, J ¼ 9.0 Hz,1H), 4.81 (s,
2H), 4.38 (d, J ¼ 6.0 Hz, 2H), 3.39 (t, J ¼ 6.5 Hz, 4H), 1.89e1.85 (m,
1H NMR (500 MHz, CDCl3)
d 9.55 (s, 1H), 7.87e7.82 (m, 1H), 7.70 (d,
4H). 13C NMR (151 MHz, DMSO‑d6)
d 169.50, 155.09, 152.21, 141.91,
J ¼ 8.0 Hz, 2H), 7.34 (d, J ¼ 8.0 Hz, 1H), 7.21e7.12 (m, 4H), 6.85e6.47
(m, 1H), 4.88 (s, 2H), 4.57 (d, J ¼ 6.0 Hz, 2H), 3.39 (s, 4H), 3.00 (s,
3H), 1.90 (s, 4H). LC-MS (ESI), m/z:440[MþH]þ. HRMS-ESI (m/z):
Calcd. for C23H26N3O4S (M þ H)þ: 440.1639; Found: 440.1646.
140.62, 137.62, 133.42, 130.54, 127.35, 127.27, 126.24, 123.95, 122.55,
121.27, 116.38, 111.51, 71.16, 46.83, 41.73, 25.38. LC-MS (ESI), m/z:
396[MþH]þ. HRMS-ESI (m/z): Calcd. for C22H23ClN3O2 (M þ H)þ:
396.1474; Found: 396.1482, 398.1443.
4.1.2.12. N-(2,6-dichlorobenzyl)-2-((2-(pyrrolidin-1-yl)quinolin-8-yl)
oxy)acetamide 1l. According to the general procedure, employing 6
and 2,6-dichlorobenzylamine afforded compound 1l as a white
4.1.2.17. N-(furan-2-ylmethyl)-2-((2-(pyrrolidin-1-yl)quinolin-8-yl)
oxy)acetamide 1q. According to the general procedure, employing
6 and furfurylamine afforded compound 1q as a white solid, 52%
solid, 47% yield, mp: 108e110 ꢁC. 1H NMR (500 MHz, CDCl3)
d
8.20
yield, mp: 148e150 ꢁC. 1H NMR (500 MHz, DMSO‑d6)
d 8.83 (t,
(s, 1H), 7.76 (d, J ¼ 9.0 Hz, 1H), 7.29 (d, J ¼ 8.0 Hz, 1H), 7.18 (d,
J ¼ 8.0 Hz, 2H), 7.11 (d, J ¼ 7.5 Hz, 1H), 7.09e7.07 (m, 2H), 6.58 (d,
J ¼ 9.0 Hz, 1H), 4.82 (s, 2H), 4.77 (d, J ¼ 5.0 Hz, 2H), 3.40 (t,
J ¼ 6.0 Hz,1H), 7.98 (d, J ¼ 9.0 Hz,1H), 7.49 (s,1H), 7.36 (d, J ¼ 8.0 Hz,
1H), 7.21 (d, J ¼ 7.5 Hz,1H), 7.08 (t, J ¼ 7.5 Hz, 1H), 6.87 (d, J ¼ 9.0 Hz,
1H), 6.35 (s, 1H), 6.14 (s, 1H), 4.75 (s, 2H), 4.37 (d, J ¼ 5.5 Hz, 2H),
3.48e3.45 (m, 4H), 1.96e1.93 (m, 4H). 13C NMR (151 MHz,
J ¼ 5.0 Hz, 4H), 1.98 (s, 4H). 13C NMR (151 MHz, DMSO‑d6)
d 169.00,
154.92, 151.75, 140.64, 137.35, 135.78, 132.73, 130.77, 129.02, 123.82,
122.15,121.12,115.03,111.36, 70.09, 46.64, 39.04, 25.34. LC-MS (ESI),
m/z:430[MþH]þ. HRMS-ESI (m/z): Calcd. for C22H22Cl2N3O2
(M þ H)þ: 430.1084; Found: 430.1104, 432.1084.
DMSO‑d6) d 169.10, 155.16, 152.10, 142.76, 140.59, 137.53, 123.82,
122.32, 121.21, 115.80, 111.53, 110.81, 107.49, 70.74, 46.87, 35.65,
25.46. LC-MS (ESI), m/z:352[MþH]þ. HRMS-ESI (m/z): Calcd. for
C
20H22N3O3 (M þ H)þ: 352.1656; Found: 352.1646.
9

M. Wang, G. Zhang, J. Zhao et al.
European Journal of Medicinal Chemistry 214 (2021) 113208
4.1.2.18. N-(cyclopropylmethyl)-2-((2-(pyrrolidin-1-yl)quinolin-8-yl)
oxy)acetamide 1r. According to the general procedure, employing 6
and cyclopropanemethylamine afforded compound 1r as a white
solid, 56% yield, mp: 147e149 ꢁC. 1H NMR (500 MHz, DMSO‑d6)
were washed by saturated brine, dried over Na2SO4. After filtration,
the solvent was removed under reduced pressure to give the crude
compounds 7we7y as yellow oils.
A mixture of 7w (116.2 mg, 0.35 mmol), morpholine (45.3 mg,
0.52 mmol) and potassium carbonate (96.7 mg, 0.70 mmol) in DMF
(2 mL) was stirred for 20 h at 50 ꢁC under an atmosphere of ni-
trogen. The mixture was diluted with water and extracted with
ethyl acetate (20 mL ꢂ 3). The combined extracts were washed by
saturated brine, dried over Na2SO4. After filtration, the solvent was
removed under reduced pressure. The residue was purified by
column chromatography (silica gel) eluting with petroleum ether
and ethyl acetate (1:2, v/v) to get compound 1we1y as off-white
solids or yellow oil.
d
8.33 (t, J ¼ 6.0 Hz, 1H), 8.00 (d, J ¼ 9.0 Hz, 1H), 7.36 (d, J ¼ 8.0 Hz,
1H), 7.19 (d, J ¼ 7.5 Hz, 1H), 7.08 (t, J ¼ 8.0 Hz, 1H), 6.91 (d, J ¼ 9.0 Hz,
1H), 4.68 (s, 2H), 3.56 (s, 4H), 3.05 (t, J ¼ 6.5 Hz, 2H), 1.98 (s, 4H),
0.90e0.80 (m, 1H), 0.34 (d, J ¼ 7.5 Hz, 2H), 0.10 (d, J ¼ 5.0 Hz, 2H).
13C NMR (151 MHz, DMSO‑d6)
d 168.84, 155.22, 152.03, 140.54,
137.60, 123.84, 122.14, 121.24, 115.25, 111.43, 70.32, 46.96, 43.08,
25.47, 11.24, 3.51. LC-MS (ESI), m/z:326[MþH]þ. HRMS-ESI (m/z):
Calcd. for C19H24N3O2 (M þ H)þ: 326.1863; Found: 326.1855.
4.1.2.19. 1-Morpholino-2-((2-(pyrrolidin-1-yl)quinolin-8-yl)oxy)
ethan-1-one 1s. According to the general procedure, employing 6
and morpholine afforded compound 1s as an off-white solid, 53%
4.1.3.1. 4-(3-((2-(pyrrolidin-1-yl)quinolin-8-yl)oxy)propyl)morpho-
line 1w. According to the general procedure, employing 7w and
morpholine afforded compound 1w as a white solid, 28% yield, mp:
yield, mp: 70e72 ꢁC. 1H NMR (500 MHz, DMSO‑d6)
d 7.97 (d,
J ¼ 9.5 Hz, 1H), 7.31 (d, J ¼ 7.5 Hz, 1H), 7.06e7.01 (m, 2H), 6.87 (d,
84e86 ꢁC. 1H NMR (500 MHz, CDCl3)
d
7.81 (d, J ¼ 9.0 Hz, 1H), 7.20
J ¼ 9.0 Hz, 1H), 4.98 (s, 2H), 3.69e3.43 (m, 12H), 1.99e1.97 (m, 4H).
(d, J ¼ 8.0 Hz,1H), 7.06 (t, J ¼ 8.0 Hz,1H), 6.97 (d, J ¼ 8.0 Hz,1H), 6.72
(d, J ¼ 9.0 Hz,1H), 4.24 (t, J ¼ 6.5 Hz, 2H), 3.74 (t, J ¼ 5.0 Hz, 4H), 3.64
(s, 4H), 2.69 (t, J ¼ 8.0 Hz, 2H), 2.53 (s, 4H), 2.17 (t, J ¼ 7.0 Hz, 2H),
13C NMR (151 MHz, DMSO‑d6)
d 170.82, 155.01, 151.83, 140.46,
137.46, 123.83, 121.60, 121.07, 113.86, 111.13, 68.85, 66.69, 47.01,
45.86, 25.50. LC-MS (ESI), m/z:342[MþH]þ. HRMS-ESI (m/z): Calcd.
for C19H24N3O3 (M þ H)þ: 342.1812; Found: 342.1817.
2.04 (t, J ¼ 6.0 Hz, 4H). 13C NMR (151 MHz, DMSO‑d6)
d 154.91,
152.92, 140.67, 137.34, 123.74, 121.22, 120.74, 113.13, 110.85, 67.71,
66.58, 55.59, 53.84, 46.88, 37.95, 25.49. LC-MS (ESI), m/z:342
[MþH]þ. HRMS-ESI (m/z): Calcd. for C20H28N3O2 (M þ H)þ:
342.2176; Found: 342.2164.
4.1.2.20. N-phenyl-2-((2-(pyrrolidin-1-yl)quinolin-8-yl)oxy)acet-
amide 1t. According to the general procedure, employing 6 and
aniline afforded compound 1t as an off-white solid, 77% yield, mp:
130e132 ꢁC. 1H NMR (500 MHz, DMSO‑d6)
d
10.25 (s, 1H), 8.02 (d,
4.1.3.2. 4-(4-((2-(pyrrolidin-1-yl)quinolin-8-yl)oxy)butyl)morpho-
line 1x. According to the general procedure, employing 7x and
morpholine afforded compound 1x as a white solid, 22% yield, mp:
J ¼ 9.0 Hz,1H), 7.52 (d, J ¼ 8.0 Hz, 2H), 7.39 (d, J ¼ 8.0 Hz,1H), 7.31 (t,
J ¼ 8.0 Hz, 2H), 7.27 (d, J ¼ 7.5 Hz, 1H), 7.13e7.06 (m, 2H), 6.94 (d,
J ¼ 8.5 Hz, 1H), 4.92 (s, 2H), 3.59e3.49 (m, 4H), 1.93 e (m, 4H). 13
C
94e96 ꢁC. 1H NMR (500 MHz, CDCl3)
(d, J ¼ 8.0 Hz,1H), 7.06 (t, J ¼ 8.0 Hz,1H), 6.95 (d, J ¼ 7.5 Hz,1H), 6.72
(d, J ¼ 9.0 Hz, 1H), 4.20 (t, J ¼ 6.5 Hz, 2H), 3.75 (s, 4H), 3.64 (s, 4H),
2.54 (s, 6H), 2.06e1.96 (m, 6H), 1.89e1.81 (m, 2H). 13C NMR
d
7.81 (d, J ¼ 9.0 Hz, 1H), 7.19
NMR (151 MHz, DMSO‑d6)
d
168.10, 155.24, 152.05, 140.64, 138.53,
137.76, 129.24, 124.36, 124.01, 122.51, 121.31, 120.25, 116.15, 111.55,
70.82, 47.06, 25.44. LC-MS (ESI), m/z:348[MþH]þ. HRMS-ESI (m/z):
Calcd. for C21H22N3O2 (M þ H)þ: 348.1707; Found: 348.1698.
(151 MHz, DMSO‑d6) d 154.91, 152.94, 140.54, 137.34, 123.70, 121.23,
120.53, 112.57, 110.84, 68.99, 53.48, 46.88, 37.94, 27.29, 25.49. LC-
MS (ESI), m/z:356[MþH]þ. HRMS-ESI (m/z): Calcd. for C21H30N3O2
(M þ H)þ: 356.2333; Found: 356.2334.
4.1.2.21. N-(2-ethoxyphenyl)-2-((2-(pyrrolidin-1-yl)quinolin-8-yl)
oxy)acetamide 1u. According to the general procedure, employing
6 and 2-ethoxybenzamine afforded compound 1u as a faint yellow
solid, 33% yield, mp: 110e112 ꢁC. 1H NMR (500 MHz, DMSO‑d6)
4.1.3.3. 4-(5-((2-(pyrrolidin-1-yl)quinolin-8-yl)oxy)pentyl)morpho-
line 1y. According to the general procedure, employing 7y and
morpholine afforded compound 1y as a yellow oil, 31% yield. 1H
d
9.51 (s, 1H), 8.06 (d, J ¼ 8.0 Hz, H), 8.01 (d, J ¼ 7.5 Hz, H), 7.40 (d,
J ¼ 8.0 Hz,1H), 7.22 (d, J ¼ 7.5 Hz,1H), 7.08 (t, J ¼ 8.0 Hz, 2H), 7.04 (d,
J ¼ 8.0 Hz, 1H), 6.96e6.89 (m, 2H), 4.91 (s, 2H), 3.99 (q, J ¼ 7.0 Hz,
2H), 3.48 (s, 4H), 1.88 (s, 4H), 1.10 (t, J ¼ 7.0 Hz, 3H). 13C NMR
NMR (500 MHz, CDCl3)
d
7.81 (d, J ¼ 9.0 Hz, 1H), 7.18 (d, J ¼ 8.0 Hz,
1H), 7.05 (t, J ¼ 8.0 Hz,1H), 6.94 (d, J ¼ 7.5 Hz,1H), 6.71 (d, J ¼ 9.0 Hz,
1H), 4.17 (t, J ¼ 6.5 Hz, 2H), 3.72 (t, J ¼ 5.0 Hz, 4H), 3.63 (s, 4H), 2.46
(s, 4H), 2.39 (t, J ¼ 7.0 Hz, 2H), 2.04 (s, 4H), 1.99 (t, J ¼ 7.0 Hz, 2H),
(151 MHz, DMSO‑d6)
d 167.67, 155.15, 151.60, 148.60, 137.55, 127.09,
125.05, 124.01, 122.67, 121.07, 120.90, 115.59, 112.57, 111.46, 70.49,
64.40, 46.84, 25.40, 14.64. LC-MS (ESI), m/z:392[MþH]þ. HRMS-ESI
(m/z): Calcd. for C23H26N3O3 (M þ H)þ: 392.1969; Found: 392.1960.
1.62 (s, 4H). 13C NMR (151 MHz, DMSO‑d6)
d 154.90, 153.03, 140.62,
137.33, 123.72, 121.22, 120.55, 112.74, 110.81, 69.30, 66.47, 58.68,
53.71, 46.86, 37.94, 29.38, 25.50, 24.11. LC-MS (ESI), m/z:370
[MþH]þ. HRMS-ESI (m/z): Calcd. for C22H32N3O2 (M þ H)þ:
370.2489; Found: 370.2484.
4.1.2.22. N-(adamantan-1-yl)-2-((2-(pyrrolidin-1-yl)quinolin-8-yl)
oxy)acetamide 1v. According to the general procedure, employing 6
and Amantadine afforded compound 1v as a white solid, 50% yield,
mp: 222e224 ꢁC.1H NMR (500 MHz, CDCl3)
d
7.85 (d, J ¼ 9.0 Hz,1H),
4.1.4. General procedure for the synthesis of compounds 1aae1ai
To a solution of benzylamine (8) (1.3g, 12.1 mmol) and trie-
thylamine (1.5 g, 14.5 mmol) dissolved in dichloromethane (8 mL)
was added bromoacetyl bromide (2.7 g, 13.3 mmol) dropwise
at ꢀ10 ꢁC and then stirred for 1 h at room temperature. The mixture
was concentrated under reduced pressure and purified by column
chromatography (silica gel) eluting with petroleum ether and ethyl
acetate (8:1, v/v) to get compound 10 (0.97 g, 35%) as off-white
7.27 (s, 1H), 7.17e7.05 (m, 2H),6.96 (d, J ¼ 7.5 Hz, 1H), 6.76 (d,
J ¼ 9.0 Hz, 1H), 4.57 (s, 2H), 3.65 (s, 4H), 2.12e2.03 (m, 13H),
1.74e1.67 (m, 6H). LC-MS (ESI), m/z:406[MþH]þ. HRMS-ESI (m/z):
Calcd. for C25H32N3O3 (M þ H)þ: 406.2489; Found: 406.2486.
4.1.3. General procedure for the synthesis of compounds 1we1y
A mixture of 4 (138.2 mg, 0.64 mmol), cesium carbonate
(417.0 mg, 1.28 mmol) and DMF (4 mL) was stirred for 10 min at
room temperature and 1,3-dibromopropane (156.3 mg, 0.77 mmol)
(1,4-dibromobutane or 1,5-dibromopentane) was added, and then
stirred overnight at the same temperature. The mixture was diluted
with water and extracted with ethyl acetate. The combined extracts
solid. 1H NMR (500 MHz, DMSO‑d6)
d
8.78 (t, J ¼ 6.0 Hz, 1H), 7.33
(t, J ¼ 7.5 Hz, 2H), 7.29e7.22 (m, 3H), 4.30 (d, J ¼ 5.9 Hz, 2H), 3.91 (s,
2H). LC-MS (ESI), m/z:228[MþH]þ.
To a solution of 3 (0.69 g, 3.86 mmol) and potassium carbonate
(1.07 g, 7.72 mmol) dissolved in DMF (5 mL) was added 10 (0.97 g,
10

M. Wang, G. Zhang, J. Zhao et al.
European Journal of Medicinal Chemistry 214 (2021) 113208
4.24 mmol) and stirred for 2 h at 65 ꢁC and then poured into water
(50 mL), extracted with ethyl acetate (40 mL ꢂ 2). The combined
extracts were dried over anhydrous Na2SO4, filtrated and concen-
trated under reduced pressure. The residue was purified by column
chromatography (silica gel) eluting with petroleum ether and ethyl
acetate (1:1, v/v) to get compound 11 (1.24 g, 98% from 3) as white
139.41, 138.12, 128.74, 127.46, 127.31, 124.38, 122.42, 121.84, 115.01,
110.98, 70.34, 54.64, 45.89, 44.62, 42.20. LC-MS (ESI), m/z:391
[MþH]þ. HRMS-ESI (m/z): Calcd. for C23H27N4O2 (M þ H)þ:
391.2129; Found: 391.2125.
4.1.4.5. Tert-butyl 4-(8-(2-(benzylamino)-2-oxoethoxy)quinolin-2-
yl)piperazine-1- carboxylate 1ae. According to the general proced-
ure, employing 11 and N-bocpiperazine afforded compound 1ae as
a white solid, 23% yield, mp: 152e154 ꢁC. 1H NMR (600 MHz,
solid. 1H NMR (500 MHz, DMSO‑d6)
d
8.69 (t, J ¼ 6.0 Hz, 1H), 8.43 (d,
J ¼ 8.5 Hz, 1H), 7.62 (t, J ¼ 9.0 Hz, 2H), 7.56 (t, J ¼ 8.0 Hz, 1H), 7.30 (t,
J ¼ 7.5 Hz, 2H), 7.27e7.21 (m, 4H), 4.84 (s, 2H), 4.36 (d, J ¼ 6.0 Hz,
2H). LC-MS (ESI), m/z:327 [MþH]þ.
DMSO‑d6)
d
8.63 (d, J ¼ 6.0 Hz, 1H), 8.06 (d, J ¼ 9.0 Hz, 1H), 7.39 (dd,
To a solution of 11 (134.2 mg, 0.41 mmol) and potassium car-
bonate (113.3 mg, 0.82 mmol) dissolved in DMF (3 mL) was added
secondary amines (0.82 mmol) and stirred for 8 h at 110 ꢁC. After
cooling to room temperature, the mixture was poured into water
(30 mL) and extracted with ethyl acetate (15 mL ꢂ 2). The combined
extracts were dried over anhydrous Na2SO4, filtrated and concen-
trated under reduced pressure. The residue was purified by column
chromatography (silica gel) eluting with petroleum ether and ethyl
acetate (1:1, v/v) to get the target compound 1aae1ai.
J ¼ 6.5,1.0 Hz,1H), 7.30e7.13 (m, 8H), 4.77 (s, 2H), 4.40 (d, J ¼ 5.0 Hz,
2H), 3.60e3.54 (m, 4H), 3.39e3.33 (m, 4H), 1.44 (s, 9H). 13C NMR
(151 MHz, DMSO‑d6)
d 168.90, 156.80, 154.38, 152.25, 139.56,
139.44, 138.21, 128.74, 127.49, 127.33, 124.46, 122.55, 121.80, 114.89,
111.05, 79.52, 70.21, 44.71, 42.20, 40.45, 28.57. LC-MS (ESI), m/z:477
[MþH]þ. HRMS-ESI (m/z): Calcd. for C27H33N4O4 (M þ H)þ:
477.2497; Found: 477.2508.
4.1.4.6. N-benzyl-2-((2-(dimethylamino)quinolin-8-yl)oxy)acet-
amide 1af. According to the general procedure, employing 11 and
dimethylamine afforded compound 1af as a white solid, 74% yield,
4.1.4.1. N-benzyl-2-((2-(diethylamino)quinolin-8-yl)oxy)acetamide
1aa. According to the general procedure, employing 11 and
diethylamine afforded compound 1aa as an off-white solid. Due to
the low boiling point of diethylamine, the reaction was incomplete
resulting in a lower yield of 12%. mp: 107e108 ꢁC. 1H NMR
mp: 112e114 ꢁC. 1H NMR (500 MHz, CDCl3)
d 8.73 (s, 1H), 7.89 (s,
1H), 7.35 (d, J ¼ 8.0 Hz, 1H), 7.25 (d, J ¼ 5.0 Hz, 4H), 7.17 (s, 3H), 6.88
(s, 1H), 4.87 (s, 2H), 4.56 (d, J ¼ 6.0 Hz, 2H), 3.04 (s, 6H). 13C NMR
(151 MHz, DMSO‑d6)
d 169.10, 157.13, 152.17, 140.13, 139.30, 137.77,
(500 MHz, CDCl3)
d
8.28 (s, 1H), 7.80 (d, J ¼ 9.0 Hz, 1H), 7.25e7.17
128.71, 127.60, 127.31, 123.73, 122.09, 121.58, 115.55, 110.38, 70.65,
42.35, 37.96. LC-MS (ESI), m/z:336[MþH]þ. HRMS-ESI (m/z): Calcd.
for C20H22N3O2 (M þ H)þ: 336.1707; Found: 336.1704.
(m, 6H), 7.12e7.01 (m, 2H), 6.80 (d, J ¼ 9.0 Hz, 1H), 4.80 (s, 2H), 4.55
(d, J ¼ 6.0 Hz, 2H), 3.48 (q, J ¼ 7.0 Hz, 4H), 1.10 (t, J ¼ 7.0 Hz, 6H). 13
C
NMR (151 MHz, DMSO‑d6)
d 172.87, 156.01, 144.04, 138.56, 138.06,
134.38, 130.03, 128.63, 128.60, 128.52, 127.38, 123.68, 120.81, 110.53,
60.44, 52.26, 42.73, 13.53. LC-MS (ESI), m/z:364[MþH]þ. HRMS-ESI
(m/z): Calcd. for C22H26N3O2 (M þ H)þ: 364.2020; Found: 364.2016.
4.1.4.7. N-benzyl-2-((2-(methylamino)quinolin-8-yl)oxy)acetamide
1 ag. According to the general procedure, employing 11 and
methylamine afforded compound 1 ag as an off-white solid.
Because of the low boiling point of methylamine and the use of
methylamine in ethanol solution, the reaction was incomplete and
there was a secondary reaction with ethanol resulting in a lower
4.1.4.2. N-benzyl-2-((2-(piperidin-1-yl)quinolin-8-yl)oxy)acetamide
1 ab. According to the general procedure, employing 11 and
piperidine afforded compound 1 ab as a white solid, 31% yield, mp:
yield of 10%. mp: 113e114 ꢁC. 1H NMR (600 MHz, DMSO‑d6)
d 9.04
167e169 ꢁC. 1H NMR (600 MHz, DMSO‑d6)
7.98 (d, J ¼ 7.5 Hz, 1H), 7.36 (d, J ¼ 6.5 Hz, 1H), 7.29e7.08 (m, 9H),
4.77 (s, 2H), 4.38 (d, J ¼ 5.0 Hz, 2H), 3.58 (d, J ¼ 4.5 Hz, 4H),
1.62e1.53 (m, 2H), 1.52e1.41 (m, 4H). 13C NMR (151 MHz, DMSO‑d6)
d
8.74 (d, J ¼ 5.0 Hz, 1H),
(d, J ¼ 5.0 Hz, 1H), 7.83 (d, J ¼ 7.5 Hz, 1H), 7.32 (d, J ¼ 6.5 Hz, 1H),
7.27e7.18 (m, 4H), 7.17e7.14 (m, 2H), 7.08 (t, J ¼ 6.5 Hz, 2H), 6.74 (d,
J ¼ 7.5 Hz, 1H), 4.78 (s, 2H), 4.38 (d, J ¼ 5.0 Hz, 2H), 2.76 (d,
J ¼ 4.0 Hz, 3H). 13C NMR (151 MHz, DMSO‑d6)
d 169.31, 157.47,
d
169.09, 156.96, 152.20, 139.97, 139.40, 137.94, 128.72, 127.45,
152.31, 140.38, 139.44, 136.85, 128.71, 127.47, 127.28, 124.37, 122.29,
121.43, 115.93, 113.87, 70.98, 42.25, 27.83. LC-MS (ESI), m/z:322
[MþH]þ. HRMS-ESI (m/z): Calcd. for C19H20N3O2 (M þ H)þ:
322.1550; Found: 322.1554.
127.28, 124.08, 121.98, 121.91, 115.28, 111.08, 70.53, 45.92, 42.22,
25.67, 24.72. LC-MS (ESI), m/z:376[MþH]þ. HRMS-ESI (m/z): Calcd.
for C23H26N3O2 (M þ H)þ: 376.2020; Found: 376.2027.
4.1.4.3. N-benzyl-2-((2-morpholinoquinolin-8-yl)oxy)acetamide 1ac.
According to the general procedure, employing 11 and morpholine
afforded compound 1ac as a white solid, 31% yield, mp: 153e155 ꢁC.
4.1.4.8. Tert-butyl (S)-(1-(8-(2-(benzylamino)-2-oxoethoxy)quinolin-
2-yl)pyrrolidine- 3-yl)carbamate 1ah. According to the general
procedure, employing 11 and (S)-3-(boc-amino)pyrrolidine affor-
ded compound 1ah as an off-white solid, 49% yield, mp:
1H NMR (500 MHz, DMSO‑d6)
d
8.68 (t, J ¼ 6.0 Hz, 1H), 8.06 (d,
J ¼ 9.0 Hz, 1H), 7.40 (d, J ¼ 7.5 Hz, 1H), 7.29e7.20 (m, 5H), 7.19e7.14
(m, 3H), 4.78 (s, 2H), 4.39 (d, J ¼ 6.5 Hz, 2H), 3.60 (t, J ¼ 5.0 Hz, 4H),
111e112 ꢁC. 1H NMR (500 MHz, CDCl3)
d 8.80 (s, 1H), 7.88 (d,
J ¼ 9.0 Hz, 1H), 7.35 (d, J ¼ 7.0 Hz, 1H), 7.30 (s, 1H), 7.28e7.24 (m,
2H), 7.17 (s, 4H), 6.67 (d, J ¼ 9.0 Hz, 1H), 4.87 (s, 2H), 4.59e4.51 (m,
2H), 4.25 (s, 1H), 3.62 (s, 1H), 3.42 (s, 2H), 3.23 (s, 1H), 2.13 (s, 1H),
1.90e1.70 (m, 2H), 1.51 (s, 9H). 13C NMR (151 MHz, DMSO‑d6)
3.52 (t, J ¼ 5.0 Hz, 4H). 13C NMR (151 MHz, DMSO‑d6)
d 172.79,
157.61, 143.33, 138.46, 138.38, 135.00, 130.12, 128.68, 128.53, 127.61,
127.37, 124.44, 122.14, 110.95, 66.43, 60.47, 52.35, 45.26. LC-MS
(ESI), m/z:378[MþH]þ. HRMS-ESI (m/z): Calcd. for C22H24N3O3
(M þ H)þ: 378.1812; Found: 378.1821.
d
167.43, 155.75, 155.08, 152.24, 140.51, 139.30, 137.60, 131.98,
129.13, 128.68, 127.62, 127.27, 122.37, 115.98, 111.33, 78.34, 70.93,
52.45, 50.24, 45.18, 42.32, 30.49, 28.72. LC-MS (ESI), m/z:477
[MþH]þ. HRMS-ESI (m/z): Calcd. for C27H33N4O4 (M þ H)þ:
477.2497; Found: 477.2516.
4.1.4.4. N-benzyl-2-((2-(4-methylpiperazin-1-yl)quinolin-8-yl)oxy)
acetamide 1ad. According to the general procedure, employing 11
and N-methylpiperazine afforded compound 1ad as a white solid,
47% yield, mp: 154e156 ꢁC. 1H NMR (500 MHz, CDCl3)
d
8.44 (s, 1H),
4.1.4.9. Tert-butyl (R)-(1-(8-(2-(benzylamino)-2-oxoethoxy)quino-
line-2-yl)pyrrolidine- 3-yl) carbamate 1ai. According to the general
procedure, employing 11 and (R)-3-(boc-amino)pyrrolidine affor-
ded compound 1ai as an off-white solid, 55% yield, mp: 112e113 ꢁC.
7.87 (d, J ¼ 9.0 Hz,1H), 7.32 (d, J ¼ 8.0 Hz,1H), 7.24 (d, J ¼ 7.0 Hz, 2H),
7.20e7.13 (m, 3H), 7.11 (d, J ¼ 8.0 Hz, 1H), 6.93 (d, J ¼ 9.0 Hz, 1H),
4.82 (s, 2H), 4.54 (d, J ¼ 6.0 Hz, 2H), 3.60 (s, 4H), 2.38 (s, 4H), 2.32 (s,
3H).13C NMR (151 MHz, DMSO‑d6)
d
169.00, 156.89, 152.30, 139.67,
1H NMR (500 MHz, CDCl3)
d
8.80 (s, 1H), 7.88 (d, J ¼ 9.0 Hz, 1H), 7.35
11

M. Wang, G. Zhang, J. Zhao et al.
European Journal of Medicinal Chemistry 214 (2021) 113208
(d, J ¼ 7.0 Hz, 1H), 7.30 (s, 1H), 7.28e7.23 (m, 2H), 7.17 (s, 4H), 6.67
(d, J ¼ 9.0 Hz, 1H), 4.87 (s, 2H), 4.61e4.48 (m, 2H), 4.24 (s, 1H), 3.62
(d, J ¼ 10.5 Hz, 1H), 3.42 (s, 2H), 3.23 (s, 1H), 2.13 (s, 1H), 1.90e1.66
“Key New Drug Creation and Manufacturing Program”, China (No.
2019ZX09201001-003).
(m, 2H). 13C NMR (151 MHz, DMSO‑d6)
d 167.43, 155.75, 155.08,
Appendix A. Supplementary data
152.25, 140.51, 139.30, 137.60, 131.97, 129.13, 128.67, 127.62, 127.26,
122.37, 115.99, 111.33, 78.34, 70.94, 52.46, 50.24, 45.18, 42.33, 30.49,
28.72. LC-MS (ESI), m/z:477[MþH]þ. HRMS-ESI (m/z): Calcd. for
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.ejmech.2021.113208.
C
27H33N4O4 (M þ H)þ: 477.2497; Found: 477.2495.
Abbreviations
4.2. Viruses and cells
RSV
IAV
BXM
CEN
SAR
respiratory syncytial virus
influenza A virus
baloxavir marboxil
cap-dependent endonuclease
structure-activity relationship
O-Benzotriazole-N,N,N0,N0-tetramethyl-uronium-
hexafluorophosphate
Green Fluorescent Protein expressing recombinant RSV (RSV-
mGFP; kindly provided by Prof. Jean-Francois Eleouet, Unite de
Virologie et Immunologie Moleculaires (UR892), INRA, Jouy-en-
Josas, France) and wild type subgroup A RSV Long strain (wtRSV,
kindly provided by Prof. Y. Qian, Capital Institute of Pediatrics,
Beijing, China) were propagated in HEp-2 cells (ATCC, Rockefeller,
MD, USA) in DMEM (Gibco BRL, Gaithersburg, MD, USA) supple-
mented with 2% fetal bovine serum (FBS, Hyclone, Logan, UT, USA),
L-glutamine (2 mmol/L), penicillin G (40 U/ml), streptomycin
HBTU
DIPEA
N,N-diisopropylethylamine
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~
~
~
~
Declaration of competing interest
The authors declare that they have no known competing
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