Inhibition of zika virus infection by fused tricyclic derivatives of 1,2,4,5-tetrahydroimidazo[1,5-a]quinolin-3(3aH)-one

Article abstract of DOI:10.1016/j.bioorg.2020.104205

Zika virus (ZIKV) infection represents a significant threat to the global health system, and the search for efficient antivirals to ZIKV remains necessary and urgent. In this study, we extended the exploration of our previously discovered scaffold of 1H-pyrrolo[1,2-c]imidazol-1-one and revealed that two trans isomers of compounds 2 and 7 and one mixture with major trans isomer of compound 3 as novel tetrahydroquinoline-fused imidazolone derivatives are active against ZIKV infection but they are not virucidal. Western Blot and ELISA analyses of ZIKV NS5 and NS1 further demonstrate that compounds of (±)-2, (±)-3 and (±)-7 act as effective agents against ZIKV infection. We show that the N10′s basicity is not the basic requirement for these compounds’ antiviral activity in the current work. Importantly, tuning of some pharmacophores including substituents at arene can generate promising candidates for anti-ZIKV agents.

Full text of DOI:10.1016/j.bioorg.2020.104205

Bioorganic Chemistry 104 (2020) 104205
Contents lists available at ScienceDirect
Bioorganic Chemistry
journal homepage: www.elsevier.com/locate/bioorg
Inhibition of zika virus infection by fused tricyclic derivatives of 1,2,4,5-
tetrahydroimidazo[1,5-a]quinolin-3(3aH)-one
Bin Xu , Emily M. Lee , Angelica Medina , Xia Sun , Decai Wang , Hengli Tangb,⁎,
a,1
b,1
b,1
a
a
a,⁎
Guo-Chun Zhou
a
School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing, Jiangsu 211800, China
b
Department of Biological Science, Florida State University, Tallahassee, FL 32306, USA
A R T I C L E I N F O
A B S T R A C T
Keywords:
Arboviruses
Zika virus
Antiviral
Zika virus (ZIKV) infection represents a significant threat to the global health system, and the search for efficient
antivirals to ZIKV remains necessary and urgent. In this study, we extended the exploration of our previously
discovered scaffold of 1H-pyrrolo[1,2-c]imidazol-1-one and revealed that two trans isomers of compounds 2 and
7
and one mixture with major trans isomer of compound 3 as novel tetrahydroquinoline-fused imidazolone
1
H-pyrrolo[1,2-c]imidazol-1-one
derivatives are active against ZIKV infection but they are not virucidal. Western Blot and ELISA analyses of ZIKV
NS5 and NS1 further demonstrate that compounds of ( ± )-2, ( ± )-3 and ( ± )-7 act as effective agents against
ZIKV infection. We show that the N10′s basicity is not the basic requirement for these compounds’ antiviral
activity in the current work. Importantly, tuning of some pharmacophores including substituents at arene can
generate promising candidates for anti-ZIKV agents.
Tetrahydroquinoline-fused imidazolone
derivatives
The major arboviruses, primarily spreading through ar-
thropod vectors (mainly ticks and mosquitoes), are flaviviruses such as
Zika virus (ZIKV), dengue virus (DENV), West Nile virus (WNV) and
Japanese encephalitis virus (JEV), and alphaviruses such as chi-
kungunya virus (CHIKV). These viruses have a monopartite, linear,
positive sense single-stranded RNA genome, which encodes a single
polyprotein with multiple transmembrane domains that is cleaved, by
both host and viral proteases, into structural and non-structural pro-
teins (NS). ZIKV was first isolated from a febrile sentinel rhesus monkey
in Uganda in 1947 [1] and the first confirmed human infection was
reported in Uganda in 1962–63 [2]. Due to clinical similarity, geo-
graphic overlap and serological cross-reactivity with closely related
viruses, ZIKV infection was not only originally understood to be a mild
self-resolving infection but also frequently misdiagnosed with dengue
and chikungunya infection. [3–6] However, it is now recognized that
ZIKV can cause significant neurological defects in both neonates as
pediatric microcephaly [7–8] and adults as Guillain–Barré syndrome,
supportive care, and the best way to prevent ZIKV infection is to avoid
mosquito bites. On the other hand, increased air travel means that it is
more likely that a virus could be imported from one country into other
countries in the tropical and subtropical regions, [14] which is capable
of establishing imported and local transmission [15–17]. Thus, the
endemic viruses are of significant concern and mosquito transmitted
diseases remain an ongoing global threat. The search for efficient an-
tivirals to ZIKV is of great medical significance.
In our previous studies of antiviral drug discovery, we demonstrated
that certain derivatives of 1H-pyrrolo[1,2-c]imidazol-1-one, the fused
bicyclic of pyrrolidine and 4-imidazolidinone, are potent NS2B-NS3
protease inhibitors of type II dengue virus (DENV-II). Among the
compounds, compound 1 was discovered to be active against wild type
DENV-II infection with EC50 values of 39.4 μM [18]. In order to im-
prove the efficacy and to discover efficient antivirals targeting ZIKV, we
extended our exploration of structure–activity relationship (SAR) by
functionalization of 1H-pyrrolo[1,2-c]imidazol-1-one derivatives by
designing, synthesizing and screening a series of tetrahydroquinoline-
fused imidazolone compounds against ZIKV infection (Fig. 1).
[
9] which are different characteristics from other flaviviruses. Since the
last major epidemic in the Americas in 2016, great efforts have been
conducted in research of prevention and therapy development, but
currently there is still no approved vaccine or specific antiviral against
ZIKV [10–13]. Clinical treatment of infected patients consists of only
We sought to functionalize 1H-pyrrolo[1,2-c]imidazol-1-one scaf-
fold structure by enlargement of the ring size to a 6-membered ring and
also by introduction of fused phenyl group based on the importance of
⁎
Corresponding authors.
E-mail addresses: tang@bio.fsu.edu (H. Tang), gczhou@njtech.edu.cn (G.-C. Zhou).
1
These authors contributed equally to the work.
https://doi.org/10.1016/j.bioorg.2020.104205
Received 29 May 2019; Received in revised form 24 May 2020; Accepted 2 August 2020
Available online 01 September 2020
0045-2068/ © 2020 Elsevier Inc. All rights reserved.

B. Xu, et al.
Bioorganic Chemistry 104 (2020) 104205
6
5
7
5
6
9
7
8
4
7
a
1
2
O
10
N13a
2: R = OTBS, R = OMe
N
4
3
1
O
2
1
2
3
3: R = OMe, R = OH
N
N 2
HN
1
2
4
: R = R = OTBS
1
'
1
2
5
: R = OH, R = OMe
2
'
4
'
3'
1
2
6
: R = R = OH
1
NO2
R1
1
2
7: R = Cl, R = H
O N
2
R2
EC50 = 39.4 M
against DENV-II
previous work
C1-H and C3a-H in trans
18
this work
Fig. 1. Evolution of the previous DENV-II inhibitor (1) [18] to the designed ZIKV inhibitors (2 to 7).
quinoline moiety against infectious diseases [19–22]. It is also pre-
dicted that phenyl reduces the electron density of the N10 to lessen the
propensity to be protonation, resulting in more stability of the acetal.
As the low electron density of the N10 makes the loss of the N10′s
basicity, we can investigate the necessity of the basicity of the nitrogen
in the scaffold for the antiviral activity. Meanwhile, analogs of phenyl
hydrazine were investigated and substituent changes were made.
( ± )-1-(phenyl)-2-(phenylamino)-1,2,4,5- tetrahydro imidazo[1,5-a]-
quinolin-3(3aH)-one 2, 3, 4 and 7 were synthesized by the catalysis of
trifluoroacetic acid (TFA) according to our previously reported method
[18]. Furthermore, desilylation of ( ± )-2 and ( ± )-4 afforded corre-
sponding ( ± )-5 and ( ± )-6, respectively. Similar to the reported re-
sults [18] of 1H-pyrrolo[1,2-c]imidazol-1-one derivatives, the electron-
donating substitution at 3′ and 4′ of C1-Ar makes cis isomers of ( ± )-2,
and ( ± )-4 to ( ± )-6 inseparable from its trans isomer. As none of pure
trans and cis isomers of ( ± )-3 were isolated by silica gel chromato-
graphy, compound ( ± )-3 used for anti-ZIKV assay in this study is the
mixture of 5:1 trans and cis isomers (Fig. S1). Meanwhile, different from
the separable chloro counterpart of 1H-pyrrolo[1,2-c]imidazol-1-one
derivative, [18] no pure cis isomer of ( ± )-7 (Fig. S2) was afforded but
pure trans isomer of ( ± )-7 was obtained.
1
The synthetic procedure and H NMR data of C1-H and C3a-H are
illustrated in Scheme 1. Unlike hydrogenation of heterocycle ring of
quinaldic acid catalyzed by expensive PtO , [23–24] convenient re-
2
duction of methyl quinoline-2-carboxylate by NaBH in acetic acid gave
4
(
± )-1,2,3,4-tetrahydroquinoline (( ± )-8) as racemic mixture. Then,
protection of amine group by Cbz chloride afforded N-Cbz protected
intermediate of ( ± )-1-benzyl 2-methyl 3,4-dihydroquinoline-1,2(2H)-
dicarboxylate (( ± )-9). After hydrolysis of the ester (( ± )-9) into the
acid (( ± )-10), phenyl hydrazine was introduced to form acyl hy-
drazine (( ± )-11). To avoid migration of benzyl group under acid-
catalysis (data not shown here), [25] deprotection of Cbz group from
In order to analyze the relative configuration of these compounds,
the single crystal of the major isomer of compound ( ± )-7 was cropped
and its crystal structure (CCDC 1915004) of the relative trans config-
uration of C1-H and C3a-H was determined as shown in Fig. 2. Since the
electron-donating substitution and weak electron-withdrawing group
(EWG) of chloro group at C1-Ar generates less quantity of minor cis
(
± )-11 was conducted by 10% Pd/C to yield the corresponding key
intermediate ( ± )-12. Finally, diverse fused tricyclic ring derivatives of
a
CO Me
b
c
N
N
N
N
CO Me
CO Me
CO H
2
2
2
2
H
methyl quinoline-
Cbz
Cbz
(±)-10
(±)-8
(±)-9
2
-carboxylate
e
d
H
N
H
N
f
N
N
N
H
N
aldehydes
of 13 to 16
H
H
Cbz O
±)-11
O
(±)-12
(
1H NMR ( , ppm)
C1-H C3a-H
Cmpd No.
CHO
(
±)-2 trans
(±)-3 trans
±)-3 cis
5.68
5.62
5.92
5.65
5.69
5.57
5.81
6.12
4.54
4.44
4.18
4.44
4.51
4.41
4.54
4.25
1
2
g
13: R = OTBS, R = OMe
13 to (±)-2
14 to (±)-3
15 to (±)-4
16 to (±)-7
(±)-5
(±)-6
1
2
1
4: R = OMe, R = OH
5: R = R = OTBS
16: R = Cl, R = H
(
g
1
2
1
(
(
(
(
±)-4 trans
±)-5 trans
±)-6 trans
±)-7 trans
R2
1
2
R1
13 ~ 16
starting materials of
aldehydes of 13 ~ 16
(
±)-7 cis
Scheme 1. Reagents and conditions: (a) AcOH, NaBH
4
, 5 °C, 6 h. (b) DCM, CbzCl, NaHCO
3
, 30 °C, 9 h. (c) MeOH/H O (V/V 3/2), NaOH, 60 °C, 2 h. (d) DCM,
2
phenylhydrazine, IBCF, TEA, 0 °C, 2 h. (e) THF, H , Pd/C, rt, 6 h. (f) MeCN, N
2
2
atmosphere, aldehyde 13 ~ 16, TFA, 60 °C, 1.5 h. (g) THF, TBAF, 0 °C, 5 min.
2

B. Xu, et al.
Bioorganic Chemistry 104 (2020) 104205
Table 1
The EC50 (50% effective concentration), CC50 (50% toxic concentration) and SI
(
selectivity index, CC50/EC50) of these compounds.
a
To Vero cell lineb
CC50 (μM) SI
Cmpd
EC50 (μM)
To SNB-19 cell line
CC50 (μM)
SI
(
(
±
±
)-2
1.56 ± 0.21
7.40 ± 0.37
> 100
> 100
> 64.1 27.00 ± 0.61 17.3
> 13.5 59.30 ± 0.43 8.0
)-3 (trans/
cis 5/1)
)-4
c
d
(
(
(
(
±
±
±
±
NA
> 100
/
/
/
> 100
/
/
/
)-5
NA
NA
> 100
> 100
)-6
94.60 ± 1.0
50.40 ± 0.16
)-7
3.40 ± 0.38 52.60 ± 1.1 15.5
44.00 ± 1.18 12.9
a
b
c
Incubated for 24 h.
Incubated for 48 h.
NA: not active as EC50 values are higher than 40 μM.
not available.
d
screening to generate EC50 values with at least 7 gradient concentra-
tions. The cytotoxicity (Table 1) of each compound in this study was
tested in SNB-19 cells (24 h treatment) and Vero cells (48 h treatment)
for the duration corresponding to the incubation time in anti-ZIKV
screening. Among the compounds reported in this study, three com-
pounds of ( ± )-2, ( ± )-3 and ( ± )-7 were active against ZIKV infec-
tion as shown in Table 1. In particular, compound ( ± )-2 exhibits low
micromolar EC50 value (1.56 μM) with SIs of higher than 64.1 in SNB-
19 cell line and 17.3 in Vero cell line. Compound ( ± )-6 with two
hydroxyl groups at 3′- and 4′-positions and compound ( ± )-5 with 3′-
methoxy group and 4′-hydroxyl group are inactive; in contrast, com-
pound 3 with 3′-hydroxyl group and 4′-methoxy group is active against
ZIKV infection with 7.40 μM of EC50 value and SI values of 13.5 and 8.0
in SNB-19 and Vero cell lines, respectively. As trans isomer of ( ± )-3 is
the major isomer, the inhibitory activity of ( ± )-3 may be attributed to
its trans isomer; however, the precise EC50 value of trans isomer of
( ± )-3 against ZIKV can only be determined after the pure trans isomer
of ( ± )-3 is obtained. Silylation of 4′-hydroxyl group of compound
( ± )-5 makes compound ( ± )-2 exhibit very potent anti-ZIKV activity,
which is possibly attributed to the introduction of TBS group consistent
with a previously reported observation [28]. Whereas, bis-silylation of
3′,4′-hydroxyl groups of compound ( ± )-6 is not able to enhance the
anti-ZIKV activity of compound ( ± )-4. Interestingly, compounds of
( ± )-4, and ( ± )-5 are almost not cytotoxic to SNB-19 and Vero cell
lines. 4′-Chloride compound ( ± )-7 possesses good anti- ZIKV activity,
with an EC50 of 3.40 μM and SIs are 15.5 in SNB-19 cell line and 12.9 in
Vero cell line. Some images from the titer plates used to calculate the
EC50 values of the compounds are shown in Fig. S3. With these anti-
ZIKV results, we further conducted the virucidal tests (Supplementary
data-2) [29–31] of these active compounds of ( ± )-2, ( ± )-3 and
( ± )-7 at 4 concentrations around their EC50 values, and virucidal test
results showed that they are not virucidal, indicating that anti-ZIKV
activity of this series of compounds is not due to virucidal (neutralising)
effect. As a whole, these results revealed that this structural scaffold has
a valuable pharmacological feature and it is possible that the reduced
N10′s basicity is not the key for the antiviral activity, and importantly,
tuning of some pharmacophore/s including substituents can produce
effective antiviral drug candidates against ZIKV infection.
Fig. 2. The crystal structure of compound ( ± )-7 trans isomer (CCDC
1
915004).
isomer and two isomers are quite difficult to isolate by silica gel
chromatography, pure trans isomer and the mixture of trans and cis
isomers were used for the structure analysis (Supplementary data-1,
1
Fig. S2). Compared with H NMR data (Scheme 1) of pure ( ± )-7 trans
isomer with the mixture of ( ± )-7 trans and cis isomers, the chemical
shifts (δ) of C1-H and C3a-H of ( ± )-7 trans isomer are recognized 5.81
and 4.54 ppm while those of ( ± )-7 cis isomer are 6.12 and 4.25 ppm
(
Supplementary data-1, Fig. S2). Based on the current and previous
facts that the chemical shift of C1-H of cis isomer is higher than that of
trans isomer but the chemical shift of C3a-H of cis isomer is lower than
1
that of trans isomer, it is concluded from H NMR data of the mixture of
trans and cis isomers of ( ± )-3 that the chemical shifts (δ) of C1-H and
C3a-H of ( ± )-3 trans isomer is 5.62 and 4.44 ppm while those of
(
± )-3 cis isomer is 5.92 and 4.18 ppm (Supplementary data-1, Fig.
S1). The chemical shift (δ) difference of C3-H between two isomers is
around 0.6 ppm in the reported results of 1H-pyrrolo[1,2-c]imidazol-1-
one derivatives; meanwhile, the chemical shift (δ) difference of C1-H
between two isomers is about 0.3 ppm in this study. Even though the
chemical shift (δ) difference of C7a-H between two isomers is not ob-
vious in the reported results of 1H-pyrrolo[1,2-c]imidazol-1-one deri-
vatives, the chemical shift (δ) difference of C3a-H between two isomers
is significantly 0.2 to 0.3 ppm for compounds ( ± )-3 and ( ± )-7 in this
1
study. H NMR data of C1-H and C3a-H of compounds of ( ± )-2 to
(
(
±
±
)-7 are in Scheme 1 and the stereochemistry of the major isomers of
)-2 to ( ± )-6 was designated as trans configuration as ( ± )-7 trans
isomer even though no pure cis isomer was got for the structure analysis
in this study. The weak electron-withdrawing group (EWG) property of
chloro at para-position makes higher chemical shifts of C1-H and C3a-H
of ( ± )-7 compared with ( ± )-2 to ( ± )-6 bearing two electron-do-
nating groups (EDGs) of hydroxyl, methoxy and t-butyldimethylsilyloxy
(
OTBS) at 3′- and 4′-positions.
Anti-ZIKV activity of compounds ( ± )-2, ( ± )-3 and ( ± )-7 were
confirmed with additional assays including Western Blot (Fig. 3) and
ELISA (enzyme-linked immunosorbent assay) (Fig. 4). As shown in
Fig. 3, Western Blot experiments indicate that expressions of both ZIKV
NS5 and NS1 were effectively reduced by treatment of 5 µM of ( ± )-2,
( ± )-3 and ( ± )-7 as 5 µM of the positive control Niclosamide com-
pared to vehicle control (ZIKV DMSO). Meanwhile, ELISA experiments
(Fig. 4) demonstrate that amount of ZIKV NS1 in the supernatant of
infected cell culture was also decreased by 10 µM of Niclosamide,
( ± )-2, ( ± )-3, and ( ± )-7 relative to vehicle control (ZIKV DMSO). It
should be noted that ZIKV NS1 expressions detected by ELISA were
For the compounds of ( ± )-2 to ( ± )-7, we investigated their in-
hibitory activity against ZIKV infection in a viral titer assay (in Vero
cells for 48 h) [26] (Supplementary data-1). We measured ZIKV pro-
duction in compound-treated human glioblastoma cells (SNB-19 line)
(
incubation for 24 h) infected by PRVABC59 strain at multiplicity of
infection (MOI) of 1 as illustrated in Supplementary data. Niclosamide,
one of the previously identified active compounds against ZIKV infec-
tion, [26–27] was used as a positive control in each antiviral assay. We
conducted initial antiviral screening using one concentration in triple
experiments and then advanced the active compounds from initial
3

B. Xu, et al.
Bioorganic Chemistry 104 (2020) 104205
Fig. 3. Expression of viral NS proteins of ZIKV NS5 and NS1 detected by Western Blot analysis. SNB-19 cells were infected by ZIKV for 4 hrs using PRVABC59
strain (MOI = 1) and then treated with vehicle control (0.1% DMSO) of ZIKV DMSO or 5 µM of Niclosamide, 2, 3 and 7, respectively, and after 24 hrs, proteins were
extracted and then subjected to Western blot analysis to determine the expression level of ZIKV NS5 and NS1. GAPDH was used as a loading control. A compound not
included in this report was loaded in the red arrow-indicated lane, therefore this band was not quantified. The intensity of protein bands were quantitated by ImageJ
image analysis software. The fold change value was calculated normalizing NS5/NS1 bands to GAPDH then normalized to the DMSO control, as follows: (compound’s
NS5 or NS1/compound’s GAPDH)/(DMSO control’s NS5 or NS1/DMSO control’s GAPDH). The error bars show mean ± SD (p value; *** < 0.0005, **** < 0.0001
for significance respective to ZIKV DMSO control, by one-way ANOVA). (For interpretation of the references to colour in this figure legend, the reader is referred to
the web version of this article.)
more significantly inhibited by addition of ( ± )-2 at 24 hrs than at 16
hrs after cells were infected. As a whole, compounds of ( ± )-2, ( ± )-3
and ( ± )-7 act as effective agents against ZIKV infection.
( ± )-7 possess anti-ZIKV activity. However, the anti-ZIKV activity was
not related to virucidal effect. It seems that the N10′s basicity is not the
basic requirement for the current compounds’ antiviral activity in this
work but the conclusion needs further SAR study. Our results show that
optimal substitution at arene and its modification of C1-phenyl will
benefit the antiviral activity. This study validates our concept of de-
veloping novel tetrahydroquinoline-fused imidazolone-based ther-
apeutics as antiviral (specifically, anti-ZIKV) drugs. We are planning to
test these compounds’ activity against DENV and other arboviruses in
the future.
In summary, we designed and synthesized several tetra-
hydroquinoline-fused imidazolone derivatives based on our previously
discovered lead against DENV [18] and discovered that trans isomers of
compounds ( ± )-2, ( ± )-3 (5/1 trans/cis) and ( ± )-7, as major iso-
mers, exhibit good antiviral activity against ZIKV infection. Western
Blot experiments for ZIKV NS1 and NS5 and ELISA experiments for
ZIKV NS1 also demonstrated that compounds of ( ± )-2, ( ± )-3 and
Fig. 4. Quantification of ZIKV NS1 protein detected by ELISA analysis. SNB-19 cells were infected by ZIKV for 16 hrs (A) or 24 hrs (B), using PRVABC59 strain
(
MOI = 1), and then treated with vehicle control (0.1% DMSO) of ZIKV DMSO or 10 µM of Niclosamide, 2, 3 and 7, respectively, and after 24 hrs, cell supernatant
was subjected to ELISA analysis of ZIKV NS1 to determine the concentration of secreted ZIKV NS1 to the medium of infected and treated cells. The error bars show
mean ± SD, p values are indicated in the figure, by one-way ANOVA as compared to the ZIKV control group.
4

B. Xu, et al.
Bioorganic Chemistry 104 (2020) 104205
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