Identification of 2-(4-(Phenylsulfonyl)piperazine-1-yl)pyrimidine Analogues as Novel Inhibitors of Chikungunya Virus

Article abstract of DOI:10.1021/acsmedchemlett.9b00662

The chikungunya virus (CHIKV) is a mosquito-transmitted alphavirus, and it is the causative agent of chikungunya fever (CHIKF). Although it has re-emerged as an epidemic threat, so far there are neither vaccines nor pharmacotherapy available to prevent or treat an infection. Herein, we describe the synthesis and structure-activity relationship studies of a class of novel small molecule inhibitors against CHIKV and the discovery of a new potent inhibitor (compound 6a). The starting point of the optimization process was N-ethyl-6-methyl-2-(4-(4-fluorophenylsulfonyl)piperazine-1-yl)pyrimidine-4-amine (1) with an EC50 of 8.68 μM, a CC50 of 122 μM, and therefore a resulting selectivity index (SI) of 14.2. The optimized compound 6a, however, displays a much lower micromolar antiviral activity (EC50 value of 3.95 μM), considerably better cytotoxic liability (CC50 value of 260 μM) and consequently an improved SI of greater than 61. Therefore, we report the identification of a promising novel compound class that has the potential for further development of antiviral drugs against the CHIKV.

Full text of DOI:10.1021/acsmedchemlett.9b00662

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Letter
Identification of 2-(4-(phenylsulfonyl)piperazine-1-yl)pyrimidine
analogues as Novel Inhibitors of Chikungunya Virus
Julia Moesslacher, Verena Battisti, Leen Delang, Johan Neyts, Rana
Abdelnabi, Gerhard Pürstinger, Ernst Urban, and Thierry Langer
ACS Med. Chem. Lett., Just Accepted Manuscript • DOI: 10.1021/
acsmedchemlett.9b00662 • Publication Date (Web): 05 Mar 2020
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Identification of 2-(4-(phenylsulfonyl)piperazine-1-
yl)pyrimidine analogues as Novel Inhibitors of Chikungunya
Virus
Julia Moesslacher†,§,◊, Verena Battisti‡,§, Leen Delangl, Johan Neytsl, Rana Abdelnabil, Gerhard
Pürstinger†, Ernst Urban‡, Thierry Langer‡,*
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This paper is dedicated to the memory of Prof. Maurizio Botta, who passed away much too early in August 2019.
†University of Innsbruck, Department of Pharmacy, Innrain 80/82, 6020 Innsbruck, Austria
‡University of Vienna, Department of Pharmaceutical Chemistry, Althanstraße 14, A-1090 Vienna, Austria
l KU Leuven Department of Microbiology and Immunology, Rega Institute for Medical Research, Laboratory of
Virology and Chemotherapy, Herestraat 49, B-3000 Leuven, Belgium
KEYWORDS. Novel small-molecule antivirals, Chikungunya virus, Structure-activity relationship studies, Medicinal
chemistry.
ABSTRACT: The chikungunya virus (CHIKV) is a mosquito-transmitted alphavirus and it is the causative agent of
chikungunya fever (CHIKF). Although its re-emergence as an epidemic threat, so far there are neither vaccines nor
pharmacotherapy available to prevent or treat an infection. Herein, we describe the synthesis and structure-activity
relationship studies of a class of novel small molecule inhibitors against CHIKV and the discovery of a new potent inhibitor
(compound 6a). The starting point of the optimisation process was the N-ethyl-6-methyl-2-(4-(4-
fluorophenylsulfonyl)piperazine-1-yl)pyrimidine-4-amine (1) with an EC50 of 8.68 µM, a CC50 of 122 µM and therefore a
resulting selectivity index (SI) of 14.2. The optimised compound 6a, however, displays a much lower micromolar antiviral
activity (EC50 value of 3.95 μM), considerably better cytotoxic liability (CC50 value of 260 μM) and consequently an improved
SI of greater than 61. Therefore, we report the identification of a promising novel compound class that has the potential for
further development of antiviral drugs against the CHIKV.
.
INTRODUCTION
neither vaccines nor pharmacotherapy are available to
13, 14
prevent or treat an infection.12,
To date, the only
The chikungunya virus (CHIKV) is a member of the
Togaviridae, genus alphavirus and was first described in
East Africa (southern province of Tanzania) in 1952-1953.1,
available treatment is the alleviation of symptoms by using
NSARs like ibuprofen, naproxen, or acetaminophen.
Occasionally, corticosteroids are administered to patients
to relieve symptoms like fever and pain.15, 16, 17 Up to now,
the antiviral activity of small molecules, compounds from
natural sources, and immune modulators on the replication
of chikungunya virus have been investigated. Several
compounds - ranging from antivirals with a broad spectrum
like ribavirin to harringtonine (a cephalotaxine alkaloid)
and IFN-α - were found to be active, targeting different
stages in the alphavirus life cycle. Despite the demonstrated
effectiveness and, in some cases, potent antiviral activity in
vitro, none of these drugs passed the clinical trial phase. 18,
19, 20, 21, 22, 23, 24, 25 Also, the utilization of the already known
antimalaria drug chloroquine as possible antiviral
treatment is highly discussed regarding the potential risks
2
This mosquito-transmitted alphavirus (mainly by Aedes
spp.) is the causative agent of chikungunya fever (CHIKF), a
disease characterized by myalgia, polyarthralgia, fever,
nausea, headaches, maculopapular rash, and complications
including lymphopenia, lethal hepatitis, dermatologic
lesions and encephalitis.3, 4, 5 Although chikungunya fever is
rarely fatal, symptoms such as myalgia and arthralgia have
been reported to last for years after clearance of the
infection, resulting in an impaired quality of life.6, 7, 8 Since
the re-emerging of the virus in 2005, outbreaks have
occurred in more than 40 countries throughout the world,
not only in Southeast Asia and Africa but also in Europe
(Italy and France) as well as America.9,
Currently,
10, 11
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Scheme 1. Synthesis of the initial hit 1a
4
5
6
7
O
S
O
N
N
O
NH
O
H
H
H
H
N
N
N
Cl
N
Cl
N
N
Cl
N
N
N
N
N
N
a
b
c
d
F
+
H2N
N
N
N
N
N
8
9
2a
3a
4a
1
aReagents and conditions: (a) EtOH, 24-48 h, rt; (b) EtOH, µwave, 3 min, 155 °C, 250 Watt, 12 bar, tert-butyl piperazine-1-carboxylate; (c) 4.5 M HCl,
Dioxane/THF, 24 h rt; (d) DCM, N(CH2CH3)3, 24 h rt, 4-fluorobenzenesulfonyl chloride.
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Scheme 2. Synthesis of the compounds from Group A (5a–5r) and Group B (6a-6b)a
R
N
NH
H
N
H
N
a
N
N
N
N
R
+
Cl
N
N
4a
5a-5r, 6a-6b
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
S
S
S
S
S
S
S
S
S
S
S
5b, R=
5i, R=
5c, R=
5d, R=
5e, R=
5f, R=
5g, R=
5a, R=
Cl
Br
I
CF3
NO2
CN
O
O
O
O
F
O
O
F
O
O
O
O
O
O
O
O
O
O
S
S
S
S
F
F
F
F
F
S
5j, R=
5q, R=
5k, R=
5r, R=
5l, R=
6a, R=
5m, R=
6b, R=
5n, R=
5h, R=
5o, R=
OMe
F
F
F
F
F
F
O
F
S
F
S
F
F
F
Cl
Cl
F
F
5p, R=
F
F
aReagents and condition: (a) DCM, N(CH2CH3)3, 24 h rt
and benefits for the patients.26, 27, 28, 29, 30 Therefore, the
development of safe and effective new antivirals against
CHIKV is highly desirable.31 This problem was addressed
within the EU FP7 collaborative project SILVER. In this
project, the small molecular hit CIM016321 (later referred
as 1, Figure 1), which was identified previously by high-
throughput screening by the Center for Innovation and
Stimulation of Drug Discovery (CISTIM) and the University
of Leuven (KU Leuven), was further investigated and a hit
to lead program was initiated.
To optimise 1, we divided the structure of this compound
into five parts suitable for systematic variation (shown in
Figure 1). The aim of the optimisation was i) to achieve an
increase in antiviral activity and ii) a decrease in
cytotoxicity, therefore resulting in a compound exhibiting
an improved selectivity index (SI). As guidance for
systematic structural variations of the molecule,
approaches like the concept of bioisosterism and the
Topliss decision tree were applied.32, 33, 34, 35
Figure 1. For optimisation, we divided the initial hit 1 into five parts.
Compounds with modifications at the same part of the molecule are
summarized to “Groups”.
.
RESULTS AND DISCUSSION
The initial hit 1 was prepared using a 4-step-synthesis and
was also established to give access to the entire com-pound
series. The synthesis of these compounds is summarized in
Scheme 1, starting from 2-chloro-N-ethyl-6-methylpyrimidin-
4-amine (2a), which was synthesised following the procedures
reported by Martyn et al.36 The reaction with tert-butyl-
piperazine-1-carboxylate, obtained according to the protocol
from Moussa et al.37, under microwave conditions gave a high
yield of 85% of the desired Boc-protected piperazine-
pyrimidine inter-mediate. The following deprotection and the
N-sulfonamidation of piperazine were performed according to
Martyn et al.36, but with additional THF. The fourth step of the
synthesis with para-fluorobenzene sulfonyl chloride afforded
the desired target in a moderate yield of 32%.
In this study, we have identified that analogues of 1 are
potent and safe inhibitors of chikungunya virus in vitro.
Moreover, structure-activity relationship studies unveiled
the molecular requirements for highly active and safe
antiviral compounds.
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Scheme 3. Synthesis of the compounds from Group C (7a–7b)a
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aReagents and conditions: (a) EtOH, µwave, 3 min, 155 °C, 250 Watt, 12 bar; 3b: tert-butyl 1,4-diazepane-1-carboxylate/4c: 1,2,3,4-
tetrahydroquinoxaline; (b) 4b: 4.5 M HCl, Dioxane/THF, 24 h rt; (c) DCM, N(CH2CH3)3, 24 h rt, 4-fluorobenzenesulfonyl chloride.
Scheme 4. Synthesis of the compounds from Group D (8a-8d), from Group E (9a-9d) and 10a-10ba
2b/3c/
4d/8a
N
2c/3d/
4e/8b
N
2d/3e/
4f/8c
N
2e/3f/
4g/8d
N
2f/3g/
4h/9a
N
2g/3h/
4i/9b
C
2h/3i/
4j/9c
N
2i/3j/
4k/9d
N
3k/4l/
10
N
2j/3l/4m
R1
R2
R3
N
C
C
C
C
N
N
C
N
C
N
N
N
N
N
C
N
N
C
N
C
R4 -CH3
R5
-CH3
-CH3
-CH3
-CH3
-CH3
-H
-H
-H
-CH3
aReagents and conditions: (a) EtOH, 24-48 h rt, 2b, 2j: propane-2-amine/2c: 2-methylpropan-2-amine/2d: sodium ethoxide/2e: pyrrolidine/2f-i:
Ethylamine (b) EtOH, µwave, 3 min, 155 °C, 250 Watt, 12 bar, tert-butyl piperazine-1-carboxylate; (c) 4.5 M HCl, Dioxane/THF, 24 h rt; (d) DCM,
N(CH2CH3)3, 24 h rt, 4-fluorobenzenesulfonyl chloride.
The first alteration was performed using modifications
on-, or replacement of the 4-fluorophenyl ring (Group A). All
compounds from this group (5a-5s), except 5s were
synthesised following Scheme 2. Synthesis of 5s was
achieved by reducing the nitro group using tin (II) chloride
5f to the corresponding amine. The first three steps of the
synthesis remained the same as for 1, as well as the reaction
conditions as described before. For the preparation of
analogues, in the fourth step, instead of the 4-
fluorobenzenesulfonyl chloride, a suitable sulfonyl chloride
was used. The conditions for the reaction remained
unchanged and provided analogues in 13-92% yield.
synthesis route, with a small alteration for 7b: 2-chloro-N-
ethyl-6-methylpyrimidin-4-amine (2a) was reacted directly
with the tetrahydro quinoxaline (as modified linker) under
microwave irradiation to access 4c. This reaction was
performed without protecting one of the two amino groups
before and gave still a high yield of 75%. The third step of
the synthesis was identical to the fourth step of the
previously used standard procedure – performed with 4-
fluorobenzenesulfonyl chloride and triethylamine as a base
in dichloromethane at room temperature for 24 hours (7a:
55% yield, 7b: 28% yield; Scheme 3).
For Group D, the target compounds were accessed via the
alteration of the first synthesis step. Instead of ethylamine
as reactant, propane-2-amine, 2-methylpropan-2-amine,
sodium ethoxide or pyrrolidine were used to prepare the
analogue compounds 8a-8d. The successive reaction
between the substituted pyrimidine and the piperazine,
following the sulfonamidation as the last step, was adopted
according the established synthesis route (Scheme 4).
The synthesis of the analogues 6a and 6b from Group B,
replacing the sulfonamide linker with an amide or a methyl
group was carried out with the established synthesis route.
The conditions and reagents remained the same as for 1 and
Group A, however with employing 4-fluorobenzoyl chloride
or 4-fluorobenzyl chloride instead of the benzene sulfonyl
chlorides (Scheme 2).
Substituents of the piperazine linker (Group C) where
introduced to investigate the function of this group. The
reaction for Group C (7a and 7b) followed the established
Compounds of Group E (9a-9d) were synthesised
following Scheme 4. The synthesis remained the same as for
1, as well as the reaction conditions. To prepare the
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5r
10 ± 1
22 ± 3
4.0 ± 1
2.5 ± 1
77 ± 5
16 ± 1
9.5 ± 2
12 ± 2
>197
13 ± 3
51 ± 16
20 ± 8
5 ± 1
15 ± 3
analogues of this group, a differently substituted pyrimidine
building block was used as starting reactant in the first step
of the synthesis. The pyrimidine ring 2f (4-chloro-N-ethyl-
6-methylpyrimidin-2-amine), used to prepare 9a, was
obtained as a product out in the first step of the synthesis of
1 in a moderate yield of 17%.
5s
183 ± 17
>260
6a
6b
7a
7b
8a
8b
8c
69 ± 7
123 ± 0.2
29 ± 8
17 ± 4
ND
202 ± 18
106 ± 69
66 ± 6
Finally, the modifications with the most promising
antiviral activities were combined, utilizing the established
synthesis route described above (Scheme 4 and Scheme 5).
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19 ± 3
>197
ND
Scheme 5. Synthesis of 11a-11ca
8d
9a
9b
9c
33 ± 7
3.2 ± 0.2
48 ± 9
14 ± 3
70 ± 0.2
37 ± 4
32 ± 2
51 ± 7
92 ± 9
34 ± 1
14 ± 4
98 ± 34
29 ± 2
124 ± 1
55 ± 8
108 ± 3
88 ± 17
102 ± 17
50 ± 8
59 ± 18
>329
91 ± 10
217 ± 3
76 ± 16
202 ± 27
204 ± 1
159 ± 31
9d
10
11a
11b
11c
4h
11a
4k
11b
4m 11c
R1
R2
R3
H
-CH3
Cl
H
H
-CH3
-CH3
F
Cl
aReagents and conditions: (a) DCM, N(CH2CH3)3, 24 h rt, 11a/11b: 4-
chlorobenzoyl chloride/ 11c: 4-fluorobenzoyl chloride.
aEC50, EC90 and CC50 data represent median values ± standard deviation
from at least three independent experiments. ND - not detectable. bThe
50% effective concentration (EC50) is the concentration of compound
that is required to inhibit virus-induced cell death by 50%. The 90%
effective concentration (EC90) is the concentration of compound that is
required to inhibit virus-induced cell death by 90%. dThe 50%
c
All compounds were evaluated for their potential
antiviral activity against CHIKV by determining the
inhibition of CHIKV-induced cytopathogenic effect (CPE) in
Vero cells (Table 1).
cytostatic/cytotoxic concentration (CC50
) is the concentration of
compound that reduces the overall metabolic activity of the uninfected,
compound-treated cells by 50% as compared to the untreated,
uninfected cell.
Table 1. Antiviral Evaluation of 1 and Analogues against
CHIKV in Vero Cellsa
The purpose of Group A was to investigate if a fluorine
atom as substituent is essential – which turned out not to be
the case: the analogue with the non-substituted phenyl ring
(5a) also showed antiviral activity, although 5a was less
active than 1 (EC50 = 14 ± 3 µM). In a next step, para fluorine
was replaced by other halogens such as chlorine (5b),
bromine (5c), and iodine (5d). All these compounds were
more active than the initial hit: the chlorine-substituted 5b
gave the best result with an EC50 of 5.3 µM, the iodine-
substituted 5d showed similar antiviral activity with an
EC50 of 5.9 µM, while the bromine-substituted 5c was less
active (EC50 = 7.1 µM). The nitro-substituted 5f (EC50 = 14 ±
3 µM) and the methyl-substituted 5i (EC50 = 15 ± 2 µM) were
also less active than 1. On the contrary, the trifluoromethyl
substituted 5e was inactive, as well as 5g with CN-
substitution. The other para-substituted compounds (5h
and 5s) showed less antiviral activity than the initial hit 1.
Compound
1
EC50 (µM)b
8.7 ± 1
14 ± 3
EC90 (µM)c
14 ± 1
28 ± 6
7 ± 1
CC50 (µM)d
122 ± 24
156 ± 35
51 ± 19
44 ± 19
19 ± 2
5a
5b
5c
5 ± 0.4
7.1 ± 0.01
5.9 ± 0.2
>233
13 ± 2
8.7 ± 1
>233
5d
5e
45 ± 1
5f
14 ± 3
24 ± 7
>250
62 ± 1
5g
>259
ND
5h
5i
82 ± 11
15 ± 2
125 ± 3
22 ± 2
52 ± 17
31 ± 2
19 ± 10
16 ± 4
ND
178 ± 31
95 ± 74
91 ± 7
5j
27 ± 9
Shifting the para fluorine atom to other positions on the
benzene ring resulted in less active compounds than the
initial hit 1 (5j and 5k). Also, combining the ortho or meta
to the para substitution did not result in an additive
antiviral effect compared to 1: 5l with two fluorine atoms
on the meta and para position and 5m with an ortho/para
di-substitution pattern were less active than 1. Additionally,
neither of the triple substituted compounds showed an
improved additive antiviral effect (5n, 5o and 5p). 5q, in
which all hydrogen atoms on the phenyl ring were replaced
5k
5l
20 ± 3
131 ± 43
53 ± 7
12 ± 5
5m
5n
5o
16 ± 6
67 ± 13
29 ± 3
19 ± 5
10 ± 0.2
28 ± 5
17 ± 5
36 ± 14
>166
181 ± 0.4
55 ± 3
5p
5q
75 ± 19
122 ± 23
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by fluorine, was found to be poorly active. Conclusively,
for actively enhancing the antiviral activity, although its
pure absence seemed to decrease the activity. Taken
together with the results from Group D, the nitrogen atom
of the ethylamine side chain seems to be essential for
antiviral activity, while the hydrogen bond donor is not.
Also, a bifurcation at the ethylamine side chain may be
taken into consideration with caution.
concerning the antiviral activity of the mono-substituted
analogues, the 4-F substituted analogue is more active than
3-F-substituted one, which is more active than the 2-F-
substituted compound. Concerning the double- and triple-
substituted compounds, the 3,4-F substituted 5l and the
2,3,4-F-substituted 5o are active; while the compounds
with 2,4-F (5m) and 3,4,5-F substitution pattern (5n) are
both only moderately active compared to 1.
In Group E, in a first step the optimal positions for the
nitrogen atoms in the pyrimidine ring were investigated. In
a second step, it was investigated whether the methyl group
as a substituent on the pyrimidine ring is essential or not.
The nitrogen at position R1 seemed to be necessary for good
antiviral activity. Shifting the nitrogen from position R1/3
(as in the initial hit 1) to position R1/2 (9a) resulted in an
improved antiviral activity.
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To investigate if the double substitution on the aromatic
ring with different halogens would also decrease the
antiviral activity, 5r was prepared. It showed moderate
activity against the virus, confirming our previous
observation, that the chloride substitution enhances the
antiviral activity. Nevertheless, the doubly substituted ring
also showed a weaker antiviral effect using chlorides (5r)
than the matching single substituted ring (5b).
Finally, the most interesting modifications were
combined to either reach a higher antiviral activity (11a
and 11c) or to deepen the knowledge of the chosen
variation (10, 11b). The result of 10 and 11b underline the
importance of the methyl group on the pyrimidine ring and
the shifting of the nitrogen to position R1/2. Moreover, the
decrease of activity with the cyclopropylamine side chain
(10) - although its size is comparable to the original
ethylamine - can possibly be explained by his impaired
flexibility and different three-dimensional geometry.
Summarizing the results from Group A, 17 out of the 19
compounds were active against CHIKV, with 3 compounds
being more potent than 1 (5b, 5c, and 5d). In those 3
compounds, other halogens replaced the fluorine at the
para position. Therefore, replacing fluorine on the benzene
ring by another halogen leads to an improvement in
antiviral activity (chlorine > iodine > bromine > fluorine).
5b with the chlorine atom as substituent on the para
position of the benzene ring showed the best test results;
therefore, the fluorine/chlorine replacement should be
considered for further optimisation.
Surprisingly, the combination of the most promising
alterations (Group B: amide and Group E: shifted N to
position R1/2) in combination with either the best alteration
of Group A (para-chloride, 11a) or with the introduction of
an isopropyl-side chain (Group D, 11c) gave not the desired
gain of antiviral activity.
In Group B, both compounds showed impressive test
results – 6a has an EC50 of 4.0 ± 1 µM, and 6b has an EC50 of
2.5 μM. Conclusively, both compounds are more than twice
as active as 1. Although 6b is even more active than 6a,
compound 6a should be considered for further
optimisation due to cytotoxicity reasons (1: CC50 = 122 μM,
SI = 14.2; 6a: CC50 = 260 μM, SI = 60.9; 6b: CC50 = 69.3 μM,
SI = 19.7). Therefore, compared to 1, the modification in 6a
led to an improvement in activity, cytotoxicity and
selectivity; while the modification in 6b led to a higher
cytotoxicity.
.
CONCLUSION
this study,
In
we
present
several
2-(4-
(phenylsulfonyl)piperazine-1-yl)pyrimidine and analogues
as selective and potent inhibitors of CHIKV. All compounds
described are easily accessible in a four-step synthesis
route: starting from the required substituted pyrimidine
reacting with the Boc-protected piperazine or other
suitable nitrogen-containing functional groups under
microwave irradiation, followed by deprotection and finally
reaction with a benzene sulfonyl chloride. Additionally, the
structural requirements for a significant anti-CHIKV activity
have been determined on all five structural molecular-
subgroups. During this optimisation process, 6a was
identified as a potent and selective inhibitor of CHIKV,
demonstrating a much better profile than the starting point,
hit 1, and a selectivity index greater than 61. Furthermore,
the optimised compound showed a wide-spectrum antiviral
activity against all tested strains of CHIKV (data will be
published elsewhere). Further structure-activity studies
and optimisation of the antiviral activity are ongoing and
mechanism of action studies are being performed to
determine the molecular target of this novel class of anti-
CHIKV compounds. These studies point towards the viral
capping machinery and more specifically to the viral protein
nsP1 as the antiviral target of these compounds. Cross-
resistance with another class of capping inhibitors, the
In Group C, the prepared analogues were less active than
1. Conclusively, 1,4-piperazine as a linker has proven to be
the better choice to reach a potent antiviral activity.
The replacement of the ethylamine side chain with
isopropylamine (8a) or tert butylamine (8b) demonstrated
good activity against the CHIKV, which unfortunately was
accompanied by increased cytotoxicity (8a: CC50 = 66.4 μM,
SI = 9.83; 8b: CC50 = 18.6 μM, SI = 1.17). In addition, it was
investigated whether the nitrogen or the hydrogen atom of
the ethylamine side chain is essential for activity and
whether the antiviral activity of the compound would
increase with higher molecular lipophilicity. Therefore, 8c
was prepared in which an ethoxy side chain replaced the
ethylamine side chain. However, 8c did not show any
antiviral activity. To understand whether this loss of
activity depends on the missing nitrogen atom or the
absence of the hydrogen bond donor function, 8d was
synthesised, in which a pyrrolidine ring replaced the
ethylamine side chain. The result from 8d (EC50 of 33 ± 7
µM) indicated that the hydrogen bond donor is not essential
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Pathogenesis and Therapy. Antiviral Res. 2013, 99, 345–370.
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MADTP series, was confirmed in antiviral assays (data not
shown). As other classes of inhibitors that target the viral
capping have been reported, the capping machinery of
alphaviruses might be a hot spot for antiviral molecules.
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Burt, F. J.; Chen, W.; Miner, J. J.; Lenschow, D. J.; Merits, A.;
Schnettler, E.; Kohl, A.; Rudd, P. A.; Taylor, A.; Herrero, L. J.; et al.
Chikungunya Virus: An Update on the Biology and Pathogenesis of
This Emerging Pathogen. Lancet Infect. Dis. 2017, 17 (4), e107–
e117. https://doi.org/10.1016/S1473-3099(16)30385-1.
ASSOCIATED CONTENT
Supporting Information
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Couderc, T.; Lecuit, M. Chikungunya Virus Pathogenesis:
The Supporting Information is available free of charge on the
ACS Publications website.
Experimental procedure, HPLC-determined purity data and
NMR spectra for all the compounds (PDF)
From Bedside to Bench. Antiviral Res. 2015, 121, 120–131.
https://doi.org/10.1016/j.antiviral.2015.07.002.
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(2), 165–172. https://doi.org/10.1016/j.jinf.2012.04.005.
Moro, M. L.; Grilli, E.; Corvetta, A.; Silvi, G.; Angelini, R.;
AUTHOR INFORMATION
Corresponding Author
(7)
Couturier, E.; Guillemin, F.; Mura, M.; Leon, L.; Virion, J.-
*Univ. Prof. Dr. Thierry Langer
M.; Letort, M.-J.; De Valk, H.; Simon, F.; Vaillant, V. Impaired Quality
of Life after Chikungunya Virus Infection: A 2-Year Follow-up
E-mail: thierry.langer@univie.ac.at
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(8) Rodriguez-Morales, A. J.; Restrepo-Posada, V. M.;
Acevedo-Escalante, N.; Rodríguez-Muñoz, E. D.; Valencia-Marín, M.;
Castrillón-Spitia, J. D.; Londoño, J. J.; Bedoya-Rendón, H. D.; de Jesús
Cárdenas-Pérez, J.; Cardona-Ospina, J. A.; et al. Impaired Quality of
Life after Chikungunya Virus Infection: A 12-Month Follow-up
Study of Its Chronic Inflammatory Rheumatism in La Virginia,
Risaralda, Colombia. Rheumatol. Int. 2017, 37 (10), 1757–1758.
https://doi.org/10.1007/s00296-017-3795-1.
Rheumatology
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Present Addresses
◊CURA Marketing GmbH, Dr.-Franz-Werner-Straße 19, A-6020
Innsbruck, Austria.
Author Contributions
§Moesslacher Julia and Battisti Verena have contributed
equally to this manuscript. All authors have given approval to
the final version of the manuscript.
(9)
Rezza, G.; Nicoletti, L.; Angelini, R.; Romi, R.; Finarelli, A.
C.; Panning, M.; Cordioli, P.; Fortuna, C.; Boros, S.; Magurano, F.; et
al. Infection with Chikungunya Virus in Italy: An Outbreak in a
Temperate Region. Lancet 2007, 370 (9602), 1840–1846.
https://doi.org/https://doi.org/10.1016/S0140-6736(07)61779-
6.
Funding Sources
This work was funded in parts (University of Innsbruck, KU
Leuven) by European Union Seventh Framework Program
(FP7/2007–2013) under SILVER grant (No. HEALTH-F3-2010-
260644).
(10)
Delisle, E.; Rousseau, C.; Broche, B.; Leparc-Goffart, I.;
L’ambert, G.; Cochet, A.; Prat, C.; Foulongne, V.; Ferré, J. B.;
Catelinois, O.; et al. Chikungunya Outbreak in Montpellier, France,
September to October 2014; European Centre for Disease
Prevention
https://doi.org/10.2807/1560-7917.ES2015.20.17.21108.
(11) Rashad, A. A.; Mahalingam, S.; Keller, P. A. Chikungunya
Virus: Emerging Targets and New Opportunities for Medicinal
Chemistry. J. Med. Chem. 2014, 57 (4), 1147–1166.
https://doi.org/10.1021/jm400460d.
Notes
The authors declare no competing financial interest.
and
Control,
2015;
Vol.
20.
ACKNOWLEDGMENT
We thank S. Delmotte, T. Bellon and K. Donckers for their
excellent technical assistance in the acquisition of the antiviral
data. Furthermore, we are grateful to J. Wackerlig and D.
Dobusch for the support with the chemical analysis of the
compounds.
(12)
Subudhi, B.; Chattopadhyay, S.; Mishra, P.; Kumar, A.
Current Strategies for Inhibition of Chikungunya Infection. Viruses
2018, 10 (5), 235. https://doi.org/10.3390/v10050235.
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Vaccine Development: A Historical Perspective. Hum. Vaccin.
Immunother. 2019, 15 (10), 2351–2358.
https://doi.org/10.1080/21645515.2019.1574149.
(14) Silva, J. V. J.; Lopes, T. R. R.; De Oliveira-Filho, E. F.;
Oliveira, R. A. S.; Durães-Carvalho, R.; Gil, L. H. V. G. Current Status,
Challenges and Perspectives in the Development of Vaccines
against Yellow Fever, Dengue, Zika and Chikungunya Viruses. Acta
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Reyes-Sandoval, A. 51 Years in of Chikungunya Clinical
ABBREVIATIONS
THF, tetrahydrofuran; EtOAc, ethyl acetate; TEA, triethylamine;
DIPE, diisopropyl ether; DMSO-d6, deuterated dimethyl
sulfoxide; dia, diazepane; Ph, phenyl; pyr, pyrimidine; pip,
piperazine; ipr, isopropyl; qu, quinoxaline; TLC, thin layer
chromatography; N.d. not detectable.
2018,
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257–263.
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