Identification of Broad-Spectrum Dengue/Zika Virus Replication Inhibitors by Functionalization of Quinoline and 2,6-Diaminopurine Scaffolds

Article abstract of DOI:10.1002/cmdc.201800178

Social and demographic changes across the world over the past 50 years have resulted in significant outbreaks of arboviruses such as dengue virus (DENV) and Zika virus (ZIKV). Despite the increased threat of infection, no approved drugs or fully protectiv

Full text of DOI:10.1002/cmdc.201800178

Accepted Article
Title: Identification of broad-spectrum dengue/Zika virus replication
inhibitors by functionalization of quinoline and 2,6-diaminopurine
scaffolds
Authors: Suzanne J. F. Kaptein, Paolo Vincetti, Emmanuele Crespan,
Jorge I. Armijos-Rivera, Gabriele Costantino, Giovanni Maga,
Johan Neyts, and Marco Radi
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To be cited as: ChemMedChem 10.1002/cmdc.201800178
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ChemMedChem
10.1002/cmdc.201800178
COMMUNICATION
Identification of broad-spectrum dengue/Zika virus replication
inhibitors by functionalization of quinoline and 2,6-diaminopurine
scaffolds
[
a]
[b]
[c]
[c]
Suzanne J. F. Kaptein, Paolo Vincetti, Emmanuele Crespan, Jorge I. Armijos Rivera, Gabriele
[
b]
[c]
[a]
[b]
Costantino, Giovanni Maga, Johan Neyts, and Marco Radi*
[
[
a]
b]
Dr. Suzanne J. F. Kaptein, Prof. Johan Neyts
KU Leuven, Department of Microbiology and Immunology, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, B-3000 Leuven,
Belgium
Dr. Paolo Vincetti, Prof. Gabriele Costantino, Prof. Marco Radi (ORCID ID: 0000-0002-0874-6697)
Dipartimento di Scienze degli Alimenti e del Farmaco
Università degli Studi di Parma
Viale delle Scienze, 27/A, 43124 Parma, Italy
E-mail: marco.radi@unipr.it
[
c]
Dr. Emmanuele Crespan, Dr. Jorge I. Armijos Rivera, Dr. Giovanni Maga
Institute of Molecular Genetics IGM-CNR, National Research Council , Via Abbiategrasso 207, I-27100 Pavia, Italy.
Supporting information for this article is given via a link at the end of the document
Abstract: Social and demographic changes over the past 50 years
available to counteract DENV and ZIKV spreading. The only
approved tetravalent DENV vaccine (CYD-TDV) did not meet the
expectations by exhibiting 60% efficacy in symptomatic dengue
and only limited efficacy in yet unexposed dengue recipients, who
resulted in important outbreaks of arboviruses such as dengue virus
(
DENV) and Zika virus (ZIKV) all over the world. Despite such
potential threat, no approved drugs or fully protective vaccines are
available to counteract DENV and ZIKV spreading. The development
of “broad spectrum” antivirals (BSAs) targeting common components
of multiple viruses, can be a more effective strategy to limit the rapid
rise of emerging viral pathogens than the classic “one-bug/one-drug”
approach. Starting from previously identified multitarget DENV
inhibitors, we report herein the identification of novel 2,6-
diaminopurine derivatives able to block the replication of both Zika
virus and all serotypes of dengue virus (DENV 1-4) in infected cells.
[
5]
may thus develop an aggravated form of the disease. On the
ZIKV front, Sanofi Pasteur recently pulled the plug on the
[
6]
development of a Zika vaccine, leaving a few open questions on
the real value of flavivirus vaccines. In contrast, a small-molecule
drug delivered early or even taken prophylactically may have a
significant impact on the prevention and progression of these
arthropod-borne diseases by lowering the viral load in the blood
and reducing the number of carrier mosquitoes that get infected
after feeding on a viraemic patient, thus lowering transmission.
Among the possible antiviral approaches, developing small-
molecule “broad-spectrum” antivirals (BSAs) that target common
mechanisms of action of multiple viruses, can be a more effective
strategy to limit the rapid rise of emerging viral pathogens than
the classic “one-bug/one-drug” approach. BSAs may allow to
immediately initiate a prophylactic or therapeutic treatment in an
outbreak setting of unknown, yet suspected, etiology for which a
specific antiviral drug is still not available. In addition, BSAs may
offer better treatment options for multi-species co-infections,
which is one of the greatest challenges to global health, creating
confusion and delay in diagnosis/treatment and leading to
Infectious diseases still represent a major public health
threat. Although a number of vaccines and antiviral drugs have
been developed in the last century, the vast majority of infectious
diseases (i.e. more than 200) caused by viruses belonging to
[
1]
different families are still untreatable. In addition, increased
globalization and climate changes have led to an expansion in the
worldwide spread of (sub-)tropical viruses and, as a result, these
viruses are no longer confined to geographically limited risk areas.
In the case of mosquito-borne viruses, insecticide resistance,
poor sanitation, unplanned urbanization and inadequate health
services have also contributed to the endemicity of arboviruses in
many regions of the world. Of these, DENV and ZIKV (genus
Flavivirus), which are spread by mosquitos of the Aedes spp., are
endemic in Asia, Africa and Latin America, but multiple outbreaks
recently also occurred in Europe as a result of the spreading urge
[7]
additive or synergistic morbidities. Co-infection with arboviruses
(
e.g. DENV, ZIKV, CHIKV) co-circulating within the same vector
creates significant difficulties in diagnosing, controlling and
treating infected individuals and leads to complicated immune
responses towards other viruses or host proteins (Guillain-Barrè
[
2]
of the vectors. Current estimates indicate ca. 300-500 million
DENV infections each year. Although the mortality rate of many
flavivirus infections is relatively low (roughly 2.5%), these
infections can cause severe disease, such as microcephaly in
fetuses and Guillain–Barré syndrome in adults that are caused by
[8]
syndrome).
As part of our continuous efforts to find innovative antiviral
[9]
candidates, we recently reported the identification of multitarget
compounds that are able to inhibit DENV replication by targeting
both host kinases c-Src/Fyn and an allosteric site on the thumb of
[
3]
the host’s immune response to the neurotropic ZIKV, or
hemorrhagic fever or shock in the case of the non-neurotropic
viral NS5 required to form the functional NS5-NS3 replication
[10]
complex.
We here describe the further optimization of these
[
4]
DENV. Recent studies also found high loads of flavivirus RNA
DENV, ZIKV) in breast milk and saliva, suggesting that these
DENV inhibitors into compounds that block the replication of
multiple flaviviruses (namely DENV and ZIKV). This may
represent an effective and cheap strategy for controlling the
spread of both viruses and related co-infections by a single
molecule.
(
vertical and sexual transmission routes can also contribute to the
increased spreading of these viruses. Despite such potential
threat, no approved drugs or fully protective vaccines are
1
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ChemMedChem
10.1002/cmdc.201800178
COMMUNICATION
Figure 1. Selected flavivirus inhibitors and their in vitro inhibition (expressed as EC50) of DENV-2 replication.
The urgency of finding effective countermeasures to the
increasing flavivirus spreading is testified by the fact that most
compounds so far tested in dengue clinical trials are repurposed
aiming for the contemporary inhibition of Src/Fyn kinases and
NS3-NS5 interaction, which are both involved in DENV
[
23]
replication. Compared to ribavirin (EC50 = 42.0 µM; SI > 10),
compounds 1 and 2 showed a promising antiviral profile with an
EC50 of 5.3 and 7.4 µM and a selectivity index (SI = CC50/EC50) of
168 and >175, respectively. As can be expected from the large
homology between DENV NS5 and ZIKV NS5, a number of DENV
NS5 inhibitors (e.g. BCX4430, 7DMA, 2’CMA, NITD008; Figure 1)
were also found to inhibit ZIKV replication at comparable
[
18]
molecules initially developed for other indications. Despite their
in vivo safety profile, these repurposed molecules were not
suitable for application as dengue therapeutics. However, they
may provide useful indications on which scaffolds could be further
pursued in lead optimization studies (e.g. purine and quinoline
scaffolds). At the same time, ex novo targeted approaches
against host or viral proteins have been pursued to develop new
drug candidates with broad-spectrum activity against
[
24]
concentrations.
For this reason, we decided to test our
multitarget inhibitors 1 and 2 as ZIKV replication inhibitors. To our
surprise, both compounds were completely inactive against ZIKV
(see Table 1). However, considering i) the high homology
between DENV and ZIKV NS5, ii) the presence of a highly
[
19]
flaviviruses.
Among the different approaches, the NS5
polymerase still represents the most promising and exploited
target for the development of broad-spectrum anti-flaviviral
agents. This protein is in fact highly conserved among flaviviruses, conserved and functionally relevant allosteric site (cavity B) within
lacks a eukaryotic homologue, and is effectively inhibited by
nucleoside derivatives (chain terminator antivirals; NIs), whose
main drawback for clinical application is off-target toxicity and low
phosphorylation in DENV-infected patients by host kinases. A few
DENV non-nucleoside inhibitors (NNIs) targeting an allosteric
pocket close to the priming loop (N-pocket) have also been
discovered. However, because of their toxicity in an animal model,
flavivirus NS5, and iii) the privileged structure of quinoline and
purine scaffolds among flavivirus inhibitors, we decided to further
explore derivatives within these two classes.
Focused synthetic modifications of our previously reported
quinolines/purines were herein conducted to better understand
their structural requirements to properly interact with cavity B of
both DENV and ZIKV and inhibit their replication using a single
molecule. Quinoline derivative 3 is a bosutinib analogue that was
proposed to interact with DENV cavity B and, at the same time,
inhibit Src/Fyn kinase activity. We found this compound quite
cytotoxic and unable to inhibit DENV replication at concentrations
[
20]
high predisposition to resistance selection , and the fact that the
same priming loop adopts a closer conformation in ZIKV NS5
(
resulting in a smaller N-pocket that is unfit to bind these DENV
[
21]
NNIs),
they may not represent the most promising anti-
[
10]
flavivirus drug candidates. NS5 polymerase also presents an
allosteric pocket (cavity B) that binds NS3 to form the functional
replication complex. This pocket is highly conserved among
flaviviruses and represents an underexplored site to develop
below its CC50
.
Repurposing of kinase inhibitors as antivirals is
quite risky due to their broad effect on the kinome and their anti-
metabolic/cytotoxic profile. In addition, although dasatinib and
saracatinib were earlier proposed to impede DENV replication via
inhibition of Src/Fyn, we suggested that the inhibition of Src/Fyn
[
22]
resistance-robust non-nucleoside anti-flaviviral agents.
[
10]
Previously, we reported the discovery of the first multitarget
inhibitors (i.e. 1 and 2) that inhibited DENV replication at low
micromolar concentrations (Figure 1) by interfering with the NS3-
alone may not result in an antiviral effect.
Consequently, we
decided to convert 3 in a derivative unable to interact with the
Src/Fyn hinge domain by masking the endocyclic quinoline
nitrogen that acts as a hydrogen bond acceptor in the interaction
with the kinase hinge domain. Treatment of 3 with methyl iodide
[
10]
NS5 interaction. These inhibitors were rationally designed by
repurposing Src kinase scaffolds to bind NS5 cavity B, thus
2
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ChemMedChem
10.1002/cmdc.201800178
COMMUNICATION
Cl
Cl
Cl
Cl
Cl
N
HN
OH
HN
OH
HN
N
N
CN
CN
N
N
a
N
N
b
N
a
R1
N
H
N
H
N
H
N
N
H
Cl
Cl
N
MeO
N
MeO
N
1
0
11
12a-f
3
4
12d: R1 = 3,5-Me-Ph
12e: R = 2,4-Me-Ph
12f: R NH = morpholine
1
2a: R1 = phenoxyethyl
2b: R1 = 4-phenylbenzyl
1
1
1
Scheme 1. Reagents and conditions: a) MeI, NaH, THF, r.t., 68h.
2c: R1 = Ph
1
Scheme 3. Reagents and conditions: a) 3-Aminophenol, n-BuOH, µW, 80 °C,
and sodium hydride generated 1-methyl derivative 4 with 50%
yield (Scheme 1). At the same time, we also prepared a series of
analogues of compound 3 by installing different moieties in
position C4 of the quinoline core. Starting from 3-methoxyaniline
1
1
2
0 min; b) R NH , TFA, µW, 170 °C, 10 min then 150 °C 10 min.
Table 1. DENV-2/ZIKV replication inhibitory effect
(
5), a one-pot two-step microwave-assisted Gould-Jacobs
cyclization allowed to easily obtain the key intermediate 7, which
was then chlorinated and finally submitted to nucleophilic
substitution with different amines to give final compounds 9a-f
Compound
DENV-2
ZIKV
EC50
CC50
[b]
(µM)
EC50
CC50
[
a]
(
µM)
(µM)
(µM)
(
Scheme 2)
[
c]
[d]
3
4
NA
19
ND
ND
ND
ND
ND
a
CN
CO Et
>140
<1.9
<1.7
>140
<1.9
<1.7
ND
ND
ND
MeO
NH
2
MeO
N
H
5
6
2
9
9
a
b
b
R1
X
N
HN
N
9
9
9
c
d
e
<1.6
8.8
<1.6
ND
ND
CN
CN
d
44.4
ND
ND
MeO
MeO
NA
29.3
ND
ND
9a-f
7 X = OH
X = Cl
c
8
a: R1 = 4Cl-Ph
9d: R1 = 3Cl,4F-Ph
9e: R1 = 4CF
-Ph
9f: R1 = 2-naphthyl
9f
1
NA
2.0
ND
ND
9
9
b: R1 = 2CF
c: R1 = 2Cl,4NO
-Ph
2
-Ph
3
3
[e]
2.4 ± 0.9
7.4 ± 0.7
10.0 ± 1.9
2.8 ± 1.0
12.6
168 ± 38
>175
69.4 ± 12.5
14.6 ± 7.7
26.3
>100
>100
>100
>100
>138
37.2 ± 34
ND
9
2
Scheme 2. Reagents and conditions: a) Ethyl 2-cyano-3-ethoxyacrylate, neat,
1
µW 120 °C, 5 min; b) Ph
DMF, NaH, 2h, reflux.
2
O, µW 230 °C, 5-7 min; c) POCl
3
, reflux, 2h; d) R NH
2
,
12a
5.0 ± 10
1.5 ± 7.6
ND
1
1
2b
2c
Previous SAR data on our purine series showed that the most
promising anti-DENV compounds possess a 3-aminophenol
substituent in position C6. For this reason, in the present work we
have kept this moiety fixed in position C6 and focused on the
functionalization of position C2: starting from commercially
available 2,6-dichloro purine (10), regioselective C4 nucleophilic
substitution with 3-aminophenol led to key intermediate 11 that
was submitted to a C2 nucleophilic substitution with primary or
secondary amines to give final compounds 12a-f (Scheme 3). As
suggested in our previous study, position C2 of active purines
12d
3.1
4.5
ND
ND
1
1
2e
2f
4.9
19.3
ND
ND
40.6
122
ND
ND
[
f]
RBV
11.9 ± 4.0
ND
> 409
ND
ND
ND
[g]
7
DMA
5.6 ± 11
>357
[
a] EC50 values were generated using the virus-yield reduction assay; [b] CC50
[
10]
may tolerate different functional groups.
Docking studies on
values were assessed by MTS method; [c] NA = not active; [d] ND = not
determined; [e] Values are the mean of at least three independent experiments;
DENV cavity B also suggested that the introduction of an
hydrophobic moiety in C2 of the purine scaffold may allow to
better fill the hydrophobic cavities surrounding the key residue
Lys330. Compounds 12a-e where thus prepared to better
understand the effect of additional hydrophobic interactions
around Lys330 while compound 12f was prepared as analogue of
compound 2 to evaluate the need of a hydrogen bond donor in
position C2 for biological activity. All synthesized compounds
were biologically evaluated for their ability to inhibit DENV
serotype 2 (DENV-2) replication using a virus yield reduction
[
f] RBV = ribavirin; [g] 7DMA = 7-deaza-2'-C-methyladenosine.
assay. Results are reported in Table 1 in comparison with
previously reported hits 1-3, ribavirin (RBV) and 7-deaza-2'-C-
[25]
methyladenosine (7DMA),
which were included as reference
compounds. Testing of quinoline derivatives showed that N1
methylation (cpd 4) reduced cytotoxicity, although it was still
incapable of inhibiting DENV replication. Among C4 substituted
quinolines 9a-f, only compound 9d displayed antiviral activity,
albeit with a low selectivity index (SI = 5). Other quinolines were
3
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ChemMedChem
10.1002/cmdc.201800178
COMMUNICATION
either cytotoxic or inactive. As anticipated, the most interesting
reference compounds flavopyridol and dasatinib. In addition,
considering that similar purine derivatives proved to be active
data were obtained from the purine series. Contrary to hit 2, the
[
32]
2
-morpholino derivative 12f did not exhibit a clear antiviral effect,
against serine/threonine-protein kinases (e.g. BRAF), we also
tested compounds 12a,b against few representative
suggesting that the NH hydrogen bond donor moiety in position
C2 is needed for antiviral activity. For what concerns C2
hydrophobic-extended compounds 12a-e: i) 2-aniline derivatives
a
serine/threonine-protein kinases (DYRK1a, GSK3b, CHK1 and
LRRK2) but they were completely inactive when tested at their
CC50 concentration (data not shown). It is therefore reasonable to
assume that our new compounds (12a,b) may inhibit flavivirus
replication by establishing an optimal interaction with NS5 cavity
B of both DENV and ZIKV, while progenitors 1 and 2 establish
profitable interactions with DENV cavity B only. Considering the
large homology of NS5 cavity B of different flaviviruses, we
evaluated the effect of 12a and 12b in inhibiting the replication of
other DENV serotypes. As expected, both compounds inhibited
the replication of DENV-1, -3 and -4 with EC50 values comparable
to those found for DENV-2, whereas the broad-spectrum
reference drug ribavirin shows only a very moderate antiviral
effect against DENV serotypes -1, -3 and -4 (Table 3).
1
2c-e showed sub-to-low micromolar activity against DENV-2, but
were also quite cytotoxic; ii) compounds 12a and 12b showed the
most promising results by inhibiting DENV-2 replication at low
micromolar concentrations and by displaying a more favourable
cytotoxicity profile. More importantly, 12a and 12b also proved to
inhibit ZIKV replication with comparable EC50s, whereas their
progenitors 1 and 2 were completely inactive against ZIKV (see
Table 1). Compounds 12a,b were also tested in a small panel of
selected kinases that were reported to play a role in the replication
of DENV/ZIKV (Fyn, Abl, Src) and other viruses (CDK9, CDK4).
As shown in Table 2, selected kinases retained much of their
activity when treated with compounds 12a,b (with the exception
of 12a vs Src) at a fixed concentration (corresponding to its lowest
CC50 value), while they were almost completely inhibited by the
To understand why compounds 12a and 12b were active
against DENV and ZIKV while progenitors 1 and 2 were only
active against DENV, we conducted docking experiments on NS5
cavity B of both viruses. During the past year, four different
research groups reported almost simultaneously on the crystal
Table 2. Inhibitory effect of synthesized compounds against selected kinases
[
26-29]
structure of ZIKV NS5 polymerase.
Analysis of these
Compound
Residual enzymatic activity (%)
structures revealed that cavity B is highly conserved among
DENV and ZIKV (RMSD ranging from 0.34 – 0.56 Å), with the
CDK9
cT1
CDK9/
cK
CDK4
/cD1
Fyn
Abl
Src
[
29]
/
structure reported by Zhao et al.
showing the best global
similarity (RMSD = 0.99 Å) with DENV NS5. This structure (PDB
code 5U0C) was therefore selected for docking studies, which
[
a]
1
1
1
1
2a @60.5 µM
76.4 ±
93.8
13.4
±
70.1 ±
27.7
±
±
±
±
62.8
9.6
±
±
±
±
1
0.2
9.5
4.5
± 7.4
0.8
[
30]
were conducted using Autodock Vina. In agreement with the
lack of activity against ZIKV replication, docking of compounds 1
and 2 did not show any cluster of molecules bound to cavity B
among the top ranked positions. In contrast, compounds 12a and
[
b]
2a @5.0 µM
-
-
-
45.0
65.0
59.0
9.4
6
.9
± 5.6
[
a]
2b @20.5 µM
90.2 ±
94.0
8.8
±
±
66.0 ±
63.2
8.1
57.7
21.5
3.9
1
1.5
7.2
± 6.2
[
b]
2b @1.5 µM
-
-
-
81.0
100.0
-
91.0
12.8
1
0.1
Flavopyridol
0.1 µM
0.1
±
0.1
41.1±
-
-
@
0. 01
0.01
0.5
Dasatinib
0.5 µM
-
-
-
0.1
±
0.1 ±
0.8
±
@
0.01
0.01
0.01
[
a] Compound was tested at a fixed concentration corresponding to its lowest
CC50 value; [b] Compound was tested at a fixed concentration corresponding to
its lowest EC50 value. Values are the mean of two independent experiments.
Error bars represent ± SD
Table 3. Dengue inhibitory activity and cytotoxicity of 12a,b against serotypes -
1
, -3, and -4.
Compound
DENV-1
DENV-3
DENV-4
EC50
CC50
[b]
(µM)
EC50
CC50
EC50
CC50
[
a]
(
µM)
(µM)
(µM)
(µM)
(µM)
1
1
2a
2b
14.0
1.38
143
60.5
20.5
410
12.9
1.93
138
60.5
20.5
410
11.6
2.19
68
60.5
20.5
410
[
c]
RBV
Figure 2. Binding mode of compounds 12a (yellow sticks) and 12b (pink sticks)
[
a] EC50 values were generated using the virus-yield reduction assay; [b] CC50
within DENV cavity B (left) and ZIKV cavity B (right). Hydrogen bonds are
[
31]
values were assessed by MTS method; [c] RBV = ribavirin.
depicted as yellow dotted lines. Images were generated by PyMOL.
4
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ChemMedChem
10.1002/cmdc.201800178
COMMUNICATION
1
2b showed profitable interactions and similar binding modes with
Angeli, L.; Dumas, P.; Maga, G.; Botta, M.; Ennifar, E. Angew. Chem. Int.
Ed. 2010, 49, 1805-1808.
both cavities, which is fully in line with the in vitro data on the
inhibition of DENV and ZIKV replication (Figure 2).
[
[
10] Vincetti, P.; Caporuscio, F.; Kaptein, S.; Gioiello, A.; Mancino, V.; Suzuki,
Y.; Yamamoto, N.; Crespan, E.; Lossani, A.; Maga, G.; Rastelli, G.;
Castagnolo, D.; Neyts, J.; Leyssen, P.; Costantino, G.; Radi, M. J. Med.
Chem. 2015, 58, 4964–4975.
In summary, exploration of the chemical space around two
chemical scaffolds previously identified by us (quinoline and 2,6-
diaminopurine) allowed to convert the multitarget inhibitor of
DENV replication and Src/Fyn kinases (1) into novel inhibitors
11] Ojwang, J. O.; Ali, S.; Smee, D. F.; Morrey, J. D.; Shimasaki, C. D.;
Sidwell, R. W. Antiviral Res. 2005, 68, 49–55.
(
12a and 12b) with broad-spectrum anti-flavivirus activity and no
[12] Delvecchio, R.; Higa, L. M.; Pezzuto, P.; Valadão, A. L.; Garcez, P. P.;
Monteiro, F. L.; Loiola, E. C.; Dias, A. A.; Silva, F. J.; Aliota, M. T.; Caine,
E. A.; Osorio, J. E.; Bellio, M.; O'Connor, D. H.; Rehen, S.; de Aguiar, R.
S.; Savarino, A.; Campanati, L.; Tanuri, A. Viruses 2016 8, 322.
significant adverse effect on the activity of a mini-panel of host
kinases. Although the pharmacological and antiviral profile is still
unsuitable for evaluation in in vivo studies, compounds 12a and
[
13] Boonyasuppayakorn, S.; Reichert, E. D.; Manzano, M.; Nagarajan, K.;
Padmanabhan, R. Antiviral Res. 2014, 106, 125–134.
1
2b can be regarded as one of the few non-nucleoside, broad-
[
19]
spectrum flavivirus inhibitors reported so far.
Since these
[
14] Warren, T. K.; Wells, J.; Panchal, R. G.; Stuthman, K. S.; Garza, N. L.;
Van Tongeren, S. A.; Dong, L.; Retterer, C. J.; Eaton, B. P.; Pegoraro,
G.; Honnold, S.; Bantia, S.; Kotian, P.; Chen, X.; Taubenheim, B. R.;
Welch, L. S.; Minning, D. M.; Babu, Y. S.; Sheridan, W. P.; Bavari, S.
Nature, 2014, 508, 402–405.
compounds are cheap to produce and easy to be functionalized,
they represent a promising starting point for optimizing their
pharmacological profile. Further studies in this direction will be
reported in due course.
[
15] Olsen, D. B.; Eldrup, A. B.; Bartholomew, L.; Bhat, B.; Bosserman, M. R.;
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Acknowledgements
This work has been supported by the University of Parma (to MR).
We thank Charlotte Vanderheydt, Caroline Collard, Ruben
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ChemMedChem
10.1002/cmdc.201800178
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One purine-ring to rule them all: chemistry-driven exploration of 2,6-diaminopurines led us to the discovery of novel broad-spectrum
antivirals (BSAs) blocking the replication of both Zika virus and all serotypes of dengue virus (DENV 1-4) in infected cells. These
compounds are cheap to produce, easy to be functionalized and can be regarded as one of the few non-nucleoside, broad-spectrum
flavivirus inhibitors reported so far. Our findings may lead to drug-candidates for the treatment of flavivirus-infected and co-infected
individuals.
6
This article is protected by copyright. All rights reserved.