First discovery of novel 3-hydroxy-quinazoline-2,4(1H,3H)-diones as specific anti-vaccinia and adenovirus agents via ‘privileged scaffold’ refining approach

Article abstract of DOI:10.1016/j.bmcl.2016.09.071

A series of 1,2,3-triazolyl 3-hydroxy-quinazoline-2,4(1H,3H)-diones was constructed utilizing Cu(I)-catalyzed azide-alkyne 1,3-dipolar cycloaddition (CuAAC) method. The biological significance of the novel synthesized quinazolines was highlighted by evaluating them in vitro for antiviral activity, wherein several compounds exhibited excellent activity specifically against vaccinia and adenovirus. Especially, 24b11 displayed the most potent inhibitory activity against vaccinia with an EC₅₀value of 1.7 μM, which was 15 fold than that of the reference drug Cidofovir (EC₅₀= 25 μM). 24b13 was the most potent compound against adenovirus-2 with an EC₅₀value of 6.2 μM, which proved lower than all the reference drugs. Preliminary structure–activity relationships were also discussed. To the best of our knowledge, no data are present in the literature on antiviral activity of 3-hydroxy-quinazoline-2,4(1H,3H)-diones against DNA-viruses. Thus, these findings warrant further investigations (library expansion and compound refinement) on this novel class of antiviral agents.

Full text of DOI:10.1016/j.bmcl.2016.09.071

Accepted Manuscript
First Discovery of Novel 3-Hydroxy-quinazoline-2,4(1H,3H)-diones as Specif-
ic Anti-Vaccinia and Adenovirus Agents via “Privileged Scaffold” Refining
Approach
Dongwei Kang, Heng Zhang, Zhongxia Zhou, Boshi Huang, Lieve Naesens,
Peng Zhan, Xinyong Liu
PII:
S0960-894X(16)31020-4
DOI:
http://dx.doi.org/10.1016/j.bmcl.2016.09.071
BMCL 24295
Reference:
To appear in:
Bioorganic & Medicinal Chemistry Letters
Received Date:
Revised Date:
Accepted Date:
16 August 2016
12 September 2016
28 September 2016
Please cite this article as: Kang, D., Zhang, H., Zhou, Z., Huang, B., Naesens, L., Zhan, P., Liu, X., First Discovery
of Novel 3-Hydroxy-quinazoline-2,4(1H,3H)-diones as Specific Anti-Vaccinia and Adenovirus Agents via
“Privileged Scaffold” Refining Approach, Bioorganic & Medicinal Chemistry Letters (2016), doi: http://dx.doi.org/
1
0.1016/j.bmcl.2016.09.071
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First Discovery of Novel 3-Hydroxy-quinazoline-2,4(1H,3H)-diones
as Specific Anti-Vaccinia and Adenovirus Agents
via“Privileged Scaffold” Refining Approach
a
a
a
a
b,
a,
Dongwei Kang, Heng Zhang, Zhongxia Zhou, Boshi Huang, Lieve Naesens, * Peng Zhan, *
a,
and Xinyong Liu *
a
Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of
Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road,
250012 Ji’nan, Shandong, PR China
b
Rega Institute for Medical Research, K.U.Leuven, Minderbroedersstraat 10, B-3000 Leuven,
Belgium
ABSTRACT: A series of 1,2,3-triazolyl 3-hydroxy-quinazoline-2,4(1H,3H)-diones was
constructed utilizing Cu(I)-catalyzed azide-alkyne 1,3-dipolar cycloaddition (CuAAC)
method. The biological significance of the novel synthesized quinazolines was
highlighted by evaluating them in vitro for antiviral activity, wherein several
compounds exhibited excellent activity specifically against vaccinia and adenovirus.
Especially, 24b11 displayed the most potent inhibitory activity against vaccinia with
an EC50 value of 1.7 μM, which was 15 fold than that of the reference drug Cidofovir
(
EC50 = 25 μM). 24b13 was the most potent compound against adenovirus-2 with an
EC50 value of 6.2 μM, which proved lower than all the reference drugs. Preliminary
structure-activity relationships were also discussed. To the best of our knowledge, no
data
are
present
in
the
literature
on
antiviral
activity
of
3
-hydroxy-quinazoline-2,4(1H,3H)-diones against DNA-viruses. Thus, these findings
warrant further investigations (library expansion and compound refinement) on this
novel class of antiviral agents.
1

1
Poxvirus-associated diseases are a major threat for human health . Smallpox, a
highly transmissible and infectious disease with high morbidity and mortality, was the
2
most dangerous human pathogen of poxviruses group . Although smallpox was
declared eradicated in 1980 by the World Health Organization (WHO) after an
intensive immunization campaign with the vaccinia virus vaccine of the global, there
are stocks of VARV were kept in two WHO-approved laboratories: the U.S. Center for
Disease Control and Prevention (CDC) in Atlanta and the Russian State Research
3
, 4
Center of Virology and Biotechnology in Novosibirsk . By the fact that the vaccinia
5
virus vaccines have substantial side effects , the vaccination programs have been
terminated since the last century, which led to the human population today more
susceptible to a smallpox disaster. In addition, the emergence of zoonotic poxvirus
infections such as the monkeypox virus in both the US and Western Africa in human
6
populations aggravated the people’s panic . For all of these reasons, special attention
has been paid to establish efficient safe therapies for dealing with poxvirus infections.
In spite of number of potential antipoxviral agents have been reported recently,
there have no approved drugs by US Food and Drug Administration (FDA) for the
prevention and treatment of smallpox infections available on the market currently.
Cidofovir (CDV, 1) is a potent and selective anti-DNA virus agent and can inhibit
viral DNA replication (Figure 1), so it has a broad-spectrum activities and has been
approved for the treatment of smallpox virus. But the low oral bioavailability of CDV
2

and potential nephrotoxicity accompany with its intravenous administration limited
the clinical application of the CDV. Recently, the lipophilic prodrug of CDV,
hexadecyloxypropyl ester (HDP-CDV, 2), was demonstrated that have improved
bioavailability and equivalent effectiveness against orthopoxvirus infections and is in
7
phase I/II clinical studies currently . Moreover, Tecovirimat (ST-246, 3), an orally
bioavailable compound that targets the F13L protein of the virus, which inhibit the
growth of multiple orthopoxviruses and has significant antiviral activity in various
poxvirus disease animal models, was demonstrated favorable safety, tolerability, and
8
, 9
pharmacokinetics in phase I clinic trial . In 2010, Tecovirimat was received both
orphan drug designation and fast-track status from the US FDA and with the hope that
it can be approved for the prevention and treatment of smallpox infections.
Figure 1. Structures of CDV, HDP-CDV and tecovirimat.
Adenoviruses (AdVs) are double-stranded DNA viruses (about 60 to 100 nm in
9
size) with a nonenveloped icosahedral capsid and a genome of 26 to 45 kb . AdVs
comprise more than 50 human Ad serotypes, which have been identified and
classified into six species (A-F) in terms of their biological, physiochemical and
1
0
genetic properties . AdVs are opportunistic pathogens and associated with a wide
variety of severe clinical symptoms in healthy individuals, such as respiratory illness,
11-13
renal disease, gastroenteritis, hemorrhagic cystitis, and so on
. However, they are
generally not considered to be highly pathogenic viruses for the reason that the
adenovirus infections are most often self-limited in immunocompetent individuals.
But an adenovirus infection might led to severe and life-threatening disease (multiple
1
4
organ failure) in the immunocompromised individuals . During the last two decades,
a number of adenovirus serotypes that largely from species A, B, and C were isolated
3

from immunocompromised patients successfully. Ad2, a species A serotype that has
been most detailed studied of adenovirus so far, are often associated with respiratory
illness with a lethal outcome occasionally. Currently, there have no available drugs for
treatment of AdVs infections. Cidofovir was proved to be the most promising
anti-adenoviral agent of those currently used in clinical settings, but the outcome in
the hematopoietic stem cell recipients has been found to be poor adenovirus infections
1
5
.
Therefore, there is compelling need for the discovery of new antiviral drugs of
vaccinia and adenovirus that possess an improved safety property and oral
bioavailability.
Over the past few decades, serendipitous or high-throughput screen (HTS)
campaign of heterocyclic compound collections continues to remain a major paradigm
1
6, 17
for antiviral hits or leads discovery
importance, hydroxy-(iso)quinazoline-2,4(1,3)-dione and its analogues are attractive
privileged structures” in antiviral medicinal chemistry. Recently,
-hydroxyisoquinoline-1,3(2H,4H)-dione and 3-hydroxypyrimidine-2,4-dione
derivatives were reported as miscellaneous inhibitors targeting bridged dinuclear
. Due to their chemical and biological
“
2
1
8
metalloenzymes, such as HIV RNase H and integrase (IN) dual inhibitors 4-7 , 8, 9
1
9
20
21-23
24
,
10 , HIV RNase H active-site inhibitors MB-76 (11)
and 12 , as well as
25
Hepatitis C virus (HCV) NS5B polymerase inhibitor 13 (Figure 2), suggesting that
these divalent metal ion chelators could be useful inhibitor scaffolds with a broad
2
6
range of biological activity via various modifications .
Evolved from the concept of drug repositioning, “privileged structure”-guided
scaffold refining is a very effective strategy to exploit undescribed bioactivites by
making full use of readily derivatized scaffolds with well-established synthetic
2
7
methods . In this context, in view of the above fact and to discover completely new
anti-vaccinia and adenovirus agents with a novel skeleton and unique mode of action,
a
relatively
small
library
of
6
-(1-benzyl-1H-1,2,3-triazol-4-yl)-3-hydroxyquinazoline-2,4(1H,3H)-dione
compounds (the general formula in Scheme 1) was constructed via the
2
8
copper(I)-catalyzed azidealkyne cycloaddition (CuAAC) reaction and the biological
4

significance of the novel synthesized quinazolines was highlighted by evaluating them
in cell culture-based antiviral high-throughput screening (HTS) assays against a broad
panel of DNA viruses, retroviruses and several RNA viruses.
Figure 2. The reported 2-hydroxyisoquinoline-1,3(2H,4H)-diones (4-11,13) and
3
-hydroxypyrimidine-2,4-dione 12 as antiviral agents.
The library of 3-hydroxyquinolin-2(1H)-one compounds was constructed by the
following general synthetic route, which was straightforward and depicted in Scheme
. The starting material 2-hydroxyisoindoline-1,3-dione (14) was firstly reacted with
1
benzyl bromide to obtain 2-(benzyloxy)isoindoline-1,3-dione (15). Then 15 was
treated with hydrochloric acid and acetic acid via an acidulation reaction to form the
2
9
key intermediate O-benzylhydroxylamine hydrochloride (16) . Meanwhile, the
commercially available material 2-amino-5-iodobenzoic acid (17) was treated with
methanol in the presence of concentrated H
2
SO
-amino-5-iodobenzoate (18) via an esterification reaction. The intermediate
-(benzyloxy)-6-iodoquinazoline-2,4(1H,3H)-dione (19) was obtained by ring closure
4
gave the intermediate methyl
2
3
of 18 with carbonyldimidazole (CDI) and 16 under the condition of sodium hydroxide
3
0, 31
.
Then this heterocyclic scaffold was alkylated with iodomethane and iodoethane
in DMF afforded the N -methylation product 20a and N -ethylation product 20b
1
1
respectively. The key alkyne building block 22a or 22b was prepared from 20a or 20b
via the Sonogashira cross-coupling reaction and trimethylsilyl-removal reaction
5

successfully. Copper(I) catalyzed click reaction (CuAAC) of the alkyne key
intermediate 22a or 22b with different azido substituent groups generated the
corresponding key 1,2,3-triazole intermediates (23a01-23a13 and 23b01-23b13),
which were deprotected under basic condition affording two series of target
compounds 1,2,3-triazole-substituted 3-hydroxy-quinazoline-2,4(1H,3H)-diones
1
2
4a01-24a13 and 24b01-24b13. Their structures were determined by their H NMR,
1
3
1
C NMR, and MS (ESI) spectra. Notably, the H NMR spectrum showed a singlet at
1
3
8
.50 corresponding to the triazolyl proton while the C NMR spectrum showed peaks
at 125.73-125.90 and 149.12-149.65 corresponding to CH and qC characteristic to the
triazole core unit.
The newly synthesized 1,2,3-triazole-linked 3-hydroxy-quinazoline-2,4 (1H,3H)-
diones were performed to evaluate against their antiviral activity against a broad panel
of DNA virus, including Herpes simplex virus-1 (KOS), Herpes simplex virus-2 (G),
Herpes simplex virus-1 TKKOS ACVr, vaccinia virus and Adeno virus-2 (evaluated in
infected human embryonic lung fibroblast (HEL) cells). In addition, all the
compounds were also examined against retroviruses [i.e., human immunodeficiency
virus type 1 (HIV-1) and type 2 (HIV-2)] and several RNA viruses [i.e., human
coronavirus and influenza virus]. The results were expressed as EC50 and MCC
(
Minimum cytotoxic concentration) (Table 1).
a
Scheme 1. Synthetic Route to 3-Hydroxy-quinazoline-2,4(1H,3H)-diones.
6

a
Reagents and condition: (a) (bromomethyl)benzene, K
8%; (c) CH OH, H SO , 94%; (d) (i) CDI, THF, 2h; (ii) NH
I or C I, DMF, rt, 98% and 96%; (f) CuI,
N, trimethylsilylacetylene, THF, 76% and 78%; (g) K CO , CH OH, rt, 88% and
0%; (h) VcNa, CuSO .5H O, H O/t-BuOH, 65°C,67 % to 90 %; (i) HBr, CH COOH, reflux; or,
Pd/C, H , MeOH, rt.
2
CO
3
, DMSO, 92%; (b) CH
3
COOH, HCl,
7
3
2
4
2
OBn, reflux, 2h; (iii) NaOH, EtOH,
reflux, 2h; (iv) CH₃ COOH, 62%; (e) CH
PdCl (PPh , Et
3
2 5
H
2
3
)
2
3
2
3
3
9
4
2
2
3
2
As shown in Table 1, some compounds exhibited remarkable inhibitory efficacy
against vaccinia with EC50 values ranging from 1.7 μM to 15 μM and adenovirus with
EC50 values ranging from 6.2 μM to 13 μM respectively in HEL cell cultures. Most of
the active compounds exhibited higher inhibitory activity than those of the reference
drugs Brivudin, Cidofovir, Zalcitabine and Alovudine. Especially, 24b11 displayed
the most potent inhibitory activity against vaccinia with an EC50 of 1.7 μM, which
was 8-15 fold than that of Brivudin (EC50 = 15 μM) and Cidofovir (EC50 = 25 μM).
2
4b13 was the most potent compound against adenovirus with EC50 values of 6.2 μM,
which proved lower than all the reference drugs. In addition, most of the compounds
showed no cytotoxicity (as determined by microscopy) at the highest concentration
(
MCC > 100 μM) tested in HEL cells. In addition, none of the compounds showed
considerable activity against the rest of the DNA virus and any of the RNA viruses
tested at nontoxic concentrations. To the best of our knowledge, no data are present in
7

the literature on antiviral activity of 3-hydroxy-quinazoline-2,4(1H,3H)-diones on
vaccinia and adenovirus and this study can help to relate the structural characteristics
of this complexes to their antiviral activity.
Table 1. Antiviral Activity, Cytostatic Activity and Selection Index of the Test Compounds against
Vaccinia and Adenovirus in HEL Cell Cultures.
a
EC50 (μM)
1
b
Compd
R
R
Vaccinia
virus
Adeno virus-2
MCC
(μM)
>100
>100
>100
>100
>100
100
2
2
2
4a01
4a02
4a03
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
2-F
4-F
>100
>100
>100
>100
>100
>100
5.0±0.75
>100
>100
>100
2.4±0.55
>100
>100
>100
>100
>100
>100
15±5
>100
1.9±0.1
>100
>100
>100
1.7±0.3
>100
>100
15
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
12±8
6.5±2.5
>100
13±7
12±8
>100
8±4
>100
>100
>100
>100
>100
>100
6.2±3.8
-
3-F
2
2
2
2
2
2
2
4a04
4a05
4a06
4a07
4a08
4a09
4a10
H
4-CN
2,6-diF
3,4-diF
2,5-diF
2,4-diF
100
>100
100
2-CH
4-NO
2,6-diCl
3
100
24a11
2
>100
>100
>100
>100
100
2
2
4a12
4a13
4-OCH
3
24b01
24b02
24b03
24b04
24b05
24b06
24b07
24b08
24b09
24b10
24b11
24b12
24b13
2-F
Et
4-F
Et
3-F
>100
>100
>100
>100
20
Et
Ph
Et
4-CN
Et
2,6-diF
3,4-diF
2,5-diF
2,4-diF
Et
Et
20
Et
20
Et
2-CH
4-NO
2,6-diCl
4-OCH
3
20
Et
2
>100
>100
>100
>250
>250
Et
Et
3
Brivudin
Cidofovir
25
10
8

Zalcitabine
Alovudine
-
-
7.2
10
>250
>250
a
b
Required to reduce virus-induced cytopathogenicity by 50 %.
Required to cause a microscopically detectable alteration of normal cell morphology.
Preliminary investigation of the structure-activity relationships (SARs) revealed
that the nature of the N -R substituent and the aryl group which connected to the
triazole influenced the antiviral activity remarkably. For instance, the result revealed
that the antiviral activity of N -ethyl substituted analogues are more potent than that
of the corresponding N -methyl substituted counterparts (EC50: 24b07 > 24a07,
4b11 > 24a11 and 24b13 > 24a13). Especially, most of N -ethyl substituted
analogues showed favorable activity against adenovirus, but nearly all the compounds
lost their activity when the compounds with N -methyl substituted counterparts with
1
1
1
2
1
1
an exception of compound 24a12. Introduction of an electron-withdrawing group at
the para substituents of the aryl can remarkable improve the anti-vaccinia activities
(
NO
2
> CN > F > CH ). To the contrary, a strong electron-withdrawing group can
3
result in the compound lost their adenovirus activities, but the compounds with
electrondrawing group (24b13 and 24a13) exhibited the most potent antiviral activity
against adenovirus. When comparing compound 24b01 with 24b02, 24b03, 24b06,
2
4b07 and24b08, only compound with fluorine substituted in the meta and para
position of the aryl simultaneous can display potent inhibitory activity towards
vaccinia (24b07, EC50 = 1.9 μM). But for the adenovirus, compounds with ortho or
meta substituted showed moderate inhibitory activity (24b01, EC50 = 6.5 μM; 24b03,
EC50 = 13 μM), and para-substituted counterpart was inactive (24b02, EC50 > 100μM);
Moreover, changing the pattern of substitution on the aryl to disubstituted resulted in
reduced activity (24b06, EC50 = 8 μM), even completely lost inhibitory activity
(
24b08 and 24b09, EC50 > 100 μM).
In conclusion, a series of novel 1,2,3-triazole-containing 3-hydroxy-quinazoline-
2
,4(1H,3H)-diones has been synthesized using CuAAC reaction, and was firstly
identified as potent and specific vaccinia and adenovirus inhibitors in vitro. Among
them, 24b11 and 24b13 was demonstrated with the most potent vaccinia and
adenovirus inhibitory activity respectively, which were promising compounds for
9

further exploration as drug candidates for anti-poxvirus or adenovirus therapy.
Preliminary SARs were discussed with the hope to provide a helpful guidance for the
design of next-generation of quinolinone analogues. Obviously, the mechanism of
action
-hydroxy-quinazoline-2,4(1H,3H)-diones derivatives presented here remain to be
identified. Consequently, a detailed study on further elaboration of these
-hydroxy-quinazoline-2,4(1H,3H)-diones and investigation of their prospective
and
precise
viral
target
of
these
1,2,3-triazolyl
3
3
mechanism of action is currently underway in our lab and would be disclosed in due
course.
Acknowledgments
The financial support from the National Natural Science Foundation of China
(
NSFC Nos. 81273354, 81573347), Key Project of NSFC for International
Cooperation (No. 81420108027), Young Scholars Program of Shandong University
YSPSDU, no. 2016WLJH32, to P.Z.), the Science and Technology Development
(
Project of Shandong Province (Nos. 2014GSF118175, 2014GSF118012) and the
Major Project of Science and Technology of Shandong Province (2015ZDJS04001) is
gratefully acknowledged.
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11

First Discovery of Novel 3-Hydroxy-quinazoline-2,4(1H,3H)-diones
as Specific Anti-Vaccinia and Adenovirus Agents
via“Privileged Scaffold” Refining Approach
a
a
a
a
b,
a,
Dongwei Kang, Heng Zhang, Zhongxia Zhou, Boshi Huang, Lieve Naesens, * Peng Zhan, *
a,
and Xinyong Liu *
a
Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of
Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road,
250012 Ji’nan, Shandong, PR China
b
Rega Institute for Medical Research, K.U.Leuven, Minderbroedersstraat 10, B-3000 Leuven,
Belgium
Graphical abstract
First discovery of novel 3-hydroxy-quinazoline-2,4(1H,3H)-diones as specific
anti-vaccinia and adenovirus agents via “privileged scaffold” refining approach.
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First Discovery of Novel 3-Hydroxy-quinazoline-2,4(1H,3H)-diones
as Specific Anti-Vaccinia and Adenovirus Agents
via“Privileged Scaffold” Refining Approach
a
a
a
a
b,
a,
Dongwei Kang, Heng Zhang, Zhongxia Zhou, Boshi Huang, Lieve Naesens, * Peng Zhan, *
a,
and Xinyong Liu *
a
Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of
Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road,
250012 Ji’nan, Shandong, PR China
b
Rega Institute for Medical Research, K.U.Leuven, Minderbroedersstraat 10, B-3000 Leuven,
Belgium
Highlights
•
First discovery of novel 3-hydroxy-quinazoline-2,4(1H,3H)-diones as specific
anti-vaccinia and adenovirus agents
24b11 displayed the most potent inhibitory activity against vaccinia with an EC50
value of 1.7 μM
24b13 was the most potent compound against adenovirus-2 with an EC50 value of 6.2
μM
Preliminary SARs of these novel analogues were detailed.
•
•
•
13