Discovery of potent antiviral (HSV-1) quinazolinones and initial structure-activity relationship studies

Article abstract of DOI:10.1016/j.bmcl.2017.09.026

The discovery of antiviral activity of 2,3-disubstituted quinazolinones, prepared by a one-pot, three-component condensation of isatoic anhydride with amines and aldehydes, against Herpes Simplex Virus (HSV)-1 is reported. Sequential iterative synthesis/a

Full text of DOI:10.1016/j.bmcl.2017.09.026

Accepted Manuscript
Discovery of potent antiviral (HSV-1) quinazolinones and initial structure-ac-
tivity relationship studies
Carla E. Brown, Tiffany Kong, James McNulty, Leonardo D'Aiuto, Kelly
Williamson, Lora McClain, Paolo Piazza, Vishwajit L. Nimgaonkar
PII:
S0960-894X(17)30922-8
DOI:
http://dx.doi.org/10.1016/j.bmcl.2017.09.026
BMCL 25290
Reference:
Bioorganic & Medicinal Chemistry Letters
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11 September 2017
12 September 2017
Please cite this article as: Brown, C.E., Kong, T., McNulty, J., D'Aiuto, L., Williamson, K., McClain, L., Piazza,
P., Nimgaonkar, V.L., Discovery of potent antiviral (HSV-1) quinazolinones and initial structure-activity
relationship studies, Bioorganic & Medicinal Chemistry Letters (2017), doi: http://dx.doi.org/10.1016/j.bmcl.
2017.09.026
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Carla E. Brown, Tiffany Kong, James McNulty, Leonardo D’Aiuto, Kelly Williamson, Lora McClain,
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Bioorganic & Medicinal Chemistry Letters
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Discovery of potent antiviral (HSV-1) quinazolinones and initial structure-
activity relationship studies
Carla E. Brown,a Tiffany Kong,a James McNulty,a,∗ Leonardo D’Aiuto,b Kelly Williamson,b Lora
McClain,b Paolo Piazza,b and Vishwajit L. Nimgaonkarb,*
aDepartment of Chemistry & Chemical Biology, McMaster University, Hamilton, Ontario, Canada L8S 4M1
bDepartment of Psychiatry, WPIC, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA, 15213
ARTICLE INFO
ABSTRACT
The discovery of antiviral activity of 2,3-disubstituted quinazolinones, prepared by a one-pot,
three-component condensation of isatoic anhydride with amines and aldehydes, against Herpes
Simplex Virus (HSV)-1 is reported. Sequential iterative synthesis/antiviral assessment allowed
structure-activity relationship (SAR) generation revealing synergistic structural features required
for potent anti-HSV-1 activity. The most potent derivatives show greater efficacy than acyclovir
against acute HSV-1 infections in neurons and minimal toxicity to the host.
Article history:
Received
Revised
Accepted
Available online
Keywords:
Quinazolinone
Multi component coupling
antiviral
2009 Elsevier Ltd. All rights reserved
.
HSV-1
Herpesvirus
———
∗ Corresponding authors: Chemistry: e-mail: jmcnult@mcmaster.ca. Antiviral activity: vishwajitNL@upmc.edu.

Herpes Simplex Virus 1 (HSV-1), a virus belonging to the
family herpesviridae and a common human pathogen,1 affects
approximately 67% of the global population and is causing
increasing concern for neonatal and immunocompromised
patients.2 HSV-1 displays both lytic and latent forms of infection
in humans.3 Recently, HSV-1 infection has been associated with
cognitive impairment among persons with schizophrenia4,5 and
even persons without psychiatric illnesses.6,7 Lytic HSV-1
infections are characterized by active viral replication causing
substantial morbidity through recurrent cold sores,
gingivostomatitis, and corneal infections that can culminate in
blindness through stromal keratitis. While HSV-1 encephalitis is
rare, the incidence of neonatal encephalitis is rising and survivors
suffer from severe cognitive deficits. In the latency phase, the
viral genome persists in neurons, only a handful of loci are
transcribed. Latent infections can be reactivated by systemic or
localized stress and is uncontrollable and unpredictable.8 During
latency, viral gene repression is controlled by host-cell epigenetic
regulation, specifically by binding of deactylated histones to viral
DNA, and reactivation of latent infections involves histone
acetylation.9,10 Reactivation of latent infections can be induced by
treatment of histone deacetylase inhibitors.11,12 HSV-1 is
currently treated with nucleoside analogs such as acyclovir
(ACV), but these drugs do not affect latent infection.1
Additionally, resistance to ACV is increasing, particularly in
immunocompromised patients who receive treatment for
extended periods. There is a need to discover structurally novel
compounds (i.e. non-nucleoside based) and/or mechanisms for
treating lytic HSV-1 and reactivation.13
The quinazolinone core is found within both natural products
and in pharmaceuticals, representing a privileged scaffold given
the range of activity (antimicrobial,14 antitubercular,15 and
anticancer activity16) noted for certain constituents. A number of
quinazolinones have been identified as antiviral agents with
activity against influenza,17 HIV,18 and TMV.19 Quinazolinone
analogs are also known to affect epigenetic regulation through
inhibition of bromodomains (BET).20 On the basis of these data,
we hypothesized that quinazolinones may exhibit novel activity
against HSV-1 and recently reported a comparative HSV-1 drug
screening assay that demonstrated preliminary antiviral activity
of
at least two synthetic steps. In addition, to generate
quinazolinones 5 from dihydroquinazolinones 4, additional
oxidants are sometimes employed.28,29 Multicomponent
approaches to quinazolinone synthesis have also been reported in
the literature.30 We initiated the present work directed toward
development of
a
one-pot, three-component-coupling to
quinazolinones (Scheme 1) following a recent report of such a
process from isatoic anhydride, primary amines and aldehydes
using catalytic iodine.24 In our hands, following this procedure,
the direct condensation of isatoic anhydride 1 with an amine 2
and aldehyde 3 was found to proceed readily in alcoholic
solvents such as EtOH, however we found that incomplete
oxidation yielded intractable mixtures of dihydroquinazolinone 4
and quinazolinone 5 products. A catalyst-free method employing
urea and thiourea as ammonia equivalents has also been
reported,31 however under these conditions, no cyclization
products were obtained.
Further experimentation with various catalysts, solvents and
temperatures resulted in the discovery of distinct reaction
conditions leading exclusively to either dihydroquinazolinone 4
or quinazolinone product 5, separately through one-pot
processes. The reaction of isatoic anhydride, NH4OAc or an
amine, and aldehydes or ketones using a catalytic amount of the
mild Bronsted acid camphor sulfonic acid (CSA) (Scheme 1)
conducted in ethanol at room temperature led to
dihydroquinazolinone 4 products in 39-88% isolated yield. In all
cases, the product precipitated from the reaction mixture and
could be purified simply by washing with ethanol. The
dihydroquinazolinones proved to be devoid of antiviral activity in
all cases and were not further pursued in the present
investigation.
In contrast, when the same reaction was performed in
dimethyl sulfoxide (DMSO) at 110 ˚C in air with a catalytic
amount of CSA, aromatic quinazolinone products 5 were isolated
exclusively. The 2-substituted quinazolinones so prepared
precipitated as described for the dihydroquinazolinones leading
to a first generation of derivatives 5a-5i, Figure 1 (top). A second
generation of 2,3-disubstituted quinazolinones 6a-6i, Figure 1
(centre) was similarly accessed from anilines or amines in
isolated yields of 27-83%.
The array of compounds (Figure 1) was screened for activity
against acute HSV-1 using a previously published protocol.32
Briefly, iPSC-derived neurons were infected with recombinant
HSV-1 expressing EGFP under the control of the ICP0 promoter.
iPSC-neurons were then treated with quinazolinones two hours
after infection. After 72h, the number of fluorescent cells was
measured by flow cytometry (See Supplementary Figure S1).
ACV was used as a positive control, and the % fluorescent cells
was normalized to the infected, untreated control. At 50 µM, 6c
and 6i showed decreased % fluorescent cells compared to
untreated controls (Figure 1). This indicates reduced expression
of ICP0 and thus inhibition of viral replication. The structure-
activity
Scheme 1. The dichotomous solvent and temperature-dependent Bronsted
acid catalyzed three component coupling of isatoic anhydride 1, amines 2 and
aldehydes 3 to yield dihydroquinazolinones 4 and quinazolinones 5.
quinazolinones.21 In this Letter, we describe the synthesis of
dihydroquinazolinones 4 and quinazolinones 5 via a three-
component coupling of isatoic anhydride 1, amines 2 and
aldehydes 3 (Scheme 1), optimizing this new potent antiviral
HSV-1 pharmacophore through successive rounds of SAR.21
While the synthesis of quinazolinones has been reported through
various methods, we were attracted to reports describing the
condensation of o-aminobenzamides and carbonyl compounds.22-
30
These have been conducted under a variety of conditions
including the use of Bronstead acid,22,23 Lewis acid,24 and other
catalysts.25,26 Aldehydes and ketones are common substrates,
however diketones,27 ß-ketoesters,22 and alcohols28 have also
been incorporated. These reactions often require the prior
preparation of the substituted o-aminobenzamide, thus involving

R
R'
O
R'
HO
O
N
O
B
O
OH
N
OH
N
O
Cu(OAc)2
DIPEA
DCM
R'
N
R
O
9a-9d
7a-b
CSA, DMSO
110ºC
OH
NH2
N
H
O
X
OH
O
R
O
N
N
O
N
CSA, DMSO
110ºC
NaH, DMF
0ºC RT
NO2
11a-11e
R
R'
O
R'
R'
O
HO
O
N
B
Fe, HCl
N
OH
N
EtOH
NO2
N
8
N
Cu(OAc)2
DIPEA
DCM
7c
10a
NH2
N
H
Scheme 2. Synthesis of 2nd generation quinazolinones. Phenols 7a-b can be coupled with aryl boronic acids or aryl
halides to afford diaryl ethers and benzylethers. Aniline 8 was used to prepare the diarylamine analog 10.
O
O
O
NH
NH
NH
O
N
N
N
5b
5a
O
5c
O
O
O
O
O
NH
NH
NH
O
N
N
N
CF3
5e
5d
5f
O
N
O
O
O
NH
NH
NH
N
N
N
5i
5h
5g
Figure 1. Analysis of 2- and 2,3-disubstituted quinazolinones and their
antiviral activity. Top panel: Structures of 2- and 2,3-disubstituted
F
N
Br
O
O
quinazolinones. BotOtom panel.OHeat map ofOquinazolinones antiviral activity.
O
+
NThe drug effect was calculated as the proportiNon of EGFP cells exposed to a
N
+
specific drug by theNproportion of EGFP cells in untreated infected cultures.
O
N
N
6a
6c
At 50 µM, 6c and 66ibshow significant reduction in fluorescence, indicating
O
O
Br
inhibition of viral replication. 6i shows significant inhibition of HSV-1 at 10
O
O
O
µM.
N
N
N
evaluation of our first- and second-generation series of
N
N
N
6d
6f
quinazolinone compoundBsr (Figure 1) revealed many interesting
6e
O
O
trends, however most notably, compound 6i showed stronger
inhibitBiron of viral replication than ACV and was also active at 10
Br
Br
O
O
µM. Two structural features also stand out as synergistically
O
N
N
Nrequired for potency. The presence of a benzyloxybenzyl
>
1
substituent at C62h in conjunction wiNth an aryl substituent at N3
N
N
1.0
-
ACV 50 µM
1
2
3
4
5
6i
6g
O
Br
correlated strongly with the antiviral activity.OCompounds 5c and
6f containing a C2 benzyloxybenzyl substituent and an alkyl or
no substituent at N3 proved relatively inactive. The activity of
the series 6g, 6h and 6i, containing the same 4-bromophenyl
substituent at N3, highlights the superior activity of the C2
benzyloxybenzyl substituent. Compound 6i, containing a 4-
bromophenyl substituent at N3 was more active than 6c and 5c,
which contain an electron rich 4-methoxyphenyl moiety or
hydrogen at N3. The overall results demonstrate that
quinazolinones with a benzyloxybenzyl group at C2 and an
electron deficient 4-bromophenyl group at N3 work
synergistically in this new potent anti-HSV-1 pharmacophore.
Compounds that showed activity in our initial screen were
ACV 10 µM
5a
5b
5c
0.8
0.8
5d
5e
6
7
8
9
10
11
12
5f
0.60.6
5g
5h
51
6a
6b 13
0.4
0.4
further tested for toxicity against iPSC-neurons using
a
6c
14
15
16
17
LIVE/DEAD Fixable Aqua dead cell stain kit according to
previously published protocols.32 Although 6c and 6i had little
affect on cell viability,21 we observed some morphological
6d
6e
6f
0.20.2
6g

10 µM
50 µM
>
1
1.0
-
ACV
9a
1
2
changes to neurons after they had been treated with 6c and 6i for
48-72 hours. As this toxicity was not immediately observed, we
hypothesized that these molecules could be unstable under the
assay conditions, and thus decomposing or being metabolized to
more toxic species. We identified the benzyloxybenzyl group as a
particularly labile site. The functional group is crucial for anti-
HSV activity, but we thought analogs with similar large,
hydrophobic groups at C2 might retain antiviral activity while
minimizing toxicity to the host. We thus envisioned a third
generation of quinazolinones with substituted benzyl ethers,
diaryl ethers, and diaryl amines at C2.
To prepare the third generation of quinazolinones,
compounds 7a-b were prepared from the cyclization of isatoic
anhydride, 4-hydroxybenzaldehyde, and p-anisidine (7a) or 4-
bromoaniline (7b) (Scheme 2). These phenols were then coupled
to boronic acids under Chan-Lam33 conditions affording diaryl
ethers, or alkylated using benzyl halides producing
0.8
Figur
e 2.
0.8
9b
3
Analy
sis of
third
9c
4
9d
5
0.6
gener
ation
quina
zolino
nes
0.6
10a
6
11a
11b
11c
11d
11e
7
0.4
contai
ning
0.4
8
diaryl
ether,
benzy
loxyet
her,
9
0.2
10
11
0.2
and
diaryl
amine
benzyloxybenzyl ethers.
A number of diaryl ethers and
benzyloxybenzyl ethers with different substituents on the
terminal aryl ring were prepared. Additionally, a diarylamine
analog was prepared from the three component coupling of
isatoic anhydride, p-anisidine, and 4-nitrobenzaldehyde, followed
by the reduction of the nitro group and Chan-Lam coupling. In
total, a collection of ten third generation compounds was
prepared, summarized in Figure 3.
functionality. Top panel: Molecular structures. Bottom panel: Heat map of
antiviral activity. The drug effect was calculated as the proportion of EGFP+
cells exposed to a specific drug by the proportion of EGFP+ cells in untreated
infected cultures. At 10 µM and 50 µM, 11a, 11c, 11d, and 11e show
significant reduction in fluorescence, indicating inhibition of viral replication.
Our third-generation quinazolinones were again tested for
activity against HSV-1 (Figure 2). To our surprise, replacement
of the benzyloxybenzyl substituent with a diaryl ether (9a-d) or a
diaryl amine (10a) completely eliminated antiviral activity. This
large difference in activity suggests the terminal ring in the C2
substituent is very important for anti-HSV activity. The benzyl
methylene may be required for this ring to reach its binding site,
either as a spacer or by providing additional flexibility to the
chain. Some of the substituted benzyloxybenzyl ethers (11a, 11c,
11d-e) did retain activity against HSV-1. The derivatives
containing a 3- or 4-bromobenzyloxybenzyl moiety were more
Toxicity in different cell types for 11a
2.0
Vero
NSCs
1.5
Neurons
Vehicle
1.0
0.5
0.0
active
than
the
methoxybenzyloxybenzyl analog.
corresponding
electron
rich
4-
1×106
1000 10000 100000
10
100
Drug Concentration nM
Toxicity in different cell types for 11c
2.0
Vero
NSCs
1.5
1.0
0.5
0.0
Neurons
Vehicle
1×106
1000 10000 100000
10
100
Drug Concentration nM
Figure 3. Toxicity of 11a and 11c to Vero cells, neural stem cells, and
neurons compared to vehicle. No decrease in cell viability is observed at high
concentrations, and at low concentrations a small increase in cell viability is
apparent.
This may be due to the changes induced in the
electronegativity of the benzyl ring. Additionally, we were
pleased to find that 11a and 11c were less toxic than 6c and 6i
(Figure 3). This suggests substitution of the benzyl ring may
prevent oxidation of this compound by CYP450 enzymes and
thus minimize the formation of toxic biproducts.

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Acknowledgments
We thank the Stanley Medical Research Institute for support
of this work. CEB is the holder of an NSERC postgraduate
fellowship.