New acetamide derivatives containing (ω-p-bromophenoxyalkyl)uracil moiety and their anticytomegalovirus activity

Article abstract of DOI:10.1016/j.mencom.2020.09.016

New N-aryl-2-{3-[ω-(4-bromophenoxy)alkyl]-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl}acetamides have been obtained from 1-[ω-(4-bromophenoxy)alkyl]uracil and 2-chloro-N-(4-phenoxyphenyl)acetamide derivatives. Investigation of their antiviral properties again

Full text of DOI:10.1016/j.mencom.2020.09.016

Mendeleev
Communications
Mendeleev Commun., 2020, 30, 602–603
New acetamide derivatives containing (ω -p-bromophenoxyalkyl)uracil
moiety and their anticytomegalovirus activity
Maria P. Paramonova,a Robert Snoeck,b Graciela Andrei,b
Anastasia L. Khandazhinskaya*c and Mikhail S. Novikova
a Department of Pharmaceutical & Toxicological Chemistry, Volgograd State Medical University,
400131 Volgograd, Russian Federation
b Rega Institute for Medical Research, KU Leuven, B-3000 Leuven, Belgium
c V. A. Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow,
Russian Federation. Fax: +7 499 135 1405; e-mail: khandazhinskaya@bk.ru
DOI: 10.1016/j.mencom.2020.09.016
O
New N-aryl-2-{3-[ω -(4-bromophenoxy)alkyl]-2,6-dioxo-3,6-
dihydropyrimidin-1(2H)-yl}acetamides have been obtained
from 1-[ω -(4-bromophenoxy)alkyl]uracil and 2-chloro-N-(4-
phenoxyphenyl)acetamide derivatives. Investigation of their
antiviral properties against human cytomegalovirus revealed
that the representative with dodecane-1,12-diyl linker
exhibited powerful virus inhibitory activity in vitro.
H
N
N
Rm
Br
O
N
O
O
n
O
anti-HCMV, 7 examples
R = Me, Cl
n = 8, 10, 12
m = 0–2
Keywords: human cytomegalovirus, uracil derivative, acetamide, diaryl oxide, bromoarene, antiviral activity.
H
N
Human cytomegalovirus (HCMV) is a member of the family
H2N
Herpesviridae and belongs to the subfamily Betaherpesvirinae.
One of the key characteristics of herpes viruses, including
HCMV, is their ability to establish a latent infection, which can
be reactivated when the immune status is lowered.1–10 The anti-
HCMV drugs currently used in the clinic to treat HCMV
infection include ganciclovir,11 cidofovir12 and foscarnet.13
These drugs inhibit the synthesis catalyzed by HCMV
polymerase and reduce the viral reproduction in patients with
established clinical symptoms of HCMV infection. However,
their use is accompanied by undesirable effects.14–17 Therefore,
the search for new effective anti-HCMV agents represent an
urgent task.
Cl
i
O
OAr
OAr
1a–e
a Ar = Ph
b Ar = 4-MeC6H4
c Ar = 4-ClC6H4
d Ar = 3,4-Me2C6H3
e Ar = 3,4-Cl2C6H3
O
OSiMe3
N
ii
NH
Br
O
+
Br
n Br
N
O
N
OSiMe3
n
O
Earlier, we synthesized uracil derivatives containing
acetanilide fragment at N3 atom of the uracil residue.18,19
Compounds of this series demonstrated a broad spectrum of
antiviral activity against cytomegaloviruses, varicella-zoster
virus19 and hepatitis C virus.20 We also recently obtained uracil
derivatives containing coumarin residue at the 3-position, which
were active against HCMV and varicella-zoster virus.21 This
allows one to suggest that the size of the substituent at N3 atom
of the uracil residue plays a key role in the antiviral properties. In
continuation of these studies, we have synthesized a family of
compounds based on acetanilide uracil derivatives containing a
longer polymethylene bridge, as well as various substituents in
the acetanilide fragment.
The synthesis of this series of compounds (Scheme 1)
consisted of the preparation of starting chloroacetanilides 1a–e,
which included treatment of 4-phenoxyaniline and its substituted
derivatives with chloroacetyl chloride in 1,2-dichloroethane in
the presence of K2CO3 at 0 °C under the conditions described.18
The preparation of 1-[8-(4-bromophenoxy)octyl]uracil 2a was
known.19 The synthesis of its decane-1,10-diyl and dodecane-
1,12-diyl homologues 2b,c was carried out under the conditions
of silyl version of the Hilbert–Johnson reaction by condensation
2a–c
a n = 8
b n = 10
c n = 12
O
N
H
N
iii
Br
O
2a–c
N
O
OAr
n
O
3a–g
a Ar = 4-MeC6H4, n = 8
b Ar = 4-ClC6H4, n = 8
c Ar = Ph, n = 10
e Ar = 4-ClC6H4, n = 12
f Ar = 3,4-Me2C6H3, n = 12
g Ar = 3,4-Cl2C6H3, n = 12
d Ar = Ph, n = 12
Scheme 1 Reagents and conditions: i, ClCH2C(O)Cl, K2CO3, 1,2-dichloro-
ethane, 0 °C, 2 h, 75–78%; ii, 4-BrC6H4O(CH2)nBr, 160–170 °C, 1 h, 80–
82%; iii, 1a–e, K2CO3, DMF, room temperature, 24 h, 72–81%.
of equimolar amounts of 2,4-bis(trimethylsilyloxy)pyrimidine
and the corresponding 1-bromo-ω-(p-bromophenoxy)alkanes at
160–170 °C for 1 h (see Scheme 1) as described.21,22 The yields
of products 2b and 2c were 82 and 80%, respectively. Subsequent
treatment of compounds 2a–c with chloroacetanilides 1a–e in
DMF in the presence of K2CO3 at room temperature afforded the
© 2020 Mendeleev Communications. Published by ELSEVIER B.V.
on behalf of the N. D. Zelinsky Institute of Organic Chemistry of the
Russian Academy of Sciences.
– 602 –

Mendeleev Commun., 2020, 30, 602–603
desired amides 3a–g in 72–81% yields (for details, see Online
Supplementary Materials).
This work was supported by the Russian Foundation for Basic
Research (grant no. 19-015-00094 A). The biological part of this
work was supported by KU Leuven, Belgium.
Antiviral properties of new compounds 3a–g against HCMV
strains AD-169 and Davis were studied in a culture of HEL cells
(Table 1). Earlier, we detected a noticeable anti-HCMV activity
of 1-[8-(4-bromophenoxy)octyl]uracil containing unsubstituted
acetanilide fragment at N3 atom of the pyrimidine ring,19
however, accompanied by high cytotoxicity. The introduction of
methyl group (compound 3a) or chlorine atom (compound 3b)
into the acetanilide moiety did not improve their expected
properties. Homologous derivative 3c with (CH2)10 linker was
also toxic. Fortunately, lengthening the bridge to (CH2)12 in
compound 3d caused a significant decrease in cytotoxicity.
Product 3d did not affect the morphology and cell growth at
concentrations up to 100 µm. Moreover, its inhibitory effect
value EC50 against HCMV replication was 0.8 and 1.52 µm for
strains AD-169 and Davis, respectively, which was comparable
to that of cidofovir and was an order of magnitude better than the
effect of ganciclovir. Further modifications of structure 3d,
namely the introduction of chlorine atoms (compounds 3e and
3g) or methyl groups (compound 3f) into the acetanilide
fragment, led to complete loss of anti-HCMV activity.
Online Supplementary Materials
Supplementary data associated with this article can be found
in the online version at doi: 10.1016/j.mencom.2020.09.016.
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a
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Compound
Morphology, Cell growth,
AD-169 strain Davis strain
b
c
MEC/µm
GI50 /µm
d
3a
<0.032
<0.032
0.032
0.8
<0.032
<0.032
0.032
1.52
–
³0.032
0.16
0.8
d
3b
–
3c
86.77
>100
3d
>100
20
d
3e
>20
>20
–
d
3f
>20
>20
>20
>20
100
–
d
3g
100
–
Ganciclovir
Cidofovir
7.05
1.01
4.73
1.27
350
>350
>300
300
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a Concentration required to reduce virus plaque formation by 50% at virus
input of 100 plaque forming units (PFU). b Minimum concentration that
causes
a microscopically detectable alteration of cell morphology.
c Concentration required to reduce cell growth by 50%. d Not determined.
Received: 19th April 2020; Com. 20/6199
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