Synthesis of uracil–coumarin conjugates as potential inhibitors of virus replication

Article abstract of DOI:10.1016/j.mencom.2019.11.010

A series of 1-[(bromophenoxy)alkyl]uracil–coumarin conjugates has been obtained through the preparation of starting 1-[(bromophenoxy)alkyl]uracil derivatives, followed by their treatment with 7-(ω-bromoalkoxy)-4-methyl-2H-chromen-2-ones. Two of the synthesized uracil–coumarin conjugates demonstrated a pronounced inhibitory activity against HCMV and VZV replication in vitro.

Full text of DOI:10.1016/j.mencom.2019.11.010

Mendeleev
Communications
Mendeleev Commun., 2019, 29, 638–639
Synthesis of uracil–coumarin conjugates as potential
inhibitors of virus replication
Maria P. Paramonova,a Alexander A. Ozerov,a Alexander O. Chizhov,b Robert Snoeck,c
Graciela Andrei,c Anastasia L. Khandazhinskaya*d and Mikhail S. Novikova
a Department of Pharmaceutical and Toxicological Chemistry, Volgograd State Medical University,
400131 Volgograd, Russian Federation
b N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991 Moscow,
Russian Federation
c Rega Institute for Medical Research, KU Leuven, 3000 Leuven, Belgium
d 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.2019.11.010
A series of 1-[(bromophenoxy)alkyl]uracil–coumarin conju-
gates has been obtained through the preparation of starting
1-[(bromophenoxy)alkyl]uracil derivatives, followed by their
treatment with 7-(ω-bromoalkoxy)-4-methyl-2H-chromen-
2-ones. Two of the synthesized uracil–coumarin conjugates
demonstrated a pronounced inhibitory activity against HCMV
and VZV replication in vitro.
O
N
Linker
O
O
O
N
R1
O
R2
O
Linker
Me
Anti-HCMV and anti-VZV activity
Coumarins are a large family of heterocyclic compounds found
in higher plants and localized in their roots, bark and fruits. Natural
andsyntheticcoumarinderivativesareknownasantidepressants,1
antimicrobials,2 antioxidants,3 as well as anti-inflammatory,4 anti-
asthmatic5 and antitumor6 agents. Coumarins were also found to
exhibit inhibitory activity against HIV-1,7 HCV,8 and herpes-
virus.9 As well, antiviral effect was shown for the conjugates of
coumarin with nucleic bases10 and nucleosides.11
of 7-hydroxy-4-methyl-2H-chromen-2-one with an excess of the
corresponding a,ω-dibromoalkane in acetone in the presence of
K2CO3. 7-(2-Bromoethoxy)-3,4-dimethyl-2H-chromen-2-one 2f
was synthesized in 72.5% yield by treatment of 7-hydroxy-3,4-
dimethyl-2H-chromen-2-one with a fourfold molar excess of
1,2-dibromoethane under similar conditions.
O
As an example of antiviral nucleic base conjugates, we syn-
thesized 1-[ω-(aryloxy)alkyl]-3-[(4-phenoxyphenyl)aminocarbonyl-
methyl]uracil derivatives and demonstrated their inhibitory effect
towards HCMV, VZV12,13 and HCV14 replication. In this work, we
synthesized and tested a series of new uracil conjugates bearing
coumarin moiety.
NH
O
O
O
Br
N
O
n
R1
+
X
R2
O
Me
1a–d
2a–f
a R1 = 4-Br, X = CH2
b R1 = 3-Br, X = CH2
c R1 = 2-Br, X = CH2
d R1 = 4-Br, X = O
a R2 = H, n = 1 d R2 = H, n = 4
The synthesis of starting 1-[5-(4-bromophenoxy)pentyl]uracil
1a was described.15 1-[5-(3-Bromophenoxy)pentyl]uracil 1b and
1-[5-(2-bromophenoxy)pentyl]uracil 1c precursors were obtained
in 82 and 70% yields, respectively, by condensation of 2,4-bis(tri-
methylsilyloxy)pyrimidine with 1-bromo-3-[(5-bromopentyl)oxy]-
benzene or 1-bromo-2-[(5-bromopentyl)oxy]benzene in equimolar
amounts by heating without solvent under dry conditions as
described.15,16 1-{2-[2-(4-Bromophenoxy)ethoxy]ethyl}uracil 1d
could not be obtained by this way, because bromotrimethylsilane,
released during interaction of 2,4-bis(trimethylsilyloxy)pyrimidine
with 1-bromo-4-[2-(2-bromoethoxy)ethoxy]benzene, cleaved the
dialkyl ether moiety under the conditions employed. For this
reason, the synthesis of uracil derivative 1d was carried out by
treatment of the latter with a fourfold molar excess of uracil in
DMF in the presence of potassium carbonate. This alternative
process led to 1-substituted uracil 1d in 56% yield. Details of the
synthesis and properties for precursors 1b–d are given in Online
Supplementary Materials.
b R2 = H, n = 2
c R2 = H, n = 3
e R2 = H, n = 5
R2 = Me, n = 1
f
O
O
O
O
i
N
n
N
O
R2
R1
X
Me
O
3a–i
a R1 = 4-Br, R2 = H, X = CH2, n = 1
b R1 = 4-Br, R2 = H, X = CH2, n = 2
c R1 = 4-Br, R2 = H, X = CH2, n = 3
d R1 = 4-Br, R2 = H, X = CH2, n = 4
e R1 = 4-Br, R2 = H, X = CH2, n = 5
f
R1 = 3-Br, R2 = Me, X = CH2, n = 1
g R1 = 2-Br, R2 = Me, X = CH2, n = 1
h R1 = 4-Br, R2 = Me, X = CH2, n = 1
i
R1 = 4-Br, R2 = H, X = O, n = 1
Preparation of 7-(ω-bromoalkoxy)-4-methyl-2H-chromen-
2-ones 2a–e is well documented,17–19 they were obtained by reaction
Scheme 1 Reagents and conditions: i, DMF, K2CO3, 80°C, 18 h.
© 2019 Mendeleev Communications. Published by ELSEVIER B.V.
on behalf of the N. D. Zelinsky Institute of Organic Chemistry of the
Russian Academy of Sciences.
– 638 –

Mendeleev Commun., 2019, 29, 638–639
Table 1 Anti-HCMV and anti-VZV activity of uracil–coumarin conjugates
3a–i in HEL cell culture.
Online Supplementary Materials
Supplementary data associated with this article can be found
in the online version at doi: 10.1016/j.mencom.2019.11.010.
a
Antiviral activity, EC50/mm
Cytotoxicity
Compound
VZV
Oka
VZV
07-1
Cell Cell
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1.37
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4
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4
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20
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4
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>20
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2.01
0.38
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100
5.72 <0.8
Ganciclovir 2.4
–
–
350
300
196.41
129.43
Cidofovir
Acyclovir
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a
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12.01 100
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–
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The synthesis of the target uracil–coumarin conjugates was
carried out in 74–86% yields by the treatment of 1-substituted uracil
derivatives 1a–d with an equimolar amount of bromides 2a–f in
DMF in the presence of K2CO3 (Scheme 1). Details of the syn-
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in Online Supplementary Materials.
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Activity of the obtained uracil–coumarin conjugates against HCMV
strains AD-169 and Davis as well as against VZV strains Oka
and 07-1 was tested in HEL cell culture (Table 1). Compounds 3b
and 3e have been found to inhibit HCMV replication with EC50
0.39–0.51 mm, which is more effective than ganciclovir and com-
parable with cidofovir, though the test compounds are much more
cytotoxic than both ganciclovir and cidofovir. The uracil–coumarin
conjugates 3b and 3e have also been found to effectively block
VZV replication with EC50 0.16–0.52 mm. Note that, unlike
acyclovir or brivudine, these two compounds demonstrate a similar
inhibitory effect on both VZV strains tested, namely the wild type
Oka strain and the thymidine kinase-deficient (TK–) mutant 07-1
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interact with viral thymidine kinase, and the mechanism of their
anti-VZV effect differs from that for acyclovir or brivudine.
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This work was supported by the Russian Foundation for Basic
Research (project no. 17-54-30016 NIH_a). The biological part of
this work was supported by KU Leuven. The authors are grateful
to Mrs. Ellen De Waegenaere for her excellent technical assis-
tance.
Received: 15th April 2019; Com. 19/5884
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