1-Benzyl derivatives of 5-(arylamino)uracils as anti-HIV-1 and anti-EBV agents

Article abstract of DOI:10.1016/j.bmc.2010.09.070

Pyrimidine analogs have long found use over a broad chemotherapeutic spectrum. In an effort to further explore the antiviral potential of several uracil derivatives previously synthesized in our laboratories, a series of benzylated pyrimidines were design

Full text of DOI:10.1016/j.bmc.2010.09.070

Bioorganic & Medicinal Chemistry 18 (2010) 8310–8314
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
1-Benzyl derivatives of 5-(arylamino)uracils as anti-HIV-1 and anti-EBV agents
Mikhail S. Novikov a, Robert W. Buckheit Jr. b, Kartik Temburnikar c, Anastasia L. Khandazhinskaya d,
Alexander V. Ivanov d, Katherine L. Seley-Radtke c,
⇑
a Pavshikh Bortsov Sq., 1, Department of Pharmaceutical & Toxicological Chemistry, Volgograd State Medical University, Volgograd 4000131, Russia
b ImQuest BioSciences, Inc., 7340 Executive Way, Suite R, Frederick, MD 21704, USA
c 1000 Hilltop Circle, Department of Chemistry & Biochemistry, University of Maryland, Baltimore County, Baltimore, MD 21250, USA
d Engelhardt Institute of Molecular Biology, Russian Academy of Science, Moscow 119991, Russia
a r t i c l e i n f o
a b s t r a c t
Article history:
Pyrimidine analogs have long found use over a broad chemotherapeutic spectrum. In an effort to further
explore the antiviral potential of several uracil derivatives previously synthesized in our laboratories, a
series of benzylated pyrimidines were designed and synthesized. Introduction of the benzyl residue onto
the 5-phenylaminouracil scaffold was carried out using 2,4-bis(trimethylsilyloxy)pyrimidine with the
corresponding benzyl bromides. Similarly, 1-benzyl-5-(benzylamino)- and 1-benzyl-5-(phenethylami-
no)uracils were obtained via amination of 1-benzyl-5-bromouracils with benzylamine or phenylethyl-
amine. The results of the broad screen antiviral studies revealed that compounds 5 and 11 exhibit
promising inhibitory activity against HIV-1 in CEM-SS culture. A 50% protective effect was observed at
Received 6 August 2010
Revised 27 September 2010
Accepted 29 September 2010
Available online 7 October 2010
Keywords:
Pyrimidine
Uracil
HIV
EBV
concentrations of 11.9 and 9.5 lM, respectively. Moreover, compounds 8 and 3 exhibited good inhibitory
effects against EBV in AKATA cell culture with EC50 values of 2.3 and 12
lM, respectively. The synthesis
and biological studies are detailed herein.
Antiviral
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
less attention. There are, however, several 5-aryl substituted
pyrimidine nucleosides known in the literature, including from our
laboratory (Fig. 2), some of which have exhibited potent biological
activity.19–24 Similar to Tenofovir25 and Etravirine,26–28 both FDA-ap-
proved HIV-1-RT inhibitors, our compounds’ inherent flexibility
allows them to overcome resistance mechanisms related to point
mutations.29,30 The concepts of conformational flexibility and posi-
tional adaptability, or the ability to ‘wiggle and jiggle’ in a binding site
when confronted with an active site mutation have now been
shown26–28 to be critical for avoiding resistance mechanisms for
non-nucleoside HIV-1-RT inhibitors, thus provide additional impetus
for our approach.
Nucleosides and their corresponding nucleobases are key
components in nucleic acids and many other biologically signifi-
cant systems, thus modification to their structure can have a signif-
icant effect. In that regard, many nucleoside and nucleobase
derivatives have exhibited a broad spectrum of activity, in particu-
lar, in the area of antiviral chemotherapy.1–4 Inhibition of a key
step in the viral replication pathway can lead to potent activity
against many viruses including HIV, hepatitis B and C (HBV and
HCV), the herpes viruses (HSV-1 and -2), Epstein-Barr virus
(EBV), and human cytomegalovirus (HCMV), just to name a
few.1,5–7 In the realm of non-nucleoside pyrimidine analogs, a vast
number of 6-thiophenyl-,7–11 6-selenylphenyl-,12,13 6-phenoxy-,14
6-benzyl-,15–17 and 6-benzyluracil-18 pyrimidines bearing different
substituents at position 1 are known. Potent activity against HIV in
cell culture has been noted for these compounds, most notably,
analogs possessing a 1-benzyl or 4-pyrimidyl-methyl substituent
(Fig. 1). These compounds were found to block HIV-1 reverse trans-
criptase (HIV RT)12,16,17 at nanomolar concentrations, thus inhibit-
ing viral replication at an early stage.12
Additional examples pertinent to our approach can be found in
the 1,3-dibenzyl-derivatives of uracil from Maruyama et al.31,32
Moreover, although numerous 6-aryl non-nucleoside derivatives
are known, the analogous 5-aryl pyrimidines have received far
⇑
Corresponding author. Tel.: +1 410 455 8684; fax: +1 410 455 2608.
E-mail address: kseley@umbc.edu (K.L. Seley-Radtke).
Figure 1.
0968-0896/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2010.09.070

M. S. Novikov et al. / Bioorg. Med. Chem. 18 (2010) 8310–8314
8311
O
N
Br
R'
(CH3)3SiO
NH
R"
R'
HN
NH
N
O
R"
1,2-DCE
(H3C)3SiO
N
Δ
2-8
1
R'=H, CH3, Cl, OPh
R"=H, CH3
Scheme 1.
Figure 2. 5-Substituted pyrimidine nucleosides.
1,2-dichloroethane (Scheme 1). The silyl derivative 1 was prepared
and characterized as previously reported.38 The yields of com-
pounds 2–8 ranged from 61% to 77%. It is notable that the formation
of 1,3-substitution products was not observed (TLC).
Similarly, 1-benzyl derivatives of 5-(benzylamino)- and 5-(phen-
ethylamino)uracils 11–13 were obtained by amination of 1-(3,5-
dimethylbenzyl)- and 1-(2,4-dichlorobenzyl)-5-bromouracil (9
and 10, respectively) with excess benzylamine or phenethylamine
in refluxing ethylene glycol for 1 h (Scheme 2) in yields averaging
70–75%. Notably, formation of 1-benzyl-5-(phenylamino)uracils
was not observed under these conditions. The physical properties
of the synthesized compounds are shown in Table 1.
3. Biological assays
The compounds were then subjected to screening across a
broad range of viruses in order to evaluate their biological poten-
tial both in Southern Research Institute’s high-throughput screen-
ing program, as well as in our collaborator’s laboratory at ImQuest
BioSciences. Not surprisingly, two of the compounds (5 and 11)
demonstrated promising inhibitory activity against HIV. As shown
in Table 2, a 50% protective effect was observed at concentrations
Figure 3.
of 11.9 and 9.5 lM, respectively, in CEM-SS cell culture. Some of
the other 1-benzyl-5-(arylamino)uracils tested were less active
or, as in the case of 2, 3, and 7, completely inactive. It is noteworthy
that both compounds 5 and 11 possess the same benzyl fragment,
that is, a 3,5-dimethylphenylmethyl residue at the N1 position of
the uracil ring. From this it appears that the presence of the methyl
substituents in meta positions of the benzyl fragment favorably af-
fects the inhibitory properties of these compounds.
In addition to the anti-HIV activity noted, several of the com-
pounds also exhibited activity against Epstein-Barr virus in AKATA
cell culture.18 As shown in Table 3, results revealed that most of
the compounds demonstrated some level of antiviral effect. The
most active compound was 1-(3-phenoxybenzyl)-5-(phenylami-
(Fig. 3). These aryl substituted uracils were shown to block HIV-1
and HCMV replication in vitro in sub-micromolar concentra-
tions.31,32 Potent activity was also noted for a similar 1,3-dibenzyl
inhibitor developed by Nair et al., which exhibited potent activity
against the HIV integrase (Fig. 3).33 On the basis of the leads out-
lined above, we have designed a series of aryl substituted pyrimi-
dines where the aromatic fragment has been relocated from C-6 or
N-3 to C-5 of the uracil pharmacophore, as well as to introduce a
nitrogen into the bridging group (Fig. 3) to increase potential inter-
actions in enzymatic binding sites. We believe these strategic mod-
ifications will lead to potential inhibition in the replication of
viruses of a number of biologically significant diseases.
no)uracil (8) with an EC50 value of 2.3
at a concentration of 100 M. A second active compound was
1-(2-methylbenzyl)-5-(phenylamino)uracil (3) whose EC50 was
12 M. While several uracil nucleosides modified at the sugar and/
lM and no toxicity observed
l
2. Chemistry
l
The synthesis 5-(arylamino)-1-benzyluracils can be realized by
way of a modification to the Hilbert–Johnson reaction widely used
for the synthesis of pyrimidine nucleosides and their acyclic ana-
logs. The method involves treatment of 2,4-bis(trimethylsilyl-
oxy)pyrimidines with highly reactive alkylating agents under
mild conditions.14,18,34–36 Use of alkylating agents with decreased
reactivity however requires more harsh conditions. For example,
Malik et al. have described addition of a benzyl residue to uracil
by coupling 2,4-bis(trimethylsilyloxy)pyrimidine with benzyl chlo-
ride in boiling 1,2-dichloroethane for 96 h in the presence of a cat-
alytic amount of iodine.37 In an effort to optimize this reaction, we
found that the use of benzyl bromides in place of benzyl chlorides
considerably shortened the reaction time from 96 h to 14 h.
In that regard, 1-benzyl-5-(phenylamino)uracils 2–8 were
prepared by coupling 2,4-bis(trimethylsilyloxy)-5-phenylamino-
uracil 1 with the corresponding benzyl bromides in refluxing
or base have demonstrated potent anti-Epstein-Barr virus (EBV)
activity at the sub-micromolar level14,39,40 to our knowledge, similar
Scheme 2.

8312
M. S. Novikov et al. / Bioorg. Med. Chem. 18 (2010) 8310–8314
Table 1
very similar substituents showed a significant difference in activ-
Physical properties for the synthesized compounds
ity. Efforts are currently underway to address this issue by investi-
gating additional substituents that would impart greater solubility
under physiological conditions.
4. Summary
As an extension of the ongoing research in our laboratories, the
search for new and more effective antiviral agents based on the
pyrimidine scaffold was undertaken. Results showed that the elec-
tronic nature of the aromatic amine moiety was critical to the
yield. As a result, a new and more facile route was developed to
realize the synthesis of several new types of 1-benzyl-substituted
5-arylaminouracils. The antiviral properties of the target com-
pounds were studied and several compounds were observed to
have promising activity against HIV and EBV. Issues with solubility
may be a factor in truly realizing their full potential however, thus
current SAR efforts are now underway to explore alternative sub-
stituents as a solution to this problem. Additional biological studies
are also currently underway and the results of those investigations
will be published elsewhere as they become available.
Compound
R0
R00
X
Yield (%)
Mp (°C)
Rfa
2
3
4
5
6
7
8
11
12
13
H
H
H
H
H
H
4-Me
H
H
H
—
—
—
—
—
—
—
CH2
CH2
(CH2)2
77
61
64
69
72
62
61
71
75
70
230–232
191–192
222–223
197–198
235–236
204–205
192–194
152–153
177–178
167–168
0.37
0.49
0.43
0.55
0.51
0.64
0.58
0.71
0.78
0.79
2-Me
3-Me
3,5-Me
3-Cl
2,4-Cl
3-OPh
3,5-Me
2,4-Cl
2,4-Cl
H
a
Elution with ethyl acetate.
Table 2
5. Experimental
Anti-HIV-1 activity measured in CEM-SS cell culture
Compound
EC50
(
lM)
CC50 (lM)
SIc
a
b
All chemicals were obtained from commercial sources and used
without further purification unless otherwise noted. Anhydrous
DMF, isopropanol, and ethylene glycol were purchased from
Sigma–Aldrich Co. Anhydrous acetone, CH2Cl2, 1,2-dichloroethane,
and ethyl acetate were obtained by distillation over P2O5. Melting
points ware measured on Mel-Temp 3.0 Pro apparatus (Laboratory
Devices Inc.) and uncorrected. All 1H and 13C NMR spectra were
obtained on a Varian Mercury 300B (300 MHz) NMR, operated at
300 and 75 MHz, respectively, and referenced to internal tetrameth-
ylsilane (TMS) at 0.0 ppm. The spin multiplicities are indicated by
the symbols s (singlet), d (doublet), dd (doublet of doublets), t (trip-
let), q (quartet), m (multiplet), and br (broad). Reactions were mon-
itored by thin-layer chromatography (TLC) using 0.25 mm silica gel
precoated plates. Column chromatography was performed using
silica gel (63–200 m) from Merck Chemicals, and eluted with ethyl
acetate. Yields refer to chromatographically and spectroscopically
(1H and 13C NMR) homogeneous materials. Mass spectra were
recorded at the Johns Hopkins Mass Spectrometry Facility.
2
3
4
5
6
7
8
11
12
13
AZT
>100.0
>100.0
44.7
11.9
ND
ND
>100.0
9.5
54.6
42.7
>100.0
>100.0
>200.0
>200.0
ND
—
—
>4.5
>16.8
ND
ND
—
17.8
>1.8
>2.34
>125.0
ND
>100.0
168.0
>100.0
>100.0
>1.0
0.008
ND—not determined.
a
Effective concentration, giving 50% inhibition of viral replication.
Cytotoxic concentration, concentration producing 50% cytotoxicity.
Selectivity index, CC50/EC50
b
c
.
Table 3
Anti-EBV activity in AKATA cell culture
a
b
Compound
EC50
(
lM)
CC50
ND
(
lM)
SIc
2
3
4
5
6
7
8
11
ND
12
ND
>8.3
>1
<4.8
>5
2.1
>43
ND
2.4
>1.5
>3030
5.1. General procedure for preparation of 1-benzyl-5-(phenyl-
amino)uracils 2–8
>100
>100
96.2
>100
92.3
>100
ND
96.3
>100
>100
99.1
>20
20
43.3
2.3
A solution of the specific benzyl bromide (6.81 mmol) in 1,2-
dichloroethane (20 mL) was added to a solution of 2,4-bis(trimethyl-
silyloxy)-5-(arylamino)pyrimidine 1 in 1,2-dichloroethane (50 mL).
The resulting mixture is refluxed for 14 h, cooled to room tempera-
ture and EtOH (10 mL) added. The precipitate was filtered and air
dried. The filtrate was evaporated by two thirds and cooled to 0 °C.
The resulting precipitate was filtered and combined with the previ-
ously obtained solid and purified by column chromatography eluting
with EtOAc/CH2Cl2 (1:1) or by recrystallization from isopropanol/
DMF (2:1).
ND
12
13
L-I-OddU
39.6
67.2
0.033
ND—not determined.
a
Effective concentration, concentration which reduces viral replication by 50%
Cytotoxic concentration, concentration which 50% of the cells are destroyed.
Selectivity index, CC50/EC50
b
c
.
activity has not been noted for non-nucleoside pyrimidine-like
inhibitors such as ours.
5.1.1. 1-Benzyl-(phenylamino)uracil (2)
1H (DMSO-d6): d 4.85 (s, 2H, CH2), 6.61 (t, 1H, J = 7, H-6’),
6.69–6.71 (m, 2H, aromatic H), 7.00–7.07 (m, 3H, aromatic H,
NH), 7.22–7.34 (m, 5H, C6H5), 7.65 (s, 1H, H-6), 11.54 (s, 1H, NH).
13C (DMSO-d6): d 48.2, 112.4, 114.7, 116.1, 125.5, 126.6, 126.8,
132.9, 135.1, 143.6, 148.0, 159.7. HRMS calculated for
Although the activity noted for some of these compounds is
encouraging, one problem noted during their synthesis and screen-
ing was their poor solubility in aqueous solution. Even in the pres-
ence of DMSO a precipitate was noted for some analogs, which
could be one explanation for why some of the compounds with
C17H15N3O2, [M+H]+ 293.11643; found 293.11677.

M. S. Novikov et al. / Bioorg. Med. Chem. 18 (2010) 8310–8314
8313
5.1.2. 1-(2-Methylbenzyl)-5-(phenylamino)uracil (3)
1H (DMSO-d6): d 2.23 (s, 3H, CH3), 4.85 (s, 2H, CH2), 6.61 (t, 1H,
J = 7, aromatic H), 6.68–6.71 (m, 1H, H-50), 6.99–7.05 (m, 6H, C6H5,
NH), 7.13–7.16 (m, 2H, H-30, H-60), 7.43 (s, 1H, H-6), 11.58 (s, 1H,
NH). 13C (DMSO-d6): d 16.6, 46.2, 112.5, 114.9, 116.2, 124.1,
124.8, 125.4, 126.8, 128.4, 131.9, 132.8, 133.6, 143.4, 147.9,
159.7. HRMS calculated for C18H17N3O2, [M+H]+ 307.13208; found
307.13138.
5.2.1. 5-(Benzylamino)-1-(3,5-dimethylbenzyl)uracil (11)
1H (DMSO-d6): d 2.14 (s, 6H, CH3), 4.02 (d, 2H, J = 6, CH2Ph), 4.59
(s, 2H, CH2Ar), 5.10 (t, 1H, J = 6, NHCH2Ph), 6.47 (s, 1H, H-40), 6.68
(s, 2H, H-20, H-60), 6.81 (s, 1H, aromatic H), 7.14–7.22 (m, 4H, aro-
matic H), 7.23 (s, 1H, H-5), 11.37 (s, 1H, NH). 13C (DMSO-d6): d 18.9,
44.6, 48.0, 114.9, 123.1, 124.8, 125.2, 126.1, 126.8, 135.4, 146.6,
158.7.
5.2.2. 5-(Benzylamino)-1-(2,4-dichlorobenzyl)uracil (12)
1H (DMSO-d6): d 3.96 (d, 2H, J = 6.3, CH2Ph), 4.73 (s, 2H, CH2Ar),
5.13 (t, 1H, J = 6.3, NHCH2Ph), 6.37 (s, 1H, H-30), 6.93–6.95 (m, 1H,
H-60), 7.12–7.19 (m, 5H, C6H5), 7.26–7.30 (m, 1H, H-50), 7.54 (s, 1H,
H-6), 11.48 (s, 1H, N3-H). 13C (DMSO-d6): d 44.6, 45.7, 114.5, 122.1,
124.7, 125.1, 125.5, 126.2, 126.8, 127.9, 130.8, 131.5, 136.7, 146.7,
158.8. HRMS calculated for C18H15Cl2N3O2, [M+H]+ 375.05413;
found 375.05395.
5.1.3. 1-(3-Methylbenzyl)-5-(phenylamino)uracil (4)
1H (DMSO-d6): d 2.24 (s, 3H, CH3), 4.81 (s, 2H, CH2), 6.61 (t, 1H,
J = 7, aromatic H), 6.69–6.72 (m, 1H, aromatic H), 6.99–7.09 (m, 6H,
C6H5, NH), 7.17–7.22 (m, 2H, H-20, H-60), 7.63 (s, 1H, H-6), 11.53 (s,
1H, NH). 13C (DMSO-d6): d 18.9, 48.1, 112.3, 114.6, 116.1, 122.6,
126.0, 126.3, 126.6, 126.8, 133.1, 135.0, 135.8, 143.8, 147.9,
159.8. HRMS calculated for C18H17N3O2, [M+H]+ 307.13208; found
307.13279.
5.2.3. 1-(2,4-Dichlorobenzyl)-5-(phenethylamino)uracil (13)
1H (DMSO-d6): d 2.73 (m, 2H, J = 7, CH2CH2Ph), 2.94 (m, 2H,
J = 7, CH2CH2Ph), 4.45 (t, 1H, J = 6, NH), 4.82 (s, 2H, CH2Ar), 6.65
(s, 1H, H-30), 7.02–7.05 (m, 1H, H-60), 7.10–7.24 (m, 5H, C6H5),
7.34–7.38 (m, 1H, H-50), 7.61 (s, 1H, H-6), 11.49 (s, 1H, N3-H). 13C
(DMSO-d6): d 32.1, 43.0, 46.0, 114.3, 122.7, 124.1, 125.6, 126.2,
126.6, 126.8, 127.2, 130.6, 131.8, 146.8, 158.8. HRMS calculated
for C19H17Cl2N3O2, [M+H]+ 389.06978; found 389.07049.
5.1.4. 1-(3,5-Dimethylbenzyl)-5-(phenylamino)uracil (5)
1H (DMSO-d6): d 2.20 (s, 6H, CH3), 4.77 (s, 2H, CH2), 6.61 (t, 1H,
J = 7, aromatic H), 6.68–6.71 (m, 2H, aromatic H), 6.88 (s, 3H, aro-
matic H, NH), 7.00–7.07 (m, 2H, aromatic H), 7.61 (s, 1H, H-6),
11.51 (s, 1H, NH). 13C (DMSO-d6): d 18.8, 48.0, 112.3, 114.6,
116.1, 123.3, 126.8, 127.1, 133.2, 134.9, 135.7, 143.8, 148.0,
159.8. HRMS calculated for C19H19N3O2, [M+H]+ 321.14773; found
321.14809.
6. Biological evaluation
Antiviral activity of the compounds was measure by inhibition
of virus-induced cytopathic effects (CPE) using CEM-SS cells in-
fected with HIV-1.41 Briefly, compound-induced protection from
virus-induced cytopathic effects (cytoprotection) was measured
using a mitochondria-activated dye with quantification by a color-
imetric endpoint. AZT was utilized as a positive control compound
in all studies performed and exhibited the expected level of activity
ranging between 1 and 10 nM. For the CEM-SS assay 2,3-bis(2-
methoxy-4-nitro-5-sulfophenyl)-5-[(phenylamino)carbonyl]-2H-
tetrazolium hydroxide (XTT) dye reduction following activation
with phenazine methosulfate (PMS) at 450/650 nM was used to
measure cell survival at 6 days post infection. For both assays the
EC50 (concentration resulting in 50% reduction in virus replication)
and CC50 (concentration resulting 50% loss of cell viability in cells
without virus) values are calculated by linear regression analysis.
A therapeutic index (TI) is calculated by dividing the TC50 by the
5.1.5. 1-(3-Chlorobenzyl)-5-(phenylamino)uracil (6)
1H (DMSO-d6): d 4.85 (s, 2H, CH2), 6.61 (t, 1H, J = 7, aromatic H),
6.69–6.72 (m, 2H, aromatic H), 7.00–7.07 (m, 3H, aromatic H, NH),
7.22–7.29 (m, 4H, aromatic H), 7.65 (s, 1H, H-6), 11.55 (s, 1H, NH).
13C (DMSO-d6): d 47.7, 112.4, 114.9, 116.2, 124.2, 125.4, 125.6,
126.8, 128.6, 131.2, 132.6, 137.6, 143.6, 147.9, 159.8. HRMS calcu-
lated for C17H14ClN3O2, [M+H]+ 327.07745; found 327.07758.
5.1.6. 1-(2,4-Dichlorobenzyl)-5-[(4-methylphenyl)amino]uracil
(7)
1H (DMSO-d6): d 2.11 (s, 3H, CH3), 4.89 (s, 2H, CH2), 6.71–6.73
(m, 2H, aromatic H), 6.87–6.89 (m, aromatic H, NH), 7.17–7.20
(m, 1H, H-60), 7.37–7.40 (m, 1H, H-50), 7.46 (s, 1H, H-30), 7.62 (s,
1H, H-6), 11.60 (s, 1H, NH). 13C (DMSO-d6): d 18.2, 46.3, 113.5,
116.0, 125.6, 126.9, 127.3, 127.9, 128.6, 130.8, 131.6, 140.2,
147.6, 159.6. HRMS calculated for
375.05413; found 375.05409.
C18H15Cl2N3O2, [M+H]+
EC50
.
Acknowledgments
5.1.7. 1-(3-Phenoxybenzyl)-5-(phenylamisno)uracil (8)
1H (DMSO-d6): d 4.83 (s, 2H, CH2), 6.62 (t, 1H, J = 7, aromatic H),
6.68–6.71 (m, 2H, aromatic H), 6.86–7.11 (m, 9H, aromatic H, NH),
7.29–7.35 (m, 3H, aromatic H), 7.66 (s, 1H, H-6), 11.53 (s, 1H, NH).
13C (DMSO-d6): d 47.9, 112.4, 114.8, 115.6, 116.1, 116.6, 120.5,
121.7, 126.8, 128.1, 128.4, 132.7, 137.3, 143.6, 147.9, 154.3, 159.7,
181.3. HRMS calculated for C23H19N3O3, [M+H]+ 385.14264; found
385.14412.
This work was supported by grants from the Russian Founda-
tion For Basic Research (10-04-0056, 09-04-12204, and 08-04-
00549), and by the Presidium of the Russian Academy of Sciences
(Programme ‘Molecular and Cellular Biology’). The authors would
also like to thank Southern Research Institute for additional anti-
viral screening, including the EBV assays described herein as part
of their high-throughput screening program.
5.2. General procedure for preparation of 5-benzylamino- and
5-phenethylamino-derivatives of 1-benzyluracil 11–13
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zyl)-5-bromouracil (10) (5.08 mmol), benzylamine or phenethy-
amine (18.31 mmol) and ethylene glycol (10 mL) was refluxed for
1 h, cooled to room temperature and the crystallized mass was
treated with cold water (100 mL). The precipitate was filtered off,
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