N1,N3-disubstituted uracils as nonnucleoside inhibitors of HIV-1 reverse transcriptase

Article abstract of DOI:10.1016/j.bmc.2012.12.027

A series of phenyloxyethyl and cinnamyl derivatives of substituted uracils were synthesized and found to exhibit potent activity against HIV-RT and HIV replication in cell culture. In general, the cinnamyl derivatives proved superior to the phenyloxyethyl derivatives, however 1-[2-(4-methylphenoxy)ethyl] -3-(3,5-dimethylbenzyl)uracil (19) exhibited the highest activity (EC ₅₀ = 0.27 μM) thus confirming that the 3-benzyluracil fragment in the NNRTI structure can be regarded as a functional analogue of the benzophenone pharmacophore typically found in NNRTIs.

Full text of DOI:10.1016/j.bmc.2012.12.027

Accepted Manuscript
N1-substituted 3-benzylpyrimidines as nonnucleoside inhibitors of HIV-1 re‐
verse transcriptase
Mikhail S. Novikov, Vladimir T. Valuev-Elliston, Denis A. Babkov, Maria P.
Paramonova, Alexander V. Ivanov, Sergey A Gavryushov, Anastasia L.
Khandazhinskaya, Sergey N. Kochetkov, Christophe Pannecouque, Graciela
Andrei, Robert Snoeck, Jan Balzarini, Katherine L. Seley-Radtke
PII:
S0968-0896(12)01000-0
DOI:
http://dx.doi.org/10.1016/j.bmc.2012.12.027
BMC 10493
Reference:
To appear in:
Bioorganic & Medicinal Chemistry
Received Date:
Revised Date:
Accepted Date:
12 November 2012
18 December 2012
25 December 2012
Please cite this article as: Novikov, M.S., Valuev-Elliston, V.T., Babkov, D.A., Paramonova, M.P., Ivanov, A.V.,
Gavryushov, S.A., Khandazhinskaya, A.L., Kochetkov, S.N., Pannecouque, C., Andrei, G., Snoeck, R., Balzarini,
J., Seley-Radtke, K.L., N1-substituted 3-benzylpyrimidines as nonnucleoside inhibitors of HIV-1 reverse
transcriptase, Bioorganic & Medicinal Chemistry (2013), doi: http://dx.doi.org/10.1016/j.bmc.2012.12.027
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Graphical Abstract
N1-substituted 3-benzylpyrimidines as
nonnucleoside inhibitors of HIV-1 reverse
transcriptase
Leave this area blank for abstract info.
Mikhail S. Novikova, Vladimir T. Valuev-Ellistonb, Denis A. Babkova, Maria P. Paramonovaa, Alexander V.
Ivanovb, Sergey A Gavryushovb, Anastasia L. Khandazhinskayab, Sergey N. Kochetkovb, Christophe
Pannecouquec, Graciela Andreic, Robert Snoeckc, Jan Balzarinic, Katherine L. Seley-Radtked

Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com
N1-substituted 3-benzylpyrimidines as nonnucleoside inhibitors of HIV-1 reverse
transcriptase
Mikhail S. Novikova, Vladimir T. Valuev-Ellistonb, Denis A. Babkova, Maria P. Paramonovaa, Alexander
V. Ivanovb, Sergey A Gavryushovb, Anastasia L. Khandazhinskayab, Sergey N. Kochetkovb, Christophe
Pannecouquec, Graciela Andreic, Robert Snoeckc, Jan Balzarinic, Katherine L. Seley-Radtked
aDepartment of Pharmaceutical & Toxicological Chemistry, Volgograd State Medical University, Pavshikh Bortsov Sq., 1, Volgograd 400131, Russia;
bEngelhardt Institute of Molecular Biology, Russian Academy of Science, Vavilov Str., 32, Moscow 119991, Russia;
cRega Institute for Medical Research, KU Leuven, Minderbroedersstraat 10, Leuven B-3000, Belgium;
dDepartment of Chemistry & Biochemistry, University of Maryland, Baltimore County, 1000 Hilltop Circle, Baltimore, MD 21250, USA.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A series of phenyloxyethyl and cinnamyl derivatives of substituted uracils were synthesized and
found to exhibit potent activity against HIV RT and HIV replication in cell culture. The
cinnamyl derivatives proved superior to the phenyloxyethyl derivatives, with 1-[2-(4-
methylphenoxy)ethyl]-3-(3,5-dimethylbenzyl)uracil (19) exhibiting the highest activity (EC50
=
Available online
0.27 µM) thus confirming that the 3-benzyluracil fragment in the NNRTI structure can be
regarded as a functional analogue of the benzophenone pharmacophore typically found in
NNRTIs.
Keywords:
Keyword_1
Keyword_2
Keyword_3
Keyword_4
Keyword_5
2009 Elsevier Ltd. All rights reserved.
Recent reports from the UNAIDS reveal that there are 34
million HIV-infected patients worldwide.1 The number of annual
AIDS-related deaths is estimated to be 2.5-3.3 million, or 25
million deaths overall.1 Despite the development of resistance to
many currently used therapeutics, HIV reverse transcriptase
(HIV-RT) remains one of the major biological targets in the
search of new drugs against HIV. HIV-RT plays a key role at
early stages of viral replication by catalyzing the RNA-dependent
frequent mutant HIV strains with enhanced safety profiles.
synthesis, ribonuclease H and DNA-dependent DNA synthesis of
proviral double-stranded DNA.2 Compounds inhibiting HIV-RT
are categorized as nucleoside/nucleotide (NRTI) and
nonnucleoside (NNRTI) inhibitors. Nucleoside/nucleotide
inhibitors bind in the active site of HIV-RT, while the NNRTIs
comprise a structurally diverse spectrum of compounds capable
of initiating conformational changes in HIV-RT by binding
allosterically, which then results in the loss of HIV-RT
polymerase activity.3
The first generation of NNRTIs (nevirapine,4 delavirdine,5
efavirenz6) displayed potent activity and low toxicity. However
due to the high genetic variability of the virus, resistant strains
with one or more point mutations in the RT binding pocket
rapidly developed, and these first generation drugs proved to be
problematic.7 In contrast, second generation FDA-approved
drugs including etravirine (TMC125)8 and rilpivirine (TMC278)9
proved to be highly active against both wild-type and the most
Figure 1.

Etravirine and rilpivirine are classified as diarylpyrimidines.
More recently biaryl esters such as MK-4965 have further
increased the structural diversity of the NNRTI inhibitors (Figure
1).10 These biaryl ethers are also active against both wild-type
and mutant RTs at nanomolar concentrations. Notably, the
common feature of these two NNRTI types, as well as many
others, particularly, the benzophenone derivatives 111 is the
presence of three aromatic rings connected by short linkers
(Figure 2).
Scheme 1.
ethyl]thymine (21) was obtained in a yield of 87% from 1-[2-(4-
methylphenoxy)ethyl]thymine and benzyl chloride.
Next, with a goal of studying the bridge linking the phenyl
residue and the pyrimidine N3 we synthesized the 3-(2-
phenylethyl)- (22) and 3-(1-phenylethyl)- derivatives of 1-[2-(4-
methylphenoxy)ethyl] uracil (23). In an analogous manner as
before, starting with 3 (R1 = 4-Me), treatment with 2- or 1-
chloroethylbenzene gave derivatives 22 and 23 (Figure 4),
respectively. Interestingly, the yield of compound 22 did not
exceed 35% due to the highly favorable elimination of hydrogen
chloride which was not observed in the case of 1-
chloroethylbenzene.
Figure 2.
Related to this, the uracil ring system has found many
applications in the construction of therapeutically useful
molecules. It is more attractive than a benzene ring because of
increased potential to form polar intermolecular interactions and
hydrogen bonding interactions, both of which can improve
enzyme affinity and the pharmacokinetic properties of target
compounds. Drawing upon the structural features of other highly
13
active NNRTIs,12,
we previously reported14 a series of
Figure 4.
The corresponding naphthyl and quinazolyl derivatives 25 and
27 were also sought. Compound 25 was prepared using the
addition of a benzyl substituent to the uracil N-3 of 1-[2-(2-
naphthoxy)ethyl]uracil (24) synthesized previously in our
laboratories15 (Scheme 2). The synthesis of analogue 27 is shown
in Scheme 3. Employing 3-benzylquinazolin-2,4(1Н,3Н)-dione
(26), 27 was synthesized as described by Kirincich16 using
amination of benzoxazin-2,4(1Н,3Н)-dione with benzylamine in
ethylene glycol. The resulting 3-benzyl derivative was then
treated with 1-bromo-2-(4-methylphenoxy)ethane in DMF in the
presence of K2CO3 to give the target 3-benzyl-1-[2-(4-
methylphenoxy)ethyl]quinazolin-2,4(1Н,3Н)-dione (27) in 84%
yield.
Figure 3.
benzophenone derivatives of pyrimidines
2 with potent
antiretroviral activity. Like the original benzophenones
1
12
reported by GlaxoSmithKline (Figure 2)11,
our compounds
featured replacement of the distal benzene ring by uracil. As a
logical extension of our previous investigations, herein we have
prepared a new series of compounds with the central aromatic
system replaced by uracil (Figure 3).
Two groups of N1,N3-disubstituted uracil derivatives were
designed as potential HIV-RT inhibitors.
Scheme 2.
As shown in Figure 3, the N1-atom of uracil is connected to
the aryl fragment by a three-atom linker containing either an
ether (oxygen) or a double bonded (alkenyl) moiety.
The generalized synthesis of the first group of target
compounds is shown in Scheme 1. The various 1-[2-(phenoxy)-
ethyl]uracils 3 were obtained according to literature procedures.15
Each uracil was then treated with the appropriate benzyl halide in
DMF in the presence of K2CO3 to give the target compounds 4 –
20 (80-94%). In addition, 3-benzyl-1-[2-(4-methylphenoxy)-
Scheme 3.
Synthesis of the unsaturated targets was then undertaken. In
that regard, 3-benzyl-1-cinnamyluracils 29 – 34 and their 3-(1-
naphthylmethyl) derivative 35 were synthesized in two steps as
shown in Scheme 4. Next, 1-cinnamyluracil (28) was prepared by

condensation of 2,4-bis(trimethylsilyloxy)pyrimidine with
cinnamyl bromide. The reaction mixture was refluxed in 1,2-
dichloroethane for 20 h to give 28 in a 90% yield. As noted by
TLC, 1-cinnamyluracil (28) was the only product. The
physicochemical and spectral data matched those published
previously whereby different synthetic routes were used.17-19 It
should be noted that Malik et al.20, 21 initially incorrectly assigned
the structure of 1-cinnamyluracil (28) to its isomerization
product22 when 28 and some of its analogues were synthesized
using I2 as a catalyst. The product of the isomerization is
apparently the oxazolo[3,2-a]pyrimidin-7-one heterocyclic
system as previously reported by Skaric.22
Table 1. Antiviral activity of the studied compounds against
HIV-1.
Comp.
R1=X
R2
R3
CC50
HIV-1 (IIIB) wild RT
(µM)1 type
Next, 1-cinnamyluracil (28) was treated with the
corresponding benzyl halides in DMF solution in the presence of
K2CO3 (1.5 molar excess) at room temperature.23 This reaction
afforded the corresponding 3-benzyl-1-cinnamyl derivatives of
uracil 29 – 34 with yields ranging between 71-81%.
EC50
SI3
Ki
(µM)2
(µM)4
4
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
193
117
207
187
63
9.5
20
-
68
5
2-Me
3-Me
4-Me
4-t-Bu
4-Ph
4-Cl
4-F
> 117
31
> 100
> 100
52
6
6.7
17
-
7
11
8
> 63
8.3
15
9
31
3.8
-
8.1
10
11
12
13
36
> 36
27
22
187
166
60
6.9
3.9
-
71
4-CN
43
51
3,4-
Me2
> 60
> 100
14
3,5-
Me2
H
H
46
> 46
-
> 100
15
16
17
18
19
20
4-Me
4-Me
4-Me
4-Me
4-Me
4-Me
2-Me
H
H
H
H
H
H
46
> 46
3.4
-
> 100
6.6
3-Me
≥ 38
250
≥ 11
-
4-Me
> 250
47
Scheme 4.
2,5-Me2
3,5-Me2
> 343 5.2
> 66
>1270
-
10
1-Cinnamyl-3-(1-naphthylmethyl)uracil (35, shown below in
Figure 5) was obtained in a similar manner with a yield of 72%.
> 343 0.27
0.26
> 100
2,4,6-
Me3
133
> 133
21
22
23
25
27
29
30
31
32
33
34
-
-
Me > 356 > 356
-
1
-
-
H
H
H
-
129
132
37
> 129
6.5
-
6.5
12
-
-
20
-
-
-
> 37
> 25
7.85
1.27
8.4
1
-
-
25
-
1
Figure 5.
H
H
H
H
H
H
H
H
H
H
H
H
H
160
257
31
20
202
4
29
The structures of the synthesized compounds and their purity
were confirmed by NMR (1Н and 13С) spectroscopy, TLC and
mass-spectrometry.
3,5-Me2
3,5-F2
3,5-Cl2
3,5-Br2
0.55
12
The results of the biological studies revealed that several
oxyethyl (4 – 23, 25 and 27), and cinnamyl derivatives (29 – 35)
demonstrated anti-HIV-1 activity in MT-4 cell culture and
proved to be inhibitors of the recombinant RT in vitro. However,
their activity was lower than structurally related benzophenone
49
1.99
1.72
1.36
24
134
73
0.67
0.31
0.31
231
100
3-Br-5-
Me
analogues 1 and 211,
or several known NNRTIs.10,
12, 14, 24
16, 25
35
H
-
H
293
>4
13
22
6.6
7.2
Analysis of the structure-activity relationship study revealed that
Nevirapine
0.048
>400
the highest activity was displayed for the uracils bearing a 3,5-
27
disubstituted benzyl group.26,
In that regard, 1-[2-(4-
(19)
1CC50, cytotoxic concentration; the concentration affording 50% death of
noninfected MT-4 cells; 2EC50, Effective concentration; the concentration
affording 50% inhibition of virus replication in MT-4 cells; 3SI, selectivity
index, ratio CC50/ IC50; 4Ki, inhibition constant; the concentration of a non-
competitive RT inhibitor ensuring 50% inhibition of the enzymatic activity;
*Compound precipitation was detected at higher compound concentrations.
methylphenoxy)ethyl]-3-(3,5-dimethylbenzyl)uracil
exhibited the highest activity (EC50: 0.27 µM) and the selectivity
index was greater than 1270 (see Table 1). This compound also
showed the most pronounced inhibitory activity toward HIV-1

35
14 (7)
6.4 (16)
5.7 (23)
1.0 (63)
≥100
132
63
RT, thus confirming the mechanism of anti-HIV-1 activity for the
described compounds. This implies that the 3-benzyluracil
fragment in the NNRTI structure can be regarded as a functional
analogue of the benzophenone pharmacophore, although the
latter ensures higher antiviral activity. In general, the cinnamyl
derivatives showed a stronger inhibitory activity against HIV and
HIV RT than the phenyloxyethyl derivatives, although the
highest activity was demonstrated by the phenoxyethyl-
containing compound 19 (Table 1).
Ganciclovir
Cidofovir
6.3 (21)
0.98 (64)
The compounds were also tested as potential inhibitors of a
large panel of viruses including Feline Corona Virus, Herpes
simplex virus-1, Herpes simplex virus-2, Vaccinia virus,
Vesicular stomatitis virus, Coxsackie virus B4, Respiratory
syncytial virus, Influenza A H1N1 subtype, Influenza A H3N2
subtype, Influenza B, Para-influenza-3 virus, Reovirus-1, Sindbis
virus, Punta Toro virus, varicella-zoster virus and human
cytomegalovirus, but found inactive, except for the three
cinnamyl derivatives that exhibited notable antiviral activity
towards human cytomegalovirus (HCMV) (Table 3).
The most active compounds were then tested against a double
mutant of HIV-1 RT, K103N/Y181C, in MT-4 cell culture.
However, neither of them showed any activity in the range of the
concentrations studied. This may be due to the replacement of the
anilide fragment in the linker region, as compared to the
benzophenone NNRTIs, which apparently results in a loss of
stacking interactions with the Tyr181 residue. Analysis of the
inhibitory activity of several compounds against a panel of
single- and double-mutated RTs revealed that N1,N3-disubstituted
uracils retained pronounced activity against the L100I and the
G190A mutants (Table 2). They also inhibit RTs with a V106A
or Y181C substitution, although at much higher concentrations.
Against mutant K103N/Y181C RT, all tested compounds proved
inactive.
In order to rationalize the anti-HIV activity observed,
molecular modeling studies were employed. Cross-docking was
performed with AutoDock Vina 1.1.2 and MGLTools 1.5.4
software.28 Preliminary studies show the ability to reproduce
experimentally observed binding modes in various HIV-1
RT/NNRTI complexes (PDB entries 2BE2, 3DLE, 3DLG,
3DM2, 3DOK, 3DRP, 3DYA) with an average RMSD (root
mean square deviation) value as low as 0,67Å. The accuracy of
predicted modes was also ascertained by visual observations
according to the Interactions-Based Accuracy Classification
protocol.29
Table 2. Inhibitory activity of the selected compounds against
mutant RTs.
HIV-1 RT
Ki (µМ)
The most active compound in the series (19) was docked into
HIV-1 WT RT (3DYA13) and K103N RT (3DOK11) mutants and
the results are shown in Fig. 6. An excellent correlation between
the benzyl of 19 and the corresponding moiety of the original
3DYA ligand was revealed. The uracil ring also forms a close
hydrophobic contact with the Leu100 residue (omitted for
clarity), while the phenoxy core is sandwiched between the
Val106 and Pro236 residues. However, a complete lack of
interactions with the phenoxyethyl side chain was also noted.
19
30
32
33
34
NVP
EFV
0.01
0.08
0.58
0.05
0.03
0.06
0.14
WT
0.26
0.13
>26
7.5
0.55
0.76
12
0.67
0.92
15.5
11
0.31
0.36
9.4
4.2
25
0.31
0.24
6.9
2.3
20
7.2
L100I
273
K103N
V106A
Y181C
G190A
K103N/Y181C
>2000
>2000
>2000
>2000
>2000
2.9
169
0.36
>26
75
43
0.4
0.55
0.3
0.18
85
In comparison to the benzophenone derivative GW78248,
significant differences in the benzyl and benzoyl cores'
orientations were observed, although the overall binding mode
was retained. Strong correlation between the benzophenone’s and
uracil’s carbonyl groups is also noteworthy and hypothesized to
be a consequence of steric preferences. As depicted in Fig. 6,
unfavorable π-stacking interactions associated with mutations at
Tyr181 and Tyr188 are also predicted, along with the lack of H-
bonding at Asn103. These findings may explain the dramatic loss
in activity against K103N and some other mutant HIV strains. As
a result, further optimization of this region should be pursued.
Cinnamyl derivatives 28 – 34 were modeled in analogous manner
and follow similar binding patterns (data not shown).
>100
>100 >100
*Compound precipitation was observed at higher concentrations.
Table 3. Anti-HCMV activity of the synthesized compounds.
Comp.
IC50 (µM) (SI)
CC50 (µM)
AD169
Davis
31
37 (1.38)
9.4 (11)
45 (1.13)
12 (9)
51
32
34
≥100
≥100
16 (6)
≥20 (5)

Figure 6. Predicted binding modes for 19 overlaid with original ligands (pale-yellow colored) in 3DYA (left) and 3DOK (right) crystal structures.
Only key residues are shown. Orange lines indicate stacking interactions.
As seen from Tables 1 and 2, the presence of the methyl
groups in positions (3 and 5) of the proximal phenyl ring and a
polar group in position 4 of the distal phenyl ring (R1) lead to the
best binding for ligands 7 – 12 and 17 – 19. This can be
explained by the interactions of the groups of ring R2 with
Trp229 (Fig. 3), while proton substitution in position 4 disrupts
the favorable CH-π stacking (compounds 17 and 20). In contrast,
the extended groups in position 4 of ring R1 are not favorable as
they reach solvent accessible area at the entrance of the pocket.
The absence of binding for compound 20 is due to steric
restrictions between the methyl group in the ortho position of the
R2 ring and the carbonyl oxygens in the central uracil ring R3
since they are densely packed in the pocket. However it appears
there are still enough degrees of freedom to properly orientate the
R2 ring when only one methyl group in the ortho position is
present (compound 18).
(Moscow, Russia). Ni-NTA-agarose resin and Rosetta (DE3)
E.coli strain were from Novagen (Madison, WI). All other
reagents of highest grade were obtained from Sigma (St. Louis,
MI). 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. NMR spectra were registered on a Bruker
1
Avance 400 spectrometer (400 MHz for H and 100 MHz for
13C) in CDCl3 or DMSO-d6 with tetramethylsilane as an internal
standard. Mass spectra were registered on Hewlett Packard 5973
MSD and FINNIGAN POLARIS Q mass-spectrometers (70 eV,
the ion chamber temperature 250 °С). TLC was performed on
Merck TLC Silica gel 60 F254 plates eluted with ethyl acetate and
developed with iodine. Melting points were determined in glass
capillaries on a Mel-Temp 3.0 (Laboratory Devices Inc., США).
Yields refer to spectroscopically (1H and 13C NMR)
homogeneous materials.
Conclusion:
A series of phenyloxyethyl and cinnamyl derivatives of
substituted uracils were synthesized and found to be inhibitory
against HIV RT and HIV replication in cell culture. In general,
the cinnamyl derivatives proved somewhat superior to the
phenyloxyethyl derivatives, however inhibition of mutant HIV-1
RT was less pronounced when additional NNRTI-characteristic
mutations were present in the enzyme. Moreover, the double
mutant K103N/Y181C was detrimental for anti-HIV-1 activity.
Some cinnamyl derivatives showed moderate anti-HCMV
activity, however this was not the case for the phenyloxyethyl
derivatives, which were essentially inactive. Efforts are currently
underway to improve the promising activity noted by several of
the compounds. New structural modifications guided by
additional docking efforts are currently being explored. For
example, it may prove that the N1-side chain can be optimized for
maximizing interactions with the amino acid landscape by use of
H-bond donors and/or introducing conformational restrictions.
These results will be reported elsewhere as they are obtained.
3-Benzyl-1-[2-(phenoxy)ethyl]uracil (4). A suspension of 1-
[2-(phenoxy)ethyl]uracil15 (3) (0.85 g, 3.66 mmol) of and К2СО3
(0.6 g, 4.34 mmol) in DMF (8 mL) was stirred at 80 °С for 1 h.
Benzyl chloride (0.44 mL, 3.82 mmol) was added and the
mixture stirred at the same temperature for 24 h. The reaction
mixture was cooled to room temperature, poured into cold H2O
(250 mL) and kept at 4 °С for 10 h. The resulting precipitate was
filtered and recrystallized from mixture of acetone (30 mL) and
H2O (10 mL) to give colorless crystals which were filtered and
air-dried to give 4 (1.05 g, 89 %), mp: 101-103 °C, Rf 0.50
1
(hexane-ethyl acetate, 1:1); H NMR (CDCl3):  4.12 (2H, t, J =
4.5 Hz, CH2), 4.20 (2H, t, J = 4.5 Hz, CH2), 5.15 (2H, s, CH2Ph),
5.77 (1H, d, J = 8 Hz, H-5), 6.88 (2H, d, J = 8.6 Hz, H-2’, H-6’),
7.01 (1H, t, J = 7.3 Hz, H-4’), 7.27-7.35 (7H, m, H-3’, H-5’,
C6H5), 7.50 (1H, d, J = 7 Hz, H-6). 13C NMR (CDCl3):  43.9,
48.8, 65.1, 100.9, 114.0, 121.2, 127.2, 128.0, 128.5, 129.3, 136.4,
143.1, 151.1, 157.5, 162.6. MS (ES+): m/z (%) 229.1 (65), 91.3
(100).
1. Experimental
3-Benzyl-1-[2-(2-methylphenoxy)ethyl]uracil (5). Was
synthesized in a similar manner as 4 to give 5 (1.2 g, 3.57 mmol,
88%) as colorless crystals, mp: 108-109 °C, Rf 0.52 (hexane-
1.1. General
Activated DNA was purchased from GE Healthcare (Little
Chalfont, UK) [α-32P]dATP (5000 Ci/mmol) was from Izotop

1
ethyl acetate, 1 : 1); H NMR (CDCl3):  2.21 (3H, s, CH3), 4.16
101.0, 115.3, 126.0, 127.2, 128.0, 128.5, 129.1, 136.3, 143.0,
151.1, 156.1, 162.5. MS (ES+): m/z (%) 229.1 (69), 91.1 (100).
(2H, t, J = 5.3 Hz, CH2), 4.22 (2H, t, J = 5.0 Hz, CH2), 5.17 (2H,
s, CH2Ph), 5.79 (1H, d, J = 7.8 Hz, H-5), 6.78 (1H, d, J = 8.2 Hz,
H-6’), 6.94 (1H, dt, J = 7.4 and 0.8 Hz, H-4’), 7.17-7.20 (2H, m,
H-5’, H-6’), 7.29-7.36 (5H, m, C6H5), 7.51 (1H, dd, J = 8 and 1.2
Hz, H-6). 13C NMR (CDCl3):  16.0, 43.9, 49.0, 64.9, 100.8,
110.3, 120.8, 126.0, 126.6, 127.2, 128.0, 128.6, 130.6, 136.4,
143.3, 151.1, 155.6, 162.6. MS (ES+): m/z (%) 229.1 (75), 91.1
(100).
3-Benzyl-1-[2-(4-fluorophenoxy)ethyl]uracil (11). Was
synthesized in a similar manner as 4 to give 11 (1.7 g, 4.99
mmol, 89%) as long needle crystals, mp: 95-96 °C, Rf 0.56
(hexane-ethyl acetate, 1:1); 1H NMR (CDCl3):  4.10 (2H, d, J =
4.2 Hz, CH2), 4.16 (2H, d, J = 4.4 Hz, CH2), 5.14 (2H, s, CH2Ph),
5.76 (1H, d, J = 8 Hz, H-5), 6.76-6.80 (2H, aromatic H), 6.94-
6.99 (2H, aromatic H), 7.25-7.34 (4H, m, aromatic H), 7.47-7.49
(2H, m, aromatic H, H-6). 13C NMR (CDCl3):  43.9, 48.8, 65.8,
100.9, 115.1, 115.5, 115.7, 127.2, 128.0, 128.5, 136.4, 143.1,
151.1, 153.7, 156.0, 158.4, 162.5. MS (ES+): m/z (%) 229.1 (81),
91.1 (100).
3-Benzyl-1-[2-(3-methylphenoxy)ethyl]uracil (6). Was
synthesized in a similar manner as 4 to give 6 (1.13 g, 3.36
mmol, 83%) as colorless crystals, mp: 102-103 °C, Rf 0.53
1
(hexane-ethyl acetate, 1:1); H NMR (CDCl3):  2.36 (3H, s,
CH3), 4.11 (2H, t, J = 4.8 Hz, CH2), 4.20 (2H, t, J = 4.8 Hz,
CH2), 5.16 (2H, s, CH2Ph), 5.78 (1H, d, J = 8 Hz, H-5), 6.69 (1H,
d, J = 8.2 Hz, H-4’), 6.72 (1H, s, H-2’), 6.84 (1H, d, J = 7.6 Hz,
H-6’), 7.19 (1H, t, J = 7.8 Hz, H-5’), 7.29-7.35 (5H, m, C6H5),
7.51 (1H, d, J = 6.9 Hz, H-6). 13C NMR (CDCl3):  21.1, 43.9,
48.8, 65.1, 100.9, 110.8, 115.0, 122.0, 127.2, 128.0, 128.5, 129.0,
136.4, 139.4, 143.2, 151.1, 157.6, 162.6. MS (ES+): m/z (%)
229.1 (77), 91.1 (100).
3-Benzyl-1-[2-(4-cyanophenoxy)ethyl]uracil (12). Was
synthesized in a similar manner as 4 to give 12 (0.95 g, 2.73
mmol, 88%) as needle crystals, mp: 126-127.5 °C, Rf 0.36
(hexane-ethyl acetate, 1:1); 1H NMR (CDCl3):  4.13 (2H, d, J =
4.6 Hz, CH2), 4.25 (2H, d, J = 4.6 Hz, CH2), 5.11 (2H, s, CH2Ph),
5.76 (1H, d, J = 7.8 Hz, H-5), 6.90 (2H, d, J = 8.8 Hz, H-3’, H-
5’), 7.23-7.31 (4H, m, aromatic H), 7.44-7.46 (2H, m, aromatic
H, H-6), 7.53-7.56 (2H, m, aromatic H). 13C NMR (CDCl3): 
43.9, 48.7, 65.4, 101.2, 104.4, 114.8, 118.5, 127.3, 128.0, 128.5,
133.7, 136.3, 142.8, 151.1, 160.7, 162.4. MS (ES+): m/z (%)
229.1 (100), 91.1 (94).
3-Benzyl-1-[2-(4-methylphenoxy)ethyl]uracil (7). Was
synthesized in a similar manner as 4 to give 7 (1.1 g, 3.27 mmol,
81%) as white lamellar crystals, mp: 99-101 °C, Rf 0.52 (hexane-
1
ethyl acetate, 1:1); H NMR (CDCl3):  2.31 (3H, s, CH3), 4.11
3-Benzyl-1-[2-(3,4-dimethylphenoxy)ethyl]uracil (13). Was
synthesized in a similar manner as 4 to give 13 (1.25 g, 3.57
mmol, 93%) as white prismatic crystals, mp: 111-112.5 °C, Rf
0.64 (hexane-ethyl acetate, 1:1); 1H NMR (CDCl3):  2.23 (3H, s,
CH3), 2.26 (3H, s, CH3), 4.11 (2H, d, J = 4.3 Hz, CH2), 4.19 (2H,
d, J = 4.4 Hz, CH2), 5.16 (2H, s, CH2Ph), 5.78 (1H, d, J = 7.8 Hz,
H-5), 6.63 (1H, dd, J = 8.2 and 2.6 Hz, H-5’), 6.71 (1H, d, J = 2.4
Hz, H-2’), 7.05 (1H, d, J = 8.3 Hz, H-6’), 7.27-7.36 (5H, m,
C6H5), 7.51 (1H, d, J = 6.7 Hz, H-6). 13C NMR (CDCl3):  18.4,
19.6, 43.9, 48.8, 65.2, 100.8, 110.9, 115.7, 127.2, 128.0, 128.5,
129.1, 130.1, 136.4, 137.6, 143.2, 151.1, 155.7, 162.6. MS
(ES+): m/z (%) 229.1 (69), 91.1 (100).
(2H, t, J = 4.6 Hz, CH2), 4.20 (2H, t, J = 4.5 Hz, CH2), 5.15 (2H,
s, CH2Ph), 5.77 (1H, d, J = 7.8 Hz, H-5), 6.77 (2H, d, J = 8.5 Hz,
H-3’, H-5’), 7.10 (2H, d, J = 8.3 Hz, H-2’, H-6’), 7.26-7.34 (5H,
m, C6H5), 7.49 (1H, d, J = 7.1 Hz, H-6). 13C NMR (CDCl3): 
20.1, 43.9, 48.8, 65.3, 100.9, 113.9, 127.2, 128.0, 128.5, 129.7,
130.4, 136.4, 143.1, 151.1, 155.4, 162.6. MS (ES+): m/z (%)
229.1 (73), 91.1 (100).
3-Benzyl-1-[2-(4-tert-butylphenoxy)ethyl]uracil (8). Was
synthesized in a similar manner as 4 to give 8 (0.75 g, 1.98
mmol, 82%) as white crystals, mp: 121-122 °C, Rf 0.58 (hexane-
1
ethyl acetate, 1:1); H NMR (CDCl3):  1.34 (9H, s, CH3), 4.12
(2H, t, J = 4.2 Hz, CH2), 4.22 (2H, t, J = 4.3 Hz, CH2), 5.16 (2H,
s, CH2Ph), 5.77 (1H, d, J = 7.8 Hz, H-5), 6.83 (2H, d, J = 6.7 Hz,
H-3’, H-5’), 7.29-7.36 (7H, m, C6H5, H-2’, H-6’), 7.51 (1H, d, J
= 8.1 Hz, H-6). 13C NMR (CDCl3):  31.1, 43.9, 48.9, 65.2,
100.9, 113.5, 126.0, 127.2, 128.0, 128.6, 136.4, 143.2, 143.9,
151.1, 155.3, 162.6. MS (ES+): m/z (%) 377.8 (1) [M+], 229.1
(88), 91.1 (100).
3-Benzyl-1-[2-(3,5-dimethylphenoxy)ethyl]uracil (14). Was
synthesized in a similar manner as 4 to give 14 (1.2 g, 3.42
mmol, 90%) as white crystals, mp: 78-79.5 °C, Rf 0.62 (hexane-
1
ethyl acetate, 1:1); H NMR (CDCl3):  2.32 (6H, s, CH3), 4.11
(2H, t, J = 4.3 Hz, CH2), 4.20 (2H, t, J = 4.2 Hz, CH2), 5.16 (2H,
s, CH2Ph), 5.78 (1H, d, J = 7.8 Hz, H-5), 6.52 (2H, s, H-2’, H-
6’), 6.67 (1H, s, H-4’), 7.29-7.36 (5H, m, C6H5), 7.50 (1H, d, J =
7 Hz, H-6). 13C NMR (CDCl3):  21.0, 43.9, 48.8, 65.1, 100.9,
111.8, 122.9, 127.2, 128.0, 136.4, 139.1, 143.2, 151.1, 157.6,
162.6. MS (ES+): m/z (%) 229.1 (74), 91.1 (100).
3-Benzyl-1-[2-(4-phenylphenoxy)ethyl]uracil (9). Was
synthesized in a similar manner as 4 to give 9 (1.1 g, 2.76 mmol,
85%) as white crystals, mp: 125-126 °C, Rf 0.53 (hexane-ethyl
1
acetate, 1:1); H NMR (CDCl3):  4.14 (2H, t, J = 4.5 Hz, CH2),
3-(2-Methylbenzyl)-1-[2-(4-methylphenoxy)ethyl]uracil
(15). Was synthesized in a similar manner as 4 to give 15 (1.05 g,
3.00 mmol, 92%) as white crystals, mp: 107-108 °C, Rf 0.57
4.27 (2H, t, J = 4.5 Hz, CH2), 5.18 (2H, s, CH2Ph), 5.80 (1H, d, J
= 8 Hz, H-5), 6.95 (2H, d, J = 8.8 Hz, H-3’, H-5’), 7.28-7.38 (7H,
m, C6H5, H-2’, H-6’), 7.45-7.48 (2H, aromatic H), 7.52-7.59 (4H,
m, aromatic H, H-6). 13C NMR (CDCl3):  43.9, 48.8, 65.3,
101.0, 114.4, 126.4, 126.5, 127.3, 127.6, 127.9, 128.1, 128.4,
128.6, 134.3, 136.4, 140.1, 143.1, 143.9, 151.1, 157.1, 162.6. MS
(ES+): m/z (%) 397.9 (1) [M+], 229.1 (100), 91.2 (97).
1
(hexane-ethyl acetate, 1:1); H NMR (CDCl3):  2.34 (3H, s,
CH3), 2.49 (3H, s, CH3), 4.12 (2H, t, J = 4.3 Hz, CH2), 4.20 (2H,
t, J = 4.3 Hz, CH2), 5.17 (2H, s, CH2Ar), 5.82 (1H, d, J = 8 Hz,
H-5), 6.81 (2H, d, J = 8.4 Hz, H-3’, H-5’), 7.03-7.05 (1H, m,
aromatic H), 7.12-7.21 (5H, m, H-2’, H-6’, aromatic H), 7.37
(1H, d, J = 8 Hz, H-6). 13C NMR (CDCl3):  18.9, 20.1, 41.4,
48.9, 65.3, 100.7, 114.0, 125.4, 125.7, 126.7, 129.7, 129.9, 130.5,
134.1, 135.4, 143.4, 151.2, 155.5, 162.7. MS (ES+): m/z (%)
243.0 (74), 139.2 (100), 105.3 (42).
3-Benzyl-1-[2-(4-chlorophenoxy)ethyl]uracil (10). Was
synthesized in a similar manner as 4 to give 10 (1.63 g, 4.57
mmol, Yield: 94%) as white crystals, mp: 102-103 °C, Rf 0.49
(hexane-ethyl acetate, 1:1); 1H NMR (CDCl3):  4.10 (2H, d, J =
4.4 Hz, CH2), 4.17 (2H, d, J = 4.4 Hz, CH2), 5.13 (2H, s, CH2Ph),
5.76 (1H, d, J = 7.8 Hz, H-5), 6.78 (2H, d, J = 9 Hz, H-3’, H-5’),
7.22 (2H, d, J = 9 Hz, H-2’, H-6’), 7.26-7.34 (7H, m, C6H5), 7.48
(1H, d, J = 8.2 Hz, H-6). 13C NMR (CDCl3):  43.9, 48.8, 65.4,
3-(3-Methylbenzyl)-1-[2-(4-methylphenoxy)ethyl]uracil
(16). Was synthesized in a similar manner as 4 to give 16 (1.0 g,
2.85 mmol, 88%) as white crystals, mp: 102-103 °C, Rf 0.63
1
(hexane-ethyl acetate, 1:1); H NMR (CDCl3):  2.32 (3H, s,
CH3), 2.35 (3H, s, CH3), 4.11 (2H, t, J = 4.4 Hz, CH2), 4.20 (2H,

t, J = 4.4 Hz, CH2), 5.12 (2H, s, CH2Ar), 5.77 (1H, d, J = 7.9 Hz,
H-5), 6.77 (2H, d, J = 8.7 Hz, H-3’, H-5’), 7.10 (2H, d, J = 8.3
Hz, H-2’, H-6’), 7.22 (1H, t, J = 7.5 Hz, H-5”), 7.28-7.33 (4H, m,
H-2”, H-4”, H-6”, H-6). 13C NMR (CDCl3):  20.1, 21.0, 43.9,
48.8, 65.3, 100.9, 113.9, 125.5, 127.9, 129.2, 129.7, 130.4, 136.3,
137.6, 143.1, 151.1, 155.4, 162.6. MS (ES+): m/z (%) 243.0 (74),
105.3 (100).
which were filtered and air-dried to give 21 (1.4 g, 87 %), mp:
143-144 °С, Rf 0.73 (hexane-ethyl acetate, 1:1); 1H NMR
(CDCl3):  1.97 (3Н, s, СН3), 2.32 (3H, s, CH3), 4.10 (2H, t, J =
4.5 Hz, CH2), 4.20 (2H, t, J = 4.6 Hz, CH2), 5.17 (2H, s, CH2Ph),
5.76 (1H, d, J = 7.9 Hz, H-5), 6.78 (2H, d, J = 8.6 Hz, H-3’, H-
5’), 7.10 (2H, d, J = 8.5 Hz, H-2’, H-6’), 7.16 (1H, s, H-6), 7.26-
7.35 (3H, m, aromatic H), 7.51-7.53 (2H, m, aromatic H). 13C
NMR (CDCl3):  12.6, 20.1, 44.2, 48.6, 65.5, 109.0, 113.9,
127.1, 128.0, 128.7, 129.7, 130.4, 136.6, 139.3, 151.2, 155.5,
163.3. MS (ES+): m/z (%) 243.1 (100), 91.1 (92).
3-(4-Methylbenzyl)-1-[2-(4-methylphenoxy)ethyl]uracil
(17). Was synthesized in a similar manner as 4 to give 17 (1.05 g,
3.00 mmol, 84%) as white crystals, mp: 124-125 °C, Rf 0.63
1
(hexane-ethyl acetate, 1:1); H NMR (CDCl3):  2.32 (3H, s,
1-[2-(4-Methylphenoxy)ethyl]-3-(2-phenylethyl)uracil (22).
CH3), 2.35 (3H, s, CH3), 4.11 (2H, t, J = 4.3 Hz, CH2), 4.19 (2H,
t, J = 4.5 Hz, CH2), 5.12 (2H, s, CH2Ar), 5.76 (1H, d, J = 7.9 Hz,
H-5), 6.78 (2H, d, J = 8.4 Hz, H-3’, H-5’), 7.10 (2H, d, J = 8.3
Hz, H-2’, H-6’), 7.14 (2H, d, J = 7.7 Hz, H-3”, H-5”), 7.30 (1H,
d, J = 7.8 Hz, H-6), 7.41 (2H, d, J = 7.7 Hz, H-2”, H-6”). 13C
NMR (CDCl3):  20.1, 20.8, 43.6, 48.8, 65.3, 100.9, 113.9,
125.5, 128.6, 128.7, 129.7, 130.4, 133.5, 136.9, 143.1, 151.1,
155.4, 162.6. MS (ES+): m/z (%) 243.0 (78), 139.1 (100), 105.3
(33).
A
suspension of 0.8
g
(3.25 mmol) of 1-[2-(4-
methylphenoxy)ethyl]uracil (1)15 and 0.55 g (3.98 mmol) of
К2СО3 in DMF (8 mL) was stirred at 80 °С for 1 h. 2-Phenyl
chloroethane (0.5 mL, 3.98 mmol) was added and the mixture
was stirred at the same temperature for 2 h and then refluxed for
an additional 4 h. The reaction mixture was cooled to room
temperature, poured into cold H2O (150 mL) and kept at 4 °С for
10 h. The aqueous layer was decanted and the solid residue
recrystallized from a mixture of acetone (25 mL) and H2O (8
mL). The precipitate was filtered and air dried to give 22 (0.4 g,
35 %) as small white crystals, mp: 86-87 °С, Rf 0.65 (hexane-
1-[2-(4-Methylphenoxy)ethyl]-3-(2,5-dimethylbenzyl)uracil
(18). Was synthesized in a similar manner as 4 to give 18 (1.2 g,
3.29 mmol, 83%) as white crystals, mp: 143-144 °C, Rf 0.64
1
ethyl acetate, 1:1); H NMR (CDCl3):  2.32 (3H, s, CH3), 2.96
(2H, t, J = 5.8 Hz, CH2), 4.11 (2H, t, J = 4.1 Hz, CH2), 4.16-4.22
(4H, m, CH2), 5.75 (1H, d, J = 7.9 Hz, H-5), 6.80 (2H, d, J = 8.6
Hz, H-3’, H-5’), 7.12 (2H, d, J = 8.4 Hz, H-2’, H-6’), 7.25-7.33
(6H, m, C6H5, H-6). 13C NMR (CDCl3):  20.8, 33,2 42.0, 48.9,
65.2, 100.8, 113.9, 126.0, 128.0, 128.6, 129.7, 130.4, 138.1,
143.1, 150.9, 155.4, 162.5. MS (ES+): m/z (%) 243.1 (78), 139.1
(100).
1
(hexane-ethyl acetate, 1:1); H NMR (CDCl3):  2.22 (3H, s,
CH3), 2.33 (3H, s, CH3), 2.44 (3H, s, CH3), 4.14 (2H, t, J = 4.5
Hz, CH2), 4.20 (2H, t, J = 4.7 Hz, CH2), 5.13 (2H, s, CH2Ar),
5.83 (1H, d, J = 7.8 Hz, H-5), 6.79-6.83 (3H, m, H-3’, H-5’, H-
6”), 6.97 (1H, d, J = 7.4 Hz, H-4”), 7.06-7.13 (3H, m, H-2’, H-6’,
H-3”), 7.39 (1H, d, J = 7.8 Hz, H-6). 13C NMR (CDCl3):  18.5,
20.1, 20.7, 41.4, 48.9, 65.4, 100.8, 113.9, 126.1, 127.4, 129.7,
129.8, 130.5, 132.3, 133.8, 135.0, 143.3, 151.1, 155.5, 162.8. MS
(ES+): m/z (%) 257.1 (100), 139.1 (99), 119.2 (49).
1-[2-(4-Methylphenoxy)ethyl]-3-(1-phenylethyl)uracil (23).
A
suspension of 0.9
g
(3.55 mmol) of 1-[2-(4-
methylphenoxy)ethyl]uracil (1)15 and 0.6 g (4.83 mmol) of
К2СО3 in DMF (8 mL) was stirred at 80 °С for 1 h. 1-
Phenylchloroethane (0.6 g, 4.27 mmol) was added and the
mixture stirred at the same temperature for 4 h. The reaction
mixture was cooled to room temperature, poured into cold H2O
(250 mL) and kept at 4 °С for 10 h. The aqueous layer was
decanted and the solid residue recrystallized from mixture of
acetone (30 mL) and H2O (10 mL). The precipitate was filtered
and air-dried to give 23 (0.87 g, 70 %) as small lamellar white
1-[2-(4-Methylphenoxy)ethyl]-3-(3,5-dimethylbenzyl)uracil
(19). Was synthesized in a similar manner as 4 to give 19 (1.07 g,
2.94 mmol, 80%) as white crystals, mp: 126-127 °C, Rf 0.66
1
(hexane-ethyl acetate, 1:1); H NMR (CDCl3):  2.31 (6H, s,
CH3), 2.32 (3H, s, CH3), 4.12 (2H, t, J = 4.2 Hz, CH2), 4.20 (2H,
t, J = 4.4 Hz, CH2), 5.09 (2H, s, CH2Ar), 5.78 (1H, d, J = 7.9 Hz,
H-5), 6.78 (2H, d, J = 8.6 Hz, H-3’, H-5’), 6.92 (1H, s, H-4”),
7.09-7.11 (4H, m, H-2’, H-6’, H-2”, H-6”), 7.31 (1H, d, J = 8 Hz,
H-6). 13C NMR (CDCl3):  20.1, 20.9, 43.8, 48.8, 65.3, 100.9,
113.9, 126.2, 128.9, 129.7, 130.4, 133.5, 136.2, 137.5, 143.1,
151.1, 155.4, 162.7. MS (ES+): m/z (%) 257.1 (92), 119.1 (100).
1
crystals, mp: 103-105 °С, Rf 0.57 (hexane-ethyl acetate, 1:1); H
NMR (CDCl3):  1.90 (3Н, d, J = 7.1 Hz, СН3), 2.33 (3Н, s,
СН3), 4.04-4.18 (4Н, m, СН2), 5.74 (1Н, d, J = 7.9 Hz, Н-5),
6.35 (1Н, q, J = 7.1, PhСН), 6.77 (2H, d, J = 8.5 Hz, H-3’, H-5’),
7.11 (2Н, d, J = 8.4 Hz, H-2’, H-6’), 7.27-7.36 (5Н, m, С6Н5),
7.44 (1Н, d, J = 7.5 Hz, Н-6). 13C NMR (CDCl3):  15.3, 20.1,
48.7, 50.0, 65.4, 100.9, 113.9, 126.6, 126.8, 127.7, 129.7, 130.4,
139.9, 143.1, 150.5, 155.5, 163.0. MS (ES+): m/z (%) 243.1 (24),
139.1 (100).
1-[2-(4-Methylphenoxy)ethyl]-3-(2,4,6-trimethylbenzyl)-
uracil (20). Was synthesized in a similar manner as 4 to give 20
(1.15 g, 3.04 mmol, 83%) as white crystals, mp: 142-142.5 °C, Rf
0.67 (hexane-ethyl acetate, 1:1); 1H NMR (CDCl3):  2.26 (3H, s,
CH3), 2.33 (9H, s, CH3), 4.08 (2H, t, J = 4.4 Hz, CH2), 4.14 (2H,
t, J = 4.4 Hz, CH2), 5.15 (2H, s, CH2Ar), 5.74 (1H, d, J = 7.8 Hz,
H-5), 6.78 (2H, t, J = 9 Hz, H-3’, H-5’), 6.83 (2H, s, H-3”, H-5”),
7.25 (2H, d, J = 9 Hz, H-2’, H-6’), 7.29 (1H, d, J = 7.8 Hz, H-6).
13C NMR (CDCl3):  19.8, 20.5, 39.6, 48.7, 65.5, 100.7, 115.3,
126.0, 128.9, 129.1, 129.5, 136.2, 137.0, 142.9, 150.8, 156.2,
162.7. MS (ES+): m/z (%) 271.1 (100), 132.1 (55).
3-Benzyl-1-[2-(2-naphthyloxy)ethyl]uracil
suspension of 1.0 (3.54 mmol)
(25).
of 1-[2-(2-
A
g
naphthyloxy)ethyl]uracil (24)15 and К2СО3 . (0.6 g, 4.34 mmol)
of in DMF (8 mL) was stirred at 80 °С for 1 h. Benzyl chloride
(0.45 mL, 3.91 mmol) was added and the mixture stirred at the
same temperature for 24 h. The reaction mixture was cooled to
room temperature, poured into cold water (250 mL) and kept at 4
°С for 10 h. The solids were filtered, dried and recrystallized
from a mixture of toluene (10 mL) and hexanes (5 mL) and air-
dried to give 25 (1.1 g, 80 %) as white crystals, mp: 88-90 °С, Rf
0.65 (hexane-ethyl acetate, 1:1); 1H NMR (CDCl3): 4.16 (2H, t, J
= 4.5 Hz, CH2), 4.32 (2H, t, J = 4.5 Hz, CH2), 5.17 (2H, s,
CH2Ph), 5.79 (1H, d, J = 7.9 Hz, H-5), 7.10-7.13 (2H, m,
aromatic H), 7.27-7.7.35 (5H, m, aromatic H), 7.38-7.42 (1H, m,
3-Benzyl-1-[2-(4-methylphenoxy)ethyl]thymine (21).
A
suspension of 1.2 g (4.61 mmol) of 1-[2-(4-methylphenoxy)-
ethyl]thymine15 and 0.8 g (5.79 mmol) of К2СО3 in DMF (8 mL)
was stirred at 80 °С for 1 h. Benzyl chloride (0.5 mL, 4.34 mmol)
was added and the mixture stirred at the same temperature for 24
h. The reaction mixture was cooled to room temperature, poured
into cold H2O (250 mL) and kept at 4 °С for 10 h. The resulting
precipitate was filtered and recrystallized from mixture of
acetone (25 mL) and H2O (6 mL) to give large colorless crystals

aromatic H), 7.47-7.53 (3H, m, aromatic H, H-6), 7.73-7.82 (3H,
m, aromatic H). 13C NMR (CDCl3): 44.0, 48,7, 65.2, 101.0,
106.6, 117.9, 123.7, 126.3, 126.4, 127.2, 127.3, 128.0, 128.6,
128.9, 129.3, 134.0, 136.4, 143.0, 151.2, 155.4, 162.6. MS
(ES+): m/z (%) 229.0 (100), 91.1 (82).
1-Cinnamyl-3-(3,5-dimethylbenzyl)uracil
(30).
Was
synthesized in a similar manner as 29 to give 30 (1.7 g, 4.91
mmol, 75%,) as white crystals, mp: 144.5-146 ºC, Rf 0.58
(hexane-ethyl acetate, 1:1); 1H NMR (CDCl3), δ: 2.27 (6H, s,
CH3), 4.49 (2H, dd, J = 6.7 and 1.25 Hz, NCH2), 5.07 (2H, s,
CH2Ph), 5.76 (1H, d, J = 7.94 Hz, H-5), 6.19 (1H, dt, J = 15.88
and 6.53 Hz, =CH-), 6.59 (1H, d, J = 15.88 Hz, ArCH=), 6.88
(2H, s, aromatic H), 7.16 (1Н, d, J = 7.94 Hz, aromatic H), 7.24-
7.37 (6H, m, aromatic H, Н-6). 13C NMR (CDCl3): 21.3, 44.4,
50.8, 102.2, 122.5, 126.7, 126.8, 128.5, 128.8, 129.4, 135.1,
135.7, 136.7, 138.0, 141.5, 151.6, 163.0. MS (ES+): m/z (%) 346
(19), 227 (49), 115 (100).
3-Benzyl-1-[2-(4-methylphenoxy)ethyl]quinazoline-
2,4(1H,3H)-dione (27). A suspension of 2616 (0.55 g, 2.18
mmol) and К2СО3 (0.4 g, 2.89 mmol) of in DMF (8 mL) was
stirred at 80 °С for 1 h. 1-Bromo-2-(4-methylphenoxy)ethane
(0.56 g, 2.60 mmol) was added and the mixture stirred at the
same temperature for 24 h. The reaction mixture was cooled to
room temperature, poured into cold water (250 mL) and kept at 4
°С for 10 h. The aqueous layer was decanted and the residue
crystallized from mixture of acetone (30 mL) and H2O (10 mL).
The precipitate was filtered and air dried to give 27 (0.75 g, 89
%) as colorless crystals, mp: 137-138 °C, Rf 0.84 (hexane:ethyl
acetate, 1:1); 1H NMR (CDCl3):  2.30 (3H, s, CH3), 4.31 (2H, t,
J = 5.7 Hz, CH2), 4.54 (2H, t, J = 5.8 Hz, CH2), 5.32 (2H, s,
CH2Ph), 6.77 (2H, d, J = 8.6 Hz, H-3’, H-5’), 7.07 (2H, J = 8.5
Hz, H-2’, H-6’), 7.25-7.37 (5H, m, C6H5), 7.49 (1H, d, J = 8.4
Hz, quinazoline H), 7.58 (1H, d, J = 7 Hz, quinazoline H), 7.68
(1H, dt, J = 7.1 and 1.5 Hz, quinazoline H), 8.27 (1H, dd, J = 7.9
and 1.5 Hz, quinazoline H). 13C NMR (CDCl3):  20.1, 43.1,
44.6, 64.9, 113.8, 114.0, 115.2, 122.6, 127.2, 128.1, 128.6, 128.7,
129.5, 130.1, 134.5, 136.6, 140.0, 150.7, 155.7, 161.3. MS
(ES+): m/z (%) 279.2 (96), 91.1 (100).
1-Cinnamyl-3-(3,5-difluorobenzyl)uracil
(31).
Was
synthesized in a similar manner as 29 to give 31 (1.65 g, 4.66
mmol, 71%) as white crystals, mp: 77-79 ºC, Rf 0.44 (hexane-
1
ethyl acetate, 1:1); H NMR (DMSO-d6), δ: 4.54 (2H, d, J = 5.9,
NCH2), 5.02 (2H, s, CH2), 5.83 (1H, d, J = 7.8, H-5), 6.37 (1H,
dt, J = 15.9 and 6.0, =CH-), 6.58 (1H, d, J = 16.0, PhCH=), 6.95-
7.00 м (2H, aromatic Н), 7.10 (1H, dt, J = 9.4 and 2.3, aromatic
Н), 7.23-7.27 м (1H, aromatic Н), 7.33 (2H, t, J = 7.5, aromatic
Н), 7.43 (2H, d, J = 7.3, aromatic Н), 7.78 (1H, d, J = 7.9, H-6).
13C NMR (DMSO-d6): 43.0, 50.2, 100.5, 102.7 (t, J = 25.6 Hz),
110.5 (dd, J = 18.4 and 6.9 Hz), 124.0, 126.5, 128.0, 128.7,
132.7, 135.9, 141.7, 144.4, 151.1, 161.1, 163.5. MS (ES+): m/z
(%) 354 (15), 239 (88), 115 (100).
1-Cinnamyl-3-(3,5-dichlorobenzyl)uracil
(32).
Was
1-Cinnamyluracil (28). A mixture of uracil (3.0 g, 26.76
synthesized in a similar manner as 29 to give 32 (2.0 g, 5.16
mmol, 78%) as white crystals, mp: 113-114 ºC, Rf 0.59 (hexane-
ethyl acetate, 1:1); 1H NMR (CDCl3), δ: 4.52 (2H, dd, J = 6.7
and 1.25 Hz, NCH2), 5.06 (2H, s, CH2Ph), 5.79 (1H, d, J = 7.94
Hz, H-5), 6.20 (1H, dt, J = 15.88 and 6.7 Hz, =CH-), 6.62 (1H, d,
J = 15.88 Hz, ArCH=), 7.21 (1Н, d, J = 7.94 Hz, aromatic H),
7.25-7.39 (8H, m, aromatic H, Н-6). 13C NMR (CDCl3): 43.6,
51.0, 102.1, 122.1, 126.7, 127.5, 128.0, 128.6, 128.8, 135.0,
135.5, 135.6, 140.0, 141.9, 151.4, 162.7. MS (ES+): m/z (%) 386
(9), 271 (50), 115 (100).
mmol) and ammonium chloride 0.3
g (5.6 mmol) in
hexamethyldisilazane (15 mL) was refluxed for 10 hr with
exclusion of moisture until a clear solution was obtained. The
excess silylating agent was removed in vacuum, the residual clear
oil of 2,4-bis(trimethylsilyloxy)pyrimidine was dissolved in 50
mL of dry 1,2-dichloroethane (distilled with P2O5), was added
cinnamyl bromide (4.2 mL, 28.35 mmol) to the solution and the
mixture was refluxed for 20 h under N2. The reaction mixture
was treated with isopropanol (10 mL), and the resulting sediment
filtered, washed with ethylacetate-hexane (1:1) and dried at room
temperature to give 28 (5,5 g, 90%) as small crystals which were
recrystallized from iPrOH-DMF-water (2:2:1); mp: 199-200 ºC
1-Cinnamyl-3-(3,5-dibromobenzyl)uracil
(33).
Was
synthesized in a similar manner as 29 to give 33 (2.55 g, 5.36
mmol, 81%,) as white crystals, mp: 124-126 ºC, Rf 0.60 (hexane-
1
(199-200 °C lit.18), Rf 0,56 (ethylacetate-hexane 1:1); H NMR
1
ethyl acetate, 1:1); H NMR (DMSO-d6), δ: 4.53 (2H, d, J = 5.7,
(CDCl3), δ: 4.45 (2H, m, NCH2), 5.61 (1H, dd, J = 8.0 and 2.3,
H-5), 6.32 (1H, dt, J = 15.9 and 6.0, =CH-), 6.55 (1H, d, J =
16.0, PhCH=), 7.24 (1H, m, aromatic Н), 7.32 (2H, t, J = 7.6,
aromatic Н), 7.43 (2H, d, J = 7.3, aromatic Н), 7.64 (1H, d, J =
7.9, H-6), 11.32 (1H, s, H-3). 13C NMR (CDCl3): 52.2, 104.7,
127.6, 129.8, 131.3, 132.0, 135.9, 139.3, 148.7, 154.3, 167.2.
NCH2), 4.99 (2H, s, CH2), 5.82 (1H, d, J = 7.9, H-5), 6.35 (1H,
dt, J = 15.9 and 5.9, =CH-), 6.57 (1H, d, J = 16.0, PhCH=), 7.22-
7.24 (1H, m, aromatic Н), 7.32 (2H, t, J = 7.5, aromatic Н), 7.41
(2H, s, H-2’, H-6’), 7.42 (1H, s, Н-4’), 7.50 (2H, s, aromatic Н),
7.68 (1H, s, aromatic Н), 7.76 (1H, d, J = 7.8, H-6). 13C NMR
(DMSO-d6): 50.2, 100.6, 122.4, 123.9, 126.5, 127.9, 128.6,
129.7, 132.3, 132.7, 135.9, 141.8, 144.4, 151.1, 162.5. MS
(ES+): m/z (%) 361 (35), 227 (21), 115 (100).
3-Benzyl-1-cinnamyluracil (29). A suspension of compounds
28 (1.0 g, 4.38 mmol) and К2СО3 (0.8 g, 7.79 mmol) in DMF (15
ml) was stirred at 80 °С for 1 h. Benzyl chloride (0.55 mL, 4.78
mmol) was added and the mixture stirred at the same temperature
for 8 h. The reaction mixture was cooled to room temperature,
poured into cold H2O (250 mL) and kept at 4 °С for 24 h. The
aqueous layer was decanted and the solid residue recrystallized
from mixture of acetone-H2O (2:1). The precipitate was filtered
and air-dried to give 29 (1.09 g, 3.42 mmol, 78 %) as small
needle white crystals, mp: 97-99 ºC, Rf 0.61 (hexane-ethyl
acetate, 1:1); 1H NMR (DMSO-d6), δ: 4.51 (2H, dd, J = 6.6 and
1.4 Hz, NCH2), 5.18 (2H, s, CH2Ph), 5.79 (1H, d, J = 7.9 Hz, H-
5), 6.22 (1H, dt, J = 15.9 and 6.5 Hz, =CH-), 6.62 (1H, d, J =
15.8 Hz, ArCH=), 7.18 (1Н, d, J = 7.9 Hz, aromatic H), 7.27-
7.41 (8H, m, aromatic H, H-6), 7.52-7.54 (2H, m, aromatic H).
13C NMR (DMSO-d6): 44.0, 50.4, 101.6, 122.0, 126.2, 127.2,
128.0, 128.3, 128.6, 134.6, 135.2, 136.5, 141.2, 151.1, 162.5. MS
(ES+): m/z (%) 318.1 (38), 227.1 (66), 115.1 (100).
3-(3-Bromo-5-methylbenzyl)-1-cinnamyluracil (34). Was
synthesized in a similar manner as 29 to give 34 (2.1 g, 5.11
mmol, 77%) as white crystals, mp: 134-135.5 ºC, Rf 0.65
1
(hexane-ethyl acetate, 1:1); H NMR (DMSO-d6), δ: 2.23 (3H, s,
CH3), 4.52 (2H, d, J = 5.9, NCH2), 4.95 (2H, s, CH2), 5.81 (1H,
d, J = 7.9, H-5), 6.35 (1H, dt, J = 15.9 and 6.0, =CH-), 6.55 (1H,
d, J = 16.0, ArCH=), 7.09 (1H, s, aromatic Н), 7.23-7.26 (3H, m,
Н-2’, H-4’, H-6’), 7.32 (2H, t, J = 7.5, aromatic Н), 7.42 (2H, d,
J = 7.7, aromatic Н), 7.75 (1H, d, J = 7.8, H-6). 13C NMR
(DMSO-d6): 23.9, 46.3, 103.9, 124.7, 127.3, 129.8, 130.8, 131.3,
132.0, 133.9, 136.1, 139.3, 143.0, 143.7, 147.6, 154.4, 165.8. MS
(ES+): m/z (%) 227 (34), 115 (100).
1-Cinnamyl-3-(1-naphthylmethyl)uracil
(35)
Was
synthesized in a similar manner as 29 to give 35 (1.75 g, 4.75
mmol, 72%), mp: 151-152.5 ºC, Rf 0.59 (hexane-ethyl acetate,

1
1:1); H NMR (DMSO-d6), δ: 4.57 (2H, d, J = 5.3, NCH2), 5.53
1.2.4. RT enzyme assay
(2H, s, CH2Naph), 5.90 (1H, d, J = 7.8, H-5), 6.40 (1H, dt, J =
16.0 and 5.9, =CH-), 6.61 (1H, d, J = 16.0, ArCH=), 7.12 (1H, d,
J = 7.1, aromatic Н), 7.25-7.31 (1H, m, aromatic Н), 7.34 (2H, t,
J = 7.4, aromatic Н), 7.39-7.46 (3H, m, aromatic Н), 7.55-7.62
(2H, m, aromatic Н), 7.82-7.85 (2H, m, aromatic Н, H-6), 7.95-
7.97 (1H, m, aromatic Н), 8.23 (1H, d, J = 8.2, aromatic Н). 13C
NMR (DMSO-d6): 41.5, 50.2, 100.6, 122.4, 123.1, 124.1, 125.4,
125.9, 126.3, 126.5, 127.3, 128.0, 128.6, 128.7, 130.5, 132.1,
132.7, 133.3, 136.0, 144.3, 151.2, 162.6. MS (ES+): m/z (%) 256
(40), 227 (45), 115 (100).
The RT assays using activated DNA were performed as
follows: the standard reaction mixture (20 µl) contained 0.75 µg
of activated DNA, 0.05 µg p66/p66 RT, 3 µM dATP, 30 µM of
dCTP, dGTP and dTTP, 1 µCi [α-32P]dATP in a Tris-HCl buffer
(50 mM, pH 8.1) containing also 10 mM MgCl2, and 0.2 M KCl.
The test compounds were dissolved in DMSO and added to both
assays to a final 10% DMSO concentration. The reaction
mixtures were incubated for 30 minutes at 37°C, and applied
onto Whatman 3MM filters. After drying on air the filters were
washed 2X with 10% trichloroacetic acid, then 2X with 5%
trichloroacetic acid, once with ethanol and then air-dried.
Radioactivity was determined in a Perkin Elmer Tri-Carb 2810
TR liquid scintillation counter.
1.2. Biological evaluation
1.2.1. Antiviral assays
The methodology of the anti-HIV assays in MT-4 cell cultures
was as follows: virus stocks were titrated in MT-4 cells and
expressed as the 50% cell culture infective dose (CCID50). MT-4
cells were suspended in culture medium at 1 x 105 cells/ml and
infected with HIV at a multiplicity of infection of 0.02.
Immediately after viral infection, 100 µl of the cell suspension
was placed in each well of a flat-bottomed microtiter tray
containing various concentrations of the test compounds. After 4
days of incubation at 37°C, the number of viable cells was
Acknowledgments
This work was supported by Ministry of Education and
Science of Russian Federation (state contract 16.512.11.2233),
by the Russian Foundation For Basic Research (grant 10-04-
00056a), by the Presidium of the Russian Academy of Sciences
(Programme “Molecular and Cellular Biology”) and by the
K.U.Leuven (GOA no. 10/014). A.I. and V.V.-E. were supported
by grant of President of Russian Federation (МК-5035.2011.4).
The authors like to thank Kartik Temburnikar (UMBC), Lizette
van Berckelaer, Kristien Minner, Kristien Erven and Kris
Uyttersprot (Rega) for their dedicated technical assistance.
determined
using
the
3-(4,5-dimethylthiazol-2-yl)-2,5-
diphenyltetrazolium bromide (MTT) method. The selection and
characterization of mutant virus strains have been performed
previously.
1.2.2. Antiviral Activity Assays other than HIV
References and notes
The compounds were evaluated against the following viruses:
herpes simplex virus type 1 (HSV-1) strain KOS, Thymidine
kinase-deficient (TK−) HSV-1 KOS strain resistant to ACV
(ACVr), herpes simplex virus type 2 (HSV-2) strains Lyons and
G, varicella-zoster virus (VZV) strain Oka, TK− VZV strain
07−1, human cytomegalovirus (HCMV) strains AD-169 and
Davis, vaccinia virus Lederle strain, respiratory syncytial virus
(RSV) strain Long, vesicular stomatitis virus (VSV), Coxsackie
B4, Parainfluenza 3, Influenza virus A (subtypes H1N1, H3N2),
influenza virus B, Reovirus-1, Sindbis and Punta Toro. The
antiviral assays were based on inhibition of virus-induced
cytopathicity or plaque formation in human embryonic lung
(HEL) fibroblasts, African green monkey cells (Vero), human
epithelial cells (HeLa) or Madin-Darby canine kidney cells
(MDCK). Confluent cell cultures in microtiter 96-well plates
were inoculated with 100 CCID50 of virus (1 CCID50 being the
virus dose to infect 50% of the cell cultures) or with 20 plaque
forming units (PFU) (VZV) in the presence of varying
concentrations of the test compounds. Viral cytopathicity or
plaque formation was recorded as soon as it reached completion
in the control virus-infected cell cultures that were not treated
with the test compounds. Antiviral activity was expressed as the
EC50 or compound concentration required to reduce virus-
induced cytopathogenicity or viral plaque formation by 50%.
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30
previously.14,
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procedure.31
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Supplementary Material
NMR spectra for all of the synthesized compounds are
available free of charge as Supplementary Material on the web.