Sulfur analogs of pyrimidine bases: Synthesis of 2-alkylthio- and 4-alkylthio-5-bromouracils and in silico evaluation of their biological activity

Article abstract of DOI:10.1002/jhet.1098

The general reactivity of alkylthiouracils under bromination conditions has been examined. Twenty 2-alkylthio- and 4-alkylthio-5-bromouracils of potential biological activity have been prepared. The structures of these compounds were confirmed by elementa

Full text of DOI:10.1002/jhet.1098

Month 2013
Sulfur Analogs of Pyrimidine Bases: Synthesis of 2-Alkylthio-
and 4-Alkylthio-5-bromouracils and In Silico Evaluation of Their
Biological Activity
*
Grażyna Bartkowiak, Elżbieta Wyrzykiewicz, and Grzegorz Schroeder
Faculty of Chemistry, Adam Mickiewicz University, 60-780 Poznań, Poland
*
E-mail: gbartkow@amu.edu.pl
Received March 13, 2011
DOI 10.1002/jhet.1098
Published online 00 Month 2013 in Wiley Online Library (wileyonlinelibrary.com).
The general reactivity of alkylthiouracils under bromination conditions has been examined. Twenty
2-alkylthio- and 4-alkylthio-5-bromouracils of potential biological activity have been prepared. The
structures of these compounds were confirmed by elemental and spectral (UV/vis, IR, and 1H-NMR)
analyses. The pharmacotherapeutical potential of the synthesized compounds has been predicted using
Prediction of Activity Spectra for Substances (i.e., PASS) program.
J. Heterocyclic Chem., 00, 00 (2013).
INTRODUCTION
To ensure good cell barrier permeability in order to improve
pharmacokinetic properties of brominated thiouracils, the
sulfur atoms in the substrates chosen have been substituted
by long alkyl chains containing 10–18 carbon atoms,
that is, n-decyl, n-dodecyl, n-tetradecyl, n-hexadecyl,
and n-octadecyl. The sulfur position was 2 or 4 and the
substituent in position 6 of uracil ring was hydrogen, methyl,
or carboxylic group (Scheme 1). The 2-alkylthiouracils and
2-alkylthioorotic acids have been obtained earlier [14] and
analyzed as to their antibacterial activity; 4-alkylthiouracils
have also been synthesized previously [15].
The aim of our work was to introduce a substituent to
the alkylthiouracil molecule that will enable further easy
modification through the substitution reaction. Bromine
atom was chosen as it was known to cause formation of a
reactive site in the molecule as a result of making a polar
bond. It was of interest to evaluate the easiness of introduc-
ing bromine atom to position 5 of alkylthiouracil ring when
the electron-donating group is located on the sulfur atom
S-2 or S-4 and to observe the effect of the character of sub-
stituent in position 6 (neutral hydrogen, electron-donating
Thiouracils are an important class of modified
nucleobases because of their spectroscopic properties and
biological activity. 2-Thiouracil, 4-thiouracil, 5-methyl-
2-thiouracil (i.e., 2-thiothymine), and 2,4-dithiouracil
have been found as minor components of nucleic acids
1–3. 2-Thiouracil and 4-thiouracil are well known for their
pharmacological applications as anticancer agents [4], [5]
as well as in heart diseases treatment [6], [7]. 6-Methyl-2-
thiouracil and 6-propyl-2-thiouracil have been known to
be effective antithyroid drugs [8]. A series of derivatives
of 2-thiouracil and 4-thiouracil can also be found in many
pharmacological drugs for cancer [9], HIV [10], and
thyroid [11], [12] treatments.
In continuation of our works on bromothiouracil deriva-
tives [13] and in search for novel biologically active
compounds, we have performed a series of bromination
reactions of alkyl derivatives of 2-thiouracil (I–V), 2-thio-
6-methyluracil (VI–X), 2-thioorotic acid (XI–XV), 4-thio-
uracil (XVI–XX), and 4-thio-6-methyluracil (XXI–XXV).
© 2013 HeteroCorporation

G. Bartkowiak, E. Wyrzykiewicz, and G. Schroeder
Vol 000
Scheme 1. Bromination of 2-alkylthiouracils (I–X), 2-alkylthioorotic
acids (XI–XV), and 4-alkylthiouracils (XVI–XXV).
mean accuracy of LOO cross-validation is about 90%,
and the activity is described qualitatively (active or
inactive). The results of prediction are presented as the lists
of activities with appropriate probable activity (Pa) and
probable inactivity (Pi) in descending sequence of the
difference (Pa − Pi) > 0. If Pa for the particular type of
activity is more than 0.7, the compound is very likely to
exhibit this kind of activity in tests; however, it is also
highly probable that similarly active pharmaceutical agents
are already known. If 0.5 < Pa < 0.7, the compound is
likely to reveal this type of activity, but with lower proba-
bility, and the compound is supposedly not very similar to
a known pharmaceutical agent. If Pa < 0.5, the compound
is unlikely to reveal this kind of activity; however, if this
activity would be confirmed in experiment, the compound
might be a precursor of the new class of pharmacologically
valuable compounds.
RESULTS AND DISCUSSION
The biological activities of compounds 1–20 obtained
were predicted using the computer program PASS [18].
The bromination of alkylthiouracils was performed at room
temperature using a 10% (v/v) bromine solution in
tetrachloromethane and a suspension of respective thioura-
cil derivative in tetrachloromethane. 2-Alkylthiouracils I–
X underwent the reaction easily in a short reaction time
(30–60 min) and at a sixfold excess of bromine. The
products 1–10 were easily purified through crystallization
from methanol. 4-Alkylthiouracils XVI–XXV reacted with
bromine with difficulty and demanded higher excess of
bromine (30-fold) or longer reaction times (to 24 h).
Extension of reaction time or high excess of bromine
not only leads to a mixture of products containing the target
4-alkyl-5-bromothiouracils (11–20, about 20%) but also
5-bromouracil (about 30%) and intact substrate, that is,
4-alkylthiouracil (about 50%). Isolation of pure 11–20 was
realized by column chromatography on columns filled with
silica gel 60 and eluted with chloroform (100%) and chloro-
form–methanol with increasing percentage of CH3OH from
1 to 30%. The eluate compositions were monitored by thin
layer chromatography (TLC) using chloroform–methanol
9:1 as a mobile phase. The products 11–20 were eluted first
[Rf = 0.68 (11–15); Rf = 0.72 (16–20)], next unreacted
substrate (Rf = 0.45–0.55), and finally dealkylthiolated side
product, that is, 5-bromouracil (Rf = 0.25) or 5-bromo-6-
methyluracil (Rf = 0.31), respectively. The physicochemical
properties of 1–20 are given in Table 1.
CH3, or electron-withdrawing COOH) on bromination
effectiveness. It was also interesting to predict possible
biological activity of alkylthiouracils after inserting
bromine atom to position 5 of the molecule.
Biological activity of 2- or 4-alkylthio-5-bromouracils
can be predicted by means of computer-assisted methods
[16]. The computer-aided prediction of possible activities
of resulting compounds has recently attracted a lot of
attention [17] because it permits saving a lot of time and
financial expenses (unavoidable during biological tests
in vivo and in vitro) and makes it possible to eliminate
potentially toxic, harmful, or pharmacologically unsafe
compounds. Among the computer programs used for the
estimation of biological activity spectrum of substances,
particularly impressive is the Prediction of Activity Spectra
for Substances (PASS) program. A basic principle of this
program is that the activity of the chemical compound is
a function of its structure, and by comparing the structure
of a new substance with the structures of compounds with
known activity, it is possible to predict if the new com-
pound may be useful for the treatment of a particular
disease.
The computer system PASS Inet encloses data of about
3678 possible activities, including pharmacological effects,
mechanisms of action, and adverse side effects (e.g., toxic-
ity and mutagenicity) and predicts biological activity
spectrum of a compound studied on the basis of its struc-
tural formula. The leave-one-out (LOO) cross-validation
has been used to validate this prediction method. The
prediction is based on the training set containing more than
260,000 compounds of known biological activity. The
The bromination of 2-alkylthioorotic acids XI–XV
failed. Using the same reaction conditions as for
alkylthiouracils I–X or XVI–XXV, we did not obtain 2-
alkylthio-5-bromoorotic acid but only unreacted substrates
were recovered. Increasing the bromine excess to 50:1 and
the reaction time to 3–5 days resulted in the appearance of
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2013
Sulfur Analogs of Pyrimidine Bases: Synthesis of 2-Alkylthio- and
4-Alkylthio-5-Bromouracils and In Silico Evaluation of Their Biological Activity
Table 1
Physical and analytical data of compounds 1–20.
Analysis (calcd./found, %)
Compound
n
Formula (MW)
Yield (%)
m.p. (°C)
Rf TLCa
C
H
N
1
2
3
4
5
6
7
8
9
C
14H23N2OSBr (347.32)
51
45
36
35
13
55
58
60
57
40
20
18
21
22
20
23
18
22
19
18
100–102
104–106
109–112
106–108
104–105
110–113
110–111
112–116
113–115
114–116
76–78
78–80
79–82
80–83
81–84
87–89
88–90
89–92
88–91
0.67
0.67
0.68
0.68
0.70
0.77
0.80
0.80
0.80
0.80
0.68
0.68
0.68
0.68
0.68
0.72
0.72
0.72
0.72
0.72
48.41/47.85
51.20/51.13
53.59/53.31
55.67/55.39
57.50/57.29
49.86/49.44
52.44/51.99
54.67/54.32
56.62/56.33
58.34/58.09
48.41/48.50
51.20/50.91
53.59/53.33
55.67/55.60
57.50/57.35
49.86/49.57
52.44/52.30
54.67/54.59
56.62/56.54
58.34/58.09
6.67/6.29
7.25/7.27
7.75/7.42
8.18/8.02
8.55/8.43
6.97/6.99
7.51/7.81
7.97/7.70
8.37/8.79
8.73/8.42
6.67/6.68
7.25/6.95
7.75/8.00
8.18/7.99
8.55/8.48
6.97/7.20
7.51/7.69
7.97/7.88
8.37/8.29
8.73/8.65
8.07/7.62
7.46/7.19
6.94/6.72
6.49/6.17
6.10/5.88
7.75/7.56
7.19/6.99
6.71/6.45
6.29/6.01
5.92/5.88
8.07/7.79
7.46/7.58
6.94/7.12
6.49/6.42
6.10/6.01
7.75/7.56
7.19/7.01
6.71/6.60
6.29/6.35
5.92/5.87
11
13
15
17
9
11
13
15
17
9
11
13
15
17
9
11
13
15
17
C16H27N2OSBr (375.37)
C18H31N2OSBr (403.43)
C20H35N2OSBr (431.48)
C22H39N2OSBr (459.53)
C15H25N2OSBr (361.35)
C17H29N2OSBr (389.40)
C19H33N2OSBr (417.45)
C21H37N2OSBr (445.51)
C23H41N2OSBr (473.56)
C14H23N2OSBr (347.32)
C16H27N2OSBr (375.37)
C18H31N2OSBr (403.43)
C20H35N2OSBr (431.48)
C22H39N2OSBr (459.53)
C15H25N2OSBr (361.35)
C17H29N2OSBr (389.40)
C19H33N2OSBr (417.45)
C21H37N2OSBr (445.51)
C23H41N2OSBr (473.56)
9
10
11
12
13
14
15
16
17
18
19
20
87–90
aSolvent (mobile phase): CHCl3 CH3OH (9:1).
respective 2-alkylthio-5-bromouracil in the reaction prod-
ucts. The reaction time longer than 6 days leads to the
formation of almost pure 2-alkylthio-5-bromouracil using
the same or higher excess of bromine. It proves that decar-
boxylation of the starting 2-alkylthioorotic acid takes place
at the attempted bromination.
The UV/vis spectra of 1–5 (Table 2) show three absorp-
tion bands of λmax in the range 220.0–294.2 nm and
batochromic shifts relative to the corresponding UV/vis
data for the substrates. The electronic spectra of 6–10
reveal three bands in the range 210.0–292.8, also
batochromically shifted with respect to the 205.0–286.4
nm for the substrate. The UV/Vis spectra of 11–15 show
λmax in the range 210.4–290.0, whereas for 16–20, the
corresponding range is 217.6–290.0.
bromination reaction is completed and the product is
sufficiently pure.
The introduction of Br into C5 position of pyrimidine
ring causes a change in the C6-H signal from doublet at
7.84–7.85 ppm for 2-alkylthiouracils I–V into singlet at
8.12–8.17 ppm for 2-alkylthio-5-bromouracils (1–5) and
results in replacement of a C6-H doublet at 7.3–7.4 ppm
for 4-alkylthiouracils XVI–XX by a singlet at 8.02–8.03
for 4-alkylthio-5-bromouracils 11–15 (downfield shift).
The C6-CH3 signals are shifted downfield under the
influence of bromine atom in position C5 in the spectra
of 2-alkylthio compounds [from 2.25–2.27 ppm (VI–X)
to 2.54–2.58 ppm (6–10)] and slightly upfield shift in the
spectra of 4-alkylthio compounds [from 2.30–2.35 ppm
(XXI–XXV) to 2.28 ppm (16–20)]. The influence of
bromine atom in C5 position on the chemical shift of
SCH2 triplet is not very significant; it causes a ∼0.1 ppm
downfield shift for 2-thiouracil and no effect in the spectra
of 4-thiouracil derivatives.
For all synthesized compounds (1–20), their biological
activity spectra were predicted using PASS [19], [20],
and the types of activities with the highest probability
(focal activities) for particular compounds were selected.
The values obtained for representative compounds (the
ones with n-decyl group were chosen) are presented in
Table 4 It should be noted that the results for the other
alkyl groups were very similar. According to the data
obtained, 5-bromo-2-thiouracil derivatives are likely to be
spermicidic, whereas 5-bromo-4-thiouracil derivatives are
expected to be mucomembraneous protectors and antiviral
The IR spectra of all compounds studied (Table 2) show
absorption bands of medium intensities in the two charac-
teristic regions: 1041–1017 cm−1 and 670–621 cm−1,
assigned to νC Br vibrations (Table 2). These bands are
not found in the IR spectra of substrates. Intensive νC O
bands are present in the range 1650–1660 cm−1 and
νC5=C6 between 1557 and 1620 cm−1.
1
The H-NMR spectra (Table 3) of compounds 1–20 do
not show the characteristic signals of proton at C5 of the
1
pyrimidine rings when referred to the H-NMR spectra of
the substrates (i.e., doublets at 6.22–6.25 ppm for 2-
alkylthiouracils I–V [14] and 4-alkylthiouracils XVI–XX
[15] and singlets at 7.26–7.27 ppm for 2-alkylthio-6-
methyluracils (VI–X) [14] and 6.10 ppm for 4-alkylthio-
6-methyluracils XXI–XXV [15]), which confirms that the
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

G. Bartkowiak, E. Wyrzykiewicz, and G. Schroeder
Vol 000
Table 2
UV and IR spectral data of compounds 1–20.
UV/vis
IR (cm−1
)
νN3C4, νC4C5
νC2N3, νN1C6
Compound
λmax (nm)
Log ε
νC O
νC Br
νC5 = C6
νC S
δN1C2N3
1
292.6
248.4
220.0
292.2
250.6
220.0
294.2
250.2
220.0
294.2
250.6
219.8
294.0
3.87
3.84
3.95
3.86
3.84
3.97
3.85
3.83
3.94
3.84
3.82
3.93
3.84
3.82
3.92
3.88
3.92
3.81
3.83
3.85
3.77
3.83
3.81
3.96
3.81
3.82
3.95
3.80
3.78
4.10
3.81
3.79
4.09
3.81
3.78
4.08
3.79
3.72
4.05
3.75
3.72
4.02
3.74
3.71
4.01
3.63
3.52
3.91
3.64
3.50
3.93
3.62
3.50
3.90
3.62
3.48
3.90
3.61
3.48
3.89
1658
1019
669
1557
2525
1471
1428
715
715
715
715
716
723
721
721
720
721
717
717
717
718
718
725
725
725
725
726
2
1658
1658
1657
1657
1650
1650
1650
1660
1639
1649
1650
1652
1652
1652
1659
1659
1658
1657
1657
1018
669
1557
1558
1558
1575
1573
1620
1620
1570
1566
1607
1607
1605
1605
1605
1601
1600
1600
1600
1600
2532
2540
1472
1428
3
1019
670
1472
1428
4
1019
2541
1472
1428
670
1020
670
5
2541
1472
1428
∼250
220.0
290.0
248.0
210.4
289.4
247.8
6
1041
2456
1469
1423
621
1035
624
7
∼2450
∼2450
∼2450
∼2450
∼2600
∼2600
∼2600
∼2600
∼2600
2576
1470
1423
∼210
291.6
247.8
∼210
292.8
247.8
8
1020
628
1473
1423
9
1018
629
1471
1430
∼210
10
11
12
13
14
15
16
17
18
19
20
280.6
250.2
210.0
280.8
249.8
217.6
280.8
250.6
218.4
281.4
250.2
218.4
281.4
250.2
218.4
281.4
250.2
218.4
289.6
248.2
210.4
290.0
247.8
210.6
290.0
248.0
210.8
290.4
248.1
210.8
290.4
248.1
210.9
1017
1466
1423
630
1025
665
1470
1425
1025
667
1470
1428
1025
666
1471
1432
1026
664
1472
1434
1023
662
1472
1436
1020
661
1468
1440
1026
660
2580
1468
1440
1026
662
∼2600
∼2600
∼2600
1469
1440
1026
662
1468
1445
1026
663
1470
1446
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2013
Sulfur Analogs of Pyrimidine Bases: Synthesis of 2-Alkylthio- and
4-Alkylthio-5-Bromouracils and In Silico Evaluation of Their Biological Activity
Table 3
1H‐NMR shifts of 1–20 (ppm).
C6‐H
(s, 1H)
C6‐CH3
(s, 3H)
S–CH2
(t, 2H)
SCH2CH2
(quint, 2H)
(CH2)x
(s broad, 2×H)
–(CH2)xCH3
(t, 3H)
Compound
1
2
3
4
5
6
7
8
8.17
8.15
8.14
8.12
8.12
–
–
–
–
–
8.03
8.03
8.03
8.02
8.02
–
–
–
–
–
–
–
–
–
–
2.54
2.58
2.56
2.54
2.54
–
–
–
–
–
2.28
2.28
2.28
2.28
2.28
3.22
3.20
3.18
3.17
3.17
3.30
3.24
3.18
3.17
3.17
3.05
3.02
3.00
3.00
3.00
3.04
3.02
3.00
3.00
3.00
1.72
1.72
1.72
1.71
1.71
1.72
1.72
1.72
1.71
1.71
1.62
1.62
1.62
1.62
1.62
1.59
1.59
1.59
1.59
1.59
1.26
1.26
1.26
1.26
1.26
1.26
1.26
1.26
1.26
1.26
1.25
1.25
1.25
1.25
1.25
1.20
1.20
1.20
1.20
1.20
0.88
0.88
0.88
0.88
0.88
0.88
0.88
0.88
0.88
0.88
0.85
0.85
0.85
0.85
0.85
0.80
0.80
0.80
0.80
0.80
9
10
11
12
13
14
15
16
17
18
19
20
Spectra determined in dimethyl‐d6 sulfoxide at 25°C and chemical shifts are reported in ppm (δ) downfield from tetramethylsilane.
Table 4
Pa values for predicted biological activities of compounds 1, 6, 11, and 16 as representative examples.
Compound
Focal predicted activity (Pa > 0.6)
1
6
11
16
Spermicide (0.800), protein kinase (CK1) inhibitor (0.740), thioredoxin inhibitor (0.622)
Spermicide (0.746), leukopoiesis stimulant (0.719), antiulcerative (0.686), antiviral (Arbovirus) (0.657)
Mucomembranous protector (0.731), antineoplastic (0.675), antiviral (Arbovirus) (0.662)
Leukopoiesis stimulant (0.723), thrombocytopoiesis inhibitor (0.669), mucomembranous protector (0.689), antiviral (Arbovirus)
(0.675), protein kinase (CK1) inhibitor (0.645)
agents against Arbovirus. The compounds studied, which have
6-methyl substituent, that is, 2-alkylthio and 4-alkylthio-
5-bromo-6-methyluracils, are expected to act as potent
leukopoiesis stimulants. It ought to be pointed out that
the group of compounds (1–20) comprises also potential
antineoplastic and antiulcerative agents as well as vari-
ous enzyme inhibitors.
higher excess of bromine (30-fold) is needed and
dealkylthiolation as a side reaction occurs. Direct
bromination of 2-alkylthioorotic acids XI–XV does
not occur in analogous conditions. The use of 50-fold
bromine excess and long reaction time (several days)
leads to the formation of corresponding 2-alkylthio-5-
bromouracils. It is suggested that the first step of the
reaction is decarboxylation of 2-alkylthioorotic acid to
the 2-alkylthiouracil, which undergoes bromination in
the next step consecutively.
CONCLUSIONS
The reactions of 2-alkylthiouracils and 4-alkylthiouracils
1–10 with sixfold excess of bromine at room tem-
perature led easily to the corresponding 2-alkyl-5-
bromouracils. To obtain 4-alkyl-5-bromouracils 11–20,
The results obtained using PASS program for prediction
of activity spectrum of substances on the basis of their
chemical structure show the possibility of pharmacological
application of compounds 1–20.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

G. Bartkowiak, E. Wyrzykiewicz, and G. Schroeder
Vol 000
REFERENCES AND NOTES
EXPERIMENTAL
The purity of compounds 1–20 was determined by melting
points, TLC, and elemental analyses. Melting points
(uncorrected) were determined using Boetius microscope
apparatus. Rf values refer to silica gel F254 TLC plates
(Merck) developed with CHCl3 CH3OH 9:1 and observed
under UV light (λ = 254 nm). UV/vis spectra were recorded
with a Specord UV/vis spectrophotometer in methanol. IR
spectra were recorded with a FTIR Bruker ISF-113 spectro-
photometer in KBr pellets. The 1H-NMR spectra were mea-
sured in DMSO-d6 as a solvent with Varian Gemini 300
(300 MHz) spectrometer at ambient temperatures using TMS
as an internal standard. Chemical shifts are given in δ scale
(ppm). Elemental analyses were performed with Vector Euro
EA 3000 analyzer.
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2-Alkylthiouracils (I–V), 2-alkyl-6-methyluracils (VI–X), and
2-alkylthioorotic acids (XI–XV) were obtained according to ref.
[14]. 4-Alkylthiouracils (XVI–XXV) were also obtained using a
procedure described earlier [15].
Synthesis of 5-bromo-2-alkylthiouracils 1–10. A sample (1
mmol) of appropriate 2-alkylthiouracil (1–8) was suspended in
20 mL of CCl4 and stirred magnetically at room temperature.
To the stirred suspension, a solution of Br2 in CCl4 (10% v/v)
was added dropwise (6 equivalents of bromine for 1 equivalent
of 2-alkylthiouracil). The reaction mixture was next stirred at
room temperature for 30 min. The obtained crude product was
filtered off, washed twice with warm tetrachloromethane (2 × 5
mL) and dried. The resulting powder was crystallized from
methanol.
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2001; p 403.
Synthesis of 5-bromo-4-alkylthiouracils 11–20. A solution
of bromine in tetrachloromethane (10% v/v) was added
dropwise to the stirred solution of 4-alkylthiouracil (1
mmol) in 20 mL CCl4 at room temperature, using 30-fold
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Gloriozova, T. A.; Lagunin, A. A.; Borodina, Y. V.; Stepanchikova, A.
V.; Nicklaus, M. C. J Chem Inf Comput Sci 2003, 43, 228.
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Helma, C., Ed.; Taylor & Francis: New York, 2005; p 459.
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V. J Med Chem 2003, 46, 3326.
excess of bromine (30 equivalents of bromine for
1
equivalent of 4-alkylthiouracil). The obtained reaction mixture
was stirred magnetically for 30–60 min. The precipitate were
filtered off, washed twice with warm CCl4 (2 × 5 mL) and dried.
The crude product after column-chromatographic isolation was
crystallized from methanol.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet