Thio analogues of pyrimidine bases: Syntheses and spectral study of new potentially biologically active 2,4-di-ortho-(meta- and para-)bromo- (chloro and nitro)-benzylthio-5-bromouracils (and 6-methyluracils)

Article abstract of DOI:10.1080/10426500903061558

Eighteen new 2,4-di-ortho- (meta- and para-) bromo-(chloro- and nitro-)benzylthio-5-bromouracils (and 6-methyluracils) have been prepared. The structures of these compounds were confirmed by spectral (IR, UV/vis, 1H NMR) and elemental analyses. Estimation

Full text of DOI:10.1080/10426500903061558

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Phosphorus, Sulfur, and Silicon and the
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Thio Analogues of Pyrimidine Bases:
Syntheses and Spectral Study of New
Potentially Biologically Active 2,4-Di-
Ortho-(Meta- and Para-)Bromo- (Chloro
and Nitro)-Benzylthio-5-Bromouracils
(and 6-Methyluracils)
Grażyna Bartkowiak a , Elżbieta Wyrzykiewicz a , Grzegorz Schroeder
a , Anna Walkowiak a , Anna Szponar a & Ilona Pawlak a
a Faculty of Chemistry, Adam Mickiewicz University, Poznań, Poland
Version of record first published: 03 Jul 2010.
To cite this article: Grażyna Bartkowiak , Elżbieta Wyrzykiewicz , Grzegorz Schroeder , Anna
Walkowiak , Anna Szponar & Ilona Pawlak (2010): Thio Analogues of Pyrimidine Bases: Syntheses and
Spectral Study of New Potentially Biologically Active 2,4-Di-Ortho-(Meta- and Para-)Bromo- (Chloro
and Nitro)-Benzylthio-5-Bromouracils (and 6-Methyluracils), Phosphorus, Sulfur, and Silicon and the
Related Elements, 185:7, 1429-1436
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Phosphorus, Sulfur, and Silicon, 185:1429–1436, 2010
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500903061558
THIO ANALOGUES OF PYRIMIDINE BASES: SYNTHESES
AND SPECTRAL STUDY OF NEW POTENTIALLY
BIOLOGICALLY ACTIVE 2,4-Di-ORTHO-(META- AND
PARA-)BROMO- (CHLORO AND
NITRO)-BENZYLTHIO-5-BROMOURACILS
(AND 6-METHYLURACILS)
Graz˙yna Bartkowiak, Elz˙bieta Wyrzykiewicz, Grzegorz
Schroeder, Anna Walkowiak, Anna Szponar, and Ilona Pawlak
Faculty of Chemistry, Adam Mickiewicz University, Poznan´, Poland
Eighteen new 2,4-di-ortho- (meta- and para-) bromo-(chloro- and nitro-)benzylthio-5-
bromouracils (and 6-methyluracils) have been prepared. The structures of these compounds
were confirmed by spectral (IR, UV/vis, 1H NMR) and elemental analyses. Estimation of
pharmacotherapeutic potential has been made for synthesized compounds on the basis of
prediction of activity spectra for substances (PASS).
Keywords 2,4-Dibenzylthio-5-bromo-6-methyluracils; 2,4-dibenzylthio-5-bromouracils; 1H
NMR; IR; PASS; structural isomers; UV/vis
INTRODUCTION
Thio derivatives of pyrimidine bases are of interest because of their biological and
pharmacological activities, e.g., as minor components of t-RNA or as antithyroidal and
anticancer drugs, as well as sedatives.1–7 Various analogues of 5-bromo-N-benzyl substi-
tuted thiouracils constitute a novel class of central-acting agents.8 The pyrimidine thioethers
with phenylthio substituent have been reported to constitute a novel class of non-nucleoside
HIV-1 reverse transcriptase inhibitors.9
Recently, we have reported the syntheses, physicochemical properties, and results
of EI mass spectrometric study of ortho- (meta- and para-) substituted derivatives of 2-
benzylthio-5-bromo-6-methyluracils.10 However, to the best of our knowledge, no work
has been published on the synthesis and physicochemical properties of S,S-dibenzyl substi-
tuted derivatives of 2,4-dithio-5-bromouracil and 2,4-dithio-5-bromo-6-methyluracil. On
the other hand, novel pharmacological actions of these compounds have been found on
the basis of the computer-aided drug discovery approach with the computer program Pre-
diction of Activity Spectra for Substances (PASS).11–14 It is based on a robust analysis of
structure–activity relationship12 in a heterogeneous training set currently including about
Received 31 March 2009; accepted 22 May 2009.
Address correspondence to Graz˙yna Bartkowiak, Faculty of Chemistry, Adam Mickiewicz University,
Grunwaldzka 6, 60-780, Poznan´, Poland. E-mail: gbartkow@amu.edu.pl
1429

1430
G. BARTKOWIAK ET AL.
X
S
Br
N
S
N
R
1 - 18
X
1 R = H X = o-Br
2 R = H X = m-Br
3 R = H X = p-Br
4 R = H X = o-Cl
5 R = H X = m-Cl
6 R = H X = p-Cl
10 R = CH3 X = o-Br
11 R = CH3 X = m-Br
12 R = CH3 X = p-Br
13 R = CH3 X = o-Cl
14 R = CH3 X = m-Cl
15 R = CH3 X = p-Cl
7 R = H X = o-NO2 16 R = CH3 X = o-NO2
8 R = H X = m-NO2 17 R = CH3 X = m-NO2
9 R = H X = p-NO2 18 R = CH3 X = p-NO2
Figure 1 Structures of substituted 2,4-dibenzylthio-5-bromouracils 1–9 and 2,4-dibenzylthio-5-bromo-6-
methyluracils 10–18.
sixty thousand biologically active compounds from different chemical series, with about
4500 types of biological activity. Since only the structural formula of a chemical compound
is necessary to obtain a PASS prediction, this approach can be used at the earliest stage
of investigation. There are many examples of successful use of PASS approach leading to
finding new pharmacological agents.15–18
The analysis of PASS prediction results of 2,4-dibenzylthio-5-bromouracils and
2,4-di-benzylthio-5-bromo-6-methyluracils have prompted us to synthesize a series of
new 2,4-di-ortho- (meta- and para-) bromo-(chloro- and nitro-)benzylthio-5-bromouracils
1–9 and 2,4-di-ortho- (meta- and para-) bromo-(chloro- and nitro-)benzylthio-5-bromo-6-
methyluracils 10–18 (Figure 1).
This article deals with the synthesis and physicochemical properties of 1–18. Addi-
tionally the analysis of biological activity spectra prediction for 1–18 made in this publica-
tion is a good example of in silico study of chemical compounds.
RESULTS AND DISCUSSION
A series of 18 new 2,4-di-ortho- (meta- and para-) bromo-(chloro- and nitro-)
benzylthio-substituted 5-bromouracils 1–9 and 5-bromo-6-methyluracils 10–18 were
synthesized by direct bromination of the appropriate 2,4-dibenzylthiouracils and 2,4-
dibenzylthio-6-methyluracils with bromine in tetrachloromethane at room temperature.
The treatment of these ortho- (meta- and para-) bromo-(chloro- and nitro-) substituted
derivatives of 2,4- dibenzylthiouracils and 2,4-dibenzylthio-6-methyluracils with the ex-
cess of bromine in tetrachloromethane followed by short time boiling of the crude product
in ethanol solution led to 2,4-dibenzylthio-5-bromouracils 1–9 and 2,4-dibenzylthio-
5-bromo-6-methyluracils 10–18. The C5 bromine containing compounds 1–18 were
confirmed by examination of their UV/vis, IR (Table I) and 1H NMR (Table II) spectra as
well as elemental analyses (Table III).

THIO ANALOGUES OF PYRIMIDINE BASES
1431
Table I IR and UV/vis spectral data of compounds 1–18
IR (cm−1
)
UV/Vis
Compound
ν S CH2
ν C5 C6
ν C5-Br
λmax (nm)
logε
1
2445
1559
585
228.4
254.6
302.4
226.0
255.0
302.4
230.4
255.0
302.4
225.6
252.0
302.0
225.0
254.0
302.0
227.2
255.4
299.8
225.0
254.0
303.0
225.0
253.0
300.0
226.0
258.0
300.0
225.6
255.2
300.8
225.2
254.6
297.0
230.6
254.0
295.6
224.2
255.0
298.6
224.2
254.0
297.2
227.8
254.8
298.0
225.0
255.0
303.0
226.0
257.0
304.0
224.5
258.5
303.5
4.10
4.29
3.83
3.96
4.10
3.67
4.10
4.17
3.64
3.91
4.18
3.75
3.90
4.12
3.64
3.85
3.92
3.40
3.71
3.99
3.54
3.84
4.17
3.73
3.78
4.18
3.63
3.82
4.00
3.49
3.82
3.89
3.49
4.10
4.16
3.70
3.82
4.06
3.55
3.90
4.10
3.65
4.12
4.21
3.74
3.57
3.87
3.39
3.59
3.90
3.40
3.68
3.95
3.61
2
2507
2435
2471
2449
2458
2854
2858
2854
2473
2470
2466
2466
2460
2462
2482
2485
2483
1561
1557
1559
1562
1560
1562
1562
1561
1558
1558
1556
1553
1555
1559
1556
1559
1560
580
550
581
582
599
663
664
664
582
580
590
586
585
580
565
567
679
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18

1432
G. BARTKOWIAK ET AL.
Table II 1H NMR shifts of 1–18 (ppm)
X
s1
S
4
Br
3
N
5
s2
X
2
6
S
N
1
R
s
1 - 9 R = H
10 - 18 R = CH3
X
S-CH2
C6-H/C6-CH3
Comp.
s1
s2
s
m
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
4.64
4.49
4.46
4.64
4.52
4.51
4.68
4.63
4.62
4.59
4.53
4.50
4.69
4.54
4.52
4.62
4.50
4.47
4.69
4.53
4.50
4.66
4.60
4.54
4.81
4.65
4.68
4.61
4.58
4.56
4.72
4.56
4.54
4.67
4.52
4.49
8.39
8.38
8.40
8.39
8.37
8.34
8.32
8.29
8.38
2.40
2.51
2.50
2.52
2.51
2.50
2.51
2.50
2.52
7.29–7.70
7.20–7.52
7.42–7.50
7.30–7.72
7.30–7.53
7.42–7.49
7.55–8.00
7.60–8.73
7.80–8.20
7.25–7.50
7.20–7.50
7.40–7.50
7.25–7.69
7.18–7.58
7.34–7.45
7.58–8.10
7.63–8.39
7.80–8.20
Spectra determined in dimethyl-d6 sulfoxide at 25◦C, and shifts are reported in ppm (δ) downfield from
tetramethylsilane.
1
The H NMR spectra of these compounds show the lack of the characteristic res-
1
onances of the protons situated at C5 of the pyrimidine rings when referred to the H
NMR spectra of the substrates, that is the appropriate 2,4-dibenzylthiouracils and 2,4-
1
dibenzylthio-6-methyluracils. The H NMR data of 1–18 are given in Table II. Assign-
1
ments of the H NMR resonances of these compounds were deduced on the basis of the
signal multiplicities and by the concerted application of two-dimensional NMR technique
1H,1H-COSY. The 1H NMR spectra of 1–9 reveal singlets of S CH2 at 4.46–4.68 ppm and
4.50–4.81 ppm, respectively. The singlets of C6 H of 1–9 are situated at 8.29–8.40 ppm.
The signals of protons of ortho- (meta- and para-) substituted benzyl groups of 1–9 are
seen in the range 7.20–8.73 (Table II).
1
The H NMR spectra of 10–18 reveal singlets of S CH2 at 4.47–4.69 ppm and
4.49–4.72 ppm, respectively. The singlets of C6 CH3 of 10–18 are situated at 2.40–2.52
ppm. The signals of protons of ortho- (meta- and para-) substituted benzyl groups of 10–18
are seen in the range 7.18–8.39 ppm (Table II).

THIO ANALOGUES OF PYRIMIDINE BASES
1433
Table III Physical and analytical data of compounds 1–18
Analysis (calc./found.%)
Compound
Formula MW
Mp (◦C)
167–170
157–159
178–180
127–129
119–130
159–160
168–170
208–210
128–130
164–166
168–170
145–147
173–176
105–107
117–120
198–200
188–191
200–201
Yield (%)
30
Rf TLC∗
0.91
0.90
0.87
0.86
0.90
0.92
0.88
0.90
0.85
0.93
0.94
0.92
0.89
0.94
0.92
0.90
0.90
0.92
C
H
N
1
C18H13N2S2Br3
561.16
38.53
38.30
38.53
38.42
38.53
38.60
45.78
45.60
45.78
45.82
45.78
45.70
43.82
43.80
43.82
42.72
43.82
43.60
39.68
39.60
39.68
39.72
39.68
39.58
46.93
46.45
46.93
47.20
46.93
47.10
44.98
44.80
44.98
44.96
44.98
44.87
2.33
2.30
2.33
2.42
2.33
2.20
2.77
2.58
2.77
2.72
2.77
2.60
2.66
2.60
2.66
2.40
2.66
2.50
2.63
2.58
2.63
2.40
2.63
2.65
3.11
3.00
3.11
2.98
3.11
3.10
2.98
3.00
2.98
2.98
2.98
2.90
4.99
4.92
4.99
4.90
4.99
4.80
5.93
5.90
5.93
5.80
5.93
5.78
11.36
11.20
11.36
11.18
11.36
11.25
4.87
4.80
4.87
4.78
4.87
4.60
5.76
5.70
5.76
5.55
5.76
5.78
11.04
11.00
11.04
10.98
11.04
10.90
2
C
18H13N2S2Br3
561.16
18H13N2S2Br3
561.16
18H13N2S2Cl2Br
472.26
18H13N2S2Cl2Br
472.26
18H13N2S2Cl2Br
472.26
18H13N4O4S2Br
493.36
18H13N4O4S2Br
493.36
18H13N4O4S2Br
493.36
19H15N2S2Br3
575.19
19H15N2S2Br3
575.19
19H15N2S2Br3
575.19
19H15N2S2Cl2Br
486.28
19H15N2S2Cl2Br
486.28
19H15N2S2Cl2Br
486.28
19H15N4O4S2Br
507.39
19H15N4O4S2Br
507.39
19H15N4O4S2Br
507.39
35
3
C
47
4
C
54
5
C
65
6
C
45
7
C
70
8
C
69
9
C
16
10
11
12
13
14
15
16
17
18
C
72
C
62
C
48
C
50
C
65
C
89
C
68
C
69
C
56
∗Solvent: CHCl3-CH3OH, 5:1.
The IR spectra of 1–9 show absorption bands of medium intensities in the region
of 590–664 cm−1 assigned to νC-Br vibrations (Table I). The absorption bands of νC-Br
vibrations of 10–18 are seen in IR spectra of 10–18 in the region 565–679 cm−1 (Table I).
The UV/vis spectra of 1–9 show λmax in the range 225–303 nm (Table I) and bathochromic
shifts as well as increase in absorption in comparison with the corresponding UV/vis data
of ortho- (meta- and para-) substituted 2,4-dibenzyl thiouracils.19 Similarly the UV/vis
spectra of 10–18 show λmax in the range 224.2–303.5 nm (Table I) and bathochromic shifts
as well as increase in absorption in comparison with the corresponding UV/vis data of
ortho- (meta- and para-) substituted 2,4-dibenzylthio-6-methyluracils.19

1434
G. BARTKOWIAK ET AL.
In the present article, the biological activity spectra were predicted for all 18 synthe-
sized compounds (1–18) using PASS.11–14, 20 We have also selected the types of activities
that were predicted for a particular compound with the highest probability (focal activities).
They are presented in Table IV. According to these data, the most frequently predicted types
of biological activities are mucomembraneous protector, prolylaminopeptidase inhibitor,
cyclooxygenase-1 inhibitor, and antiseborrheic. It ought to be pointed out that in the series of
the derivatives of 2,4-di-ortho- (meta- and para-) bromo- (chloro- and nitro-) benzylthio-
6-methyluracils 10–18, such activities as interferon agonist, Factor VIIa inhibitor, and
glutamate receptor antagonist have also been predicted.
Table IV PA values for predicted biological activities of compounds 1–18
Comp
Focal predicted activity (Pa > 0.7)
1
2
Mucomembraneous protector (0.912), prolyl aminopeptidase inhibitor (0.864),
cyclooxygenase-1 inhibitor (0.752)
Prolyl aminopeptidase inhibitor (0.936), mucomembraneous protector (0.903),
antiseborrheic (0.808), cyclooxygenase-1 inhibitor (0.764), ferredoxin hydrogenase
inhibitor (0.719), carnitinamidase inhibitor (0.717)
3
Prolyl aminopeptidase inhibitor (0.941), mucomembraneous protector (0.915),
antiseborrheic (0.821), cyclooxygenase-1 inhibitor (0.786), carnitinamidase inhibitor
(0.740), ferredoxin hydrogenase inhibitor (0.728)
4
5
Mucomembraneous protector (0.879), cyclooxygenase-1 inhibitor (0.717)
Mucomembraneous protector (0.877), prolyl aminopeptidase inhibitor (0.867),
antiseborrheic (0.860), cyclooxygenase-1 inhibitor (0.784)
6
Mucomembraneous protector (0.892), prolyl aminopeptidase inhibitor (0.874),
antiseborrheic (0.860), cyclooxygenase-1 inhibitor (0.784)
7
Mucomembraneous protector (0.889), Factor VIIa inhibitor (0.825), glutamate receptor
antagonist (0.817)
8
Glutamate receptor antagonist (0.908), kainate receptor antagonist (0.840), Factor VIIa
inhibitor (0.773)
9
Factor VIIa inhibitor (0.832), prolyl aminopeptidase inhibitor (0.845), antiseborrheic
(0.763), glutamate receptor antagonist (0.759), mucomembraneous protector (0.743)
Prolyl aminopeptidase inhibitor (0.949), arrhythmogenic (0.876), arylacetonitrilase
inhibitor (0.859), mucomembraneous protector (0.850), ferredoxin hydrogenase
inhibitor (0.829)
10
11
12
13
14
15
16
17
18
Prolyl aminopeptidase inhibitor (0.950), mucomembraneous protector (0.896), interferon
agonist (0.825), antiseborrheic (0.819), cyclooxygenase-1 inhibitor (0.708)
Prolyl aminopeptidase inhibitor (0.950), mucombraneous protector (0.896), interferon
agonist (0.825), cyclooxygenase-1 inhibitor (0.708)
Mucomembraneous protector (0.871), interferon agonist (0.814), prolyl aminopeptidase
inhibitor (0.838), antiseborrheic (0.750)
Prolyl aminopeptidase inhibitor (0.910), mucomembraneous protector (0.868),
antiseborrheic (0.857), interferon agonist (0.806), cyclooxygenase-1 inhibitor (0.713)
Prolyl aminopeptidase inhibitor (0.915), mucomembraneous protector (0.884),
antiseborrheic (0.865), interferon agonist (0.826), cyclooxygenase-1 inhibitor (0.734)
Mucomembraneous protector (0.885), glutamate receptor antagonist (0.826), Factor VIIa
inhibitor (0.823), prolyl aminopeptidase inhibitor (0.793), anticonvulsant (0.723)
Prolyl aminopeptidase inhibitor (0.887), Factor VIIa inhibitor (0.822), antiseborrheic
(0.768), mucomembraneous protector (0.747), glutamate receptor antagonist (0.742)
Prolyl aminopeptidase inhibitor (0.892), Factor VIIa inhibitor (0.830), antiseborrheic
(0.780), glutamate receptor antagonist (0.771), mucomembraneous protector (0.729),
interferon agonist (0.705)

THIO ANALOGUES OF PYRIMIDINE BASES
1435
CONCLUSIONS
The reactions of 2,4-di-ortho- (meta- and para-) bromo- (chloro- and nitro-) ben-
zylthiouracils and 2,4-di-ortho- (meta- and para-) bromo- (chloro- and nitro-) benzylthio-
6-methyluracils with an excess of bromine in tetrachloromethane at room temperature lead
to 2,4-di-ortho- (meta- and para-) bromo- (chloro- and nitro-) benzylthio-5-bromouracils
1–9 and 2,4-di-ortho- (meta- and para-) bromo- (chloro- and nitro-) benzylthio-5-bromo-
6-methyluracils 10–18.
The results obtained by PASS method identification of the prospective pharmacolog-
ical properties of 1–18 exhibit the possibility of finding new pharmacological agents from
this class of compounds.
EXPERIMENTAL
The purity of all described compounds was checked by melting points, TLC, and ele-
mental analyses. Melting points (uncorrected) were determined on a Boetius microscope hot
stage. Rf values refer to silica gel F254 TLC plates (Merck) developed with CHCl3 CH3OH
5:1 and observed under UV light (λ = 254 and 366 nm). UV/vis spectra were recorded with
a Specord UV/vis spectrophotometer in dioxane. IR spectra were recorded with a FT-IR
Bruker IFS-113 spectrophotometer in KBr pellets. The 1H NMR spectra were determined
with Varian Gemini 300 (300 MHz) spectrometer in CD3OD solution at a concentration
between 0.25 and 0.40 M in the 5 mm sample tubes at ambient temperature. Chemical
shifts are given in δ scale (ppm). Elemental analyses were performed with a Vector Euro
EA 3000 analyser.
2,4-Di-ortho- (meta- and para-) bromo- (chloro- and nitro-) benzylthiouracils and
2,4-di-ortho- (meta- and para-) bromo- (chloro- and nitro-) benzylthio-6-methyluracils
have been obtained according to the literature.19
The Synthesis of 2,4-Di-ortho- (meta- and para-) Bromo- (chloro-
and nitro-) benzylthio-5-bromouracils 1–9 and 6-Methyluracils 10–18
A solution of bromine (1 mmol) in tetrachloromethane (20 mL) was added dropwise
over 30 min at room temperature to a stirred suspension of the appropriate 2,4-di-ortho-
(meta- and para-) bromo- (chloro- and nitro-) benzylthiouracil (0.5 mmol) or 2,4-di-ortho-
(meta- and para-) bromo- (chloro- and nitro-) benzylthio-6-methyluracil (0.5 mmol) in
tetrachloromethane (30 mL). The reaction mixture was next stirred at room temperature for
2 h. The obtained crude product was filtered off, washed with tetrachloromethane (5 mL),
and dried. The resulting powder was boiled in ethanol (10 mL) under reflux condenser for
5 min. Upon cooling, a solid crystallized from this solution. It was filtered off, washed
with cold ethanol (10 mL), and dried. Compounds 1–18 were shown to be analytically pure
without any further purification (Table III).
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