Synthesis and anti-HIV activity of new 6-thioarylpyrimidines and related compounds

Article abstract of DOI:10.1080/10426500701693453

A series of new 5-nitro- and 5-amino-6-arylsulfanyl-1-propyl-1H-pyrimidin- 2,4-diones (4-9) were synthesized with the aim to develop new non-nucleoside reverse transcriptase inhibitors (NNRTIs). Similarly, 6-arylsulfanyl-1,3- dimethyl-5-nitro-1H-pyrimidin-2,4-diones (12-15) were prepared from 10. A new 2-amino-2-phenyl-7-phenylsulfanyl-imidazo[1,2-a]pyrimidin-5-one (18) has been synthesized from reaction of 17 with α-bromoacetophenone in the presence of NaH. The newly synthesized compounds were evaluated for their anti HIV-1 and HIV-2 activity in MT-4 cells. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/10426500701693453

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Phosphorus, Sulfur, and Silicon
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Synthesis and Anti-HIV Activity
of New 6-Thioarylpyrimidines
and Related Compounds
Iman A. Al-Masoudi a , Yaseen A. Al-Soud b , Najim A.
Al-Masoudi c , Saman H. Noori d & Thilo Schuppler c
a College of Veterinary, University of Basrah, Basrah,
Iraq
b Department of Chemistry, College of Science,
University of Al al-Bayt, Al-Mafraq, Jordan
c Fachbereich Chemie, Universität Konstanz,
Postfach 5560, D-78457, Konstanz, Germany
d Department of Biochemistry, College of Medicine,
University of Sulaimani, Sulaimani, Iraq
Published online: 24 Jun 2008.
To cite this article: Iman A. Al-Masoudi , Yaseen A. Al-Soud , Najim A. Al-Masoudi ,
Saman H. Noori & Thilo Schuppler (2008) Synthesis and Anti-HIV Activity of New 6-
Thioarylpyrimidines and Related Compounds, Phosphorus, Sulfur, and Silicon and the
Related Elements, 183:7, 1571-1583, DOI: 10.1080/10426500701693453
To link to this article: http://dx.doi.org/10.1080/10426500701693453
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Phosphorus, Sulfur, and Silicon, 183:1571–1583, 2008
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500701693453
Synthesis and Anti-HIV Activity of New
6-Thioarylpyrimidines and Related Compounds
Iman A. Al-Masoudi,1 Yaseen A. Al-Soud,2
Najim A. Al-Masoudi,3 Saman H. Noori,4
and Thilo Schuppler3
1College of Veterinary, University of Basrah, Basrah, Iraq
2Department of Chemistry, College of Science, University of Al al-Bayt,
Al-Mafraq, Jordan
3Fachbereich Chemie, Universita¨t Konstanz, Postfach 5560, D-78457
Konstanz, Germany
4Department of Biochemistry, College of Medicine, University of
Sulaimani, Sulaimani, Iraq
A series of new 5-nitro- and 5-amino-6-arylsulfanyl-1-propyl-1H-pyrimidin-2,4-
diones (4–9) were synthesized with the aim to develop new non-nucleoside reverse
transcriptase inhibitors (NNRTIs). Similarly, 6-arylsulfanyl-1,3-dimethyl-5-nitro-
1H-pyrimidin-2,4-diones (12–15) were prepared from 10. A new 2-amino-2-phenyl-
7-phenylsulfanyl-imidazo[1,2-a]pyrimidin-5-one (18) has been synthesized from re-
action of 17 with α-bromoacetophenone in the presence of NaH. The newly synthe-
sized compounds were evaluated for their anti HIV-1 and HIV-2 activity in MT-4
cells.
Keywords 6-arylsulphanyl-pyrimidones; anti-HIV activity; imidazo[1,2-a]pyrimidin-5-
one; non-nucleoside reverse transcriptase inhibitors (NNRTIs)
INTRODUCTION
To the chemotherapist, the revelation of a new chemical class with po-
tent activity against the HIV-1 reverse transcriptase, the key enzyme
in the HIV replication, and the target for developing anti-HIV drugs,
is always exciting; meanwhile, the attempts are continuing to discover
drugs that can interfere with a stage in the viral replicative cycle with-
out damaging the normal processes of the host cell.
Two types of reverse transcriptase inhibitors have been
developed,1−3 nucleoside reverse transcriptase inhibitors (NRTIs)
Received 31 July 2007; accepted 27 August 2007.
Address correspondence to Najim A. Al-Masoudi, P.O. Box 10 05 52, D-78405
Konstanz, Germany. E-mail: Najim.Al-Masoudi@gmx.de
1571

1572
I. A. Al-Masoudi et al.
and non-nucleoside reverse transcriptase inhibitors (NNRTIs). Three
NNRTIs, nevirapine,4 delaviridine,5,6 and efavirenz7 have been ap-
proved by the FDA for the treatment of HIV infection. However,
significant resistance has been developed against the current NNRTIs
and therefore there is an urgent need to develop new anti-HIV agents
that are effective against these resistant mutants.8,9 Several potent
6-alkylsulfanyl or sulphonyl-5-nitrouracil family attracts significant
attention due to their chemotherapeutic importance against HIV.
Benhida et al.10 have reported the synthesis of various derivatives of
1-ethoxymethyl-6-alkylsulphanyl and 6-arylsulphonyl-1H-pyrimidine-
2,4-diones and the 5-nitro analogues with potent anti-HIV-1 activities
in CEM/SS cells. On the other hand, Yousif and Yamamoto11 have
prepared similar 6-alkyl or arylsulfanyl analogues with different
substituentes at N-1. However, 1-[(2-hydroxyethoxy)methyl]-6-
(phenylthio)thymine (1) (HEPT) has been synthesized by Miyasaka
et al.12 and Al-Soud and Al-Masoudi13 with high anti-HIV inhibitory
activity as an interesting example in this series. In our recent work, we
reported new 5-nitro-1-propyl- or 1,3-dimethyl-5-nitro-1H-pyrimidin-
2,4-diones having 6-arylsulfanyl groups and their amino analogues as
HIV-1 and HIV-2 replication inhibitors.
RESULTS AND DISCUSSION
Chemistry
Various 5-alkyl- and 5-arylsulfanyl derivatives of 4-nitroimidazole
derivatives as well as the 5-substituted-piperazine analogues have
been prepared recently in our laboratory14−19 via nucleophilic displace-
ments of the bromine group activated by an adjacent nitro group.
Several alternative potential heterocylic bases, other than imidazole
derivatives, such as pyrimidine bases substituted by various potential
groups20−28 were prepared from their chloro analogue20 via nucleophilic

Anti-HIV Activity of New 6-Thioarylpyrimidines
1573
displacements. Analogously, our efforts are focused on the preparation
of new pyrimidines carrying arylsulfanyl groups, which might lead to
biological active candidates. 6-Chloro-5-nitro-1-propyl-1H-pyrimidin-
2,4-dione (3), prepared from nitration of 2,11 has been selected for the
synthesis of our targets by treatment with different arylsulfanyl nu-
cleophiles, such as sodium phenylthiolate, 4-pyridinethiol and 4-(N-
oxidepyridine)thiol in the presence potassium carbonate in hot DMF or
ethanol to give, after purification, 4–6 in 69, 55, and 51% yield, respec-
tively. Reduction of 4 with H2/Pd-C in methanol for 5 h afforded, after
purification, 7 (79%).
Treatment of 7 with formaldehyde in acetonitrile followed by re-
duction of the inseparable product with sodium cyanoborohydride
(NaBH3CN) under reflux for 3 h afforded, after chromatographic
purification, 8 (74%). On the other hand, refluxing of 7 with 3,4-
dimethoxyphenylaldehyde in ethanol gave 9 (77%) (Scheme 1).
SCHEME 1 Reagents and conditions: (i) HNO3/H2SO4, 5◦C; (ii) ArSNa or
ArSH, DMF (120◦C) or EtOH (reflux); (iii) H2/Pd-C, MeOH, 5 h; (iv) HCOH
(10 equiv.), NaBH3CN (3 equiv.), MeCN, reflux, 3 h.
The structures of the newly synthesized compounds 4–9 were as-
signed by the 1H, 13C NMR and mass spectra. The 1H NMR spectra of
4–9 showed rather similar patterns for the N-1 propyl protons. Thus,
the multiplets in the region δ 3.67–3.38 ppm and δ 1.49–1.42 ppm were

1574
I. A. Al-Masoudi et al.
attributed to the methylene protons of C-1ꢀ and C-2ꢀ, respectively; mean-
while the triplets resonated in the region δ 0.83–0.81 ppm (J ∼ 7.0 Hz)
were attributed to CH3 of N-1-propyl group. The resonances of the aryl
moiety of 4, 7–9 appeared as multiplets in the region δ 7.63–7.22 ppm,
meanwhile the same moiety of 4 and 5 were appeared as doublets in
the region δ 8.76–7.30 ppm (J =7.6 Hz). In the 13C NMR spectra of
4–9, C-2 and C-4 of the pyrimidine ring resonated at the region δ 166.8-
157.0 ppm, and δ 151.1–148.1 ppm, respectively. C-6 of 4-6 resonated
at δ 159.1, 156.9, and 158.2 ppm, respectively, while it appeared at δ
127.2 and 125.8 ppm, respectively, for 7 and 8. C-5 bearing nitro group
of 4–8 resonated at δ 116.0–106.9 ppm, while appeared at δ 90.8 ppm
for 9.
Next, other models of 6-arylsulfanyl pyrimidine derivatives bearing
N-1 and N-3 substituted methyl groups were prepared. Thus, treatment
of 11,29,30 prepared from nitration of 10, with sodium phenylthiolate, 4-
pyridinethiol, 4-(N-oxidepyridine)thiol, and 4-chlorophenylthiolate in
the presence of triethylamine in hot ethanol gave, after purification,
12–15 in 69, 52, 61, and 53% yield, respectively (Scheme 2).
SCHEME 2
The assignment of protons and carbons of the pyrimidine ring, and
the substituents were deduced in comparison to compounds 4–6 and
the previously reported data on 6-arylsulfanyl pyrimidines.11,12
In the 1HNMR spectra of 12–15, the N-1 and N-3 methyl groups were
resonated at the region δ 3.11–3.00 ppm. The 13C NMR spectra of 12–15
were almost similar to those of the analogues 4–6.

Anti-HIV Activity of New 6-Thioarylpyrimidines
1575
Gross et al.31 have described the identification of pyrrolo-
pyrimidones, 2-arylimidazol[1,2-a]-pyrimidone series and imidazolo
[1,2-a]-pyrimid-5-ones as potent GnRH receptor antagonists by reac-
tion of 2-amino-pyrimidone derivatives with α-bromoacetophenone. We
has selected 2-amino-6-chloro-5-nitro-pyrimid-4-one (16) as a key in-
termediate in synthesis of new 5-nitro-6-phenylsulfanyl-imidazo[1,2-
a]-pyrimid-4-one (18) in attempt to evaluate its anti-HIV activ-
ity. Thus, treatment 16 with PhSNa in DMF at 120◦C, afforded
17 (65%). Compound 17 was converted into 2-amino-2-phenyl-7-
phenylsulfanyl-imidazo[1,2-a]pyrimidin-5-one (18) (51%) by treatment
with α-brmoacetophenone in the presence of NaH in DMF (Scheme 3).
SCHEME 3 Reagents and conditions. (i) PhSNa, DMF, 120◦C, 3 h; (ii) α-
bromoacetophenone, DMF, NaH, 23◦C, 5 h, followed by addition of NH4OH
at 23◦C.
1
The structures of 17 and 18 were confirmed by the H-, 13C NMR,
and mass spectra. In the 13C NMR spectrum of 18, C-5 and C-7 ap-
peared at the higher field δ 188.2 ppm and δ 173.2 ppm, respectively,
in comparison to the same atoms of the adduct 17 (C-4: δ 163.6 ppm
and C-6: 142.8 ppm). The bridge carbon atom C-9 of 18 resonated at
the lower field (δ 124.3 ppm) compared to C-2 of the adduct 17 (δ
150.2 ppm). The structure of 18 was further confirmed by the homo-
and heteronuclear NMR study. The gradient selected HMBC32 spec-
trum allowed 2 J
coupling the assignment of C-2 at δC 139.8 ppm
C,H
by correlation with H-3 at δH 7.15 ppm, while it showed 3 J
be-
C,H
tween H-3 and C-5 and C-9 at δC 188.2 ppm and δC 144.6 ppm, re-
spectively. Its mass spectra exhibited the correct molecular ion [M+H]+
(426).
In-vitro Anti-HIV Assay
Various compounds have been reported to inhibit the replication of hu-
man immunodeficiency virus type 1 (HIV-1) in vitro.33 Among these,
compound is HEPT 1, a potent and selective inhibitor of HIV-1 in

1576
I. A. Al-Masoudi et al.
TABLE I In Vitro Anti-HIV-1a and HIV-2b of Some New
6-Arylthiopyrimidines
Compound
Virus strain
EC50(µg/mL)c
CC50(µg/mL)d
SIe
3
IIIB
ROD
IIIB
ROD
IIIB
ROD
IIIB
ROD
IIIB
ROD
IIIB
ROD
IIIB
ROD
IIIB
>62.40
>62.40
>72.90
>72.90
>76.63
>76.63
>0.313
>0.313
>44.30
>44.30
>81.20
>81.20
>11.60
2.54
≥ 62.40
≥ 62.40
≤ 1
≤ 1
≤ 1
≤ 1
<1
<1
<1
<1
<1
4
5
>72.90
>72.90
76.63
76.63
0.313
6
0.313
7
≥ 44.30
≥ 44.30
<1
12
13
14
17
≥ 81.20
≤ 1
≤ 1
<1
5
<1
<1
<1
<1
<1
≥ 81.20
11.60 1.07
11.60 1.07
0.275 0.233
0.275 0.233
88.07 39.77
88.07 39.77
2.56 2.56
40
>0.275
>0.275
>88.07
>88.07
>2.56 >2.56
0.003
ROD
IIIB
ROD
IIIB ROD
IIIB
18
Efavirenz
Capravirine
13333
7857
IIIB
0.0014
11
aAnti-HIV-1 activity measured with strain IIIB.
bAnti-HIV-2 activity measured with strain ROD.
cCompound concentration required to achieve 50% protection of MT-4 cells from the
HIV-1- and 2-induced cytopathogenic effect.
dCompound concentration that reduces the viability of mock-infected MT-4 cells by 50%.
eSI: Selectivity index (CC50/EC50).
various T4 cells cultures, including peripheral blood lymphocyte (PBL)
cells.34
In this study, we explored new analogues resemble in their structure
to HEPT. The new synthesized analogues 3–7,12–14, 17, and 18 were
evaluated for their in vitro anti-HIV-1 activity by using the IIIB strain
for HIV-1 and the ROD strain for the HIV-2, and monitored by the inhi-
bition of the virus-induced cytopathic effect in the human T-lymphocyte
(MT-4) cells. The results are summarized in Table I, in which the data
for efavirenz7 and capravirine35 were included for comparison purposes.
Compound 6, 13 and 14 were found to be the only compounds from the
series inhibiting HIV-1 replication in cell culture. Compounds 6 and 14
showed anti-HIV-1 and HIV-2 with EC50 > 0.313 µg/mL and >0.275
µg/mL, respectively, but with no selectivity can be witnessed (SI < 1).

Anti-HIV Activity of New 6-Thioarylpyrimidines
1577
Compound 13 showed higher value of EC50 against HIV-2 (2.54µg/ml),
with CC50 = 11.60 µg/ml, resulting with selectivity value (SI) of 5.
CONCLUSIONS
Compound 6 and 14 are equipotent against HIV-1 and HIV-2 repli-
cation in vitro, and therefore, it is not likely an NNRTI, meanwhile
compound 13 showed some selectivity (SI = 5) against HIV-2 (EC50
=
2.54 µg/mL), confirming the typical first generation NNRTI mode of
action of this compound. The structure-activity relationships (SARs) of
6-arylparimidine derivatives have suggested the importance of thioaryl
group on the pyrimidine ring, especially the pyridine-N-oxide residue,
for potent inhibitory activity against RT, then lead to the discovery of
more potent and selective analogues that will allow the elucidation of
their molecular mode of action.
EXPERIMENTAL
General Procedure
Melting points were measured on a Bu¨chi melting point apparatus B-
¨
545 (BUCHI Labortechnik AG, Switzerland) and are uncorrected. Mi-
croanalytical data were obtained with a Vario, Elementar apparatus
(Shimadzu, Japan). NMR spectra were recorded on 300 and 600 MHz
(1H) and at 150.91 MHz (13C) spectrometers (Bruker, Germany) with
TMS as internal standard and on δ scale in ppm. Heteronuclear assign-
1
ments were verified by H-13C HMBC experiment. Mass spectra were
recorded on 70 eV EI and FAB MAT 8200 spectrometers (Finnigan MAT,
USA), using 3-nitrobenzyl alcohol (NBOH) or glycerol as matrix. Some
molecular ions were detected by doping the sample with Na+ ion.
6-Chloro-5-nitro-1-propyl-1H-pyrimidin-2,4-dione (3)11
6-Chloro-1-propyluracil (2) (1.0 g, 5.29 mmol) was added in a portion
to a stirred concentration of H2SO4 (3.0 mL), kept below 15◦C by cooling
in ice. Fuming HNO3 (3.0 mL) was added slowly—being maintained at
0–5◦C, and the solution was then poured onto ice (40 g) with stirring.
The product was at once extracted with chloroform (2 × 30 mL) and the
combined extract was dried (Na2SO4), filtered and quickly evaporated
to give 3 (78%) as a yellow solid; m.p. 90–92◦C. 1H NMR (DMSO-d6): δ
10.06 (s, 1H, NH); 3.59 (m, 2H, CH2-1ꢀ); 1.45 (m, 2H, CH2-2ꢀ); 0.80 (t,
3H, J = 7.5 Hz, CH3). 13C NMR (DMSO-d6): δ 157.6 (C-4); 150.6 (C-2);
150.1 (C-6); 123.9 (C-5), 42.0 (C-1ꢀ); 21.0 (C-2ꢀ); 11.1 (C-3ꢀ). Anal. calcd.

1578
I. A. Al-Masoudi et al.
for C7H8 ClN3O4 (233.61): C, 35.99; H, 3.45; N, 17.99. Found: C, 35.78;
H, 3.32; N, 17.79.
5-Nitro-6-arylsulfanyl-1-propyl-1H-pyrimidin-2,4-diones
(4–9, 11)—General Procedure
A solution of 3 (4.28 mmol) in DMF (20 mL) or ethanol (20 mL)
and arylmercaptan (6.42 mmol) was heated at 120◦C (DMF) or un-
der reflux (ethanol) for 8–10 h. After cooling, the solution was evap-
orated to dryness and the residue was recrystallized from ethanol or
ethanol/methanol to give the desired product.
5-Nitro-6-phenylsulfanyl-1-propyl-1H-pyrimidin-2,4-dione (4)
From sodium phenylthiolate (0.85 g). Yield: 1.36 g (69%), m.p. 109–
1
111◦C. H NMR (DMSO-d6): δ 7.59 (m, 2H, Ar-H); 7.31 (m, 3H, Ar-H);
3.61 (m, 2H, CH2-1’); 1.45 (m, 2H, CH2-2’); 0.81 (t, 3H, J = 7.1 Hz,
CH3). 13C NMR (DMSO-d6): δ 162.1 (C-4); 159.1 (C-6); 148.1 (C-2); 129.5,
128.6, 128.4, 126.1 (Ar C); 113.8 (C-5), 50.8 (C-1’); 21.8 (C-2’); 11.8 (C-
3’). Anal. Calcd. for C13H13N3O4S (307.33): C, 50.81; H, 4.26; N, 13.67.
Found: C, 50.60; H, 4.13; N, 4.02. MS: m/z (FAB) 308 (M+H)+.
5-Nitro-1-propyl-6-(pyridin-4-ylsylfanyl)-1H-pyrimidin-2,4-
dione (5)
From 4-pyridinethiol (0.72 g). Yield: 55%, m.p. 311–312◦C. 1H NMR
(DMSO-d6): δ 9.89 (s, 1H, NH); 8.76 (d, 2H, J = 7.6 Hz, Ar-H); 7.55 (d,
2H, J = 7.6 Hz, Ar H); 3.45 (m, 2H, CH2-1ꢀ); 1.49 (m, 2H, CH2-2ꢀ); 0.83
(t, 3H, J= 7.0 Hz, CH3). 13C NMR (DMSO-d6): δ 163.2 (C-4); 156.9 (C-6);
150.3 (C-2); 129.5, 128.6, 128.4, 126.1 (Ar-C); 116.0 (C-5), 45.2 (C-1ꢀ);
21.1 (C-2ꢀ); 11.1 (C-3ꢀ). Anal. calcd. for C12H12N4O4S (308.32): C, 46.74;
H, 3.92; N, 18.17. Found: C, 46.52; H, 3.79; N, 17.88. MS: m/z (FAB) 309
(M+H)+.
5-Nitro-1-propyl-6-(pyridin-N-oxide-4-ylsulfanyl)-1H-
pyrimidin-2,4-dione (6)
From 4-(N-oxidepyridine)thiol (0.81 g). Yield: 1.06 g (51%), m.p. 95–
98 dec.◦C. 1H NMR (DMSO-d6): δ 8.00 (d, 2H, J = 7.6 Hz, Ar-H); 7.30 (d,
2H, J = 7.6 Hz, Ar H); 3.58 (m, 2H, CH2-1ꢀ); 1.43 (m, 2H, CH2-2ꢀ); 0.81
(t, 3H, J = 7.0 Hz, CH3). 13C NMR (DMSO-d6): δ 166.8 (C-4); 158.2 (C-
6); 150.2 (C-2); 138.2 (Ar-Cc,e); 131.3 (Ar-Cb, f ); 113.5 (C-5); 48.5 (C-1ꢀ);
21.1 (C-2ꢀ); 11.1 (C-3ꢀ). Anal. calcd. for C12H12N4O5S (324.31): C, 44.44;
H, 3.73; N, 17.28. Found: C, 44.22; H, 3.68; N, 17.05. MS: m/z (FAB) 325
(M+H)+.

Anti-HIV Activity of New 6-Thioarylpyrimidines
1579
5-Amino-6-phenylsulfanyl-1-propyl-1H-pyrimidin-2,4-dione (7)
A solution of 3 (0.70 g, 2.27 mmol) in methanol (20 mL) and Pd/C
(150 mg) was stirred under H2 for 5 h The solid was filtered and the
solution was evaporated to dryness. The residue was recrystallized from
ethanol to give 7 (0.50 g 79%), m.p. 143–146◦C. 1H NMR (DMSO-d6): δ
9.95 (s, 1H, NH); 8.83 (br s., 2H, NH2); 7.41–7.32 (m, 5H, Ar-H); 3.59
(m, 2H, CH2-1ꢀ); 1.45 (m, 2H, CH2-2ꢀ); 0.81 (t, 3H, J = 7.1 Hz, CH3). 13
C
NMR (DMSO-d6): δ 163.5 (C-4); 150.2 (C-6); 133.8; 127.8, 125.0, 121.0
(Ar-C, C-6); 106.9 (C-5); 48.5 (C-1ꢀ); 21.1 (C-2ꢀ); 11.2 (C-3ꢀ). Anal. calc.
for C13H15N4O2S (277.34): C, 56.30; H, 5.45; N, 15.15. Found: C, 50.02;
H, 5.37; N, 14.89. MS: m/z (FAB) 300 (M+Na)+.
5-(Dimethylamino)-6-phenylsulfanyl-1-propyl-1H-pyrimidin-
2,4-dione (8)
To a suspension of 6 (0.50 g, 1.80 mmol) in acetonitrile (10 mL) were
added 37% aqueous formaldehyde (0.54 g, 18.00 mmol, 10 equiv.) and
the mixture was heated under reflux for 1 h. After cooling, sodium
cyanoborohydride (NaBH3CN) (0.34 g, 5.4 mmol, 3.0 equiv.) and the
mixture was stirred at reflux temperature for 2 h. After cooling, the
reaction mixture was evaporated to dryness and the residue was par-
titioned between chloroform (3 × 20 mL) and water (20 mL). The com-
bined organic extracts were dried (Na2SO4), filtered and evaporated to
dryness, and the residue was poured onto SiO2 column.
Elution, in gradient, with methanol (0–10%) and chloroform, as elu-
1
ent, afforded 8 (0.40 g, 74%), m.p. 139-143◦C. H NMR (DMSO d6): δ
7.48 (m, 2H, Ar-H); 7.32 (m, 3H, Ar-H); 3.38 (m, 2H, CH2-1ꢀ); 3.21 (s, 6H,
NMe2); 1.48 (m, 2H, CH2-2ꢀ); 0.83 (t, 3H, J = 7.0 Hz, CH3). 13C NMR
(DMSO-d6): δ 161.6 (C-4); 151.1 (C-2); 135.6; 129.5, 129.0 (Ar-C); 126.8
(C-6); 125.8 (C-6, ArC); 106.9 (C-5); 48.0 (C-1ꢀ); 40.1 (NMe2); 21.7 (C-2ꢀ);
11.1 (C-3ꢀ). Anal. calcd. for C15H19N3O2S (305.4): C, 58.99; H, 6.27; N,
13.76. Found: C, 58.73; H, 6.16; N, 13.51. MS: m/z (FAB) 328 (M+Na)+.
(E)-5-(3,4-Dimethoxybenzylideneamino)-6-phenylsulfanyl-1-
propyl-1H-pyrimidin-2,4-dione (9)
A solution of 7 (0.50 g, 1.80 mmol) in EtOH (20 mL) containing 2,4-
dimethoxybenzaldehyde (0.33 g, 2.00 mmol) was heated under reflux
for 3 h. After cooling, the crystals was filtered and washed with cold
1
EtOH to give 9 (0.59 g, 77%), m.p. 155–158◦C. H NMR (DMSO-d6): δ
7.63–7.25 (m, 9H, Ar-H + CH N); 3.86, 3.82 (2xs, 6H, 2xOMe); 3.67 (m,
2H, CH2-1ꢀ); 1.42 (m, 2H, CH2-2ꢀ); 0.81 (t, 3H, J = 7.0 Hz, CH3). 13C
NMR (DMSO-d6): δ 160.3 (CH N); 157.0 (C-4); 148.1 (C-2, C-6); 128.3
(Ar C OMe), 127.7, 127.6, 125.4, 123.9 (Ar-C); 90.8 (C-5), 60.0 (OMe);

1580
I. A. Al-Masoudi et al.
45.7 (C-1ꢀ); 21.2 (C-2ꢀ); 11.3 (C-3ꢀ). Anal. calc. for C22H23N3O4S (425.5):
C, 62.10; H, 5.45; N, 9.88. Found: C, 61.89; H, 5.39; N, 9.71. MS: m/z
(FAB) 426 (M+H)+.
6-Chloro-1,3-dimethyl-5-nitro-1H-pyrimidin-2,4-dione (11)
Compound 11 was prepared by Pfleiderer et al.29 and Clark
et al.30
6-Arylsulfanyl-1,3-dimethyl-5-nitro-1H-pyrimidin-2,4-diones
(12–15)—General Procedure
A solution of chloro compound 11 (1.71 g, 9.37 mmol) in DMF (20 mL)
and arylmercaptan (18.74 mmol) was heated at 120◦C (DMF) for 12 h.
After cooling, the solution was evaporated to dryness and the residue
was recrystallized from ethanol or ethanol/methanol to give the desired
products 12–15.
1,3-Dimethyl-5-nitro-6-phenylsulfanyl-1H-pyrimidin-
2,4-dione (12)
From sodium phenylthiolate (2.47 g). Yield: 1.89 g (69%), m.p. 308–
1
311◦C. H NMR (DMSO-d6): δ 7.58 (m, 2H, Ar-H); 7.31 (m, 2H, Ar-H);
3.07, 3.00 (2s, 6H, 2xCH3). 13C NMR (DMSO-d6): δ 159.4 (C-4); 156.2
(C-2); 148.1 (C-6); 130.8, 128.3, 127.5, 125.4 (Ar-C); 105.5 (C-5); 27.0,
26.7 (Me). Anal. Calc. for C12H11N3O4S (293.3): C, 49.14; H, 3.78; N,
14.33. Found: C, 48.89; H, 3.70; N, 14.01. MS: m/z (FAB) 328 (M+Na)+.
1,3-Dimethyl-5-nitro-6-(pyridin-4-ylthio)-1H-pyrimidin-2,4-
dione (13)
From 4-pyridinethiol (2.08 g). Yield: 1.43 g (52%), m.p. 211–214
dec.◦C. 1H NMR (DMSO-d6): δ 8.60 (d, 2H, J = 7.5 Hz, Ar-Hc,e); 7.61 (d,
2H, J = 7.5 Hz, Ar-Hb,f); 3.11, 3.09 (2s, 6H, 2xCH3). 13C NMR (DMSO-
d6): δ 162.2 (C-4); 157.1 (C-2); 148.6 (C-6); 129.8, 128.7, 128.9, 126.7 (Ar-
C); 108.1 (C-5); 27.5, 27.0 (Me). Anal. calcd. for C11H10N4O4S (294.29):
C, 44.89; H, 3.43; N, 19.04. Found: C, 44.65; H, 3.33; N, 18.87. MS: m/z
(FAB) 295 (M+H)+.
1,3-Dimethyl-5-nitro–6-(pyridin-N-oxide-4-ylsulfanyl)-1H-
pyrimidin-2,4-dione (14)
From 4-(N-oxidepyridine)thiol (2.38 g). Yield: 1.77 g (61%), m.p. 200–
1
202 dec.◦C. H NMR (DMSO-d6): δ 8.08 (d, 2H, J = 8.1 Hz, Ar-Hc,e);
7.37 (d, 2H, J = 8.1 Hz, Ar-Hb,f); 3.09, 3.01 (2s, 6H, 2xCH3). 13C NMR
(DMSO-d6): δ 164.2 (C-4); 157.9 (C-2); 150.1 (C-6); 136.2 (Ar-Cc,e), 131.1
(Ar-Cb,f); 112.9 (C-5); 27.7, 27.2 (Me). Anal. calcd. for C11H10N4O5S

Anti-HIV Activity of New 6-Thioarylpyrimidines
1581
(310.29): C, 42.58; H, 3.25; N, 18.06. Found: C, 42.32; H, 3.09; N, 17.89.
MS: m/z (FAB) 311 (M+H)+.
6-(4-Chlorophenylsulfanyl)-1,3-dimethyl-5-nitro-1H-pyrimidin-
2,4-dione (15)
From 4-chlorophenylmercaptan (2.69 g). Yield: 1.62 (53%), m.p. 132-
137◦C. 1H NMR (DMSO-d6): δ 8.08 (d, 2H, J = 8.1 Hz, Ar-Hc,e); 7.37 (d,
2H, J = 8.1 Hz, Ar-Hb,f); 3.09, 3.01 (2s, 6H, 2xCH3). 13C NMR (DMSO-
d6): δ 157.2 (C-4); 151.0 (C-2); 145.0 (C-6); 131.0, 129.5 (Ar-C), 111.9 (C-
5); 27.0, 26.9 (Me). Anal. calcd. for C12H10ClN3O4S (327.74): C, 43.98;
H, 3.08; N, 12.82. Found: C, 43.69; H, 2.92; N, 12.61. MS: m/z (FAB) 350
(M + Na)+.
2-Amino-5-nitro-6-phenylsulfanyl-1H-pyrimidin-4-one (17)
This compound was prepared from 16 (0.65 g, 2.96 mmol) according ro
the procedure of preparation of 3. Yield: 0.51 g (65%), m.p. 233–235◦C.
1H NMR (DMSO-d6): δ 11.27 (br s., 2H, NH2); 7.40–7.34 (m, 5H, Ar-H).
13C NMR (DMSO-d6): δ 188.2 (C-5); 173.2 (C-7); 144.6 (C-9); 139.8 (C-2);
135.0, 133.1, 129.3, 129.1, 128.7, 127.2, 125.4 (Ar-C), 124.3 (C-3); 115.1
(C-6). Anal. calcd. for C10H8N4O3S (264.26): C, 45.45; H, 3.05; N, 21.20.
Found: C, 45.19; H, 3.98; N, 20.98. MS: m/z (FAB) 328 (M+Na)+.
2-Amino-2-phenyl-7-phenylsulfanyl-imidazo[1,2-α]pyrimidin-
5-one (18)
To a solution of 17 (0.30 g, 1.13 mmol) in anhydrous DMF (10 mL)
containing NaH (0.06 g, 2.5 mmol) was added α-bromoacetophenone
(0.32 g, 1.6 mmol). The reaction mixture was stirred at 23◦C for 5 h,
followed by the addition of NH4OH solution (7 mL) at 23◦C to give, after
1
chromatography, 18 (0.21 g, 51%), m.p. 192–195◦C. H NMR (DMSO-
d6): δ 7.45–7.41 (m, 5H, C8 Ar-H); 7.26-71.8 (m, 5H, S Ar-H); 7.15 (s,
1H, H-3). 13C NMR (DMSO-d6): δ 188.2 (C-4); 173.2 (C-6); 144.6 (C-2);
139.8 (C-8); 135.0, 133.1, 129.3, 129.1, 128.7, 127.2, 125.4 (Ar-C), 124.3
(C-7); 115.1 (C-5). Anal. calcd. for C18H12N4O3S (364.38): C, 59.33; H,
3.32; N, 15.38. Found: C, 58.92; H, 3.19; N, 15.09. MS: m/z (FAB) 365
(M+H)+.
ACKNOWLEDGMENTS
We thank Professor E. De Clercq and Professor C. Pannecouque of
Rega Institute of Medical Research, Katholieke Universiteit, Leu-
ven, Belgium, for the anti-HIV screening. Miss Friemel of Konstanz

1582
I. A. Al-Masoudi et al.
University (Germany) is gratefully acknowledged for the 2 D NMR ex-
periments.
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