Synthesis and biological evaluation of novel C5 halogen-functionalized S-DABO as potent HIV-1 non-nucleoside reverse transcriptase inhibitors

Article abstract of DOI:10.1016/j.bmc.2010.03.025

A series of novel S-DABO analogues (4a1-5a12) have been synthesized by an efficient method and evaluated as inhibitors of human immunodeficiency virus type-1 (HIV-1). The biological testing results clearly indicated that the substitution of halogen at the C5 position of pyrimidine ring could increase the anti-HIV-1 RT activity. The most active compounds showed activity in the low micromole range with IC₅₀ values (IC₅₀ 0.18-3.03 μM) comparable to nevirapine (IC₅₀ 4.12 μM). The docking showed that a new halogen bond was formed between halogen and carbonyl of TYR188 in the HIV-I RT.

Full text of DOI:10.1016/j.bmc.2010.03.025

Bioorganic & Medicinal Chemistry 18 (2010) 3231–3237
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Synthesis and biological evaluation of novel C5 halogen-functionalized S-DABO
as potent HIV-1 non-nucleoside reverse transcriptase inhibitors
Hua Qin a, Chang Liu b, Ying Guo c, Ruiping Wang b, Jianfang Zhang b, Liying Ma d, Zhili Zhang c,
Xiaowei Wang c, Yuxin Cui a, Junyi Liu a,c,
*
a State key Laboratory of National and Biomimetic Drug, Peking University, Beijing 100191, PR China
b College of Pharmaceutical Sciences, Capital Medical University, Beijing 100069, PR China
c Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing 100191, PR China
d State Key Laboratory for Infection Disease Prevention and Control, National Center for AIDS/STD Control and Prevention (NCAIDS), Chinese Center for Disease Control and
Prevention, Beijing 100050, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of novel S-DABO analogues (4a1–5a12) have been synthesized by an efficient method and eval-
uated as inhibitors of human immunodeficiency virus type-1 (HIV-1). The biological testing results
clearly indicated that the substitution of halogen at the C5 position of pyrimidine ring could increase
the anti-HIV-1 RT activity. The most active compounds showed activity in the low micromole range with
Received 1 February 2010
Revised 10 March 2010
Accepted 11 March 2010
Available online 15 March 2010
IC50 values (IC50 0.18–3.03
halogen bond was formed between halogen and carbonyl of TYR188 in the HIV-I RT.
Ó 2010 Elsevier Ltd. All rights reserved.
lM) comparable to nevirapine (IC50 4.12 lM). The docking showed that a new
Keywords:
HIV-1 RT
NNRTIs
S-DABO analogues
Docking
1. Introduction
during the following years into S-DABOs, N-DABOs and related
analogues (Fig. 1).8–23 A great number of oxopyrimidines were syn-
thesized and tested as anti-HIV-1 agents to obtain more potent and
Since discovery of the human immunodeficiency virus (HIV) as
the cause of the acquired immunodeficiency syndrome (AIDS),1
many efforts have been undertaken to design and synthesize po-
tential agents against HIV. The non-nucleoside reverse transcrip-
tase inhibitors (NNRTIs) serve as an increasingly important role
in the therapy of HIV infection, due to their unique antiviral po-
tency, high specificity and low toxicity, such as nevirapine and
efavirenz.2–4 Structure–activity relationship (SAR) studies in this
field are documented by the wide number of NNRTIs identified
so far include more than fifty structurally different classes of mol-
ecules, such as MKC-442 and TMC-125, which are under clinical
trials (Fig. 1).5–7 However, patients treated with NNRTIs can rapidly
trigger the emergence of drug resistant HIV-1 variants and the
cross-resistance between these structurally unrelated drugs.
Therefore, in the NNRTIs field, it is important to develop new
agents with higher binding affinity and the capability of inhibiting
clinical resistant mutants.
O
N
NH2
Br
H
N
O
N
HN
O
N
HN
N
O
N
N
O
R
CN
CN
R = Me, MKC-442
R = Ph, TNK-651
Nevirapine
O
TMC-125
O
O
I
HN
R1
HN
HN
S
N
X
R
N
X
R2
N
Among NNRTIs, dihydro-alkoxy-benzyl-oxopyrimdines (DA-
BOs) are an interesting class of compounds active at nanomolar
concentration. It was first reported in 1992 and further developed
R1 = H, 4a1-12
X = O, DABOs
X = S, S-DABOs
X = N, N-DABOs
6c
R1 = Me, 4b1-12
R1 = X, 5a1-12
R2 = substituted alkyl
* Corresponding author. Tel.: +86 010 82801706; fax: +86 010 62015548.
E-mail addresses: yxyx@bjmu.edu.cn, oiqh818@sohu.com (J. Liu).
Figure 1. Structures of Nevirapine, TMC-125, MKC-442, TNK-651, DABOs and
designed target compounds.
0968-0896/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2010.03.025

3232
H. Qin et al. / Bioorg. Med. Chem. 18 (2010) 3231–3237
selective inhibition compounds, such as S-DABOs reported to date
(ID50 = 3 nM toward the isolated wt enzyme and EC50 = 25 pM to-
ward wt NL4-3 virus).20
HIV-1 RT (PDB entry 1RT2, complexed with TNK-651) using AUTO-
DOCK 3.05 program.28 Default parameters were used as described
in the AUTODOCK manual unless otherwise specified. The molecule
was docked with 100 genetic algorithm runs of up to 250,000 en-
ergy evaluations for each run in the docking study of 5a3 with a RT
non-nucleoside binding site (NNBS). The studies revealed that the
binding mode of 5a3 has approximate conformation as in the TNK-
651-RT complex (Fig. 2). The hydrogen bond was formed at the N3-
H moiety of 5a3 and the carbonyl group of the Lys101 as stronger
as the TNK-651 (distance N3ÁÁÁO 2.73 Å and 2.76 Å, respectively).
Besides, a distinct interaction could be formed between the C5-I
and the carbonyl of Tyr188 with a 3.25 Å distance that is less than
their respective van der Walls radius sums, as well as with halogen
bonding angles (\(C–XÁÁÁO), 146.77°), which are larger than 120°.29
There are also a less interaction between the C5-I and the carbonyl
of Val179. Based on the docking result, We hypothesized that the
introduction of the halogen at C5 position could form a halogen
bond, charactered in parallel with a hydrogen bond in terms of
strength and directionality, and affect the interaction between
5a3 and the HIV-1 RT by the electron effect and the steric hin-
drance which should yield more potent anti-HIV agents with high-
er affinity for the inhibitor binding pocket.
2. Results and discussion
2.1. Drug design
Studies carried out on crystal structures of different RT/NNRTI
complexes suggest that these NNRTIs share a common mode of ac-
tion with the HIV-1 reverse transcriptase.8–23 Substituting with
aryl moiety at C2 and C6 alkyl chains of the pyrimidine ring are
structural determinant. The extend side chain at C2 position point
toward into a pocket mainly defined by His235, Pro236 and
Val106, with the length and size of the C2 side chain having only
modulator effects on potency. The chain at C6 position with differ-
ent substituents on the aromatic or heteroaromatic moieties is lo-
cated in a hydrophobic region delimited by Tyr181, Tyr188 and
Trp229. The NHCO fragment at N3/C4-positions of pyrimidine ring,
stabilized by a hydrogen bond between the N3-H function of S-DA-
BOs and the carbonyl oxygen of Lys101, cannot be modified with-
out abolishing the antiviral activity of DABO derivatives. These
results were reviewed again by our previous work.24
The groups at the pyrimidine C5 position furnished a conforma-
tional constraint with the aim of enhancing the affinity for the en-
zyme.25 A structure–activity relationship (SAR) profile of DABOs
together with molecular modeling investigation on their putative
binding mode have shown that the groups at C5 position were
small alkyl groups such as Me, Et and i-Pr, little or no information
was available about other C5 substitution, such as halogen atom.
However, in recent years the ability of halogen atoms to function
as general, effective and reliable sites for directing molecular rec-
ognition processes is being given to more and more attention.26,27
Moreover, no studies are available on the effect of varying both
electron effect and the steric hindrance of S-DABOs at C5 position
using halogen. The halogen group at C5 position of pyrimidine ring
may have electron effect with Vall79 and Tyr188 in HIV-1 RT, and
the large atomic radius of the halogen group may also help the sta-
bilized conformation of C6 benzyl group on the interaction be-
tween the inhibitor and HIV-1 RT.
Therefore, we synthesized a new series of C5 halogen-function-
alized compounds 5a1–12 with different length and size at C2
substituted chain and tested the activity against HIV-1 RT.
2.2. Chemistry
The synthesis of the newly designed compounds is described in
Scheme 1. Treatment of benzyl cyanide with 3–5 molar excess of
a-bromo esters 1a, b in the present of activated zinc dust in reflux-
ing tetrahydrofuran obtained the b-ketoesters 2a, b in 95% and 85%
yields.30 The compounds 2a, b were converted by reaction with
thiourea and sodium in boiling ethanol to 2-thiouracil 3a, b in
86% and 60% yields.31 Next, selective S-alkylation of 3a, b with
appropriate substituted alkyl halide in the present MeONa in anhy-
R1
R1
a
b
O
O
Br
O
2a, 2b
O
O
1a, 1b
To investigate the structure and activity relationship of our de-
sign compounds, 5a3 was flexibly docked into the binding site of
1a: R1 = H
1b: R1 = Me
O
O
R1
R1
c
HN
HN
R2
S
N
H
S
N
4a1-12
4b1-12
3a, 3b
O
H
O
X
HN
S
HN
N
H
3a
S
N
H
6a
c
O
O
N
H
X
d
HN
HN
S
R2
R2
S
N
4a1-8
5a1-8, X=I
5a9-12, X=Br
Figure 2. Binding mode of 5a3 (pink) and TNK-651 (white) with HIV-RT. The bonds
are shown as red (5a3) and black (TNK-651) dashed lines and the halogen bonding
angle is shown as green dashed line.
Scheme 1. Reagents and conditions for the chemical synthesis: (a) benzyl cyanide,
Zn/THF, reflux; (b) thiourea, EtONa, EtOH, reflux; (c) substituted alkyl halide, Na/
MeOH, rt; (d) I2 or Br2, PbO2, rt, overnight.

H. Qin et al. / Bioorg. Med. Chem. 18 (2010) 3231–3237
3233
drous MeOH at room temperature afforded the designed com-
pounds 4a1–12, 4b1–12 in 30–88% yields.32 Halogenations at C5
position of 4a1–8 by PbO2 and I2 or Br2 in HOAc at room tempera-
ture led 5a1–12 in 45–94% yields. The analytical and spectral date
showed that the C5-H was substituted by I or Br and no side reac-
tions resulted in the other aromatic rings. However, this halogena-
tion approach was unsuccessful on these compounds which C2
chains were substituted by benzyloxymethyl, ethoxymethyl and
allyl such as 4a10–12. Thus, we decided to halogenate 3a at C5 po-
sition to 6a before S-alkylation. Unfortunately, some attempts with
different reagents and solvent such as NBS/DCM, NBS/DMF, NIS/
DCM, Br2/H2O and I2/H2O at room temperature or heated about
80 °C did not give the halogenated products 6a, thought to be
due to lower aromaticity of compound 3a.
interesting to note that three series of compounds reflect obvious
structure–activity relationships.
Compared the different substitutions at C5 position, we found
that the activity of C5-Me series (4b1–12) was a slightly better
than C5-H (4a1–12) (Table 1). However, if the C5 position was
substituted by I or Br, the activity was better than H and Me obvi-
ously, and the I was better than Br at concentrations sixfold or
more. For example, when the C2 group was 2-naphthyl methyl,
the halogen substituent at C5 position was key factor for the activ-
ity. The results showed that the anti-HIV-1RT activity was associ-
ated with the electrophile and atom radius of the halogen atom.
The halogen-functionalized at C5 position of S-DABO derivatives
could be new HIV-RT inhibitors. These results were accordance
with our originally envision and reviewed that the halogen bond
functioned as a direction molecular recognition to some degree.
The halogen bond acting as a new interaction for rational drug de-
sign was discussed by Zhu group recently and our result was also
consistent with their experimental result.29 It was particularly note-
2.3. Biological activity
The compounds 4a1–12, 4b1–12 and 5a1–12 were tested for
their activity against HIV in RT assay, using a poly(rA)/oligo(dT)15
homopolymer template with the HIV antigen detection ELISA
method, nevirapine and MKC-442 as references (Table 1).33 It is
worthy that compound 5a3 (IC50 = 0.18
4a3 (IC50 = 8.17 M) at concentrations 45-fold and 23-fold to nevi-
rapine (IC50 = 4.12 M) by introducing the iodine at the C5 position,.
lM) was more active than
l
l
A SAR profile of S-DABAs at C5 position was I > Br >> Me–H. In addi-
tion, we found that the small (H) or bulky (t-Bu) substituted groups
on the benzene ring of the C2 chain were not beneficial for the activ-
ity. But maintaining a three-carbon spacer between S and benzene
ring was the optimal length for the activity, which demonstrated
by 4a3 > 4a2 > 4a1, 4b3 > 4b2 > 4b1 and 5a3 > 5a2 > 5a1. Detailed
SAR studies on these compounds are under way.
Table 1
Structure and enzymatic activity valuea of 4a1–5a12
O
R1
HN
R2
S
N
b
Compd
R1
R2
IC50
NAc
(lM)
3. Conclusions
4a1
4a2
4a3
4a4
4a5
4a6
4a7
4a8
4a9
4a10
4a11
4a12
4b1
4b2
4b3
4b4
4b5
4b6
4b7
4b8
4b9
4b10
4b11
4b12
5a1
5a2
5a3
5a4
5a5
5a6
5a7
5a8
5a9
5a10
5a11
5a12
H
C6H5CH2
H
H
H
H
H
H
H
H
C6H5CH2 CH2
17.45
8.17
47.72
91.14
90.85
NA
In summary, we have designed and synthesized three series of
novel C5 halogen-functionalized S-DABO analogues as new NNRTIs
for the first time. The activity result showed that the introduction
of halogen atom at C5 position of the pyrimidine ring will increase
the activity obviously. A halogen bond could be formed between
the halogen atom and the carbonyl of TYR188. Some of the IC50 val-
ues of the tested compounds were better comparing to the nevira-
pine, although the activity were suboptimal comparing to the best
S-DABOs, the SAR exploration encouraged us to the new rational
design. Further structure modifications on the C5 position and
two chains of the pyrimidine ring are underway. Also, the synthetic
route shows combination potential in the synthesis of larger li-
braries of compounds which is ongoing in our laboratory.
C6H5CH2CH2 CH2
(O-CH3)C6H4CH2
(m-CH3)C6H4CH2
(m-OCH3)C6H4CH2
(p-t-Bu)C6H4CH2
2-Naphthyl methyl
C6H5(CH3)CH
CH3CH2OCH2
C6H5CH2OCH2
CH2@CHCH2
NA
>100
>100
12.12
>100
NA
59.61
2.93
>100
NA
48.74
NA
NA
>100
51.66
19.01
NA
10.12
2.40
0.18
4.16
3.03
8.29
5.62
2.04
13.95
24.94
26.65
12.26
H
H
H
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
I
I
I
I
I
I
I
I
C6H5CH2
C6H5CH2 CH2
C6H5CH2CH2CH2
(O-CH3)C6H4CH2
(m-CH3)C6H4CH2
(m-OCH3)C6H4CH2
(p-t-Bu)C6H4CH2
2-Naphthyl methyl
C6H5(CH3)CH
CH3CH2OCH2
C6H5CH2OCH2
CH2@CHCH2
4. Experimental
NMR spectra were recorded on a Bruker Avance II300 or Avance
II500 using TMS as an internal standard and chemical shifts are re-
ported in d (ppm). Mass spectrometer was record on Wasters Quat-
tro Micro 2000. Melting points were measured on a WBS-1B type
digital melting-point apparatus and are uncorrected. All the reac-
tions were monitored by thin-layer chromatography (TLC) on pre-
coated silica gel G plates at 254 nm under a UV lamp. Silica gel
(0.040–0.064 mm) used for column chromatography and analytical
silica gel TLC plates 60GF254. Unless otherwise stated, all reagents
were purchased from commercial sources and used without fur-
ther purification.
C6H5CH2
C6H5CH2 CH2
C6H5CH2 CH2 CH2
(O-CH3)C6H4CH2
(m-CH3)C6H4CH2
(m-OCH3)C6H4CH2
(p-t-Bu)C6H4CH2
2-Naphthyl methyl
C6H5CH2 CH2
(O-CH3)C6H4CH2
(m-CH3)C6H4CH2
2-Naphthyl methyl
Br
Br
Br
Br
4.1. General procedure for the preparation of compounds 4a1–12
a
Nevirapine and MKC-442 were used as the reference compounds here; IC50
were 4.12 M and 0.15 M, respectively.
Compound dose ( M) required to inhibit the HIV-1 RT activity by 50%; Data
l
l
b
l
Sodium (225 mg) was dissolved in anhydrous methanol (15 ml),
6-benzyl-2-thiouracil derivatives 3a (1 mmol) was added followed
by addition of appropriate substituted alkyl halide (1.1–3 mmol).
After completion of the reaction according to TLC analysis and
represent mean values for three separate experiments, variation among triplicate
samples was less than 15%.
c
No inhibition of reverse transcriptase activity was observed up to a concen-
tration of 100 lM.

3234
H. Qin et al. / Bioorg. Med. Chem. 18 (2010) 3231–3237
evaporation of the solvent, the oil residue was diluted with H2O
(80 ml) followed by addition of HOAc (1 ml). The white precipitate
was filtered off and then purified by silica gel column chromatog-
raphy to afford the white solid products 4a1–12.
CH2S), 6.00 (s, 1H, 5-H), 7.06–7.56 (m, 9H, ArH); 13C NMR
(125 MHz, CDCl3) d: 31.30 ((CH3)3C), 34.40 (CH2S), 34.51 (ArCH2),
44.01 ((CH3)3C), 108.46 (C5), 125.47, 126.83, 128.64, 128.89,
129.49, 133.36, 137.10, 150.55 (Ar), 160.50 (C6), 165.35 (C2),
167.91 (C4); m/z (ESI): 365.0 (M+H)+, 387.0 (M+Na)+; C22H24N2OS
(364.16).
4.1.1. 6-Benzyl-2-(benzylthio)pyrimidin-4(3H)-one (4a1)
Yield 80%; mp 188.8–190.5 °C; white solid; 1H NMR (300 MHz,
CDCl3) d: 3.84 (s, 2H, ArCH2), 4.38 (s, 2H, SCH2), 5.94 (s, 1H, 5-H),
7.11–7.51 (m, 10H, ArH); 13C NMR (75 MHz, CDCl3) d: 34.61
(CH2S), 43.96 (ArCH2), 108.46 (C5), 126.84, 127.51, 128.51,
128.63, 129.14, 129.45, 136.51, 136.70 (Ar), 160.21 (C6), 165.32
(C2), 167.94 (C4); m/z (ESI): 309.0 (M+H)+, 331.0 (M+Na)+;
C18H16N2OS (308.10).
4.1.8. 6-Benzyl-2-(naphthalen-2-ylmethylthio)pyrimidin-4(3H)-
one (4a8)
Yield 65%; mp 213–214 °C; white solid; 1H NMR (500 MHz,
CDCl3) d: 3.84 (s, 2H, ArCH2), 4.55 (s, 2H, CH2S), 6.02 (s, 1H, 5-H),
7.23–7.33 (m, 5H, ArH), 7.45–7.53 (m, 3H, ArH), 7.80–7.87 (m,
4H, ArH); 13C NMR (75 MHz, pyridine-d5) d: 34.73 (CH2S), 43.75
(ArCH2), 107.61 (C5), 126.15, 126.43, 126.79, 127.53, 127.85,
127.96, 128.02, 128.51, 128.75, 129.62, 132.93, 133.61, 138.38
(Ar), 162.91 (C6), 165.06 (C2), 167.06 (C4); m/z (ESI): 359.1
(M+H)+, 381.2 (M+Na)+; C22H18N2OS (358.11).
4.1.2. 6-Benzyl-2-(phenethylthio)pyrimidin-4(3H)-one (4a2)
Yield 77%; mp 139–140 °C; white solid; 1H NMR (300 MHz,
CDCl3) d: 2.97 (dd, 2H, J = 8.1, 9.9 Hz, SCH2CH2,), 3.39 (dd, 2H,
J = 8.4, 9.6 Hz, SCH2CH2), 3.86 (s, 2H, ArCH2), 6.02 (s, 1H, 5-H),
7.18–7.34 (m, 10H, ArH), 12.75 (br s, 1H, NH); 13C NMR (75 MHz,
CDCl3) d: 31.78 (CH2S), 35.73 (ArCH2), 44.00 (ArCH2CH2S), 108.41
(C5), 126.59, 126.86, 128.53, 128.58, 128.62, 129.42, 137.05,
139.74 (Ar), 160.61 (C6), 165.35 (C2), 168.01 (C4); m/z (ESI):
323.0 (M+H)+, 345.0 (M+Na)+; C19H18N2OS (322.11).
4.1.9. 6-Benzyl-2-(1-phenylethylthio)pyrimidin-4(3H)-one (4a9)
Yield 65%; mp 213–214 °C; white solid; 1H NMR (500 MHz,
CDCl3) d: 1.73 (d, 3H, J = 7.0 Hz, CH3CH), 3.86 (s, 2H, ArCH2),
5.11–5.15 (q, 1H, J = 7.2 Hz, CH3CH), 6.00 (s, 1H, 5-H), 7.24–7.38
(m, 10-H, ArH); 13C NMR (125 MHz, CDCl3) d: 22.01 (CH3CH),
44.00 (CH3CH), 44.63 (ArCH2), 108.32 (C5), 126.85, 127.54,
128.50, 128.64, 129.49, 137.13, 141.97 (Ar), 160.37 (C6), 165.72
(C2), 168.14 (C4); m/z (ESI): 323.0 (M+H)+; C19H18N2OS (322.11).
4.1.3. 6-Benzyl-2-(3-phenylpropylthio)pyrimidin-4(3H)-one (4a3)
Yield 88%, mp 149–150 °C; white solid; 1H NMR (300 MHz,
CDCl3) d: 2.03 (quintet, 2H, J = 7.5 Hz, CH2CH2CH2), 2.73 (t, 2H,
J = 7.5 Hz, ArCH2CH2), 3.18 (t, 2H, J = 7.5 Hz, CH2CH2S), 3.81 (s,
2H, ArCH2), 6.00 (s, 1H, 5-H), 7.18–7.33 (m, 10H, ArH); 13C NMR
(75 MHz, CDCl3) d: 30.09 (CH2S), 30.61 (SCH2CH2), 34.67
(CH2CH2CH2S), 43.98 (ArCH2), 108.23 (C5), 126.05, 126.82,
128.43, 128.47, 129.43, 137.10, 140.99 (Ar), 160.68 (C6), 165.24
(C2), 167.98 (C4); m/z (ESI): 337.1 (M+H)+, 359.0 (M+Na)+;
C20H20N2OS (336.13).
4.1.10. 6-Benzyl-2-(ethoxymethylthio)pyrimidin-4(3H)-one (4a10)
Yield 53%; mp 130–131 °C; white solid; 1H NMR (500 MHz,
CDCl3) d: 1.20 (t, 3H, J = 7.0 Hz, CH2CH3), 3.56 (q, 2H, J = 7.0 Hz,
OCH2CH3), 3.86 (s, 2H, ArCH2), 5.44 (s, 2H, SCH2O), 6.02 (s, 1H, 5-
H), 7.26–7.35 (m, 5H, ArH), 12.80 (br s, 1H, NH); 13C NMR
(125 MHz, CDCl3) d: 14.69 (CH2CH3), 43.91 (ArCH2), 65.40 (SCH2O),
72.25 (OCH2CH3), 109.00 (C5), 126.89, 128.63, 129.48, 136.92 (Ar),
159.67 (C6), 165.18 (C2), 168.05 (C4); m/z (ESI): 277.3 (M+H)+;
C14H16N2O2S (276.09).
4.1.4. 6-Benzyl-2-(2-methyl-benzylthio)pyrimidin-4(3H)-one (4a4)
Yield 88%; mp 170–172 °C; white solid; 1H NMR (300 MHz,
CDCl3) d: 2.36 (s, 3H, ArCH3), 3.98 (s, 2H, ArCH2), 4.67 (s, 2H,
SCH2), 6.10 (s, 1H, 5-H), 7.00–7.63 (m, 9H, ArH), 12.96 (br s, 1H,
NH); 13C NMR (75 MHz, CDCl3) d: 19.37 (ArCH3), 33.09 (CH2S),
43.87 (ArCH2), 108.38 (C5), 126.15, 126.92, 128.01, 128.66, 129.52,
130.27, 130.46, 133.67, 136.83, 136.99 (Ar), 160.68 (C6), 165.33
(C2), 167.82 (C4); m/z (ESI): 323.1 (M+H)+; C19H18N2OS (322.11).
4.1.11. 6-Benzyl-2-(benzyloxymethylthio)pyrimidin-4(3H)-one
(4a11)
Yield 50%; mp 132–133 °C; white solid; 1H NMR (300 MHz,
CDCl3) d: 3.78 (s, 2H, ArCH2), 4.60 (s, 2H, ArCH2O), 5.46 (s, 2H,
SCH2O), 6.01 (s, 1H, 5-H), 7.26–7.55 (m, 10H, ArH), 12.40 (br s,
1H, NH); 13C NMR (75 MHz, CDCl3) d: 43.87 (ArCH2), 71.19
(SCH2O), 71.54 (OCH2Ar), 109.19 (C5), 126.93, 128.12, 128.40,
128.53, 128.67, 129.31, 129.47, 136.47, 136.86 (Ar), 159.33 (C6),
164.77 (C2), 167.99 (C4); m/z (ESI): 339.0 (M+H)+, 361.0
(M+Na)+; C19H18N2O2S (338.11).
4.1.5. 6-Benzyl-2-(3-methyl-benzylthio)pyrimidin-4(3H)-one (4a5)
Yield 59%; mp 148.5–149.5 °C; white solid; 1H NMR (300 MHz,
CDCl3) d: 2.33 (s, 3H, ArCH3), 3.87 (s, 2H, ArCH2), 4.39 (s, 2H, SCH2),
6.00 (s, 1H, 5-H), 7.07–7.36 (m, 9-H, ArH), 13.20 (br s, 1H, NH); 13C
NMR (75 MHz, CDCl3) d: 21.34 (ArCH3), 34.70 (CH2S), 44.01
(ArCH2), 108.39 (C5), 126.25, 126.87, 128.33, 128.43, 128.65,
129.47, 129.89, 136.31, 137.06, 138.22 (Ar), 160.49 (C6), 165.63
(C2), 168.05 (C4); m/z (ESI): 323.1 (M+H)+; C19H18N2OS (322.11).
4.1.12. 2-(Allylthio)-6-benzylpyrimidin-4(3H)-one (4a12)
Yield 61%; mp 132–133 °C; white solid; 1H NMR (500 MHz,
CDCl3) d: 3.75 (d, 2H, J = 7.2 Hz, SCH2), 3.77 (s, 2H, ArCH2), 5.05
(d, 1H, J = 9.9 Hz, CH@CH2), 5.21 (dd, 1H, J = 16.8, 1.2 Hz, CH@CH2),
5.88 (m, 1H, CH@CH2), 6.00 (s, 1H, 5-H), 7.26–7.35 (m, 5H, ArH),
13.26 (br s, 1H, NH); 13C NMR (125 MHz, CDCl3) d: 33.31 (SCH2),
43.97 (CH2Ar), 108.34 (C5), 118.79 (CH@CH2), 132.39 (CH@CH2),
126.86, 128.61, 129.48, 137.00 (Ar), 160.23 (C6), 165.74 (C4),
168.15 (C2); m/z (ESI): 259.2 (M+H)+, 291.2 (M+Na)+; C14H14N2OS
(258.08).
4.1.6. 6-Benzyl-2-(3-methoxybenzylthio)pyrimidin-4(3H)-one (4a6)
Yield 78%; mp 159–160 °C; white solid; 1H NMR (500 MHz,
CDCl3) d: 3.79 (s, 3H, OCH3), 3.87 (s, 2H, ArCH2), 4.40 (s, 2H,
CH2S), 5.99 (s, 1H, 5-H), 6.80–7.35 (m, 9H, ArH); 13C NMR
(125 MHz, CDCl3) d: 34.75 (CH2S), 43.93 (ArCH2), 55.22 (OCH3),
108.39 (C5), 114.66, 121.51, 128.67, 129.46, 129.57, 136.94,
137.88, 160.40 (Ar), 159.70 (C6), 165.47 (C2), 168.00 (C4); m/z
(ESI): 338.9 (M+H)+, 361.0 (M+Na)+; C19H18N2O2S (338.11).
4.2. Compounds 4b1–12 were prepared by the method used for
4a1–12
4.1.7. 6-Benzyl-2-(4-tert-butylbenzylthio)pyrimidin-4(3H)-one
(4a7)
4.2.1. 6-Benzyl-5-methyl-2-(benzylthio)pyrimidin-4(3H)-one (4b1)
Yield 30%; mp 176.5–177.5 °C; 1H NMR (300 MHz, CDCl3) d:
2.04 (s, 3H, 5-CH3), 3.96 (s, 2H, ArCH2), 4.38 (s, 2H, CH2S), 7.23–
7.32 (m, 10H, ArH), 12.44 (br s, 1H, NH); 13C NMR (125 MHz, CDCl3)
Yield 79%; mp 169–170 °C; white solid; 1H NMR (500 MHz,
CDCl3) d: 1.34 (s, 9H, (CH3)3C), 3.87 (s, 2H, ArCH2), 4.39 (s, 2H,

H. Qin et al. / Bioorg. Med. Chem. 18 (2010) 3231–3237
3235
d: 10.73 (5-CH3), 34.54 (ArCH2), 41.04 (ArCH2S), 116.58 (C5),
126.50, 127.41, 128.51, 128.98, 129.09, 136.97, 137.70 (Ar),
155.90 (C6), 162.07 (C2), 165.30 (C4); m/z (ESI): 323.0 (M+H)+,
345.0 (M+Na)+; C19H18N2OS (322.11).
34.50(CH2S), 41.00 ((CH3)3C), 116.64 (C5), 125.46, 126.47, 128.49,
128.80, 128.98, 133.69, 137.89, 155.95 (Ar), 150.45 (C6), 161.88
(C2), 164.87 (C4); m/z (ESI): 379.0 (M+H)+, 401.0 (M+Na)+;
C23H26N2O2S (378.18).
4.2.2. 6-Benzyl-2-(benzylthio)-5-methylpyrimidin-4(3H)-one (4b2)
Yield 52%; mp 156.5–157.5 °C; white solid; 1H NMR (500 MHz,
CDCl3) d: 2.14 (s, 3H, 5-CH3), 2.97 (t, 2H, J = 7.5 Hz, SCH2), 3.37 (t,
2H, J = 7.5 Hz, SCH2CH2), 3.98 (s, 2H, ArCH2), 7.16–7.32 (m, 10H,
ArH); 13C NMR (125 MHz, CDCl3) d: 10.72 (5-CH3), 31.81 (CH2S),
35.83 (ArCH2), 41.05 (ArCH2CH2S), 116.59 (C5), 126.50, 126.53,
128.49, 128.51, 128.59, 128.91, 137.95, 139.88 (Ar), 156.15 (C6),
162.06 (C2), 165.06 (C4); m/z (ESI): 337.5 (M+H)+, 359.4
(M+Na)+; C20H20N2OS (336.13).
4.2.8. 6-Benzyl-5-methyl-2-(naphthalen-2-ylmethyl thio)pyrimi-
din-4(3H)-one (4b8)
Yield 74%; mp 190.5–191.5 °C; white solid; 1H NMR (500 MHz,
DMSO-d6) d: 1.96 (s, 3H, 5-CH3), 3.92 (s, 2H, ArCH2), 4.52 (s, 2H,
CH2S), 7.19–7.26 (m, 5H, ArH), 7.43–7.50 (m, 3H, ArH), 7.76–7.89
(m, 4H, ArH), 12.61 (br s, 1H, NH); 13C NMR (125 MHz, pyridine-
d5) d: 10.79 (5-CH3), 34.55 (ArCH2), 40.96 (CH2S), 115.86 (C5),
126.13, 126.40, 126.53, 127.56, 127.84, 127.94, 128.00, 128.47,
128.71, 129.25, 132.93, 133.62, 135.89, 138.84 (Ar), 157.85 (C6),
161.32 (C2), 164.72 (C4); m/z (ESI): 373.1 (M+H)+, 395.1
(M+Na)+; C23H20N2OS (372.13).
4.2.3. 6-Benzyl-5-methyl-2-(3-phenylpropylthio)pyrimidin-4(3H)-
one (4b3)
Yield 62 °C; mp 152–153 °C; white solid; 1H NMR (300 MHz,
CDCl3) d: 2.12 (s, 3H, 5-CH3), 1.99 (quintet, 2H, J = 7.2 Hz,
CH2CH2CH2), 2.69 (t, 2H, J = 7.2 Hz, ArCH2CH2), 3.14 (t, 2H,
J = 7.2 Hz, CH2CH2S), 3.91 (2H, s, ArCH2), 7.15–7.31 (10H, m,
ArH); 13C NMR (75 MHz, CDCl3) d: 10.68 (5-CH3), 30.06 (CH2S),
30.81 (SCH2CH2), 34.72 (ArCH2CH2), 41.01 (ArCH2), 116.32 (C5),
126.00, 126.43, 128.40, 128.44, 128.95, 137.95, 141.07 (Ar),
156.23 (C6), 162.03 (C2), 165.34 (C4); m/z (ESI): 351.4 (M+H)+,
373.4 (M+Na)+; C21H22N2OS (350.15).
4.2.9. 6-Benzyl-5-methyl-2-(1-phenylethylthio)pyrimidin-4(3H)-
one (4b9)
Yield 50%; mp 165–166 °C; white solid; 1H NMR (300 MHz,
CDCl3) d: 1.68 (d, 3H, J = 7.2 Hz, CH3CH), 2.03 (s, 3H, 5-CH3), 3.94
(s, 2H, ArCH2), 5.06 (q, 1H, J = 7.2 Hz, CH3CH), 7.22–7.35 (m, 10H,
ArH); 13C NMR (75 MHz, CDCl3) d: 10.68 (5-CH3), 22.06 (CH3CH),
40.96 (ArCH2), 44.73 (CH3CHS), 116.65 (C5), 126.45, 127.41,
128.46, 128.52, 128.98, 137.91, 142.08 (Ar), 155.75 (C6), 161.93
(C2), 164.88 (C4); m/z (ESI): 337.0 (M+H)+, 359.0 (M+Na)+;
C20H20N2OS (336.13).
4.2.4. 6-Benzyl-5-methyl-2-(2-methylbenzylthio)pyrimidin-4(3H)-
one (4b4)
4.2.10. 6-Benzyl-2-(ethoxymethylthio)-5-methyl pyrimidin-4(3H)-
one (4b10)
Yield 74%; mp 173–174 °C; white solid; 1H NMR (300 MHz,
CDCl3) d: 1.93 (s, 3H, 5-CH3), 2.36 (s, 3H, ArCH3), 3.98 (s, 2H,
ArCH2), 4.41 (s, 2H, CH2S), 7.05–7.33 (m, 9H, ArH); 13C NMR
(125 MHz, CDCl3) d: 10.74 (5-CH3), 19.33 (ArCH3), 32.84 (CH2S),
41.05 (ArCH2), 116.56 (C5), 126.14, 126.51, 127.86, 128.50,
128.99, 130.13, 130.45, 134.27, 136.97, 137.92 (Ar), 156.11 (C6),
162.06 (C2), 165.28 (C4); m/z (ESI): 337.2 (M+H)+, 359.1
(M+Na)+; C20H20N2OS (336.13).
Yield 33%; mp 129–130 °C; white solid; 1H NMR (500 MHz,
CDCl3) d: 1.19 (t, 3H, J = 7.0 Hz, CH2CH3), 2.13 (s, 1H, 5-CH3), 3.55
(q, 2H, J = 7.0 Hz, OCH2CH3), 3.95 (s, 2H, CH2Ar), 5.38 (s, 2H,
SCH2O), 7.22–7.32 (m, 5H, ArH), 11.99 (br s, 1H, NH); 13C NMR
(125 MHz, CDCl3) d: 10.78 (5-CH3), 14.70 (CH2CH3), 40.97 (ArCH2),
65.19 (SCH2O), 72.32 (OCH2CH3), 117.40 (C5), 126.50, 128.47,
128.56, 128.91, 129.18, 137.84 (Ar), 155.36 (C6), 161.90 (C2),
164.82 (C4); m/z (ESI): 291.0 (M+H)+, 312.9 (M+Na)+; C15H18N2O2S
(290.11).
4.2.5. 6-Benzyl-5-methyl-2-(3-methylbenzylthio)pyrimidin-4(3H)-
one (4b5)
Yield 67%; mp 198–199.5 °C; white solid; 1H NMR (300 MHz,
DMSO-d6) d: 1.95 (s, 3H, 5-CH3), 2.22 (s, 3H, ArCH3), 3.90 (s, 2H,
ArCH2), 4.29 (s, 2H, CH2S), 7.02–7.31 (m, 9H, ArH), 12.54 (br s,
1H, NH); 13C NMR (125 MHz, pyridine-d5) d: 10.79 (5-CH3), 21.00
(ArCH3), 34.34 (ArCH2), 40.93 (CH2S), 115.84 (C5), 126.45, 126.52,
128.17, 128.63, 128.69, 129.24, 123.00, 138.04, 138.13, 138.86
(Ar), 157.88 (C6), 161.22 (C2), 164.67 (C4); m/z (ESI): 337.1
(M+H)+, 359.1 (M+Na)+; C20H20N2OS (336.13).
4.2.11. 6-Benzyl-2-(benzyloxymethylthio)-5-methyl- pyrimidin-
4(3H)-one (4b11)
Yield 38%; mp 153–155 °C; white solid; 1H NMR (500 MHz,
CDCl3) d: 2.14 (s, 3H, 5-CH3), 3.95 (s, 2H, CH2Ar), 4.59 (s, 2H,
OCH2Ar), 5.43 (s, 2H, SCH2O), 7.12–7.52 (m, 1H, ArH), 11.57 (br s,
1H, NH); 13C NMR (125 MHz, CDCl3) d: 10.80 (5-CH3), 40.95
(CH2Ar), 71.08 (SCH2O), 71.75 (OCH2Ar), 117.63 (C5), 126.53,
127.87, 128.36, 128.43, 128.63, 128.90, 129.33, 136.55, 137.76
(Ar), 154.97 (C6), 161.84 (C2), 164.49 (C4); m/z (ESI): 353.0
(M+H)+, 391.0 (M+K)+; C20H20N2O2S (352.12).
4.2.6. 6-Benzyl-5-methyl-2-(3-methoxybenzylthio)pyrimidin-
4(3H)-one (4b6)
Yield 43%; mp 162–163 °C; white solid; 1H NMR (300 MHz,
CDCl3) d: 2.10 (s, 3H, 5-CH3), 3.77 (s, 2H, ArCH2), 3.96 (s, 3H,
OCH3), 4.37 (s, 2H, CH2S), 6.79–6.89 (m, 3H, ArH), 7.14–7.32 (m,
6H, ArH); 13C NMR (75 MHz, CDCl3) d: 10.74 (5-CH3), 34.67
(ArCH2), 41.09 (CH2S), 55.21 (OCH3), 121.44 (C5), 113.09, 114.54,
116.64, 126.50, 128.50, 139.55, 137.82, 138.30, 159.67 (Ar),
155.93 (C6), 162.03 (C2), 165.24 (C4); m/z (ESI): 353.0 (M+H)+,
374.9 (M+Na)+; C20H20N2O2S (352.12).
4.2.12. 2-(Allylthio)-6-benzyl-5-methylpyrimidin-4(3H)-one (4b12)
Yield 53%; mp 150.5–151.5 °C; white solid; 1H NMR (500 MHz,
CDCl3) d: 2.12 (s, 2H, 5-CH3), 3.94 (s, 2H, CH2Ar), 3.80 (d, 2H,
J = 7.0 Hz, CH2S), 5.09 (d, 1H, J = 10 Hz, CH@CH2), 5.22 (d, 1H,
J = 17.0 Hz, CH@CH2), 5.87 (m, 1H, CH@CH2), 7.23–7.33 (5H, m,
ArH), 12.61 (br s, 1H, NH); 13C NMR (75 MHz, CDCl3) d: 10.68 (5-
CH3), 33.31 (CH2Ar), 41.05 (SCH2), 118.45 (C5), 116.49 (CH@CH2),
132.80 (CH@CH2), 126.47, 128.44, 128.95, 137.91 (Ar), 155.81
(C6), 162.6 (C2), 165.4 (C4); m/z (ESI): 273.0 (M+H)+; C15H16N2OS
(272.10).
4.2.7. 6-Benzyl-5-methyl-2-(4-tert-butylbenzylthio)pyrimidin-
4(3H)-one (4b7)
Yield 55%; mp 188–189 °C; white solid; 1H NMR (300 MHz,
CDCl3) d: 1.34 (s, 9H, (CH3)3C), 1.70 (s, 3H, 5-CH3), 3.97 (s, 2H,
ArCH2), 4.36 (s, 2H, CH2S), 7.20–7.34 (m, 9H, ArH); 13C NMR
(75 MHz, CDCl3) d: 10.72 (5-CH3), 31.30 ((CH3)3C), 34.33 (ArCH2),
4.3. General procedure for the preparation of compounds 5a1–8
To a solution of 4a1–8 (0.1 mmol) in HOAc (1 ml) was added
the PbO2 (0.06 mmol) and I2 (0.06 mmol), and the mixture were

3236
H. Qin et al. / Bioorg. Med. Chem. 18 (2010) 3231–3237
stirred at room temperature for overnight. After completion of the
reaction according to TLC analysis, the mixture was poured into
H2O (40 ml). The resulting solid was then filtered, washed with
water, and purified by silica gel column chromatography to afford
the white solid products 5a1–8.
114.57, 121.36, 126.85, 129.29, 129.64, 136.94, 137.62 (Ar),
159.76 (C6), 162.05 (C2), 168.66 (C4); m/z (ESI): 465.0 (M+H)+;
C19H17IN2O2S (464.01).
4.3.7. 6-Benzyl-2-(4-tert-butylbenzylthio)-5-iodo pyrimidin-4(3H)
one (5a7)
4.3.1. 6-Benzyl-2-(benzylthio)-5-iodopyrimidin-4(3H)-one (5a1)
Yield 92%; mp 175–177 °C; white solid; 1H NMR (500 MHz,
CDCl3) d: 4.23 (s, 2H, ArCH2), 4.37 (s, 2H, CH2S), 7.11–7.51 (m,
10H, ArH), 12.00 (br s, 1H, NH); 13C NMR (125 MHz, CDCl3) d:
34.99 (ArCH2), 47.12 (ArCH2S), 85.64 (C5), 126.87, 127.64,
128.50, 128.62, 129.02, 136.28, 137.00 (Ar), 159.63 (C6), 161.82
(C4), 168.62 (C2); m/z (ESI): 435.0 (M+H)+; C18H15IN2OS (433.99).
Yield 48%; mp 180–181 °C; white solid; 1H NMR (500 MHz,
CDCl3) d: 1.32 (s, 9H, (CH3)3C), 4.24 (s, 2H, ArCH2), 4.34 (s, 2H,
CH2S), 7.17–7.40 (m, 9H, ArH), 11.42 (br s, 1H, NH); 13C NMR
(75 MHz, CDCl3) d: 31.29 ((CH3)3C), 34.53 (ArCH2), 34.75 (CH2S),
47.13 ((CH3)3C), 85.70 (C5), 125.57, 126.85, 128.50, 128.77,
129.33, 133.07, 137.04, 150.72 (Ar), 159.69 (C6), 161.54 (C2),
168.53 (C4); m/z (ESI): 491.3 (M+H)+, 513.2 (M+Na)+; C22H23IN2OS
(490.06).
4.3.2. 6-Benzyl-5-iodo-2-(phenethylthio)pyrimidin-4(3H)-one
(5a2)
4.3.8. 6-Benzyl-5-iodo-2-(naphthalen-2-ylmethylthio)pyrimidin-
4(3H)-one (5a8)
Yield 70%; mp 175–177 °C; white solid; 1H NMR (500 MHz,
CDCl3) d: 2.95 (t, 2H, J = 7.5 Hz, SCH2), 3.36 (t, 2H, J = 7.5 Hz,
SCH2CH2), 4.24 (s, 2H, ArCH2), 7.13–7.40 (m, 10H, ArH), 11.60 (br
s, 1H, NH); 13C NMR (75 MHz, CDCl3) d: 32.19 (CH2S), 35.55
(ArCH2), 47.16 (ArCH2CH2S), 85.61 (C5), 126.68, 126.87, 128.47,
128.57, 129.24, 137.10, 139.46 (Ar), 159.94 (C6), 161.69 (C2),
168.66 (C4); m/z (ESI): 449.2 (M+H)+, 471.2 (M+Na)+; C19H17IN2OS
(448.01).
Yield 85%; mp 205–206 °C; white solid; 1H NMR (500 MHz,
DMSO-d6) d: 4.33 (s, 2H, ArCH2), 4.67 (s, 2H, CH2S), 7.18–7.34 (m,
3, ArH), 7.45–7.60 (m, 5H, ArH), 7.82–7.92 (m, 4H, ArH), 8.71 (br
s, 1H, NH); 13C NMR (75 MHz, pyridine-d5) d: 34.88 (ArCH2),
47.01 (CH2S), 87.28 (C5), 126.23, 126.48, 126.86, 127.96, 128.02,
128.56, 128.68, 129.59, 132.97, 133.61, 135.36, 135.57, 138.04
(Ar), 161.32 (C6), 162.07 (C2), 167.39 (C4); m/z (ESI): 483.3
(MÀH)À; C22H17IN2OS (484.01).
4.3.3. 6-Benzyl-5-iodo-2-(3-phenylpropylthio)pyrimidin-4(3H)-
one (5a3)
4.4. Compounds 5a9–12 were prepared by the method used for
5a1–8
Yield 45%; mp 155–156 °C; white solid; 1H NMR (500 MHz,
CDCl3) d:1.97 (quintet, 2H, J = 7.5 Hz, CH2CH2CH2), 2.69 (t, 2H,
J = 7.5 Hz, ArCH2CH2), 3.12 (t, 2H, J = 7.5 Hz, CH2CH2S), 4.17 (s,
2H, ArCH2), 7.13–7.37 (m, 10H, ArH), 11.65 (br s, 1H, NH); 13C
NMR (125 MHz, CDCl3) d: 30.46 (CH2S), 30.60 (ArCH2), 34.64
(SCH2CH2), 47.10 (CH2CH2CH2S), 85.26 (C5), 126.11, 126.81,
128.40, 128.44, 128.46, 129.30, 137.12, 140.82 (Ar), 160.07 (C6),
161.74 (C2), 168.62 (C4); m/z (ESI): 463.1 (M+H)+, 485.1
(M+Na)+; C20H19IN2OS (462.03).
4.4.1. 6-Benzyl-5-bromo-2-(phenethylthio)pyrimidin-4(3H)-
one (5a9)
Yield 60%; mp 154–156 °C; white solid; 1H NMR (500 MHz,
CDCl3) d: 2.95 (t, 2H, J = 7.5 Hz, SCH2), 3.36 (t, 2H, J = 7.5 Hz,
SCH2CH2), 4.17 (s, 2H, ArCH2), 7.14–7.39 (m, 10H, ArH), 11.98 (br
s, 1H, NH); 13C NMR (125 MHz, CDCl3) d: 32.22 (CH2S), 35.55
(ArCH2), 43.33 (ArCH2CH2S), 107.72 (C5), 126.69, 126.91, 128.52,
128.58, 129.30, 130.93, 136.80, 139.47 (Ar), 158.76 (C6), 160.73
(C2), 164.77 (C4); m/z (ESI): 401.2 (M+H)+, 403.1(M+3)+;
C19H17BrN2OS (400.02).
4.3.4. 6-Benzyl-2-(2-methylbenzylthio)-5-iodo pyrimidin-4(3H)-
one (5a4)
Yield 53%; mp 176–178 °C; white solid; 1H NMR (300 MHz,
CDCl3) d: 2.34 (s, 3H, ArCH3), 4.23 (s, 2H, ArCH2), 4.38 (s, 2H,
CH2S), 7.03–7.40 (m, 9H, ArH), 11.72 (br s, 1H, NH); 13C NMR
(75 MHz, CDCl3) d: 19.28 (ArCH3), 33.36 (CH2S), 47.13 (ArCH2),
85.60 (C5), 126.22, 126.87, 128.01, 128.48, 129.31, 130.07,
130.54, 133.54, 136.94, 137.04 (Ar), 159.82 (C6), 161.82 (C2),
168.58 (C4); m/z (ESI): 449.1 (M+H)+, 471.1 (M+Na)+; C19H17IN2OS
(448.01).
4.4.2. 6-Benzyl-5-bromo-2-(2-methylbenzylthio)pyrimidin-4(3H)-
one (5a10)
Yield 62%; mp 175–177 °C; white solid; 1H NMR (500 MHz,
CDCl3) d: 2.37 (s, 3H, ArCH3), 4.17 (s, 2 h, ArCH2), 4.39 (s, 2H,
CH2S), 7.03–7.39 (m, 9H, ArH); 13C NMR (75 MHz, CDCl3) d: 19.30
(ArCH3), 33.41 (CH2S), 43.30 (ArCH2), 107.72 (C5), 126.23, 126.91,
128.13, 128.52, 129.37, 130.08, 130.54, 130.93, 133.48, 136.75,
136.95 (Ar), 159.65 (C6), 160.79 (C2), 164.78 (C4); m/z (ESI):
401.2 (M+H)+, 403.1 (M+3)+; C19H17BrN2OS (400.02).
4.3.5. 6-Benzyl-5-iodo-2-(3-methylbenzylthio)pyrimidin-4(3H)-
one (5a5)
Yield 78%; mp 182–183 °C; white solid; 1H NMR (300 MHz,
CDCl3) d: 2.31 (s, 3H, ArCH3), 4.21 (s, 2H, ArCH2), 4.34 (s, 2H,
CH2S), 7.02–7.24 (m, 4H, ArH), 7.26–7.40 (m, 5H, ArH), 12.04 (br
s, 1H, NH); 13C NMR (75 MHz, CDCl3) d: 21.33 (ArCH3), 35.03
(ArCH2), 47.10 (CH2S), 85.54 (C5), 126.10, 126.85, 128.48, 128.52,
129.30, 129.69, 136.07, 136.31, 136.99, 138.35 (Ar), 159.88 (C6),
162.06 (C2), 168.63 (C4); m/z (ESI): 449.1 (M+H)+; C19H17IN2OS
(448.01).
4.4.3. 6-Benzyl-5-bromo-2-(3-methylbenzylthio)pyrimidin-4(3H)-
one (5a11)
Yield 78%; mp 174–176 °C; white solid; 1H NMR (300 MHz,
CDCl3) d: 2.32 (s, 3H, ArCH3), 4.15 (s, 2H, ArCH2), 4.34 (s, 2H,
CH2S), 7.04–7.17 (m, 4H, ArH), 7.26–7.37 (m, 5H, ArH), 11.91 (br
s, 1H, NH); 13C NMR (75 MHz, CDCl3) d: 21.35 (ArCH3), 35.13
(ArCH2), 43.32 (CH2S), 107.77 (C5), 126.11, 126.91, 128.52,
128.53, 129.36, 129.69, 135.97, 136.71, 138.39 (Ar), 158.46 (C6),
160.66 (C2), 164.65 (C4); m/z (ESI): 401.0 (M+H)+, 402.9 (M+3)+;
C19H17BrN2OS (400.02).
4.3.6. 6-Benzyl-2-(3-methoxybenzylthio)-5-iodo pyrimidin-
4(3H)-one (5a6)
Yield 76%; mp 161.5–163 °C; white solid; 1H NMR (500 MHz,
CDCl3) d: 3.79 (s, 3H, OCH3), 4.21 (s, 2H, ArCH2), 4.35 (s, 2H,
CH2S), 6.82–6.87 (m, 3H, ArH), 7.16–7.19 (m, 1H, ArH), 7.26–7.39
(m, 5H, ArH), 12.08 (br s, 1H, NH); 13C NMR (125 MHz, CDCl3) d:
35.06 (CH2S), 47.11 (ArCH2), 55.23 (OCH3), 85.59 (C5), 113.23,
4.4.4. 6-Benzyl-5-bromo-2-(naphthalen-2-ylmethylthio)pyrimi-
din 4(3H)-one (5a12)
Yield 50%; mp 180–182 °C; white solid; 1H NMR (500 MHz,
DMSO-d6) d: 4.16 (s, 2H, ArCH2), 4.55 (s, 2H, CH2S), 7.25–7.37 (m,
6H, ArH), 7.48–7.51 (m, 2H, ArH), 7.73–7.84 (m, 4H, ArH); 13C

H. Qin et al. / Bioorg. Med. Chem. 18 (2010) 3231–3237
3237
15. Mai, A.; Artico, M.; Ragno, R.; Sbardella, G.; Massa, S.; Musiu, C.; Mura, M.;
Marturana, F.; Cadeddu, A.; Maga, G.; La Colla, P. Bioorg. Med. Chem. 2005, 13,
2065.
16. Manetti, F.; Jose, A. E.; Clotet-Codina, I.; Armand-Ugon, M.; Maga, G.; Crespan,
E.; Cancio, R.; Mugnaini, C.; Bernardini, C.; Togninelli, A.; Carmi, C.; Alongi, M.;
Petricci, E.; Massa, S.; Corelli, F.; Botta, M. J. Med. Chem. 2005, 48, 8000.
17. Mugnaini, C.; Manetti, F.; Este, J.; Clotet-Codina, I.; Maga, G.; Cancio, R.; Botta,
M.; Corelli, F. Bioorg. Med. Chem. Lett. 2006, 16, 3541.
NMR (75 MHz, CDCl3) d: 35.44 (ArCH2), 43.33 (CH2S), 107.98 (C5),
126.18, 126.36, 126.78, 126.93, 127.69, 127.80, 128.55, 129.37,
133.20, 133.54, 136.66 (Ar), 158.56 (C6), 162.62 (C2), 165.04
(C4); m/z (ESI): 435.2 (MÀH)À, 437.1 (M+1)À; C22H17BrN2OS
(436.02).
18. Togninelli, A.; Carmi, C.; Petricci, E.; Mugnaini, C.; Massa, S.; Corelli, F.; Botta,
M. Tetrahedron Lett. 2006, 47, 57.
Acknowledgements
19. Ji, L.; Chen, F.; De Clercq, E.; Balzarini, J.; Pannecouque, C. J. Med. Chem. 2007,
50, 1778.
20. Radi, M.; Contemori, L.; Castagnolo, D.; Spinosa, R.; Este, J.; Massa, S.; Botta, M.
Org. Lett. 2007, 9, 3157.
21. Mugnaini, C.; Alongi, M.; Togninelli, A.; Gevariya, H.; Brizzi, A.; Manetti, F.;
Bernardini, C.; Angeli, L.; Tafi, A.; Bellucci, L.; Corelli, F.; Massa, S.; Maga, G.;
Samuele, A.; Facchini, M.; Clotet-Codina, I.; Armand-Ugón, M.; Esté, J.; Botta, M.
J. Med. Chem. 2007, 50, 6580.
We thank the National Science Foundation of China (20672008,
20972011) and Grants from the Ministry of Science and Technol-
ogy of China (2005CB523103) for financial support.
References and notes
22. Wang, Y.; Chen, F.; De Clercq, E.; Balzarini, J.; Pannecouque, C. Bioorg. Med.
Chem. 2008, 16, 3887.
1. Gallo, R. C.; Salahuddin, S. Z.; Popovic, M.; Shearer, G. M.; Kaplan, M.; Haynes, B.
F.; Palker, T. J.; Redfield, R.; Oleske, J.; Safai, B.; White, G.; Foster, P.; Markham,
P. D. Science 1984, 224, 500.
2. Tronchet, J. M.; Seman, M. Curr. Top. Med. Chem. 2003, 13, 1496.
3. Tarby, C. Curr. Top. Med. Chem. 2005, 4, 1045.
´
23. Mai, A.; Artico, M.; Rotili, D.; Tarantino, D.; Clotet-Codina, I.; Armand-Ugon, M.;
Ragno, R.; Simeoni, S.; Sbardella, G.; Nawrozkij, M. B.; Samuele, A.; Maga, G.;
Este, J. J. Med. Chem. 2007, 50, 5412.
24. Qin, H.; Liu, C.; Zhang, J.; Guo, Y.; Zhang, S.; Zhang, Z.; Wang, X.; Zhang, L.; Liu, J.
Bioorg. Med. Chem. Lett. 2009, doi:10.1016/j.bmcl.2009.04.051.
25. Mai, A.; Sbardella, G.; Artico, M.; Ragno, R.; Massa, S.; Novellino, E.; Greco, G.;
Lavecchia, A.; Musiu, C.; La Colla, M.; Murgioni, C.; La Colla, P.; Loddo, R. J. Med.
Chem. 2001, 44, 2544.
4. Sluis-Cremer, N.; Alpay Temiz, N.; Bahar, I. Curr. HIV Res. 2004, 2, 323.
5. Campiani, G.; Ramunno, A.; Maga, G.; Nacci, V.; Fattorusso, C.; Catanalotti, E.;
Morelli, E.; Novellino, E. Curr. Pharm. Des. 2002, 8, 615.
6. Talker, R. T.; Clercq, E. D. Nucleosides Nucleotides 1995, 14, 575.
7. Sankatsing, S. U.; Weverling, G. J.; Peeters, M.; Van’t Klooster, G.; Gruzdev, B.;
Rakmanova, A.; Danner, S. A.; Jurrianns, S.; Prins, J. M.; Lange, J. M. AIDS 2003,
17, 2623.
26. Auffinger, P.; Hays, F. A.; Westhof, E.; Ho, P. S. Proc. Natl. Acad. Sci. U.S.A. 2004,
101, 16789.
27. Himmel, D. M.; Das, K.; Clark, A. D.; Hughes, S. H.; Benjahad, A.; Oumouch, S.;
Guillemont, J.; Coupa, S.; Poncelet, A.; Csoka, I.; Meyer, C.; Andries, K.; Nguyen,
C. H.; Grierson, D. S.; Arnold, E. J. Med. Chem. 2005, 48, 7582.
28. Morris, G. M.; Goodsell, D. S.; Halliday, R. S.; Huey, R.; Hart, W. E.; Belew, R. K.;
Olson, A. J. J. Comput. Chem. 1998, 19, 1639.
8. Botta, M.; Artico, M.; Massa, S.; Gambacorta, A.; Marogniu, M. E.; Pani, A.; La
Colla, P. Eur. J. Med. Chem. 1992, 27, 251.
9. Artico, A. Drugs Future 2002, 27, 159.
10. Mai, A.; Artico, M.; Sbardella, G.; Massa, S.; Loi, A. G.; Tramontano, E.; Scano, P.;
La Colla, P. J. Med. Chem. 1995, 38, 3258.
11. Mai, A.; Artico, M.; Sbardella, G.; Massa, S.; Novellino, E.; Greco, G.; Loi, A. G.;
Tramontano, E.; Marogiu, M. E.; Ca Colla, P. J. Med. Chem. 1999, 42, 619.
12. Mai, A.; Artico, G.; Sbardella, G.; Quartarone, S.; Massa, S.; Loi, A. G.; De Montis,
A.; Scintu, F.; Putzolu, M.; La Colla, P. J. Med. Chem. 1997, 40, 1447.
13. Ragno, R.; Mai, A.; Sbardella, S.; Artico, M.; Massa, S.; Musiu, C.; Mura, M.;
Marceddu, T.; Cadeddu, A.; La Colla, P. J. Med. Chem. 2004, 47, 928.
14. He, Y.; Chen, F.; Sun, G.; Wang, Y.; De Clercq, E.; Balzarini, J.; Pannecouque, C.
Bioorg. Med. Chem. Lett. 2004, 14, 3173.
29. Lu, Y.; Shi, T.; Wang, Y.; Yang, H.; Yan, X.; Luo, X.; Jiang, H.; Zhu, W. J. Med.
Chem. 2009, 52, 2854.
30. Hannick, S. M.; Kishi, Y. J. Org. Chem. 1983, 48, 3833.
31. Danel, K.; Larsen, E.; Pedersen, E. B. Synthesis 1995, 934.
32. Danel, K.; Pedersen, E. B.; Nielsen, C. J. Med. Chem. 1998, 41, 191.
33. Lu, X.; Chen, Y.; Guo, Y.; Liu, Z.; Shi, Y.; Xu, Y.; Wang, X.; Zhang, Z.; Liu, J. Bioorg.
Med. Chem. 2007, 15, 7399.