Synthesis and anti-HIV-1 activity evaluation of 5-alkyl-2-alkylthio-6- (arylcarbonyl or α-cyanoarylmethyl)-3,4-dihydropyrimidin-4(3H)-ones as novel non-nucleoside HIV-1 reverse transcriptase inhibitors

Article abstract of DOI:10.1021/jm061167r

A series of novel S-DABO analogues (S-DABOs, 1) were synthesized and evaluated as inhibitors of human immunodeficiency virus type-1 (HIV-1). Key structural modifications included replacement of the 6-arylmethyl group by a 6-arylcarbonyl or 6-(α-cyanoarylmethyl) group. Most of the compounds showed only micromolar potency against HIV-1 in MT-4 cells in vitro, though two of them (3e and 3g) were unusually potent (IC₅₀ = 0.09 and 0.002 μM, respectively) and selective (SI = 1500 and 4600, respectively). Structure-activity relationships among the newly synthesized S-DABOs are discussed.

Full text of DOI:10.1021/jm061167r

1778
J. Med. Chem. 2007, 50, 1778-1786
Synthesis and Anti-HIV-1 Activity Evaluation of 5-Alkyl-2-alkylthio-6-(arylcarbonyl or
r-cyanoarylmethyl)-3,4-dihydropyrimidin-4(3H)-ones as Novel Non-nucleoside HIV-1 Reverse
Transcriptase Inhibitors
Lei Ji,† Fen-Er Chen,†,* Erik De Clercq,‡ Jan Balzarini,‡ and Christophe Pannecouque‡
Department of Chemistry, Fudan UniVersity, Shanghai 200433, People’s Republic of China, and Rega Institute for Medical Research,
Katholieke UniVersiteit LeuVen, 10 Minderbroedersstraat, B-3000 LeuVen, Belgium
ReceiVed October 9, 2006
A series of novel S-DABO analogues (S-DABOs, 1) were synthesized and evaluated as inhibitors of human
immunodeficiency virus type-1 (HIV-1). Key structural modifications included replacement of the
6-arylmethyl group by a 6-arylcarbonyl or 6-(R-cyanoarylmethyl) group. Most of the compounds showed
only micromolar potency against HIV-1 in MT-4 cells in vitro, though two of them (3e and 3g) were unusually
potent (IC50 ) 0.09 and 0.002 µM, respectively) and selective (SI ) 1500 and 4600, respectively). Structure-
activity relationships among the newly synthesized S-DABOs are discussed.
Chart 1. Chemical Structures of S-DABOs, and Compounds
2-4
Introduction
Since they were first reported in 1992,1 2-alkoxy-3,4-dihydro-
6-benzyl-4(3H)-pyrimidin-4-ones (DABOs),2-18 a class of non-
nucleoside reverse transcriptase inhibitors (NNRTIs), have been
the object of great interest and have led in recent years to the
indentification of highly potent analogues in which the 6-benzyl
group was replaced by a substituted arylmethyl group or the 2-
and 5-substituent on the pyrimidine ring was variously modified
as depicted in Chart 1. However, few modifications of the
arylmethyl carbon at the 6-position have been described.11 We
recently prepared a series of new 6-(1-naphthylmethyl) ana-
logues (2, Chart 1) which showed strong in vitro anti-HIV-1
and anti-HIV-2 activity in MT-4 cells, together with high
selectivity for the retroviruses relative to the T-cell host.19
Surmising that suitable modification of the CH2 bridge between
the pyrimidine and aryl moieties might promote π-stacking
between the electron-deficient pyrimidine ring of the inhibitor
and the electron-rich phenyl ring of Tyr188 or Tyr181 in the
transcriptase enzyme, we have now synthesized and tested a
new series of 6-(R-cyanoarylmethyl) and 6-aroyl analogues 3
and 4 (Chart 1) as novel NNRTIs.
Besides, the nitriles 3b, 3d, 3g, 3j,k, 3m, 3t, and 3x-ac were
successfully oxidized to ketones 4a-m (series B) by passing
air through the reaction mixture in the presence of 60% NaH
in anhydrous DMF at room temperature.
Chemistry. The synthesis of the title compounds of series
A (3a-ac) and series B (4a-m) was outlined in Scheme 1and
Scheme 2. The 2-thiobarbituric acid derivatives 6a-d were
prepared according to the method of Koroniak et al.20 by
condensation of thiourea with the appropriate diethyl malonates
5a-d in the presence of sodium methoxide in methanol at
refluxing temperature. Subsequent S-alkylation of 6a-d with
various alkyl halides in the presence of sodium hydroxide gave
the corresponding 5-alkyl-2-alkylthiobarbituric acids 7a-ac,
respectively. Treatment of 7a-ac in dichloromethane with
p-toluenesulfonyl chloride and triethylamine afforded the dis-
ulfonates 8a-ac, which were reacted with various aryl aceto-
nitriles in the presence of 60% NaH in anhydrous DMF to yield
the intermediates 9a-ac, respectively, and then without puri-
fication, hydrolysis of 9a-ac with 10% aqueous sodium
hydroxide in ethanol afforded the title compounds 3a-ac of
series A.
Results and Discussion
At the outset, the title compounds of series A (3a-w) and
series B (4a-m) were tested for their ability to inhibit the HIV-1
induced cytopathogenicity, for cytotoxicity and anti-HIV-1
activity in MT-4 cells in comparison with nevirapine as reference
drug (Table 1). In series A, many compounds showed anti-
HIV-1 activity that was more potent than that of nevirapine.
Maximum activity was obtained with compounds of 3e and 3g,
which were endowed with the highest potency (IC50 ) 0.09
and 0.002 µM, respectively) and selectivity (SI ) 1500 and
4600, respectively). These results appear to confirm our as-
sumption that the introduction of a cyano group as an electron-
withdrawing substituent to the aryl methylic carbon at C-6
position might be more favorable to improve a putative
π-stacking interaction between the electron-deficient aryl ring
of the ligand and the electron-rich benzene ring of Tyr188 or
Tyr181 of reverse transcriptase (RT).
* To whom correspondence should be addressed. Tel: +86-21-65643811.
Fax: +86-21-65643811. E-mail: rfchen@fudan.edu.cn.
† Fudan University.
Compounds belonging to series B were considerably less
potent (4a, 4g-i, 4k, and 4m) or totally inactive (4b-d, 4f,
and 4j). However, a striking low cytotoxicity in this series was
‡ Katholieke Universiteit Leuven.
10.1021/jm061167r CCC: $37.00 © 2007 American Chemical Society
Published on Web 03/24/2007

Non-nucleoside HIV-1 ReVerse Transcriptase Inhibitors
Scheme 1a Synthesis of Compounds 3a-ac
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 8 1779
a Reagents and conditions: (a) thiourea, MeONa, MeOH, reflux, 8 h; (b) R2X, NaOH, H2O, 35 °C, 4-24 h; (c) TsCl, Et3N, CH2Cl2, -5 °C then rt,
overnight; (d) R3CHCN, 60% NaH, DMF, -15 °C then rt, 48-72 h; (e) 10% NaOH, EtOH, rt, 24-48 h.
Scheme 2a Synthesis of Compounds 4a-m
structural modifications at positions 2, 5, and 6 were performed.
Two compounds (4e and 4l) were found to exhibit moderate
activity. It was noteworthy that the introduction of a 6-arylcar-
bonyl substituent resulted in compounds of series B, which were
characterized by lower activity but coupled with marked
decrease in cytotoxicity. It was anticipated that this may be due
to the increase of molecule rigidity resulting in a steric clash
with adjacent residues that weaken interaction with the RT.
In an attempt to further study the SARs, we examined the
effect of R3 substituents at C-6 position of the pyrimidine ring
by use of various aryl groups. It can be seen that 1-naphthyl-
substituted compounds (3c, 3k, and 3o) were generally more
potent than the phenyl-substituted compounds (3h, 3q,r) with
the exception of the pair 3v and 3u in series A. In line with
these observations, a similar conclusion was reached about series
B. These results indicated that the 1-naphthyl substitution of
R3 was more favorably positioned to make interactions with
the π-clouds of the aromatic chain of Tyr181 or Tyr188 of RT
may be due to the higher aromatic properties and bulky steric
hindrance. It was previously reported that in other S-DABO
series the insertion of two chlorine atoms at the ortho-position
of phenyl ring at C-6 position strongly improved the anti-HIV-1
activity.18 For compounds 3, we were also testing the effect of
changing R3 ) phenyl into R3 ) 2,6-dichlorophenyl. The effect
was rather dramatic as can be seen by comparing 3v with 3w
with a decrease in activity against HIV-1. A similar change in
a Reagents and conditions: (a) 60% NaH, DMF, Air, rt, 6-12 h.
observed. For example, the majority of compounds were not
cytotoxic for MT-4 cells at doses as high as 120 µM, and only
two of them (4b and 4m) showed CC50 values at concentrations
lower than 30 µM. Inspired by these observations further

1780 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 8
Ji et al.
Table 1. Anti-HIV-1 Activity and Cytotoxicity of Compounds 3a-w, 4a-m in MT-4 Cells
compd
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
3s
3t
3u
3v
3w
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
HEPT
nevirapine
R1
R2
R3
IC50 (µM)a
CC50 (µM)b
SIc
H
H
i-Pr
1-naphthyl
1-naphthyl
1-naphthyl
1-naphthyl
1-naphthyl
1-naphthyl
Ph
0.66 ( 0.27
>22.80
53.19 ( 20.72
22.80 ( 4.52
49.39 ( 21.49
46.09 ( 1.54
163.86 ( 33.16
148.32 ( 21.24
10.81 ( 6.56
58.95 ( 15.48
53.81 ( 13.76
122.35 ( 63.98
>344.35
82
<1
61
17
1500
32
cyclopentyl
cyclopentyl
propynyl
benzoylmethyl
4-chlorobenzoylmethyl
i-Pr
cyclopentyl
benzoylmethyl
Et
Me
Me
Me
Me
Me
Me
Me
Et
Et
Et
Et
Et
0.80 ( 0.40
2.70 ( 1.16
0.09 ( 0.04
4.71 ( 0.89
0.002 ( 0.0002
6.34 ( 2.09
7.28 ( 3.17
1.17 ( 0.23
0.24 ( 0.12
0.18 ( 0.08
0.58 ( 0.33
4.85 ( 0.61
1.25 ( 0.07
4600
9
Ph
Ph
7
1-naphthyl
1-naphthyl
1-naphthyl
1-naphthyl
1-naphthyl
1-naphthyl
1-naphthyl
Ph
103
>1400
293
>585
10
i-Pr
cyclopentyl
allyl
51.88 ( 18.33
>346.26
propynyl
47.99 ( 9.50
24.52 ( 1.38
116.66 ( 13.07
58.02 ( 21.02
34.19 ( 2.14
23.46 ( 2.83
7.32 ( 1.09
Et
Et
Et
Et
4-nitrobenzyl
4-chlorobenzoylmethyl
i-Pr
4-nitrobenzyl
4-nitrobenzyl
cyclopentyl
4-methoxybenzyl
4-methoxybenzyl
4-methoxybenzyl
Et
20
e3
91
26
11
g35.73
0.64 ( 0.38
1.33 ( 0.27
2.22 ( 0.44
1.34 ( 0.38
Ph
Et
2,6-Cl2-Ph
1-naphthyl
1-naphthyl
Ph
2,6-Cl2-Ph
1-naphthyl
1-naphthyl
1-naphthyl
Ph
i-Pr
i-Pr
i-Pr
i-Pr
H
H
H
H
Me
Me
Et
Et
Et
Et
Et
Et
i-Pr
5
>2.09
3.53 ( 0.81
>23.53
37.58 ( 3.87
>21.03
2.09 ( 1.47
<1
26.79 ( 2.72
23.53 ( 1.31
241.61 ( 13.61
21.03 ( 9.80
>304.41
8
<1
6
cyclopentyl
benzoylmethyl
Et
<1
NA
<1
128
<1
7
26
12
NA
e3
13
>304.41
>246.65
246.65 ( 19.46
263.19 ( 27.08
123.56 ( 35.57
196.54 ( 112.37
178.92 ( 16.59
210.37 ( 54.09
>312.50
157.43 ( 7.73
60.37 ( 17.19
24.69 ( 2.86
405
i-Pr
propynyl
Et
i-Pr
allyl
benzyl
benzyl
Ph
2.05 ( 0.03
1-naphthyl
1-naphthyl
1-naphthyl
1-naphthyl
1-naphthyl
2-naphthyl
Ph
>123.56
27.84 ( 9.17
6.79 ( 0.51
16.94 ( 8.40
>312.50
g60.75
cyclopentyl
cyclopentyl
4.69 ( 1.31
10.87 ( 2.24
5.06
1-naphthyl
2
80
>800
0.25
>200
a IC50: concentration of compound required to protect the cell against viral cytopathogenicity by 50% in MT-4 cells. b CC50: concentration of compound
that reduces the normal uninfected MT-4 cell viability by 50%. c SI: selectivity index: ratio CC50/IC50.
activity was observed for compound 3r (IC50 ) 1.33 ( 0.27
µM) when compared with 3s (IC50 ) 2.22 ( 0.44 µM). The
results in our case suggested that the substituent at R3 is an
important criterion for activity.
pyrimidine ring affected the antiviral activity as exemplified
by 4-fold improvement of activity passing from the 2-ethylthio
homologues 3j and 4g to the corresponding 2-isopropylthio
analogues 3k and 4h. Optimal activity was obtained with
compounds bearing such 2-alkylthio substituents as isopropy-
lthio, cyclopentylthio, allylthio, and benzoylmethylthio groups.
Among these serial modifications, the 2-isopropylthio-substi-
tuted compounds of series A generally showed the best potency
with IC50 values in the low nanomolar or sub-micromolar range.
The introduction of an allylthio moiety at the C-2 position gave
compound 3m, which displayed sub-micromolar anti-HIV-1
Variations at the C-5 position of pyrimidine ring play an
important role, as previously observed,9,19 and allow compounds
with very high potent activity to be obtained. None of the
modifications at the C-5 position proved to be devoid of anti-
HIV-1 activity or less potent than the 5-methyl-substituted
compounds. However, it also should be noticed that except for
compounds 3c and 3l, substitutions of the 5-methyl with either
ethyl or the isopropyl resulted in slightly decreased activity
(from 3c,d to 3t and 3n, respectively) or markedly decreased
activity (up to 7-fold passing from 3f to 3p). Thus, within the
derivatives in series A, the best activity was provided by the
5-methyl-substituted derivative. For example, compounds 3c,
3e, and 3g containing 5-methyl substitution displayed high
potency with IC50 values ranging from 0.80 to 0.002 µM.
Just as with SARs of our previous S-DABOs,19 the nature of
the substituents at C-2 position were also essential for the anti-
HIV-1 activity both in series A and B. As shown in Table 1,
steric properties of the substituents at the C-2 position of
activity with the lowest cytotoxicity (IC50 ) 0.58 µM, CC50
>
346.26 µM). It is worth noting that the insertion of a chlorine
atom at the para-position of the benzoylmethyl ring led to
compounds 3f and 3p characterized by both low cytotoxicity
and antiviral activity.
In addition, we have chosen two compounds (3e and 3k) to
evaluate their anti-HIV-1 activity in human peripheral blood
mononuclear cells (PBMCs) (Figure 3, Table 2). It was found
that these two compounds showed moderate anti-HIV-1 activity
in human PBMCs. In particular, compound 3e exhibited low
micromolar value of IC50 of 0.99 µM. However, in comparison

Non-nucleoside HIV-1 ReVerse Transcriptase Inhibitors
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 8 1781
Figure 1. Crystal structure of compound 3k.
Figure 3. Anti-HIV-1 evaluation in PBMCs of selected compounds
3e and 3k.
Table 2. Anti-HIV-1 Activity and Cytotoxicity of Selected Title
Compounds (3e and 3k) in PBMCs
compd
IC50 (µM)a
CC50 (µM)b
SIc
70
>41
3e
3k
0.99
1.66
69.91
>68.87
a IC50: concentration of compound required to achieve 50% reduction
of p24 production in HIV-1 (IIIB) infected PBMCs. b CC50: concentration
of compound that reduces the viability of mock-infected cells by 50%.c SI:
selectivity index: ratio CC50/IC50.
Figure 2. Crystal structure of compound 4b.
with the MT-4 cell line, this cell line appears to be less sensitive.
These two compounds proved to be approximately 7 to 10-fold
less active in PBMCs than in MT-4 cells. The decreased anti-
HIV-1 activities were also coupled with increased cytotoxicity
in PBMCs. The SI values decreased by about 20- to 30-fold
for the two compounds.
Molecular Modeling Analysis. With the aim to investigate
the binding mode of our newly synthesized compounds, a
modeling study was performed by means of AutoDock for
docking. Compound 3g was chosen to be docked into the non-
nucleoside binding site (NNBS) of HIV-1 RT. Coordinates of
the NNBS were taken from the crystal structure of the RT/6-
benzyl-1-(ethoxymethyl)-5-isopropyluracil (MKC-442) complex
due to the high degree of similarity between MKC-442 and
DABOs. The theoretical binding mode of 3g to the NNBS is
shown in Figure 4.
Results showed that the pyrimidine NH moiety at position 3
was engaged in a hydrogen bond with the CdO moiety of
Lys101. The 6-(R-cyanobenzyl) moiety of 3g fits into the
aromatic-rich non-nucleoside binding pocket (NNBP), sur-
rounded by the aromatic side chains of Tyr181, Tyr188, Phe227,
Figure 4. Model of 3g docked into the RT non-nucleoside binding
site. Putative intermolecular hydrogen bonds are highlighted by dashed
lines.
and Trp229 as well as by Leu234 and Pro95. In particular, the
phenyl ring interacts favorably with the Tyr181 side chain,
giving rise to a positive π-stacking interaction. The 2-isopro-
pylthio substituent was well accommodated in the Pro236
pocket. Moreover, the methyl group at C-5 position was

1782 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 8
Ji et al.
g, 24 mmol) was added portionwise at -10 °C under a nitrogen
atmosphere. The whole was stirred at the same temperature for 1
h, warmed to room temperature, and then reacted for 48-72 h.
The resulting mixture was acidified with acetic acid under ice-
cooling and concentrated under reduced pressure to afford the crude
intermediate 9a-ac. Then without further purification, EtOH (300
mL) was added at room temperature. After the mixture was stirred
for 0.5 h, 10% NaOH (100 mL) was added dropwise under ice-
cooling. The reaction mixture was then stirred at room temperature
for 24-48 h and then acidified to pH 5-6 with acetic acid. After
most of the solvent was removed under reduced pressure, the
resulting residue was poured into water and extracted with CH2-
Cl2. The organic layer was dried over Na2SO4 and concentrated in
vacuo to give the crude product, which was first purified by flash
chromatography (eluent: CH2Cl2) and followed by recrystallization
from MeOH or AcOEt with the exception of compounds 3x-ac,
which were pure enough to be used in the next step without
recrystallization.
positioned in the hydrophobic cavity formed by the Val179 and
Val106 side chains.
In summary, the results of the AutoDocking analysis sup-
ported our newly designed and synthesized compounds. Further
optimization of 3g will consider these aspects in further design
attempts.
Conclusion
In recent years much effort has been made to exploit novel
and potent S-DABOs mainly through the modification of C-2,
C-5, or the aryl ring of the C-6 moiety. Relatively little attention
has been paid to modify the aryl methylic carbon bound to C-6
of the pyrimidine ring. Our structure-based design has led to
the discovery that the introduction of a cyano at the aryl methylic
carbon generated a series of novel S-DABO derivatives as a
novel class of highly potent NNRTIs coupled with remarkable
activity and high selectivity. And replacement of the 6-arylm-
ethyl with a 6-arylcarbonyl led to compounds endowed with
low cytotoxicity. The application of this novel and potent
structure modification is expected to provide the foundation for
the rational modification of the C-6 position and accelerate the
discovery of more potent and selective NNRTIs.
6-[r-Cyano-(1-naphthylmethyl)]-3,4-dihydro-2-isopropylthi-
opyrimidin-4(3H)-one (3a). Yield 30.5%; recrystallized from
1
AcOEt, mp 165.5-166.9 °C; H NMR (DMSO-d6, 500 MHz) δ
1.19 (d, J ) 6.7 Hz, 3H, CH3CH), 1.24 (d, J ) 6.7 Hz, 3H, CH3-
CH), 3.72 (sep, J ) 6.7 Hz, 1H, SCH), 6.19 (s, 1H, CHCN), 6.40
(s, 1H, CH), 7.57-8.25 (m, 7H, Naph), 12.87 (s, 1H, NH); 13C
NMR (DMSO-d6, 400 MHz) δ 22.16 (CH3), 22.30 (CH3), 35.98
(SCH2), 36.80 (CHCN), 107.33 (C5), 118.79 (CN), 123.37, 125.51,
126.23, 126.86, 127.40, 128.85, 129.31, 129.49, 129.97, 133.59
(Naph), 159.90 (C6), 160.29 (C2), 162.90 (C4); MS (EI) m/z 335
(M+). Anal. (C19H17N3OS) C, H, N, S.
Experimental Section
Chemistry. Melting points were measured on a WRS-1 digital
melting point apparatus and are uncorrected. Infrared (IR) spectra
(KBr) were recorded on a Jasco FT/IR-4200 instrument. 1H NMR
on a Bruker DMX 500 MHz or a Bruker AV 400 MHz spectrometer
and 13C NMR spectra on a Bruker AV 400 MHz spectrometer were
recorded in DMSO-d6 or CDCl3. Chemical shifts are reported in δ
(ppm) units relative to the internal standard tetramethylsilane (TMS).
Mass spectra were obtained on a Agilent MS/5975 mass spectrom-
eter. Elemental analyses were performed on a CARLOERBA 1106
instrument, and the results of elemental analyses for C, H, Cl, N
and S were within (0.4% of the theoretical values. All chemicals
and solvents used were of reagent grade and were purified and dried
by standard methods before use. All air-sensitive reactions were
run under a nitrogen atmosphere. All the reaction were monitored
by TLC on pre-coated silica gel G plates at 254 nm under a UV
lamp using ethyl acetate/hexane as eluents. Flash chromatography
separations were obtained on silica gel (300-400 mesh).
General Procedure for the Synthesis of 5-Alkyl-2-alkylth-
iobarbituric Acid Derivatives 7a-ac. To a suspension of 5-alkyl-
2-thiobarbituric acids 6a-d (200 mmol) in water (500 mL) was
added NaOH (8.0 g, 200 mmol) portionwise at room temperature.
After the reaction mixture was stirred for 30 min, the appropriate
alkyl halide (220 mmol) was added. Then the reaction mixture was
stirred at room temperature for 4-24 h. The precipitate which
formed was filtered off, washed with water, and dried to give 7a-
ac to be used in the next step without further purification.
General Procedure for the Synthesis of the Disulfonates 8a-
ac. To a suspension of 7a-ac (100 mmol) in anhydrous CH2Cl2
(500 mL) was added Et3N (181.8 g, 1800 mmol) at room
temperature under a nitrogen atmosphere. After the mixture was
stirred for 0.5 h and then cooled to -5 °C, a solution of TsCl (40.11
g, 210 mmol) in anhydrous CH2Cl2 (100 mL) was added dropwise.
The whole was then stirred for 1 h, warmed to room temperature,
and stirred overnight. After the resulting mixture was diluted with
ice-water, the organic layer was separated and the aqueous was
extracted with CH2Cl2. The combined organic phases were washed
with 1% HCl and water, dried, and then concentrated in vacuo to
afford the crude product to be used in the next step without further
purification.
6-[r-Cyano-(1-naphthylmethyl)]-2-cyclopentylthio-3,4-dihy-
dropyrimidin-4(3H)-one (3b). Yield 42.1%; recrystallized from
1
AcOEt, mp 185.7-187.0 °C; H NMR (DMSO-d6, 500 MHz) δ
1.28-1.32 (m, 4H, cyclopentyl), 1.47 (m, 2H, cyclopentyl), 1.63
(m, 2H, cyclopentyl), 3.32-3.33 (m, 1H, cyclopentyl), 6.57 (s, 1H,
CHCN), 6.62 (s, 1H, CH), 7.61-8.20 (m, 7H, Naph), 13.11 (s,
1H, NH); MS (EI) m/z 361 (M+). Anal. (C21H19N3OS) C, H, N, S.
6-[r-Cyano-(1-naphthylmethyl)]-2-cyclopentylthio-3,4-dihy-
dro-5-methylpyrimidin-4(3H)-one (3c). Yield 43.9%; recrystal-
lized from AcOEt, mp 214.1-215.0 °C; 1H NMR (DMSO-d6, 500
MHz) δ 1.29-1.36 (m, 4H, cyclopentyl), 1.49 (m, 2H, cyclopentyl),
1.70 (m, 2H, cyclopentyl), 1.95 (s, 3H, CH3), 3.47-3.50 (m, 1H,
cyclopentyl), 6.52 (s, 1H, CHCN), 7.57-8.71 (m, 7H, Naph), 12.96
(s, 1H, NH); 13C NMR (DMSO-d6, 400 MHz) δ 10.63 (CH3), 24.08
(2C, cyclopentyl), 24.22 (CHCN), 32.26 (2C, cyclopentyl), 43.32
(cyclopentyl), 118.63 (CN), 123.07, 124.79, 124.95, 126.56, 128.38,
128.72, 130.15, 132.05, 132.20, 133.37, 133.79 (Naph, C5), 156.07
(C6), 158.88 (C2), 163.30 (C4); MS (EI) m/z 375 (M+). Anal.
(C22H21N3OS) C, H, N, S.
6-[r-Cyano-(1-naphthylmethyl)]-3,4-dihydro-5-methyl-2-pro-
pynylthiopyrimidin-4(3H)-one (3d). Yield 47.1%; recrystallized
from MeOH, mp 218.4-218.9 °C; 1H NMR (DMSO-d6, 500 MHz)
δ 1.84 (s, 3H, CH3), 3.19 (s, 1H, tCH), 3.89-4.01 (m, 2H, SCH2),
6.53 (s, 1H, CHCN), 7.54-8.28 (m, 7H, Naph), 13.06 (s, 1H, NH);
13C NMR (DMSO-d6, 400 MHz) δ 10.09 (CH3), 18.39 (SCH2),
38.28 (CHCN), 73.43 (tCH), 79.60 (tC), 118.45 (CN), 123.03,
125.58, 126.26, 127.05, 127.08, 128.47, 128.93, 129.19, 129.68,
130.08, 133.55 (Naph, C5), 155.03 (C6), 157.44 (C2), 163.33 (C4);
MS (EI) m/z 345 (M+). Anal. (C20H15N3OS) C, H, N, S.
2-Benzoylmethylthio-6-[r-cyano-(1-naphthylmethyl)]-3,4-di-
hydro-5-methylpyrimidin-4(3H)-one (3e). Yield 33.0%; recrystal-
lized from MeOH, mp 195.6-196.8 °C; 1H NMR (DMSO-d6, 500
MHz) δ 1.87 (s, 3H, CH3), 4.76 (s, 2H, SCH2), 6.44 (s, 1H, CHCN),
7.34-8.03 (m, 12H, Naph, Ph), 13.10 (s, 1H, NH); 13C NMR
(DMSO-d6, 400 MHz) δ 11.02 (CH3), 37.08 (SCH2), 39.11
(CHCN), 117.39 (CN), 127.98 (2C), 128.69 (2C), 128.85, 128.97,
129.34, 129.96, 131.55, 133.55, 133.93, 134.18, 134.94, 135.07,
135.23, 135.69, 136.17 (Naph, Ph, C5), 156.03 (C6), 158.44 (C2),
163.26 (C4), 193.99 (CdO); MS (EI) m/z 425 (M+). Anal.
(C25H19N3O2S) C, H, N, S.
General Procedure for the Synthesis of 5-Alkyl-2-alkylthio-
6-(r-cyanoarylmethyl)-3,4-dihydropyrimidin-4(3H)-ones 3a-ac.
To a solution of 8a-ac (20 mmol) in anhydrous DMF (100 mL)
was added appropriate aryl acetonitriles (22 mmol) at room
temperature. After the mixture was stirred for 0.5 h, 60% NaH (1.0
2-(4-Chlorobenzoylmethylthio)-6-[r-cyano-(1-naphthylmethyl)]-
3,4-dihydro-5-methylpyrimidin-4(3H)-one (3f). Yield 35.9%;

Non-nucleoside HIV-1 ReVerse Transcriptase Inhibitors
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 8 1783
recrystallized from MeOH, mp 176.7-177.9 °C; 1H NMR (DMSO-
d6, 500 MHz) δ 1.89 (s, 3H, CH3), 4.69 (s, 2H, SCH2), 6.51 (s,
1H, CHCN), 7.39-8.07 (m, 11H, Naph, Ph), 13.03 (s, 1H, NH);
MS (EI) m/z 459 (M+). Anal. (C25H18ClN3O2S) C, H, Cl, N, S.
6-(r-Cyanobenzyl)-3,4-dihydro-2-isopropylthio-5-methylpy-
rimidin-4(3H)-one (3g). Yield 44.5%; recrystallized from AcOEt,
mp 161.6-163.4 °C; 1H NMR (DMSO-d6, 500 MHz) δ 1.29 (d, J
) 6.8 Hz, 3H, CH3CH), 1.42 (d, J ) 6.8 Hz, 3H, CH3CH), 1.98
(s, 3H, CH3), 3.87 (sep, J ) 6.8 Hz, 1H, SCH), 5.87 (s, 1H, CHCN),
7.35-7.46 (m, 5H, Ph), 12.80 (s, 1H, NH); 13C NMR (DMSO-d6,
400 MHz) δ 10.10 (CH3), 22.39 (CH3CH), 22.49 (CH3CH), 36.11
(SCH), 40.36 (CHCN), 118.83 (CN), 127.72 (2C), 128.25, 129.02
(2C), 129.33, 134.22 (Ph, C5), 154.75 (C6), 158.10 (C2), 162.92
(C4); MS (EI) m/z 299 (M+). Anal. (C16H17N3OS) C, H, N, S.
6-(r-Cyanobenzyl)-2-cyclopentylthio-3,4-dihydro-5-methyl-
pyrimidin-4(3H)-one (3h). Yield 39.9%; recrystallized from
12.26 (s, 1H, NH); 13C NMR (DMSO-d6, 400 MHz) δ 11.92 (CH2-
CH3), 18.27 (CH2CH3), 32.24 (CHCN), 38.26 (SCH2), 118.07 (d
CH2), 118.83 (CN), 122.38, 123.03, 125.52, 126.27, 126.92, 126.97,
128.92, 129.16, 130.02, 130.39, 133.38, 133.56 (Naph, C5, dCH),
154.28 (C6), 157.99 (C2), 162.77 (C4); MS (EI) m/z 361 (M+).
Anal. (C21H19N3OS) C, H, N, S.
6-[r-Cyano-(1-naphthylmethyl)]-3,4-dihydro-5-ethyl-2-propy-
nylthiopyrimidin-4(3H)-one (3n). Yield 41.8%; recrystallized from
1
MeOH, mp 190.4-191.1 °C; H NMR (DMSO-d6, 500 MHz) δ
0.63 (t, J ) 7.2 Hz, 3H, CH2CH3), 2.36 (q, J ) 7.2 Hz, 2H, CH2-
CH3), 3.21 (s, 1H, tCH), 3.89-4.03 (m, 2H, SCH2), 6.56 (s, 1H,
CHCN), 7.54-8.30 (m, 7H, Naph), 13.04 (s, 1H, NH); 13C NMR
(DMSO-d6, 400 MHz) δ 12.66 (CH2CH3), 18.23 (CH2CH3), 18.39
(SCH2), 38.05 (CHCN), 73.39 (tCH), 79.69 (tC), 118.67 (CN),
123.02, 125.57, 126.26, 126.33, 127.06, 127.21, 128.94,
129.20, 129.99, 130.39, 133.55 (Naph, C5), 154.45 (C6), 157.26
(C2), 164.09 (C4); MS (EI) m/z 359 (M+). Anal. (C21H17N3OS) C,
H, N, S.
1
AcOEt, mp 168.2-169.1 °C; H NMR (DMSO-d6, 500 MHz) δ
1.46-1.50 (m, 4H, cyclopentyl), 1.57-1.60 (m, 2H, cyclopentyl),
1.68-1.70 (m, 2H, cyclopentyl), 1.80 (s, 3H, CH3), 3.74-3.75 (m,
1H, cyclopentyl), 5.34 (s, 1H, CHCN), 7.55-7.89 (m, 7H, Ph),
12.81 (s, 1H, NH); 13C NMR (DMSO-d6, 400 MHz) δ 10.54 (CH3),
23.38 (CHCN), 24.26, 24.35 (cyclopentyl), 32.64, 32.81 (cyclo-
pentyl), 43.03 (cyclopentyl), 116.49 (CN), 127.76, 128.87, 129.00,
129.72, 134.23, 134.46 (Ph, C5), 155.93 (C6), 159.34 (C2), 162.94
(C4); MS (EI) m/z 325 (M+). Anal. (C18H19N3OS) C, H, N, S.
2-Benzoylmethylthio-6-(r-cyanobenzyl)-3,4-dihydro-5-meth-
ylpyrimidin-4(3H)-one (3i). Yield 37.6%; recrystallized from
6-[r-Cyano-(1-naphthylmethyl)]-3,4-dihydro-5-ethyl-2-(4-ni-
trobenzylthio)pyrimidin-4(3H)-one (3o). Yield 35.2%; recrystal-
1
lized from AcOEt, mp 182.0-183.7 °C; H NMR (CDCl3, 400
MHz) δ 1.10 (t, J ) 7.2 Hz, 3H, CH2CH3), 2.95 (q, J ) 7.2 Hz,
2H, CH2CH3), 4.08 (s, 2H, SCH2), 5.80 (s, 1H, CHCN), 7.44-
7.88 (m, 11H, Naph, Ph), 12.15 (s, 1H, NH); MS (EI) m/z 456
(M+). Anal. (C25H20N4O3S) C, H, N, S.
2-(4-Chlorobenzoylmethylthio)-6-[r-cyano-(1-naphthylmethyl)]-
3,4-dihydro-5-ethylpyrimidin-4(3H)-one (3p). Yield 32.1%; re-
1
1
MeOH, mp 156.0-157.6 °C; H NMR (DMSO-d6, 500 MHz) δ
crystallized from MeOH, mp 181.6-183.2 °C; H NMR (CDCl3,
1.95 (s, 3H, CH3), 4.75 (s, 2H, SCH2), 6.56 (s, 1H, CHCN), 7.39-
8.11 (m, 10H, Ph, Ph), 13.01 (s, 1H, NH); MS (EI) m/z 375 (M+).
Anal. (C21H17N3O2S) C, H, N, S.
400 MHz) δ 0.96 (t, J ) 7.6 Hz, 3H, CH2CH3), 2.32 (q, J ) 7.6
Hz, 2H, CH2CH3), 3.42 (s, 2H, SCH2), 4.48 (s, 1H, CHCN), 7.30-
7.93 (m, 11H, Naph, Ph), 12.05 (s, 1H, NH); MS (EI) m/z 473
(M+). Anal. (C26H20ClN3O2S) C, H, Cl, N, S.
6-[r-Cyano-(1-naphthylmethyl)]-3,4-dihydro-5-ethyl-2-eth-
ylthiopyrimidin-4(3H)-one (3j). Yield 53.6%; recrystallized from
6-(r-Cyanobenzyl)-3,4-dihydro-5-ethyl-2-isopropylthiopyri-
midin-4(3H)-one (3q). Yield 47.5%; recrystallized from AcOEt,
mp 140.5-141.9 °C; 1H NMR (DMSO-d6, 500 MHz) δ 0.92 (t, J
) 7.1 Hz, 3H, CH2CH3), 1.27 (d, J ) 6.7 Hz, 3H, CH3CH), 1.41
(d, J ) 6.7 Hz, 3H, CH3CH), 2.47 (q, J ) 7.1 Hz, 2H, CH2CH3),
3.85 (sep, J ) 6.7 Hz, 1H, SCH), 5.88 (s, 1H, CHCN), 7.30-7.88
(m, 5H, Ph), 12.79 (s, 1H, NH); 13C NMR (DMSO-d6, 400 MHz)
δ 14.36 (CH2CH3), 18.47 (CH2CH3), 22.77 (CH3CH), 22.94 (CH3-
CH), 36.39 (SCH), 36.74 (CHCN), 119.54 (CN), 122.54, 128.32
(2C), 128.87, 129.52 (2C), 134.82 (Ph, C5), 154.84 (C6), 158.96
(C2), 163.12 (C4); MS (EI) m/z 313 (M+). Anal. (C17H19N3OS) C,
H, N, S.
6-(r-Cyanobenzyl)-3,4-dihydro-5-ethyl-2-(4-nitrobenzylthio)-
pyrimidin-4(3H)-one (3r). Yield 39.3%; recrystallized from AcO-
Et, mp 89.0-90.3 °C; 1H NMR (CDCl3, 400 MHz) δ 1.04 (t, J )
7.6 Hz, 3H, CH2CH3), 2.44 (q, J ) 7.6 Hz, 2H, CH2CH3), 4.37 (s,
2H, SCH2), 5.19 (s, 1H, CHCN), 7.17-7.84 (m, 9H, Ph, Ph), 12.41
(s, 1H, NH); MS (EI) m/z 406 (M+). Anal. (C21H18N4O3S) C, H,
N, S.
1
AcOEt, mp 189.0-190.1 °C; H NMR (DMSO-d6, 500 MHz) δ
0.99 (d, J ) 7.1 Hz, 6H, 2×CH3), 2.33 (q, J ) 7.1 Hz, 2H, CH2-
CH3), 2.85 (q, J ) 7.1 Hz, 2H, SCH2), 6.06 (s, 1H, CHCN), 7.59-
8.89 (m, 7H, Naph), 13.03 (s, 1H, NH); MS (EI) m/z 349 (M+).
Anal. (C20H19N3OS) C, H, N, S.
6-[r-Cyano-(1-naphthylmethyl)]-3,4-dihydro-5-ethyl-2-iso-
propylthiopyrimidin-4(3H)-one (3k). Yield 51.9%; recrystallized
from AcOEt, mp 228.0-229.4 °C; 1H NMR (DMSO-d6, 500 MHz)
δ 0.77 (t, J ) 7.2 Hz, 3H, CH2CH3), 1.10 (d, J ) 6.7 Hz, 3H,
CH3CH), 1.33 (d, J ) 6.7 Hz, 3H, CH3CH), 2.43 (q, J ) 7.2 Hz,
2H, CH2CH3), 3.69 (sep, J ) 6.7 Hz, 1H, SCH), 6.55 (s, 1H,
CHCN), 7.55-8.18 (m, 7H, Naph), 12.85 (s, 1H, NH); 13C NMR
(DMSO-d6, 400 MHz) δ 12.16 (CH2CH3), 18.33 (CH2CH3), 22.27
(CH3CH), 22.42 (CH3CH), 36.08 (CHCN), 38.07 (SCH), 118.87
(CN), 122.42, 123.04, 125.52, 126.20, 126.87, 126.92, 128.88,
129.08, 130.02, 130.38, 133.54 (Naph, C5), 154.16 (C6), 158.29
(C2), 162.50 (C4); MS (EI) m/z 363 (M+). Anal. (C21H21N3OS) C,
H, N, S.
6-[r-Cyano-(1-naphthylmethyl)]-2-cyclopentylthio-3,4-dihy-
dro-5-ethylpyrimidin-4(3H)-one (3l). Yield 44.4%; recrystallized
from AcOEt, mp 216.3-217.2 °C; 1H NMR (DMSO-d6, 500 MHz)
δ 0.77 (t, J ) 7.2 Hz, 3H, CH2CH3), 1.29 (m, 1H, cyclopentyl),
1.45-1.53 (m, 5H, cyclopentyl), 1.62 (m, 1H, cyclopentyl), 2.15
(m, 1H, cyclopentyl), 2.44 (q, J ) 7.2 Hz, 2H, CH2CH3), 3.66-
3.69 (m, 1H, cyclopentyl), 6.54 (s, 1H, CHCN), 7.54-8.15 (m,
7H, Naph), 12.85 (s, 1H, NH); 13C NMR (DMSO-d6, 400 MHz) δ
12.07 (CH2CH3), 18.29 (CH2CH3), 24.19, 24.23, 32.37, 32.52
(cyclopentyl), 38.20 (CHCN), 43.31 (cyclopentyl), 118.86 (CN),
122.49, 123.07, 125.47, 126.18, 126.83, 126.93, 128.86,
129.00, 130.06, 130.43, 133.54 (Naph, C5), 154.35 (C6), 158.86
(C2), 162.66 (C4); MS (EI) m/z 389 (M+). Anal. (C23H23N3OS) C,
H, N, S.
6-(r-Cyano-2,6-dichlorobenzyl)-3,4-dihydro-5-ethyl-2-(4-ni-
trobenzylthio)pyrimidin-4(3H)-one (3s). Yield 31.0%; recrystal-
lized from AcOEt, mp 109.9-111.1 °C; 1H NMR (DMSO-d6, 400
MHz) δ 1.12 (t, J ) 7.2 Hz, 3H, CH2CH3), 2.32 (q, J ) 7.2 Hz,
2H, CH2CH3), 4.49 (s, 2H, SCH2), 6.47 (s, 1H, CHCN), 7.47-
9.84 (m, 7H, Ar), 13.00 (s, 1H, NH); 13C NMR (DMSO-d6, 400
MHz) δ 11.99 (CH2CH3), 12.10 (CHCN), 18.88 (CH2CH3), 32.60
(SCH2), 116.97 (CN), 119.78 (C5), 123.85 (2C), 130.03, 130.13
(2C), 130.29 (2C), 131.46, 135.70, 135.76, 146.59, 147.02 (Ar),
148.58 (C6), 159.93 (C2), 164.08 (C4); MS (EI) m/z 474 (M+).
Anal. (C21H16Cl2N4O3S) C, H, Cl, N, S.
6-[r-Cyano-(1-naphthylmethyl)]-2-cyclopentylthio-3,4-dihy-
dro-5-isopropylpyrimidin-4(3H)-one (3t). Yield 47.3%; recrystal-
1
lized from AcOEt, mp 172.6-173.8 °C; H NMR (CDCl3, 400
2-Allylthio-6-[r-cyano-(1-naphthylmethyl)]-3,4-dihydro-5-eth-
ylpyrimidin-4(3H)-one (3m). Yield 53.2%; recrystallized from
MeOH, mp 195.8-197.3 °C; 1H NMR (CDCl3, 500 MHz) δ 0.98
(t, J ) 7.5 Hz, 3H, CH2CH3), 2.49 (q, J ) 7.5 Hz, 2H, CH2CH3),
3.67-3.73 (m, 2H, SCH2), 5.02-5.20 (m, 2H, dCH2), 5.70-5.71
(m, 1H, dCH), 5.87 (s, 1H, CHCN), 7.34-8.07 (m, 7H, Naph),
MHz) δ 1.19 (d, J ) 7.2 Hz, 6H, CH(CH3)2), 1.42-1.48 (m, 4H,
cyclopentyl), 1.61-1.63 (m, 2H, cyclopentyl), 1.86-1.90 (m, 2H,
cyclopentyl), 3.11 (sep, J ) 7.2 Hz, 1H, CH(CH3)2), 3.47 (m, 1H,
cyclopentyl), 5.94 (s, 1H, CHCN), 7.23-7.83 (m, 7H, Naph), 12.16
(s, 1H, NH); 13C NMR (CDCl3, 400 MHz) δ 19.78 (2C, CH(CH3)2),
21.68 (CH(CH3)2), 24.61, 24.74 (cyclopentyl), 29.63 (CHCN), 33.04

1784 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 8
Ji et al.
(2C, cyclopentyl), 43.67 (cyclopentyl), 115.36 (CN), 122.67, 124.69,
126.57, 127.55, 128.13, 129.07, 129.61, 129.82, 130.24, 131.46,
135.17 (Naph, C5), 159.08 (C6), 159.55 (C2), 165.96 (C4); MS
(EI) m/z 403 (M+). Anal. (C24H25N3OS) C, H, N, S.
6-[r-Cyano-(1-naphthylmethyl)]-3,4-dihydro-5-isopropyl-2-
(4-methoxybenzylthio)pyrimidin-4(3H)-one (3u). Yield 40.1%;
recrystallized from MeOH, mp 104.3-105.6 °C; 1H NMR (CDCl3,
400 MHz) δ 1.18 (d, J ) 7.3 Hz, 6H, CH(CH3)2), 2.49 (sep, J )
7.3 Hz, 1H, CH(CH3)2), 3.43 (s, 3H, OCH3), 4.51 (s, 2H, SCH2),
5.91 (s, 1H, CHCN), 7.20-7.87 (m, 11H, Ar), 12.69 (s, 1H, NH);
MS (EI) m/z 455 (M+). Anal. (C27H25N3O2S) C, H, N, S.
6-Benzoyl-3,4-dihydro-2-isopropylthio-5-methylpyrimidin-
4(3H)-one (4e). Yield 88.7%; mp 121.1-122.7 °C; 1H NMR
(DMSO-d6, 400 MHz) δ 1.22 (d, J ) 7.0 Hz, 6H, (CH3)2CH), 1.78
(s, 3H, CH3), 3.67 (sep, J ) 6.8 Hz, 1H, SCH), 7.40-7.88 (m, 5H,
Ph), 12.91 (s, 1H, NH); 13C NMR (DMSO-d6, 400 MHz) δ 10.51
(CH3), 22.30 (CH3), 22.20, 22.39 (CH(CH3)2), 35.75 (SCH), 128.91,
129.01, 129.51, 129.67, 134.24, 134.31, 134.39 (Ph, C5), 155.93
(C6), 158.70 (C2), 162.87 (C4), 193.47 (CdO); MS (EI) m/z 288
(M+). Anal. (C15H16N2O2S) C, H, N, S.
3,4-Dihydro-5-methyl-6-(1-naphthoyl)-2-propynylthiopyrimi-
1
din-4(3H)-one (4f). Yield 70.6%; mp 249.0-250.7 °C; H NMR
(DMSO-d6, 500 MHz) δ 1.86 (s, 3H, CH3), 3.18 (s, 1H, tCH),
3.98 (m, 2H, SCH2), 7.50-8.29 (m, 7H, Naph), 13.11 (s, 1H, NH);
MS (EI) m/z 334 (M+). Anal. (C19H14N2O2S) C, H, N, S.
3,4-Dihydro-5-ethyl-2-ethylthio-6-(1-naphthoyl)pyrimidin-
4(3H)-one (4g). Yield 87.9%; mp 171.0-172.5 °C; 1H NMR
(DMSO-d6, 500 MHz) δ 1.01 (d, J ) 6.9 Hz, 6H, 2×CH3), 2.32
(q, J ) 6.9 Hz, 2H, CH2CH3), 2.83 (q, J ) 6.9 Hz, 2H, SCH2),
7.60-8.87 (m, 7H, Naph), 12.98 (s, 1H, NH); MS (EI) m/z 338
(M+). Anal. (C19H18N2O2S) C, H, N, S.
3,4-Dihydro-5-ethyl-2-isopropylthio-6-(1-naphthoyl)pyrimi-
din-4(3H)-one (4h). Yield 85.3%; mp 141.6-142.3 °C; 1H NMR
(DMSO-d6, 400 MHz) δ 0.94 (t, J ) 7.2 Hz, 3H, CH2CH3), 1.21
(d, J ) 6.8 Hz, 6H, (CH3)2CH), 2.21 (q, J ) 7.2 Hz, 2H, CH2-
CH3), 3.66 (sep, J ) 6.8 Hz, 1H, SCH), 6.68-7.87 (m, 7H, Naph),
12.93 (s, 1H, NH); 13C NMR (DMSO-d6, 400 MHz) δ 13.16 (CH3-
CH2), 18.47 (CH3CH2), 22.34 (2C, CH(CH3)2), 35.69 (SCH),
127.84, 128.85, 129.27, 129.66, 129.89, 130.15, 134.30, 134.44
(Naph, C5), 156.08 (C6), 158.97 (C2), 162.40 (C4), 193.34 (Cd
O); MS (EI) m/z 352 (M+). Anal. (C20H20N2O2S) C, H, N, S.
2-Allylthio-3,4-dihydro-5-ethyl-6-(1-naphthoyl)pyrimidin-
4(3H)-one (4i). Yield 80.4%; mp 133.1-134.4 °C; 1H NMR
(CDCl3, 400 MHz) δ 1.14 (t, J ) 7.4 Hz, 3H, CH2CH3), 2.51 (q,
J ) 7.4 Hz, 2H, CH2CH3), 3.62 (d, J ) 7.0 Hz, 2H, SCH2), 4.97-
5.03 (m, 2H, dCH2), 5.67-5.72 (m, 1H, dCH), 7.48-9.15 (m,
7H, Naph), 11.34 (s, 1H, NH); MS (EI) m/z 350 (M+). Anal.
(C20H18N2O2S) C, H, N, S.
2-Benzylthio-3,4-dihydro-5-ethyl-6-(1-naphthoyl)pyrimidin-
4(3H)-one (4j). Yield 91.3%; mp 219.9-221.3 °C; 1H NMR
(DMSO-d6, 500 MHz) δ 1.02 (t, J ) 7.2 Hz, 3H, CH2CH3), 2.35
(q, J ) 7.2 Hz, 2H, CH2CH3), 4.09 (s, 2H, SCH2), 7.02-8.85 (m,
12H, Naph, Ph), 13.01 (s, 1H, NH); 13C NMR (DMSO-d6, 400
MHz) δ 12.32 (CH2CH3), 16.16 (CH2CH3), 33.24 (SCH2), 127.40
(2C), 127.88 (3C), 128.44 (3C), 128.83 (3C), 130.03 (3C), 134.16,
136.17 (Ar), 145.45 (C5), 148.03 (C6), 158.39 (C2), 164.33 (C4),
191.98 (CdO); MS (EI) m/z 400 (M+). Anal. (C24H20N2O2S) C,
H, N, S.
2-Benzylthio-3,4-dihydro-5-ethyl-6-(2-naphthoyl)pyrimidin-
4(3H)-one (4k). Yield 90.7%; mp 200.0-201.1 °C; 1H NMR
(DMSO-d6, 500 MHz) δ 1.03 (t, J ) 7.4 Hz, 3H, CH2CH3), 2.34
(q, J ) 7.4 Hz, 2H, CH2CH3), 3.84 (s, 2H, SCH2), 7.17-8.92 (m,
12H, Naph, Ph), 13.11 (s, 1H, NH); 13C NMR (DMSO-d6, 400
MHz) δ 12.32 (CH2CH3), 16.16 (CH2CH3), 33.23 (SCH2), 127.41
(2C), 127.85 (3C), 128.48 (3C), 128.85 (3C), 130.04 (3C), 134.15,
136.17 (Ar), 145.46 (C5), 148.04 (C6), 158.35 (C2), 164.32 (C4),
191.96 (CdO); MS (EI) m/z 400 (M+). Anal. (C24H20N2O2S) C,
H, N, S.
6-(r-Cyanobenzyl)-3,4-dihydro-5-isopropyl-2-(4-methoxyben-
zylthio)pyrimidin-4(3H)-one (3v). Yield 33.7%; recrystallized
from MeOH, mp 69.0-70.2 °C; H NMR (DMSO-d6, 400 MHz)
δ 1.16 (d, J ) 7.2 Hz, 6H, CH(CH3)2), 2.48 (sep, J ) 7.3 Hz, 1H,
CH(CH3)2), 3.09 (s, 3H, OCH3), 4.42 (s, 2H, SCH2), 5.98 (s, 1H,
CHCN), 7.07-7.87 (m, 9H, Ar), 12.75 (s, 1H, NH); MS (EI) m/z
405 (M+). Anal. (C23H23N3O2S) C, H, N, S.
1
6-(r-Cyano-2,6-dichlorobenzyl)-3,4-dihydro-5-isopropyl-2-(4-
methoxybenzylthio)pyrimidin-4(3H)-one (3w). Yield 31.4%;
1
recrystallized from MeOH, mp 64.0-65.2 °C; H NMR (CDCl3,
400 MHz) δ 1.20 (d, J ) 7.0 Hz, 6H, CH(CH3)2), 2.50 (sep, J )
7.0 Hz, 1H, CH(CH3)2), 3.41 (s, 3H, OCH3), 4.03 (s, 2H, SCH2),
6.05 (s, 1H, CHCN), 7.29-7.42 (m, 7H, Ar), 11.05 (s, 1H, NH);
MS (EI) m/z 473 (M+). Anal. (C23H21Cl2N3O2S) C, H, Cl, N, S.
General Procedure for the Synthesis of 5-Alkyl-2-alkylthio-
6-arylcarbonyl-3,4-dihydropyrimidin-4(3H)-ones 4a-m. 5-Alkyl-
2-alkylthio-6-(R-cyanoarylmethyl)-3,4-dihydropyrimidin-4(3H)-
ones 3b, 3d, 3g, 3j,k, 3m, 3t, and 3x-ac (2 mmol) was dissolved
in anhydrous DMF (50 mL) under nitrogen atmosphere. The
solution was cooled to -10 °C, and NaH (0.10 g, 2.4 mmol) (60%
in paraffin) was added portionwise. The resulting mixture was
stirred for 0.5 h, warmed to room temperature, and then air was
passed through the reaction mixture for 6-12 h. The resulting
solution was neutralized with acetic acid, concentrated in vacuo,
and added to water (100 mL). A precipitate which formed was
filtered off, washed with water, dried, and recrystallized from
AcOEt.
3,4-Dihydro-2-ethylthio-6-(1-naphthoyl)pyrimidin-4(3H)-
one (4a). Yield 82.5%; mp 222.0-223.2 °C; 1H NMR (DMSO-d6,
500 MHz) δ 0.95 (t, J ) 7.2 Hz, 3H, CH3), 2.75 (sep, J ) 7.2 Hz,
2H, SCH2), 6.57 (s, 1H, CH), 7.60-8.26 (m, 7H, Naph), 13.09 (s,
1H, NH); 13C NMR (DMSO-d6, 400 MHz) δ 14.14 (CH3), 24.33
(CH2), 110.26 (C5), 124.46, 125.02, 125.43, 127.75, 128.57, 130.21,
130.33, 132.61, 133.07, 133.13 (Naph), 154.71 (C6), 158.70 (C2),
162.95 (C4), 195.00 (CdO); MS (EI) m/z 310 (M+). Anal.
(C17H14N2O2S) C, H, N, S.
2-Cyclopentylthio-3,4-dihydro-6-(1-naphthoyl)pyrimidin-4(3H)-
1
one (4b). Yield 86.1%; mp 186.4-187.4 °C; H NMR (DMSO-
d6, 500 MHz) δ 1.27-1.30 (m, 4H, cyclopentyl), 1.47 (m, 2H,
cyclopentyl), 1.61 (m, 2H, cyclopentyl), 3.31 (m, 1H, cyclopentyl),
6.61 (s, 1H, CH), 7.60-8.18 (m, 7H, Naph), 13.09 (s, 1H, NH);
13C NMR (DMSO-d6, 400 MHz) δ 24.00 (2C), 32.20 (2C), 43.32
(cyclopentyl), 109.71 (C5), 124.51, 125.04, 126.39, 127.60, 128.51,
129.67, 130.14, 132.25, 133.01, 133.60 (Naph), 155.02 (C6), 158.39
(C2), 163.38 (C4), 195.37 (CdO); MS (EI) m/z 350 (M+). Anal.
(C20H18N2O2S) C, H, N, S.
6-Benzoyl-2-cyclopentylthio-3,4-dihydro-5-ethylpyrimidin-
4(3H)-one (4l). Yield 84.3%; mp 162.0-163.3 °C; 1H NMR
(DMSO-d6, 500 MHz) δ 0.95 (t, J ) 7.1 Hz, 3H, CH2CH3), 1.46
(m, 4H, cyclopentyl), 1.58 (m, 2H, cyclopentyl), 1.93 (m, 2H,
cyclopentyl), 2.21 (q, J ) 7.1 Hz, 2H, CH2CH3), 3.74-3.75 (m,
1H, cyclopentyl), 7.55-7.89 (m, 5H, Ph), 12.95 (s, 1H, NH); 13C
NMR (DMSO-d6, 400 MHz) δ 13.18 (CH2CH3), 18.46 (CH2CH3),
24.24 (2C, cyclopentyl), 32.56 (2C, cyclopentyl), 43.08 (cyclopen-
tyl), 123.12, 128.83 (2C), 129.69 (2C), 134.29, 134.51 (Ph, C5),
156.09 (C6), 159.53 (C2), 162.45 (C4), 193.41 (CdO); MS (EI)
m/z 328 (M+). Anal. (C18H20N2O2S) C, H, N, S.
2-Benzoylmethylthio-3,4-dihydro-6-(1-naphthoyl)pyrimidin-
4(3H)-one (4c). Yield 30.7%; mp 183.2-183.7 °C; 1H NMR
(DMSO-d6, 500 MHz) δ 3.86 (s, 2H, SCH2), 6.97 (CH), 7.42-
8.08 (m, 12H, Naph, Ph), 13.15 (s, 1H, NH); MS (EI) m/z 400
(M+). Anal. (C23H16N2O3S) C, H, N, S.
6-Benzoyl-3,4-dihydro-2-ethylthiopyrimidin-4(3H)-one (4d).
Yield 90.3%; mp 173.2-174.5 °C; 1H NMR (DMSO-d6, 500 MHz)
δ 1.23 (t, J ) 7.3 Hz, 3H, CH3), 3.05 (q, J ) 7.3 Hz, 2H, SCH2),
6.46 (s, 1H, CH), 7.47-7.97 (m, 5H, Ph), 13.11 (s, 1H, NH); 13C
NMR (DMSO-d6, 400 MHz) δ 14.38 (CH3), 24.39 (CH2), 109.76
(C5), 128.42 (2C), 130.14, 133.77, 134.69 (Ph), 154.75 (C6), 159.06
(C2), 162.38 (C4), 192.17 (CdO); MS (EI) m/z 260 (M+). Anal.
(C13H12N2O2S) C, H, N, S.
2-Cyclopentylthio-3,4-dihydro-5-isopropyl-6-(1-naphthoyl)py-
1
rimidin-4(3H)-one (4m). Yield 87.6%; mp 155.2-157.0 °C; H
NMR (DMSO-d6, 400 MHz) δ 1.18 (d, J ) 7.1 Hz, 6H, CH(CH3)2),

Non-nucleoside HIV-1 ReVerse Transcriptase Inhibitors
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 8 1785
1.47 (m, 4H, cyclopentyl), 1.61-1.62 (m, 2H, cyclopentyl), 1.93
(m, 2H, cyclopentyl), 2.97 (sep, J ) 7.1 Hz, 1H, CH(CH3)2), 3.39-
3.42 (m, 1H, cyclopentyl), 7.52-8.13 (m, 7H, Naph), 13.06 (s, 1H,
NH); 13C NMR (DMSO-d6, 400 MHz) δ 19.89 (2C, CH(CH3)2),
21.99 (CH(CH3)2), 24.60, 24.76 (cyclopentyl), 33.16 (2C, cyclo-
pentyl), 43.61 (cyclopentyl), 122.67, 124.71, 126.55, 127.58, 128.12,
129.05, 129.59, 129.78, 130.21, 131.44, 135.18 (Naph, C5), 159.03
(C6), 159.39 (C2), 164.99 (C4), 194.00 (CdO); MS (EI) m/z 392
(M+). Anal. (C23H24N2O2S) C, H, N, S.
Methods. X-ray Crystallography of Compounds 3k and 4b.
Single crystals of 3k and 4b suitable for X-ray diffraction analysis
were obtained by recrystallization from methanol and ethyl acetate,
respectively. All measurements were made on an Enraf-Nonius
CAD-4 diffractometer.
Data were collected using CAD-4 Software (Enraf-Nonius,
Delft, The Netherlands, 1994). Cell were refined with CAD-4, and
data reduction was performed with XCAD4 (Harms & Wocadlo,
1994). The structure was solved by SHELX-S9721 and was refined
using SHELX-L97.22 Software used to prepare molecular graphics
was ORTEP-3 for Windows (Version 1.05; Farrugia, 1997).
Three-dimensional coordinates of the HIV-1 RT/MKC-442
(emivirine) complex (Brookhaven Protein Data Bank entry 1RT1)
were used as the input structure for docking calculations. For this
aim, all cocrystallized water molecules and the ligand were deleted,
all hydrogens were added, and Amber95 charges were loaded using
the appropriate tool in the Biopolymer module of Sybyl and
submitted to minimization with the steepest descent methods and
conjugated gradients methods (Tripos force field) to an energy
gradient of 0.05 kcal/(mol‚Å). The structure of the new S-DABO
derivative 3g was built using the Sybyl Sketcher model and fully
minimized with the Powell method (MMFF94 force field) to an
energy gradient of 0.05 kcal/(mol‚Å).
Docking simulations were performed with the program AutoDock
3.0.5. Grids of molecular interactions were calculated in a cubic
box (size, 25.125 Å; grid spacing: 0.375 Å). Docking was
performed 100 times using the Lamarckian genetic algorithm with
random starting position and conformation, standard parameters,
and a maximum of 250 000 energy evaluations. The 10 final docked
conformations were ranked according to their binding free energy.
Acknowledgment. We are grateful to the National Natural
Science Foundation of China (No. 30672536) for the financial
support of this research.
The data for 3k were as follows: C21H21N3OS, Mr 363.47, a )
10.822(3) Å, b ) 15.375(3) Å, c ) 12.061(4) Å, â ) 105.51(3)°,
V ) 1933.7(9) Å3, Z ) 4, space group P21/n, monoclinic, F(000)
) 768, dc ) 1.248 mg/m3, µ ) 0.18 mm-1, λ ) 0.71073 Å, T )
295(2) K. Of a total of 4116 reflections were measured, 3476 were
independent with R ) 0.044, wR(F2) ) 0.139 [I > 2σ(I)], and S )
Supporting Information Available: Elemental analysis data
for the title compounds and X-ray crystallographic information for
compounds 3k and 4b. This material is available free of charge
via the Internet at http://pubs.acs.org.
1.01. Parameters refined 343, (∆F)max ) 0.38 e Å-3, (∆F)min
)
-0.18 e Å-3, (∆/σ)max < 0.001, extinction coefficient ) 0.0036-
(11).
The data for 4b were as follows: C20H18N2O2S, Mr 350.42, a )
11.920(2) Å, b ) 10.312(3) Å, c ) 14.855(4) Å, â ) 108.43(2)°,
V ) 1732.3(7) Å3, Z ) 4, space group P21/n, monoclinic, F(000)
) 736, dc ) 1.344 mg/m3, µ ) 0.20 mm-1, λ ) 0.71073 Å, T )
295(2) K. Of a total of 3499 reflections were measured, 3109 were
independent with R ) 0.039, wR(F2) ) 0.117 [I > 2σ(I)], and S )
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