Synthesis and anti-hepatitis B virus activity of novel benzimidazole derivatives

Article abstract of DOI:10.1021/jm060330f

A series of novel benzimidazole derivatives was synthesized and evaluated for their anti-hepatitis B virus (HBV) activity and cytotoxicity in vitro. Strong activity against HBV replication and low cytotoxicity were generally observed in these benzimidazoles. The most promising compounds were 12a and 12b, with similar high antiviral potency (IC₅₀ = 0.9 and 0.7 μM, respectively) and remarkable selectivity indices (> 1111 and 714, respectively). They were selected for further evaluation as novel HBV inhibitors.

Full text of DOI:10.1021/jm060330f

4790
J. Med. Chem. 2006, 49, 4790-4794
Synthesis and Anti-Hepatitis B Virus Activity of Novel Benzimidazole Derivatives
Yun-Fei Li,†,§ Gui-Feng Wang,†,§ Pei-Lan He,† Wei-Gang Huang,† Feng-Hua Zhu,† He-Yong Gao,† Wei Tang,† Yu Luo,†
Chun-Lan Feng,† Li-Ping Shi,† Yu-Dan Ren,† Wei Lu,*,‡ and Jian-Ping Zuo*,†
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, SIBS, Chinese Academy of Sciences, 555 Zuchongzhi Road,
Zhangjiang Hi-Tech Park, Shanghai 201203, and Institute of Medicinal Chemistry, Department of Chemistry, East China Normal UniVersity,
3663 North Zhongshan Road, Shanghai 200062, China
ReceiVed March 22, 2006
A series of novel benzimidazole derivatives was synthesized and evaluated for their anti-hepatitis B virus
(HBV) activity and cytotoxicity in vitro. Strong activity against HBV replication and low cytotoxicity were
generally observed in these benzimidazoles. The most promising compounds were 12a and 12b, with similar
high antiviral potency (IC50 ) 0.9 and 0.7 µM, respectively) and remarkable selectivity indices (>1111 and
714, respectively). They were selected for further evaluation as novel HBV inhibitors.
Introduction
Hepatitis B virus (HBV) can cause both acute and chronic
infections, and constitutes the ninth leading cause of death in
the world.1 Of the approximately two billion people who have
been infected with HBV worldwide, an estimated 350-400
million are chronically infected, with 0.5-1.2 million deaths
annually from the resulting cirrhosis, liver failure, and hepato-
cellular carcinoma.2 Although new HBV infections can be
prevented by vaccination, the present vaccine is not effective
for chronic carriers. There remain millions of chronically
infected patients, who will eventually succumb to the sequela
of the infection unless treated with currently available therapies.
The major therapeutic options for HBV carriers are R-interferon
(IFN-R), lamivudine (3-TC), and adefovir dipivoxil (Figure 1).
However, they have limited efficacy in a significant proportion
of patients and often have severe adverse effects.3 Entecavir
was approved by the US Food and Drug Administration in 2005
for the treatment of chronic hepatitis B infection. However,
because its chemical structure is similar to that of lamivudine
and adefovir dipivoxil, it may exert its effects via the same
biological mechanism and encounter the same problems as
lamivudine and adefovir dipivoxil. Although the combination
therapy of lamivudine with adefovir dipivoxil, or antiviral drugs
together with immunomodulators such as R-interferon might
be more effective and safer in the therapeutic context, much
more study is required.4 Therefore, there is a tremendous clinical
need to develop novel classes of antiviral agents for the
treatment of HBV infection.
When we screened an in-house collection of compounds for
anti-HBV activity, 2-{2-[1-(4-nitro-benzenesulfonyl)-1H-ben-
zoimidazol-2-yl]-ethyl}-isoindole-1,3-dione (1, Figure 1) was
identified as a modest inhibitor of HBV, with an IC50 of 14.2
µM in inhibiting HBV DNA replication and low cytotoxicity
(CC50 ) 200 µM) in vitro. In view of its novel structural
template, which differs from those of all reported anti-HBV
agents, we were interested to study further the structure-activity
relationships of the related class of compounds. Thus, with
compound 1 as the starting point, we developed a novel series
of benzimidazole derivatives and investigated their biological
activities as potential HBV inhibitors.
Figure 1. Structures of known HBV agents and compound 1.
Chemistry. The benzimidazole scaffolds 4a,5 4b, and 4c were
prepared by condensation of o-phenylenediamine (2a), 4,5-
difluoro-o-phenylenediamine (2b),6 and 4,5-dichloro-o-phe-
nylenediamine (2c),7 respectively, with 3-phthalimidopropionic
acid (3) in polyphosphoric acid (PPA). The first subseries of
derivatives 5a-l, together with 1, were prepared with good
yields via the reaction of the appropriate sulfonyl chloride with
benzimidazole scaffolds 4a-c in CH2Cl2 using 4-(dimethyl-
amino)pyridine (DMAP) as the catalyst (Scheme 1). Clem-
mensen reduction8 of the phthalimide group of 4c with
amalgamated zinc in hydrochloric acid yielded the corresponding
lactam 6, which was then converted to the N-Ts product 7. The
amine 8, resulting from the hydrazinolysis of phthalimide 4c,
was treated with maleic anhydride in dry acetic acid9 to yield
the maleimide 9, which was also sulfonylated with tosyl chloride
to produce the N-Ts derivative 10.
Treatment of 4c with 4-methylbenzoyl chloride in the
presence of DMAP in CH2Cl2 formed the N-benzoyl derivative
11. N-Methylation of the benzimidazole of compound 4c with
iodomethane in the presence of potassium carbonate in DMF
produced the N-methyl product 12a. Compound 12b was
obtained through the reaction of compound 4c with 4-methyl-
benzyl chloride in the presence of sodium hydroxide in
acetonitrile, at the reflux temperature. Hydrazinolysis of the
phthalimide functionality of the N-benzyl compound 12b with
hydrazine hydrate in refluxing ethanol produced the correspond-
ing primary amine 13.
* To whom correspondence should be addressed. For W. Lu. Tel/fax:
+86-21-62602475. E-mail: wlu@chem.ecnu.edu.cn. For J.-P. Zuo. Tel/
fax: +86-21-50806701. E-mail: jpzuo@mail.shcnc.ac.cn.
† Shanghai Institute of Materia Medica.
‡ East China Normal University.
§ The two authors contributed equally to this work.
10.1021/jm060330f CCC: $33.50 © 2006 American Chemical Society
Published on Web 06/27/2006

Brief Articles
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 15 4791
Scheme 1a
a Reagents and conditions: (a) PPA, 170-180 °C; (b) substituted benzenesulfonyl chloride (for 1 and 5a-k) or MsCl (for 5l), DMAP, CH2Cl2, 50 °C;
(c) p-toluoyl chloride, DMAP, CH2Cl2, 50 °C; (d) Zn, HgCl2, HCl, reflux; (e) TsCl, DMAP, CH2Cl2, 50 °C; (f) hydrazine hydrate, EtOH, reflux; (g) maleic
anhydride, AcOH, reflux; (h) MeI, K2CO3, DMF, rt (for 12a), or 4-methylbenzyl chloride, NaOH, CH3CN, reflux (for 12b).
Scheme 2a
a Reagents and conditions: (a) PPA, 170-180 °C; (b) o-phthaloyl dichloride, dry pyridine, reflux; (c) TsCl, DMAP, CH2Cl2, 50 °C.
The benzimidazole scaffold 18 was synthesized by condensa-
tion of N-phthaloylglycine (16) with 2c in PPA. Similarly, the
reaction of 4-phthalimidobutyric acid (17) with 2c produced
compound 19. Compound 147 was treated with o-phthaloyl
dichloride in dry pyridine10 to afford compound 15. N-
Sulfonylation of the benzimidazole scaffolds 15, 18, and 19 with
tosyl chloride in the presence of DMAP in CH2Cl2 produced
the derivatives 20a-c (Scheme 2).
Compounds 28a-c were obtained by condensation in PPA
of 2c with 3-(4-pyridinyl)propionic acid (21), butyric acid (22),
and cyclohexanepropionic acid (23), respectively (Scheme 3).
Applying the method of Yang et al.,11 the benzimidazole 28d
was prepared with a good yield. Condensation of 2-methyl-
5,6-dichlorobenzimidazole with 2-furaldehyde at 170-180 °C
afforded compound 24, which was dehydrated in a mixed
solution of acetic acid and acetic anhydride to provide 26.
Hydrogenation of compound 26 with Raney nickel in ethanol
under a hydrogen atmosphere produced a mixture of 28e and
28f. Similarly, compound 27 was derived from 25, which was
prepared by the condensation of 2-methyl-5,6-dichlorobenzimi-
dazole with 2-thiophenecarboxaldehyde. Reduction of the
unsaturated alkyl linker in compound 27, following the method
of Fry et al.,12 produced benzimidazole 28g as the sole product.
N-Methylation of the free benzimidazole nitrogen of 28a-g with
iodomethane in the presence of potassium carbonate in DMF
at room temperature afforded 29a-g.

4792 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 15
Brief Articles
Scheme 3a
a Reagents and conditions: (a) PPA, 170-180 °C; (b) 1N Na2S2O4, EtOH, 70 °C; (c) MeI, K2CO3, DMF, rt; (d) 2-furaldehyde (for 24) or
2-thiophenecarboxaldehyde (for 25), 170-180 °C; (e) AcOH, Ac2O, reflux; (f) H2, Ra-Ni, EtOH, rt (for 28e and 28f), or I2, H3PO2, AcOH, reflux (for 28g).
Table 1. Anti-HBV Activity and Cytotoxicity of Analogues 5a-l in
Vitro
Results and Discussion
The potential anti-HBV activity and cytotoxicity of the
synthesized benzimidazoles, together with those of the reference
antiviral drugs lamivudine (3-TC) and adefovir, were evaluated
in HepG2.2.15 cells. The results are summarized in Tables 1-4.
The anti-HBV activity of each compound was expressed as the
concentration of compound that achieved 50% inhibition (IC50)
of HBV DNA synthesis. The cytotoxicity of each compound
was expressed as the concentration of compound required to
kill 50% (CC50) of the HepG 2.2.15 cells. The selectivity index
(SI), a major pharmaceutical parameter that estimates possible
future clinical development, was determined as the ratio of CC50
to IC50. The bioactivity of each compound was evaluated by
the combination of its IC50 and SI.
compd
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
R
X
Y
Z
IC50a (µM) CC50b (µM)
SIc
13
75
0.3
71
120
3
26
299
26
24
4
H
H
H
F
F
F
H
H
H
2.2
2.2
30.4
28
164
10
H
H
H
NO2
H
H
H
H
H
H
-
H
CF3
NO2
H
H
H
H
H
H
H
-
CH3
H
H
H
0.14
10
77
11
31
867
189
17
0.64
3.2
1.2
2.9
7.2
0.7
CF3
CH3
CH3
OCH3
i-Pr
NO2
-
The subseries of compounds 5a-k has different patterns of
substitution on the fused phenyl ring of the benzimidazole
pharmacophore. As shown in Table 1, these compounds
generally exhibited good antiviral potency, with IC50s of less
than 4 µM, except compounds 5c and 5k, which had only
moderate activities (IC50 ) 30 and 50 µM, respectively). This
result indicates that a range of substituents with different
lipophilic, electronic, and steric characters is tolerated at the
benzenesulfonyl group at the N-1 position of the benzimidazole
core. The three tosylates 5b, 5g, and 5h showed similar antiviral
activities (IC50 ) 1.2-2.9 µM), but the Cl analogue 5h appeared
to be less toxic than the corresponding H (5b) and F (5g)
analogues. The most potent compound in this subseries was
compound 5d (IC50 ) 0.14 µM), which was nearly three times
more potent than the reference drug lamivudine (IC50 ) 0.38
µM) and nine times more potent than adefovir (IC50 ) 1.3 µM).
However, it had pronounced cytotoxicity (CC50 ) 10 µM),
resulting in a relatively small selectivity index (SI ) 71).
Compounds 5e and 5j demonstrated similar antiviral potency,
F
Cl
Cl
Cl
Cl
Cl
-
50.2
NAd
0.38
1.3
181
175
>1000
203
5l
-
lamivudine
adefovir
-
-
-
-
-
-
>2632
156
-
a Concentrations of compounds achieving 50% inhibition of cytoplasmic
HBV-DNA synthesis. b Concentrations of compounds required for 50%
extinction of HepG 2.2.15 cells. c Selectivity index (SI) was determined as
the CC50/IC50 value. d Not active.
with IC50s of less than 0.75 µM. Of these, 5e had higher
selectivity (SI ) 120) compared to that of adefovir (SI ) 156).
The introduction of a methanesulfonyl moiety to the N-1
position of the benzimidazole core of 4c produced an inactive
compound (5l). It is noteworthy that compound 5h showed
potent antiviral activity (IC50 ) 2.9 µM) and the highest SI
(299). Thus, compound 5h was selected as the benchmark
compound for subsequent optimization.

Brief Articles
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 15 4793
Table 2. Anti-HBV Activity and Cytotoxicity of Analogues (7, 10, and
20a-c) in Vitro
Table 4. Anti-HBV Activity and Cytotoxicity of Analogues (13 and
29a-g) in Vitro
compd
n
R
IC50a (µM)
CC50b (µM)
SIc
a
b
IC50
CC50
7
10
20a
20b
20c
2
2
0
1
3
N-phthalimidino
N-maleimide
N-phthalimido
N-phthalimido
N-phthalimido
3.4
0.68
19.4
0.5
23
33
122
90
7
49
6
180
38
compd
R1
R2
(µM)
(µM)
SIc
13
4-methylbenzyl NH2
1.4
4.6
3.9
4
3
8
6
29a
29b
29c
29d
29e
29f
29g
CH3
CH3
CH3
CH3
CH3
CH3
CH3
4-pyridyl
CH3
cyclohexyl
phenyl
2-furanyl
2-tetrahydrofuranyl
2-thiophenyl
35.8
24.6
0.34
13
18.5 >500
>27
a Concentrations of compounds achieving 50% inhibition of cytoplasmic
HBV-DNA synthesis. b Concentrations of compounds required for 50%
extinction of HepG 2.2.15 cells. c Selectivity index (SI) was determined as
the CC50/IC50 value.
NAd
NA
15.3
5.9
56
16
-
-
5
-
10.3
NA
Table 3. Anti-HBV Activity and Cytotoxicity of Analogues (4c, 11,
and 12a,b) in Vitro
a Concentrations of compounds achieving 50% inhibition of cytoplasmic
HBV-DNA synthesis. b Concentrations of compounds required for 50%
extinction of HepG 2.2.15 cells. c Selectivity index (SI) was determined as
the CC50/IC50 value. d Not active.
noncytotoxic derivative 11 (CC50 > 1000 µM), which had only
moderate activity (IC50 ) 53.2 µM). An important advance was
made when the N-1 position of the benzimidazole core was
substituted with methyl or 4-methylbenzyl. The N-methyl
analogue 12a (IC50 ) 0.9 µM, SI > 1111) and the 4-methyl-
benzyl derivative 12b (IC50 ) 0.7 µM, SI > 714) exhibited
more highly potent anti-HBV activities and much higher SI
values than those of 5h (IC50 ) 2.9 µM, SI ) 299) or adefovir
(IC50 ) 1.3 µM, SI ) 156).
It is worth noting that analogues of the phthalimide (5h),
lactam (7), and maleimide (10) all exhibited potent activity
against HBV (IC50 ) 0.68-3.4 µM). The presence of amides
at the end of the alkyl linker seems to be important for anti-
HBV activity. To extend this result, we prepared another group
of new benzimidazole derivatives that differ at the right-hand
side of the structure (Scheme 3). A methyl group, which
characterized one of the optimal analogues 12a, was used as
the N-1 substituent. The free amine 13 was derived from another
optimal derivative 12b (Scheme 1). The anti-HBV activity and
cytotoxicity of analogues 13 and 29a-g are summarized in
Table 4.
The free amine 13 (IC50 ) 1.4 µM) displayed a slight decrease
in antiviral potency compared with that of compound 12b (IC50
) 0.7 µM), whereas its antiviral activity was poorly separated
from its cytotoxicity (CC50 ) 4 µM). Replacement of the
phthalimide group of 12a with different types of functional
groups led to significant decreases in antiviral potency and SI
relative to those of 12a. In particular, replacing the phthalimide
group of 12a with phenyl, 2-furanyl, or 2-thiophenyl resulted
in a complete loss of inhibitory activity, as seen in compounds
29d, 29e, and 29g. These findings suggest that the presence of
amides at the end of the alkyl linker plays an important role in
potent anti-HBV activity.
In summary, a series of novel benzimidazole analogues based
on 1 was synthesized and assessed for their anti-HBV activity
in vitro, using lamivudine and adefovir as reference controls.
Most proved to be potential HBV inhibitors (IC50 < 4 µM) with
high selectivity indices. Compounds 5b, 5d, 5e, 5h, 10, 12a,
12b, 20b, and 20c displayed optimal profiles, with IC50s of
0.14-2.9 µM and SIs of 38-1111. The most promising results
were observed for compounds 12a and 12b, with potent antiviral
activities (IC50 ) 0.9 and 0.7 µM, respectively) and extraordi-
narily high selectivity (SI > 1111 and 714, respectively). Such
activity and cytotoxicity profiles and their ease of preparation
make them attractive candidate compounds for further assess-
ment in vivo as anti-HBV agents.
compd
R
IC50a (µM)
CC50b (µM)
SIc
4c
11
12a
12b
H
300
53.2
0.9
330
>1000
>1000
>500
1
4-methylbenzoyl
CH3
4-methylbenzyl
>19
>1111
>714
0.7
a Concentrations of compounds achieving 50% inhibition of cytoplasmic
HBV-DNA synthesis. b Concentrations of compounds required for 50%
extinction of HepG 2.2.15 cells. c Selectivity index (SI) was determined as
the CC50/IC50 value.
Little change in antiviral potency was observed with the
reduction of the phthalimide 5h to the corresponding lactam 7
(Scheme 1, Table 2), whereas compound 7 had a small SI (7),
suggesting that the carbonyl group of the phthalimide 5h is an
important feature in conferring relatively low cytotoxicity.
Replacement of the phthalimide group of 5h with maleimide
(10) yielded a 4-fold improvement in antiviral potency. The SI
of compound 10 was below 50, because of its significantly
greater cytotoxicity (CC50 ) 33 µM) compared with that of 5h
(CC50 ) 867 µM). This result suggests that the phenyl moiety
in the phthalimide group of compound 5h plays less important
role in its potent inhibitory activity, although conferring an
advantageous SI on 5h. To identify the optimal chain length
between the benzimidazole and phthalimide moieties, different
alkyl linkers of variable length were introduced between the
benzimidazole and the phthalimide, producing the three deriva-
tives 20a-c (Scheme 2). Compound 20a, with no linker between
the benzimidazole and phthalimide moieties, showed moderate
activity (IC50 ) 19.4 µM), suggesting that the alkyl linker is
important for potent antiviral activity. The methylene analogue
20b was nearly six times more potent than the corresponding
ethylene analogue 5h, whereas an increase in cytotoxicity was
also noted, resulting in a relatively small selectivity index (SI
) 180). The propylene analogue 20c, with similar antiviral
potency to that of the methylene analogue 20b, displayed an
increase in cytotoxicity of about 7-fold relative to that of 20b.
The effects of introducing different kinds of substituents to
the N-1 position of the benzimidazole core were then studied.
Replacement of the benzenesulfonyl moiety of 5h with a simple
benzoyl, alkyl, or benzyl group produced the derivatives 11 and
12a,b (Scheme 1). As shown in Table 3, removal of the N-1
substituent (4c) resulted in a tremendous loss of activity (IC50
) 300 µM), suggesting that the N-1 substituent is an important
determinant of antiviral activity. Introducing 4-methylbenzoyl
to the N-1 position of the benzimidazole core resulted in the

4794 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 15
Brief Articles
(2C), 120.33, 110.77, 46.76, 35.20, 26.14, 20.71; MS (EI) m/z 463
(M+), 358, 303, 105. HRMS (EI): cal. for C25H19Cl2N3O2 463.0854,
found 463.0855. Purity: HPLC analysis.
Experimental Section
General Procedure A: Synthesis of Benzimidazole Scaffolds.
The appropriately substituted o-phenylenediamine (1 equiv) and
the appropriate carboxylic acid (1 equiv) were suspended in PPA
(1 g/mmol) under nitrogen. The suspension was heated in an oil
bath at 170-180 °C for 6 h. The reaction mixture was cooled and
poured into ice water (10 mL/mmol). The resulting mixture was
neutralized to pH 8 with 25% NH4OH. The formed precipitate was
filtered, washed with water, and dried to give the crude product.
General Procedure B: N-Sulfonylation of Benzimidazole
Scaffolds. To a suspension of the appropriate benzimidazole
scaffold (1 equiv) and the appropriate sulfonyl chloride (1 equiv)
in dry CH2Cl2 (20 mL/mmol) was added DMAP (1 equiv), and a
clear solution was obtained at once. The resulting solution was
stirred at 50 °C for 10 h, cooled to room temperature, and partitioned
between chloroform and water. The organic layer was washed with
water and brine, dried over Na2SO4, and concentrated in vacuo.
The residue was subjected to silica gel chromatography or crystal-
lization to give the target compound.
General Procedure C: N-Methylation of Benzimidazole
Scaffolds. To a solution of the appropriate benzimidazole scaffold
(1 equiv) in DMF (15 mL/mmol) were added K2CO3 (1 equiv) and
iodomethane (1.1 equiv). The reaction mixture was stirred overnight
at room temperature and poured into water (100 mL/mmol). The
resulting precipitate was filtered and dried to obtain the product.
2-[2-(5,6-Dichloro-1H-benzoimidazol-2-yl)-ethyl]-isoindole-
1,3-dione (4c). Compound 4c was synthesized from 4,5-dichloro-
o-phenylenediamine (2c) and 3-phthalimidopropionic acid (3) using
general procedure A. The crude product was recrystallized from
2-[5,6-Dichloro-1-(toluene-4-sulfonyl)-1H-benzoimidazol-2-
yl]-isoindole-1,3-dione (20a). Compound 20a was prepared from
15 and tosyl chloride using general procedure B as a pale yellow
solid. Yield ) 69%; 1H NMR (CDCl3) δ 8.03-8.06 (m, 2H), 8.00
(s, 1H), 7.88-7.91 (m, 3H), 7.78 (d, 2H, J ) 8.4), 7.31 (d, 2H, J
) 8.4), 2.41 (s, 3H); 13C NMR (CDCl3) δ 165.60 (2C), 147.12,
139.63, 138.68, 135.25 (2C), 133.70, 131.59 (2C), 131.51, 130.74,
130.39 (2C), 129.78, 127.68 (2C), 124.69 (2C), 122.44, 115.15,
21.77; MS (EI) m/z 485 (M+), 421, 330, 155, 104, 91, 76; HRMS
(EI): cal. for C22H13Cl2N3O4S 485.0004, found 485.0008. Purity:
HPLC analysis.
5,6-Dichloro-1-methyl-2-(2-pyridin-4-yl-ethyl)-1H-benzoimi-
dazole (29a). Compound 29a was prepared from 28a using general
1
procedure C as an orange solid. Yield ) 76%; H NMR (CDCl3)
δ 8.51 (d, 2H, J ) 6.0), 7.80 (s, 1H), 7.38 (s, 1H), 7.16 (d, 2H, J
) 6.0), 3.57 (s, 3H), 3.13-3.28 (m, 4H); 13C NMR (DMSO-d6) δ
157.15, 149.84, 149.53 (2C), 141.63, 135.49, 124.16, 124.05 (2C),
123.82, 119.50, 111.76, 31.32, 29.94, 26.96; MS (EI) m/z 305 (M+),
276, 227, 213, 149; HRMS (EI): cal. for C15H13Cl2N3 305.0487,
found 305.0473. Purity: HPLC analysis.
Acknowledgment. This work was financially supported by
the grants of Shanghai Science and Technology Committee
(No.03DZ19228 and No.05DZ19331). We thank Profs. Fa-Jun
Nan and Ao Zhang for insightful discussions and advice.
Supporting Information Available: Experimental details for
intermediates (4a, 4b, 6, 8, 9, 15, 18, 19, 24-27, and 28a-g) and
target compounds (1, 5a-g, 5i-l, 7, 10, 11, 13, 20b-c, and 29b-
g). HPLC purity data for target compounds: 1, 5a-l, 7, 10, 12a,b,
13, 20a-c, and 29a-g. This material is available free of charge
via Internet at http://pubs.acs.org.
1
methanol to give pale yellow crystals. Yield ) 72%; H NMR
(DMSO-d6) δ 12.6 (br s, 1H), 7.83 (br s, 4H), 7.71 (s, 2H), 4.01 (t,
2H, J ) 7.2), 3.16 (t, 2H, J ) 7.0); 13C NMR (DMSO-d6) δ 167.63
(2C), 154.81, 142.99, 134.39 (2C), 133.69, 131.64 (2C), 124.05,
123.57, 123.06 (2C), 119.38, 112.45, 36.07, 27.59; MS (EI) m/z
359 (M+), 212, 200, 160. Anal. (C17H11Cl2N3O2) C, H, N.
2-{2-[5,6-Dichloro-1-(toluene-4-sulfonyl)-1H-benzoimidazol-
2-yl]-ethyl}-isoindole-1,3-dione (5h). Compound 5h was prepared
from 4c and tosyl chloride using general procedure B as a white
References
(1) Mast, E. E.; Alter, M. J.; Margolis, H. S. Strategies to prevent and
control hepatitis B and C virus infections: a global perspective.
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1
(2) Lavanchy, D. Hepatitis B virus epidemiology, disease burden,
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crystalline solid. Yield ) 75%; H NMR (CDCl3) δ 8.13 (s, 1H),
7.80-7.86 (m, 4H), 7.71-7.74 (m, 2H), 7.67 (s, 1H), 7.34 (d, 2H,
J ) 8.1), 4.24 (t, 2H, J ) 7.2), 3.52 (t, 2H, J ) 7.2), 2.41 (s, 3H);
13C NMR (CDCl3) δ 167.97 (2C), 153.21, 146.67, 141.22, 134.68,
134.01 (2C), 132.00 (2C), 131.96, 130.56 (2C), 129.16, 128.92,
126.86 (2C), 123.32 (2C), 121.07, 114.97, 35.51, 28.62, 21.69; MS
(EI) m/z 513 (M+), 449, 358, 324, 160, 91; HRMS (EI): cal. for
C24H17Cl2N3O4S 513.0317, found 513.0307. Purity: HPLC analysis.
2-[2-(5,6-Dichloro-1-methyl-1H-benzoimidazol-2-yl)-ethyl]-
isoindole-1,3-dione (12a). Compound 12a was prepared from 4c
using general procedure C as a white solid. Yield ) 96%; 1H NMR
(CDCl3) δ 7.71-7.85 (m, 5H), 7.42 (s, 1H), 4.21 (t, 2H, J ) 7.2),
3.77 (s, 3H), 3.26 (t, 2H, J ) 7.2); 13C NMR (C5D5N) δ 168.21
(2C), 154.75, 142.81, 134.27 (2C), 132.55 (2C), 125.71, 125.31,
123.25 (2C), 120.62, 111.73, 35.56, 29.85, 26.50; MS (EI) m/z 373
(M+), 227, 160; HRMS (EI): cal. for C18H13Cl2N3O2 373.0385,
found 373.0396. Purity: HPLC analysis.
(3) Karayiannis, P. Hepatitis B virus: old, new and future approaches
to antiviral treatment. J. Antimicrob. Chemother. 2003, 51, 761-
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(4) Hanazaki, K. Antiviral therapy for chronic hepatitis B: a review.
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(5) Misra, V. S.; Shan, P.; Saxena, V. K. Synthesis of some new
benzimidazoles as antiamoebic agents. J. Indian Chem. Soc. 1982,
59, 1074-1076.
(6) Zou, R.; Drach, J. C.; Townsend, L. B. Design, synthesis, and antiviral
evaluation of 2-chloro-5,6-dihalo-1-â-D-ribofuranosylbenzimidazoles
as potential agents for human cytomegalovirus infections. J. Med.
Chem. 1997, 40, 811-818.
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benzyl)-2-substituted-5,6-dichlorobenzimidazoles as nonnucleoside
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benzisothiazolin-3-one 1,1-dioxide derivatives to phthalimidine and
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2-{2-[5,6-Dichloro-1-(4-methyl-benzyl)-1H-benzoimidazol-2-
yl]-ethyl}-isoindole-1,3-dione (12b). A mixture of compound 4c
(315 mg, 0.87 mmol) and NaOH (40 mg, 1.0 mmol) in CH3CN
(100 mL) was heated until a nearly clear solution was obtained.
4-Methylbenzyl chloride (167 mg, 1.19 mmol) was added in one
portion, and the resulting mixture was refluxed for 10 h. The
reaction mixture was filtered while hot and washed with CH3CN
(30 mL). The combined filtration was concentrated under reduced
pressure until the product crystallized from the mother liquid as a
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1
white crystalline solid (270 mg, 67% yield). H NMR (CDCl3) δ
7.80-7.82 (m, 2H), 7.78 (s, 1H), 7.70-7.72 (m, 2H), 7.32 (s, 1H),
7.09 (d, 2H, J ) 8.0), 6.92 (d, 2H, J ) 8.0), 5.31 (s, 2H), 4.17 (t,
2H, J ) 7.2), 3.21 (t, 2H, J ) 7.2), 2.29 (s, 3H); 13C NMR (CDCl3)
δ 167.60 (2C), 153.26, 141.64, 137.73, 134.32, 133.70 (2C), 131.60
(2C), 131.44, 129.49 (2C), 126.29, 125.86, 125.68 (2C), 123.00
JM060330F