Structure-activity relationships among 2-substituted 5,6-dichloro-, 4,6- dichloro-, and 4,5-dichloro-1-[(2-hydroxyethoxy)methyl]- and -1-[(1,3- dihydroxy-2-propoxy)methyl]benzimidazoles

Article abstract of DOI:10.1021/jm950556a

The sodium salt of 2,5,6-trichlorobenzimidazole (8a) was condensed with [2-(benzyloxy)ethoxy]methyl chloride (9) and [1,3-bis(benzyloxy)-2- propoxy]methyl chloride (18) to provide the corresponding protected acyclic nucleosides 10a and 19a, which on debenzylation afforded 2,5,6-trichloro-1- [(2-hydroxyethoxy)methyl]benzimidazole (11a) and 2,5,6-trichloro-1-[(1,3- dihydroxy-2-propoxy)methyl]benzimidazole (20a), respectively. A similar condensation of 2,4,6-trichlorobenzimidazole (2a) and 2,4,5- trichlorobenzimidazole (7a) followed by debenzylation yielded 11b, 20b, 11c, and 20c, respectively. A nucleophilic displacement of the 2-chloro group of 11a-c and 20a-c with liquid ammonia, methylamine, dimethylamine, and thiourea furnished several interesting 2-substituted compounds in good yields, e.g., 12-14(a-e), 2123(a-e), 15-17, and 24-26. Alkylation of the 2-thio analogs 15- 17 and 24-26 with benzyl chloride furnished the 2-alkylthio acyclic nucleosides 12d-14d and 21d-23d. Desulfurization of 15 and 24 with Raney Ni furnished 5,6-dichloro-1-[(2-hydroxyethoxy)methyl]benzimidazole (12e) and 5,6-dichloro-1-[(1,3-dihydroxy-2-propoxy)methyl]benzimidazole (21e), respectively (acyclic analog of 5,6-dichloro-1-β-D- ribofuranosylbenzimidazole). Similarly the dihalo compounds 13e, 14e, and 23e were prepared in moderate yields from the 2-thio analogs 16, 17, and 26. Treatment of 2-bromo-5,6-dichlorobenzimidazole (8b) with 27 and 30 gave the protected acyclic compounds 28a and 31a, which on deacetylation with sodium carbonate and potassium cyanide yielded 2-bromo-5,6-dichloro-1-[(2- hydroxyethoxy)methyl]benzimidazole (29a) and 2-bromo-5,6-dichloro-1-[(1,3- dihydroxy-2-propoxy)methyl]benzimidazole (32a), respectively, in moderate yields. The 2-bromo-4,6-dichlorobenzimidazole and 2-bromo-4,5- dichlorbenzimidazole analogs 29b,c and 32b,c were prepared in a similar manner. Compounds were tested for activity against human cytomegalovirus (HCMV) and herpes simplex virus type 1 (HSV-1) and for cytotoxicity. In marked contrast to the ribosylbenzimidazoles, none of the acyclic analogs were specific and potent inhibitors of HCMV. Only the 2-thiobenzyl analogs 12d, 13d, 14d, and 23d and the 2-Br analogs 32a,b were active, but activity was not well separated from cytotoxicity. The lack of specific and potent antiviral activity strongly suggests that these acyclic nucleoside analogs are not phosphorylated by HCMV or HSV-1 gene products and that the ribosylbenzimidazoles do not require phosphorylation for antiviral activity.

Full text of DOI:10.1021/jm950556a

J . Med. Chem. 1996, 39, 881-891
881
Str u ctu r e-Activity Rela tion sh ip s a m on g 2-Su bstitu ted 5,6-Dich lor o-,
4,6-Dich lor o-, a n d 4,5-Dich lor o-1-[(2-h yd r oxyeth oxy)m eth yl]- a n d
-1-[(1,3-d ih yd r oxy-2-p r op oxy)m eth yl]ben zim id a zoles
Sunita Saluja,† Ruiming Zou,‡ J ohn C. Drach, and Leroy B. Townsend*
Department of Medicinal Chemistry, College of Pharmacy, Department of Chemistry, College of Literature,
Science and Arts, and Department of Biologic and Materials Sciences, School of Dentistry, The University of Michigan,
Ann Arbor, Michigan 48109-1065
Received J uly 26, 1995X
The sodium salt of 2,5,6-trichlorobenzimidazole (8a ) was condensed with [2-(benzyloxy)ethoxy]-
methyl chloride (9) and [1,3-bis(benzyloxy)-2-propoxy]methyl chloride (18) to provide the
corresponding protected acyclic nucleosides 10a and 19a , which on debenzylation afforded 2,5,6-
trichloro-1-[(2-hydroxyethoxy)methyl]benzimidazole (11a ) and 2,5,6-trichloro-1-[(1,3-dihydroxy-
2-propoxy)methyl]benzimidazole (20a ), respectively. A similar condensation of 2,4,6-
trichlorobenzimidazole (2a ) and 2,4,5-trichlorobenzimidazole (7a ) followed by debenzylation
yielded 11b, 20b, 11c, and 20c, respectively. A nucleophilic displacement of the 2-chloro group
of 11a -c and 20a -c with liquid ammonia, methylamine, dimethylamine, and thiourea
furnished several interesting 2-substituted compounds in good yields, e.g., 12-14(a -e), 21-
23(a -e), 15-17, and 24-26. Alkylation of the 2-thio analogs 15-17 and 24-26 with benzyl
chloride furnished the 2-alkylthio acyclic nucleosides 12d -14d and 21d -23d . Desulfurization
of 15 and 24 with Raney Ni furnished 5,6-dichloro-1-[(2-hydroxyethoxy)methyl]benzimidazole
(12e) and 5,6-dichloro-1-[(1,3-dihydroxy-2-propoxy)methyl]benzimidazole (21e), respectively
(acyclic analog of 5,6-dichloro-1-â-D-ribofuranosylbenzimidazole). Similarly the dihalo com-
pounds 13e, 14e, and 23e were prepared in moderate yields from the 2-thio analogs 16, 17,
and 26. Treatment of 2-bromo-5,6-dichlorobenzimidazole (8b) with 27 and 30 gave the protected
acyclic compounds 28a and 31a , which on deacetylation with sodium carbonate and potassium
cyanide yielded 2-bromo-5,6-dichloro-1-[(2-hydroxyethoxy)methyl]benzimidazole (29a ) and
2-bromo-5,6-dichloro-1-[(1,3-dihydroxy-2-propoxy)methyl]benzimidazole (32a ), respectively, in
moderate yields. The 2-bromo-4,6-dichlorobenzimidazole and 2-bromo-4,5-dichlorbenzimidazole
analogs 29b,c and 32b,c were prepared in a similar manner. Compounds were tested for
activity against human cytomegalovirus (HCMV) and herpes simplex virus type 1 (HSV-1)
and for cytotoxicity. In marked contrast to the ribosylbenzimidazoles, none of the acyclic analogs
were specific and potent inhibitors of HCMV. Only the 2-thiobenzyl analogs 12d , 13d , 14d ,
and 23d and the 2-Br analogs 32a ,b were active, but activity was not well separated from
cytotoxicity. The lack of specific and potent antiviral activity strongly suggests that these acyclic
nucleoside analogs are not phosphorylated by HCMV or HSV-1 gene products and that the
ribosylbenzimidazoles do not require phosphorylation for antiviral activity.
In tr od u ction
nocompromised and acquired immune deficiency syn-
drome (AIDS) patients.9
Acyclic nucleoside analogs are an important class of
compounds having potent and selective antiviral activ-
ity.1 Acyclovir2 (ACV) and ganciclovir3 (GCV, DHPG)
are two important acyclic drugs whose discovery led to
an extensive search for novel nucleosides with improved
properties. Although a number of nucleoside analogs
such as vidarabine,4 ACV,4 (bromovinyl)deoxyuridine
(BVDU),5 and (fluoroiodoaracytosine (FIAC)6 are active
against herpes simplex virus type 1 (HSV-1), it has been
more difficult to find drugs active against human
cytomegalovirus (HCMV). GCV7 and foscarnet8 are the
only effective drugs for HCMV infections even though
the drugs produce certain adverse toxicological effects
and have poor oral bioavailability. The deficiencies of
these drugs have emphasized the need for more effective
agents against HCMV infections, especially in immu-
The mode of antiviral action of GCV against HSV-1
and HCMV is similar to that of ACV in that both
compounds are phosphorylated to a greater extent in
virus-infected cells than in uninfected cells.10 Both
drugs are initially phosphorylated by a virus-encoded
pyrimidine deoxynucleoside kinase (thymidine kinase)
in HSV-1-infected cells.4 HCMV, however, does not code
this enzyme, and therefore ACV is relatively inactive
against this virus.11 In contrast, GCV is active against
HCMV because it is phosphorylated in infected cells by
a kinase specified by HCMV gene UL97.12 It is inactive
or less active in HCMV strains with a mutated gene
which consequently fail to phosphorylate GCV.13,14
Once formed in infected cells, ACV and GCV monophos-
phates are metabolized to their triphosphates which
then act as potent and selective inhibitors of the virus-
encoded DNA polymerases.15
† Present address: Department of Chemistry, Hunter College of the
University of New York, New York, NY 10021.
‡ Present address: Gilead Sciences, 346 Lakeside Dr., Foster City,
CA 94404.
The success of ACV and GCV as antiviral drugs has
prompted intensive efforts by several groups to prepare
and evaluate many structurally related acyclic nucleo-
side analogs (e.g., see refs 16 and 17). As a part of our
X Abstract published in Advance ACS Abstracts, December 1, 1995.
0022-2623/96/1839-0881$12.00/0 © 1996 American Chemical Society

882 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 4
Saluja et al.
Sch em e 1a
ronitrobenzene (3). In the present work we elected to
use the sodium salt glycosylation method,30 which has
been used for the synthesis of various 2′-deoxynucleo-
sides of several heterocycles. Sodium salts of the
halogenated benzimidazoles 8a ,31 2a ,32 and 7a have
been generated by treatment of the free base with
sodium hydride in acetonitrile. These salts were then
condensed with [2-(benzyloxy)ethoxy]methyl chloride
(9)33 and 1-[1,3-bis(benzyloxy)-2-propoxy]methyl chlo-
ride (18)34 (Scheme 2) to give the blocked acyclic
nucleosides 10a -c and 19a -c (Scheme 3). These
compounds were deblocked with boron trichloride in
methylene chloride at -78 °C using a literature proce-
dure,35 followed by column chromatography, to yield
desired alcohol and diol derivatives in 30-40% yields.
The site of alkylation of 11b,c, and 20b,c was confirmed
to be at N-1 on the basis of difference NOE spectroscopic
experiments,36 which provided qualitative and semi-
quantitative information about the configurational and
conformational parameters. Thus, when H-1′ of com-
pound 11b was irradiated, a 14.1% enhancement was
observed for H-7, while a 4.6% enhancement was
observed for H-5. Similar results were obtained for
compounds 11c and 20b,c.
a
Reagents: (i) CuBr2/CH3COCH3; (ii) CuCl2/CH3COCH3; (iii)
MeOH-NH3; (iv) Raney Ni; (v) CNBr/MeOH/H2O.
search for new antiviral drugs, we have been exploring
benzimidazole nucleosides as potential drugs to treat
HCMV infections. In 1954, Tamm, Folkers, and co-
workers first reported the synthesis and antiviral activ-
ity of halogenated benzimidazole nucleosides.18,19 They
found that 5,6-dichloro-1-â-D-ribofuranosylbenzimida-
zole (DRB) has multiple biological activities including
activity against RNA19 and DNA20 viruses. DRB inhib-
its viral21 and cellular22 RNA synthesis most likely as
a consequence of inhibiting cellular RNA polymerase
II.23 Thus DRB affects multiple cellular processes so
that its antiviral activity is poorly separated from
cytotoxicity. Consequently it has little potential as an
antiviral drug.19,24 The early studies by Tamm and co-
workers prompted us to synthesize a series of 2-substi-
tuted benzimidazole ribonucleosides as potential anti-
cancer agents.25 More recently, we have examined the
2-chloro analog of DRB [2,5,6-trichloro-1-â-D-ribofura-
nosylbenzimidazole (TCRB)] for activity against HCMV
based in part on its low cytotoxicity and lack of activity
in anticancer tests.26 We found that TCRB and its 2-Br
analog (BDCRB) are potent and selective inhibitors of
HCMV replication at noncytotoxic concentrations.27
Both compounds act by a unique mechanism which does
not involve inhibition of DNA synthesis27,28 but does
involve inhibition of DNA processing.28 The potent and
new activity of TCRB and the known efficacy of ACV
and GCV prompted us to initiate a program designed
to elucidate structure-activity relationships among
some halogenated acyclic benzimidazole nucleosides; the
results of the study are presented herein.
It has been previously reported37 that a nucleophilic
displacement of the 2-chloro group from 2-chlorobenz-
imidazole is greatly facilitated by a substituent residing
at N-1. Amination of 2,5,6-trichloro-1-[(2-hydroxyethoxy)-
methyl]benzimidazole (11a ) (Scheme 2) was achieved
with liquid ammonia in a sealed reaction vessel at 70
°C. Amination of the compounds 11b,c and 20a -c was
achieved under similar conditions. Compounds 11a -c
and 20a -c were also aminated with methylamine and
dimethylamine to determine if alkyl substitution on the
2-amino group would have any influence on biological
activity. The compounds 12b,c, 13b,c, 14b,c, 21b ,c,
22b,c, and 23b,c were obtained in good yields by
treating the compounds 11a -c and 20a -c with meth-
ylamine and dimethylamine (33% in alcohol) at room
temperature.
Displacement of the 2-chloro group of 11a was also
accomplished with thiourea in ethanol to furnish 5,6-
dichloro-1-[(2-hydroxyethoxy)methyl]benzimidazole-2-
thione (15). There was observed an absorption band in
the infrared spectrum (potassium bromide) at 1605 cm-1
which was assigned as CdS stretching and part of a
-N-CdS system37,38 which indicated that 15 exists in
the thione rather than the thiol form. There was an
absence of a band at 2550-2600 cm-1 usually attribut-
able to -SH stretching, and there was observed an
1
absorption peak in the H NMR spectrum at δ 13.16 (1
proton) which was assigned to N-3 of 15 and provided
additional support for the thione form. A similar
displacement reaction was accomplished with the com-
pounds 11b,c and 20a -c. Alkylation of 15 with benzyl
chloride in aqueous ammonia solution yielded 2-(ben-
zylthio)-5,6-dichloro-1-[(2-hydroxyethoxy)methyl]benz-
imidazole (12d ) in excellent yield. A similar alkylation
reaction produced compounds 13d , 14d , 21d , 22d , and
23d . Desulfurization of 15 with Raney Ni afforded the
acyclic analog of DRB, 5,6 dichloro-1-[(2-hydroxyethoxy)-
methyl]benzimidazole (12e), in 48% yield. Desulfur-
ization of 16, 17, 24, and 26 under similar conditions
afforded 13e, 14e, 21e, and 23e in moderate yields.
The sodium salt of 8b32 was condensed with (2-
acetoxyethoxy)methyl bromide (27)39 and (1,3-diacetoxy-
Resu lts a n d Discu ssion
Ch em istr y. The requisite heterocycle 2-bromo-4,6-
dichlorobenzimidazole (2b) (Scheme 1) was prepared32
by a nonaqueous diazotization of 2-amino-4,6-dichlo-
robenzimidazole (1)29 with tert-butyl nitrite and cupric
bromide in acetone. Similarly, 2,4,5-trichlorobenzimi-
dazole and 2-bromo-4,5-dichlorobenzimidazole (7a ,b)
(Scheme 1) were prepared32 in the same fashion from
2-amino-4,5-dichlorobenzimidazole (6). Compound 6
was obtained, by a modified literature procedure, in
three steps from commercially available 2,3,4-trichlo-

SAR of 2-Substituted Benzimidazoles
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 4 883
Sch em e 2a
a
Reagents: (i) NaH/CH3CN; (ii) BCl3/CH2Cl2; (iii) liquid NH3; (iv) NHCH3; (v) NH(CH3)2; (vi) NH2CSNH2; (vii) BnCl/NH4OH; (viii)
Raney Ni. Bn ) CH2C6H5.
Sch em e 3a
and 64% yields, respectively. In a similar fashion,
compounds 28b,c and 31b,c were prepared. Treatment
of compound 28a with sodium carbonate in aqueous
ethanol (90%) at room temperature afforded 2-bromo-
5,6-dichloro-1-[(2-hydroxyethoxy)methyl]benzimida-
zole (29a ) in 62% yield. In a similar fashion, compounds
29b,c were prepared and characterized. Deblocking of
31a -c with potassium cyanide in aqueous ethanol
(90%) at room temperature followed by column chro-
matography furnished 32a -c in 40-50% yields.
Biology. Unlike the benzimidazole ribonucleosides
which are potent and selective inhibitors of HCMV,27
the acyclic analogs were either inactive or weakly active
against HCMV and HSV-1. The analogs also were not
cytotoxic or were weakly cytotoxic in both stationary or
growing cells. Of the (hydroxyethoxy)methyl derivatives
(Table 1), only the 2-thiobenzyl analogs 12d , 13d , and
14d showed any activity against HCMV. This activity,
however, was poorly separated from cytotoxicity and
may not represent specific antiviral activity. We ob-
served similar weak activity which was not well sepa-
rated from cytotoxicity in a series of ribosyl 2-thiobenzyl
benzimidazoles.41 All of the other compounds in the
series were inactive and noncytotoxic including the
direct analogs (11a and 29a ) of the very active ribosides
TCRB and BDCRB.
Likewise, compounds in the (dihydroxypropoxy)-
methyl series (Table 2) were inactive except for the
thiobenzyl analog 23d which had weak activity against
HCMV in the plaque reduction assay and the BDCRB
analogs 32a ,b which were weakly active in the yield
reduction assay. In the case of 23d , the activity was,
at best, poorly separated from cytotoxicity. In contrast,
the activity of 32a ,b in yield reduction assays appeared
to be separated from cytotoxicity. Together with the fact
that the 2-Br analog is the most active compound in the
ribosyl series,27 this result suggests that the weak
activity of 32a ,b may be from an interaction with the
a
Reagents: (i) NaH/CH3CN; (ii) BCl3/CH2Cl2; (iii) liquid NH3;
(iv) NHCH3; (v) NH(CH3)2; (vi) NH2CSNH2; (vii) BnCl/NH4OH;
(viii) Raney Ni. Bn ) CH2C6H5.
2-propoxy)methyl bromide (30)40 (Scheme 4) by using
essentially the same reaction conditions as were used
for the preparation of compound 10a . These condensa-
tions were followed by silica gel column chromatography
to yield 2-bromo-5,6-dichloro-1-[(2-acetoxyethoxy)meth-
yl]benzimidazole (28a ) and 2-bromo-5,6-dichloro-1-[(1,3-
diacetoxy-2-propoxy)methyl]benzimidazole (31a ) in 75%

884 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 4
Saluja et al.
Sch em e 4a
a
Ac ) acetyl.
Ta ble 1. Antiviral Activity and Cytotoxicity of Dichloro 2-Substituted 1-[(Hydroxyethoxy)methyl]benzimidazoles
50% or 90% inhibitory concentration (µM)
antiviral activity
HCVMa
plaque
HSV-1b
ELISA
>100
cytotoxicityc
no.
11a
R1
R2
R3
R
yield
visual
growth
H
Cl
H
Cl
Cl
H
Cl
Cl
Cl
NH2
>320d
>100
>100
>100
>100
>100
40
>100
>100
>100
>100
50
>100
>100
>100
30
>100
>100
>100
>100
>100
>100
>100
>320
>100
>100
>100
>100
>100
32
>320
11b
11c
12a
12b
12c
12d
12e
13a
13b
13c
13d
13e
14a
14b
14d
14e
15
16
17
29a
29b
29c
TCRBe
BDCRBe
Cl
Cl
H
H
H
H
H
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
H
Cl
Cl
H
Cl
Cl
H
Cl
Cl
Cl
Cl
Cl
Cl
H
H
H
H
H
Cl
Cl
Cl
Cl
Cl
H
Cl
Cl
H
>100
>100
>100
>100
45
>100
>100
>100
>100
55
>100
>100
>100
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
H
H
H
H
Cl
Cl
H
Cl
Cl
H
NHCH3
N(CH3)2
SCH2C6H5
H
NH2
>100
>100
100
NHCH3
N(CH3)2
SCH2C6H5
>100
>100
>100
32
>100
>100
>100
32
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
102
>100
>100
>100
>100
35
H
NH2
NHCH3
SCH2C6H5
H
>100
>100
>100
>100
>100
>100
>100
>100
210
SH
SH
SH
Br
Br
Br
Cl
100
>100
>100
>100
>100
>100
238
Cl
Cl
Cl
Cl
Cl
2.9
0.7
1.4
0.2
H
Br
130
118
>100
a
Plaque and yield reduction assays were performed in duplicate as described in the text. Results from plaque assays are reported as
IC50’s, those for yield reduction experiments as IC90’s. All compounds were assayed by ELISA in quadruplicate wells. c Visual cytotoxicity
b
was scored on HFF cells at time of HCMV plaque enumeration. Inhibition of KB cell growth was determined as described in the text in
d
quadruplicate assays. Results are presented as IC50’s. A greater than sign (>) indicates IC50 or IC90 was not reached at the noted
(highest) concentration tested. e Data also reported in ref 27; average derived from three to six experiments.
viral target of the ribosylbenzimidazoles. The alterna-
tive hypothesis that the weak activity of 32a ,b was a
consequence of phosphorylation by the UL97 gene
product (and subsequent inhibition of HCMV DNA
polymerase) is less attractive because the ribosylbenz-
imidazoles do not inhibit DNA synthesis.27 Further-
more, all of the compounds in Table 2 might be con-
sidered analogs of GCV but almost all were inactive.
This interpretation also is consistent with the lack of
activity against HSV-1 of the compounds in Table 1.
Because these compounds could be considered analogs
of ACV, phosphorylation by HSV-1 deoxypyrimidine

SAR of 2-Substituted Benzimidazoles
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 4 885
Ta ble 2. Antiviral Activity and Cytotoxicity of Dichloro 2-Substituted 1-[(Dihydroxypropoxy)methyl]benzimidazoles
50% or 90% inhibitory concentration (µM)
antiviral activity
HCVMa
HSV-1b
ELISA
cytotoxicityc
no.
R1
R2
R3
R
plaque
>100d
yield
visual
growth
20a
20b
20b
21a
21b
21c
21d
21e
22a
22b
22c
23a
23b
23c
23d
23e
24
H
Cl
H
Cl
Cl
H
Cl
Cl
Cl
NH2
>100
>100
>100
>100
>100
>100
>100
>100
>100
100
>100
Cl
Cl
H
H
H
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
35
>100
>100
>100
>100
>100
136
Cl
Cl
Cl
Cl
Cl
Cl
H
100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
H
H
H
H
H
Cl
Cl
H
Cl
Cl
H
NHCH3
N(CH3)2
SCH2C6H5
H
H
H
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
H
Cl
Cl
H
Cl
Cl
NH2
H
H
NHCH3
N(CH3)2
NH2
NHCH3
N(CH3)2
SCH2C6H5
H
100
>100
>100
>100
>100
55
>100
>100
>100
>100
32
>100
>100
>100
>100
60
Cl
Cl
Cl
Cl
Cl
Cl
H
Cl
Cl
H
>100
>100
>100
>100
>100
>100
161
>100
>100
>100
>100
>100
>100
>100
>100
SH
SH
SH
Br
Br
Br
55
25
26
32a
32b
32c
>100
>100
100
25
50
Cl
>100
>100
>100
>100
ganciclovire
7.4 ( 6.5
1.6 ( 1.2
3.5 ( 2.1
a
See Table 1 for footnotes a-d. e Average ( standard deviation from 108, 33, and 3 experiments, respectively, in which ganciclovir
was used as a positive control.
0.5 h, and the mixture was stirred at 60 °C for an additional
2 h. The reaction mixture was cooled to room temperature,
concentrated to 30 mL, and poured into a mixture of EtOAc/2
N HBr (48% aqueous) (35/20). The EtOAc layer was washed
with 2 N HBr (200 mL). During this process, a yellow solid
appeared in the organic layer, and it was collected by filtration
and discarded. The filtrate was washed with NaHCO3 (aque-
ous) (2 × 100 mL) and NaCl (aqueous) (2 × 100 mL), dried
(Na2SO4), and then evaporated to dryness. The resulting solid
was purified by flash column chromatography (2 × 24 cm)
(230-400 mesh). Elution of the column with hexane:EtOAc
(9:1, v/v) and evaporation of the appropriate fractions gave 3.02
g (38%) of 2b: mp 212 °C (MeOH-H2O); 1H NMR (DMSO-d6)
δ 13.80 (bs, 1 H, exchanges with D2O, NH), 7.56 (bs, 1 H, H-7),
7.39 (d, 1 H, J ) 1.5 Hz, H-5). Anal. (C7H3N2Cl2Br) C, H, N.
2-Am in o-3,4-d ich lor o-1-n itr oben zen e (4). A mixture of
1-nitro-2,3,4-trichlorobenzene. (3) (10.0 g, 44.15 mmol) (Ald-
rich) and MeOH-NH3 (120 mL) was heated in a steel reaction
vessel at 120 °C for 24 h. The reaction mixture was cooled to
0 °C, and the solid which had separated was collected by
filtration. The solid was crystallized from MeOH. The filtrate
was evaporated to dryness, extracted with EtOAc (200 mL),
washed with water (200 mL), dried (Na2SO4), and concentrated
under reduced pressure. The residue thus obtained was
recrystallized from MeOH to give 7.31 g (80%) of 4: mp 161-
kinase in infected cells would lead to activity against
the virusswhich was not observed. Thus, the weak or
lack of antiviral activity against either herpes virus
argues that these compounds are not phosphorylated
by the UL97 gene product in HCMV-infected cells nor
by a deoxypyrimidine kinase in HSV-1-infected cells.
Alternatively, if the corresponding nucleotide analogs
are formed in virus-infected cells, they are not active
and do not interfere with viral replication. This pos-
sibility, however, does not seem likely on an a priori
basis.
Exp er im en ta l Section
Gen er a l P r oced u r es. Melting points were taken on a
Thomas-Hoover capillary melting point apparatus and are
uncorrected. Nuclear magnetic resonance (1H NMR) spectra
were determined at 270 MHz with an IBM WP 270-SY
spectrometer, at 300 MHz with an IBM AM-300 spectrometer,
or at 360 MHz with an IBM WM-360 spectrometer. The
chemical shift values are expressed in δ values (part per
million) relative to the standard chemical shift of TMS.
Ultraviolet spectra were recorded on a Hewlett-Packard 8450
A spectrophotometer. Elemental analyses were performed by
M-H-W Laboratories, Phoenix, AZ. Thin-layer chromatogra-
phy (TLC) was performed on silica gel GHLF-254 plates
(Merck Reagents). E. Merck silica gel (230-400 mesh) was
used for flash column chromatography. Detection of compo-
nents on TLC was made by UV light (254 nm). Evaporations
were carried out under reduced pressure (water aspiration)
with the bath temperature below 50 °C unless specified
otherwise.
1
163 °C; H NMR (DMSO-d6) δ 8.00 (d, 1 H, J ) 9.5 Hz, H-6),
7.53 (bs, 2 H, exchanges with D2O, NH2), 6.88 (d, 1 H, J ) 9.5
Hz, H-5). Anal. (C6H4N2Cl2O2) C, H, N.
1,2-Dia m in o-3,4-d ich lor oben zen e (5). A mixture of 4
(1.41 g, 6.8 mmol), EtOH (100 mL), and Raney Ni (0.90 g, wet)
was hydrogenated at 40 psi at room temperature for 10 h. The
reaction mixture was filtered through a Celite pad and washed
with EtOH (50 mL). The filtrate and washings were combined,
evaporated, and coevaporated with EtOH gave 0.94 g (78%)
2-Br om o-4,6-d ich lor oben zim id a zole (2b). A mixture of
acetone (112 mL), tert-butyl nitrite (4.0 mL), and CuBr2 (12.7
g, 56.85 mmol) was stirred at room temperature for 15 min.
129 (5.98 g, 29.6 mmol) was added slowly to the above solution,
and the reaction mixture was stirred at 60 °C for 0.5 h. An
additional quantity of t-BuNO (2 × 4.0 mL) was added every
1
of 5: mp 81-83 °C; H NMR (DMSO-d6) δ 6.58 and 6.55 (dd,
2 H, J ) 7.2 Hz, H-6, H-5), 4.95 and 4.93 (bs, 4 H, exchanges
with D2O, 2 × NH2). Anal. (C6H6N2Cl2) C, H, N.
2-Am in o-4,5-d ich lor oben zim id a zole (6). A 5 M solution
of BrCN/CH3CN (1.0 mL) was added to H2O (10 mL). Com-

886 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 4
Saluja et al.
1
pound 5 (0.94 g, 5.3 mmol) in MeOH (10 mL) was then slowly
added, and the reaction mixture was stirred at room temper-
ature for 2.5 h. The reaction mixture was concentrated (10
mL) under reduced pressure. The product was partitioned
between EtOAc and H2O (10/5), and the EtOAc layer was
discarded. The pH of the aqueous layer was adjusted to pH 8
°C; H NMR (DMSO-d6) δ 8.12 and 7.95 (2 s, 2 H, H-7, H-4),
5.68 (s, 2 H, H-1′). Anal. (C10H9N2Cl3O2) C, H, N.
2-Am in o-5,6-dich lor o-1-[(2-h ydr oxyeth oxy)m eth yl]ben -
zim id a zole (12a ). A mixture of 11a (0.09 g, 0.3 mmol) and
liquid ammonia (condensed at -70 °C, 20 mL) was heated at
70 °C for 12 h in a sealed steel reaction vessel. The resulting
mixture was cooled to 0 °C, and the NH3 was removed. The
resulting mixture was redissolved in hot MeOH (20 mL) and
concentrated in vacuo (5 mL), SiO2 (2 g) was added, and the
solvent was removed under reduced pressure. The SiO2 gel
powder was placed on the top of a SiO2 column (2 × 14 cm)
prepared with wet SiO2 in CHCl3. Elution of the column with
CHCl3:MeOH (8:2, v/v) and evaporation of the appropriate
fractions gave 0.065 g (70%) of 12a : mp 206-208 °C (MeOH);
1H NMR (DMSO-d6) δ 7.50 and 7.29 (2 s, 2 H, H-7, H-4), 6.89
(s, 2 H, exchanges with D2O, NH2), 5.44 (s, 2 H, H-1′). Anal.
(C10H11N3Cl2O2) C, H, N.
with
a saturated aqueous solution of NaHCO3, and the
resulting suspension was extracted with EtOAc (100 mL),
washed with H2O (50 mL), dried (Na2SO4), and concentrated
in vacuo. The resulting solid was purified by a flash chroma-
tography column (SiO2, 2 × 24 cm) prepared with wet CHCl3.
Elution of the column with CHCl3:MeOH (85:15, v/v) and
evaporation of the appropriate fractions gave 0.98 g (92%) of
6: mp 239-240 °C; 1H NMR (DMSO-d6) δ 11.05 (bs, 1 H,
exchanges with D2O, NH), 7.04-6.97 (m, 2 H, H-7, H-6), 6.62
(bs, 2 H, exchanges with D2O, NH2). Anal. (C7H5N3Cl2) C, H,
N.
2,4,5-Tr ich lor oben zim id a zole (7a ). A mixture of acetone
(15 mL), tert-butyl nitrite (0.8 mL), and CuCl2 (1.07 g, 7.9
mmol) was stirred at room temperature for 15 min. Compound
6 (0.8 g, 3.9 mmol) was added slowly to the above solution,
and the reaction mixture was stirred at 60 °C for 0.5 h. Fresh
t-BuNO (2 × 0.8 mL) was added every 0.5 h, and the stirring
was continued for an additional 2 h. The reaction mixture
was cooled to room temperature, concentrated to 8 mL, and
poured into a mixture of EtOAc/2N HCl (15/10). The EtOAc
layer was washed with 2 N HCl (100 mL). During this process,
the yellow solid which separated was collected by filtration
and discarded. The filtrate was washed with NaHCO3 (100
mL) and NaCl (100 mL), dried (Na2SO4), and then evaporated
to dryness. The resulting solid was purified by flash column
chromatography (2 × 20 cm) (230-400 mesh), and elution of
the column with hexane:EtOAc (9:1, v/v) and evaporation of
the appropriate fractions gave 0.29 g (33%) of 7a : mp 252 °C
(MeOH-H2O); 1H NMR (DMSO-d6) δ 13.80 (bs, 1 H, exchanges
with D2O, NH), 7.48 (d, 1 H, J ) 8.6 Hz, H-7), 7.42 (d, 1 H, J
) 8.6 Hz, H-6). Anal. (C7H3N2Cl3) C, H, N.
2-Br om o-4,5-d ich lor oben zim id a zole (7b). Compound
7b (3.73 g, 47%) was prepared from 6 (5.98 g, 29.6 mmol) using
CuBr2 (12.7 g, 56.85 mmol), acetone (112 mL), and t-BuNO (3
× 4.0 mL) by the method described for 7a . 7b: mp 225 °C
(MeOH-H2O); 1H NMR (DMSO-d6) δ 13.80 (bs, 1 H, exchanges
with D2O, NH), 7.48 (d, 1 H, J ) 8.6 Hz, H-7), 7.42 (d, 1 H, J
) 8.6 Hz, H-6). Anal. (C7H3N2Cl2Br) C, H, N.
2,5,6-Tr ich lor o-1-[[2-(ben zyloxy)eth oxy]m eth yl]ben z-
im id a zole (10a ). NaH (0.32 g, 8.0 mmol, 60% oil disperson)
was added to a stirred suspension of 2,5,6-trichlorobenzimi-
dazole31 (8a ) (1.5 g, 6.7 mmol) in dry CH3CN (150 mL) under
a N2 atmosphere. The solution was stirred until H2 evolution
had ceased and a clear solution was obtained (20 min).
[2-(Benzyloxy)ethoxy]methyl chloride33 (9) (2.03 g, 10.66 mmol)
in CH3CN (20 mL) was then added dropwise. The reaction
mixture was stirred for an additional 20 h. The resulting
mixture was concentrated under reduced pressure, diluted
with H2O (100 mL), extracted with EtOAc (250 mL), washed
with H2O (100 mL), and dried (anhydrous Na2SO4), and the
solvent was removed under reduced pressure to yield the oil
10a (3.2 g). This oil was used as such without further
purification.
2,5,6-Tr ich lor o-1-[(2-h yd r oxyeth oxy)m eth yl]ben zim i-
d a zole (11a ). To a solution of 10a (4.10 g, 11.0 mmol) in dry
CH2Cl2 (70 mL) at -78 °C under a N2 atmosphere was added
BCl3 (5 M solution in CH2Cl2, 30 mL) dropwise while main-
taining the bath temperature at -78 °C. The reaction mixture
was stirred for an additional 4 h, MeOH (25 mL) was added
at 0 °C, and the cold solution was immediately neutralized
(pH 7) with NH4OH. The solution was allowed to warm up to
room temperature and then concentrated at 40 °C to yield an
oil. The mixture was diluted with H2O (100 mL), extracted
with EtOAc (250 mL), washed with H2O (100 mL), dried
(anhydrous Na2SO4), and concentrated in vacuo. The resulting
oil was purified by flash column chromatography (2 × 20 cm)
(230-400 mesh), prepared with wet SiO2 in CHCl3. Elution
of the column with CHCl3:MeOH (95:5, v/v) and evaporation
of the appropriate fractions gave a solid which was recrystal-
lized from EtOAc to afford 1.0 g (51%) of 11a : mp 144-146
5,6-Dich lor o-2-(m et h yla m in o)-1-[(2-h yd r oxyet h oxy)-
m eth yl]ben zim id a zole (12b). A mixture of 11a (0.09 g, 0.3
mmol) and NH2CH3 (33% solution in absolute ethanol, 10 mL)
was stirred at room temperature for 6 h or until the reaction
was complete as monitored by TLC. The excess EtOH and
NH2CH3 was removed under reduced pressure; the mixture
was coevaporated with EtOH (20 mL) and crystallized from
MeOH-H2O to give 0.068 g (77%) of 12b: mp 146-148 °C;
1H NMR (DMSO-d6) δ 7.54 and 7.37 (2 s, 2 H, H-7, H-4), 7.06
(q, 1 H, exchanges with D2O, NH), 5.41 (s, 2 H, H-1′). Anal.
(C11H13N3Cl2O2‚0.5H20) C, H, N.
2-(Dim eth yla m in o)-5,6-d ich lor o-1-[(2-h yd r oxyeth oxy)-
m eth yl]ben zim id a zole (12c). Compound 12c (0.08 g, 84%)
was prepared from 11a (0.09 g, 0.3 mmol) using NH(CH3)2
(33% solution in absolute ethanol, 12 mL) by the method
described for the preparation of 12b. 12c: mp 89-90 °C
(MeOH); 1H NMR (DMSO-d6) δ 7.71 and 7.51 (2 s, 2 H,
unsymmetrical H-7, H-4), 5.43 (s, 2 H, H-1′), 4.74 (t, 1 H,
exchanges with D2O, OH), 3.51-3.50 (m, 4 H, H-3′, H-4′), 3.04
(s, 6 H, N(CH3)2). Anal. (C12H15N3Cl2O2) C, H, N.
5,6-Dich lor o-1-[(2-h yd r oxyeth oxy)m eth yl]ben zim id a -
zole-2-th ion e (15). A mixture of 11a (0.5 g, 1.7 mmol), EtOH
(80 mL), and thiourea (0.26 g, 3.3 mmol) was heated at reflux
for 12 h or until the reaction was complete as monitored on
TLC. The excess EtOH was removed under reduced pressure,
and trituration of the resulting solid with ice cold water gave
a crystalline solid. This solid was collected by filtration, dried,
and recrystallized from MeOH-H2O to yield 0.46 g (93%) of
15: mp 174-176 °C; 1H NMR (DMSO-d6) δ 13.16 (bs, 1 H,
exchanges with D2O, NH), 7.70 and 7.37 (2 s, 2 H, H-7, H-4),
5.67 (s, 2 H, H-1′). Anal. (C10H10N2Cl2O2S) C, H, N.
2-(Ben zylth io)-5,6-d ich lor o-1-[(2-h yd r oxyeth oxy)m eth -
yl]ben zim id a zole (12d ). Compound 15 (0.09 g, 0.3 mmol)
was dissolved in a mixture of CH3CN:H2O (1:1) containing
NH4OH (aqueous, 0.01 mL). Benzyl chloride (0.08 mL) was
added to the above solution, and stirring was continued for
an additional 12 h. The resulting mixture was concentrated
to remove CH3CN. The white solid which had separated from
the solution was collected by filtration, washed with H2O (10
mL), and recrystallized from MeOH-H2O to give 0.09 g (75%)
of 12d : mp 103-105 °C; 1H NMR (DMSO-d6) δ 7.96 and 7.88
(2 s, 2 H, H-7, H-4), 7.46-7.34 (m, 2 H, C6H5), 7.31-7.23 (m,
3 H, C6H5), 5.53 (s, 2 H, H-1′). Anal. (C17H16N2Cl2O2S) C, H,
N.
5,6-Dich lor o-1-[(2-h yd r oxyeth oxy)m eth yl]ben zim id a -
zole (12e). Raney Ni (0.3 g, wet) was added to a solution of
compound 15 (0.12 g, 0.4 mmol) in EtOH (30 mL). The
reaction mixture was heated at reflux temperature for 3 days,
at which time TLC showed no starting material. The reaction
mixture was filtered through a Celite pad and washed with
ETtOH (20 mL), the filtrate and washings were combined, and
the solvent was removed in vacuo. The resulting solid was
redissolved in MeOH (10 mL), SiO2 (2 g) was added, and the
solvent was removed under reduced pressure. The SiO2 gel
powder was placed on the top of a SiO2 column (2 × 14 cm),
prepared with wet SiO2 in CHCl3. Elution of the column with
CHCl3:MeOH (9:1, v/v) gave 0.05 g (58%) of 12e: mp 119-
1
121 °C (hexane-EtOAc); H NMR (DMSO-d6) δ 8.49 (s, 1 H,

SAR of 2-Substituted Benzimidazoles
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 4 887
pared from 11c (0.1 g, 0.3 mmol) and liquid NH3 (10 mL) by
C-2), 8.03 and 7.97 (2 s, 2 H, H-7, H-4), 5.68 (s, 2 H, H-1′).
Anal. (C10H10N2Cl2O2) C, H, N.
the method described for 12a . 14a : mp 220-221 °C (MeOH-
1
H2
O); H NMR (DMSO-d6) δ 7.21 (d, 1 H, J ) 8.4 Hz, H-7),
2,4,6-Tr ich lor o-1-[[2-(ben zyloxy)eth oxy]m eth yl]ben z-
im id a zole (10b). Compound 10b was prepared from 2a 32 (1.5
g, 6.7 mmol) using NaH (0.32 g, 8.0 mmol, 60% oil dispersion),
CH3CN (120 mL), and 9 (1.6 g, 8.1 mmol) in CH3CN (20 mL)
by the method described for 10a . This oil (product) (4.24 g)
was used as such without further purification.
2,4,6-Tr ich lor o-1-[(2-h yd r oxyeth oxy)m eth yl]ben zim i-
d a zole (11b). Compound 11b was prepared from 10b (4.24
g, 11.0 mmol), BCl3 (5 M solution in CH2Cl2, 30 mL), CH2Cl2
(70 mL), and MeOH (25 mL) by the method described for 11a
to give 1.0 g (50%) of 11b: mp 100-101 °C (EtOAc); 1H NMR
(DMSO-d6) δ 7.92 (d, 1 H, J ) 1.6 Hz, H-7), 7.52 (d, 1 H, J )
1.2 Hz, H-5), 5.69 (s, 2 H, H-1′). Anal. (C10H9N2Cl3O2) C, H,
N.
2-Am in o-4,6-dich lor o-1-[(2-h ydr oxyeth oxy)m eth yl]ben -
zim id a zole (13a ). Compound 13a (0.069 g, 92%) was pre-
pared from 11b (0.08 g, 0.27 mmol) and liquid ammonia (10
mL) by the method described for 12a . 13a : mp 218 °C
(MeOH); 1H NMR (DMSO-d6) δ 7.34 (d, 1 H, J ) 1.85 Hz, H-7),
7.09 (d, 1 H, J ) 1.82 Hz, H-5), 7.00 (bs, 2 H, exchanges with
D2O, NH2), 5.44 (s, 2 H, H-1′). Anal. (C10H11N3Cl2O2) C, H,
N.
7.07 (d, 3 H, J ) 10.8 Hz, exchanges with D2O, NH2, H-6),
5.44 (s, 2 H, H-1′). Anal. (C10H11N3Cl2O2) C, H, N.
4,5-Dich lor o-2-(m et h yla m in o)-1-[(2-h yd r oxyet h oxy)-
m eth yl]ben zim id a zole (14b). Compound 14b (0.047 g, 81%)
was prepared from 11c (0.06 g, 0.2 mmol) and NH2CH3 (33%
solution in absolute ethanol, 6 mL) by the method described
1
for 12b. 14b: mp 199-200 °C (MeOH); H NMR (DMSO-d6)
δ 7.23 (d, 1 H, J ) 8.39 Hz, C-7), 7.09 (m, 2 H, exchanges with
D2O, NH, H-6), 5.42 (s, 2 H, H-1′), 2.93 (d, 3 H, J ) 4.8 Hz,
NHCH3). Anal. (C11H13N3Cl2O2) C, H, N.
4,5-Dich lor o-2-(d im eth yla m in o)-1-[(2-h yd r oxyeth oxy)-
m eth yl]ben zim id a zole (14c). Compound 14c (0.056 g, 78%)
was prepared from 11c (0.07 g, 0.23 mmol) and NH(CH3)2 (33%
solution in absolute ethanol, 6 mL) by the method described
for 12b. 14c: mp 88-90 °C; 1H NMR (DMSO-d6) δ 7.39 (d, 1
H, J ) 8.46 Hz, H-7), 7.22 (d, 1 H, J ) 8.46 Hz, H-6), 5.45 (s,
2 H, H-1′), 3.0 (s, 6 H, N(CH3)2). Anal. (C12H15N3Cl2O) C, H,
N.
4,5-Dich lor o-1-[(2-h yd r oxyeth oxy)m eth yl]ben zim id a -
zole-2-th ion e (17). Compound 17 (0.48 g, 96%) was prepared
from 11c (0.50 g, 1.7 mmol), EtOH (80 mL), and thiourea (0.26
g, 3.3 mmol) by the method described for 15. 17: mp 162-
164 °C; 1H NMR (DMSO-d6) δ 13.50 (bs, 1 H, exchanges with
D2O, NH), 7.43 (d, 1 H, J ) 8.5 Hz, H-7), 7.37 (d, 1 H, J )
8.59 Hz, H-6), 5.69 (s, 2 H, H-1′). Anal. (C10H10N2Cl2O2S) C,
H, N.
4,6-Dich lor o-2-(m et h yla m in o)-1-[(2-h yd r oxyet h oxy)-
m eth yl]ben zim id a zole (13b). Treatment of 11b (0.08 g, 0.27
mmol) with NH2CH3 (33% solution in absolute ethanol, 10 mL)
by the method described for 12b gave 0.064 g (83%) of 13b:
1
mp 168 °C (MeOH); H NMR (DMSO-d6) δ 7.37 (d, 1 H, J )
1.7 Hz, H-7), 7.12 (d, 1 H, exchanges with D2O, NH), 7.09 (d,
1 H, J ) 1.7 Hz, H-5), 5.44 (s, 2 H, H-1′). Anal. (C11H13N3-
Cl2O2) C, H, N.
4,6-Dich lor o-2-(d im eth yla m in o)-1-[(2-h yd r oxyeth oxy)-
m eth yl]ben zim id a zole (13c). Compound 13c (0.069 g, 85%)
was prepared from 11b (0.08 g, 0.27 mmol) and NH(CH3)2 (33%
solution in absolute ethanol, 10 mL) by the method described
for 12b. 13c: mp 141-143 °C (EtOH); 1H NMR (DMSO-d6) δ
7.53 (d, 1 H, J ) 1.7 Hz, H-7), 7.20 (d, 1 H, H-5), 5.43 (s, 2 H,
H-1′). Anal. (C12H15N3Cl2O2) C, H, N.
2-(Ben zylth io)-4,5-d ich lor o-1-[(2-h yd r oxyeth oxy)m eth -
yl]ben zim id a zole (14d ). Compound 14d was prepared from
17 (0.09 g, 0.3 mmol), CH3CN:H2O (1:1), NH4OH (aqueous,
0.01 mL), and benzyl chloride (0.09 mL) by the method
described for 12d to give 0.09 g (80%) of 14d : mp 109-111
°C; 1H NMR (DMSO-d6) δ 7.59 (d, 1 H, J ) 8.43 Hz, H-7), 7.49
(d, 2 H, C6H5), 7.43 (d, 1 H, J ) 8.3 Hz, H-6), 7.29-7.23 (m, 3
H, C6H5), 5.54 (s, 2 H, H-1′). Anal. (C17H16N2Cl2O2S) C, H,
N.
4,5-Dich lor o-1-[(2-h yd r oxyeth oxy)m eth yl]ben zim id a -
zole (14e). Compound 14e was prepared from 17 (0.14 g, 0.48
mmol), Raney Ni (0.2 g, wet), and EtOH (30 mL) by the method
described for 12e to give 0.053 g (43%) of 14e: mp 116-117
°C (hexane-EtOAc); 1H NMR (DMSO-d6) δ 8.53 (s, 1 H, H-2),
7.69 (d, 1 H, J ) 8.6 Hz, H-7), 7.50 (d, 1 H, J ) 8.6 Hz, H-6),
5.70 (s, 2 H, H-1′). Anal. (C10H10N2Cl2O2) C, H, N.
2,5,6-Tr ich lor o-1-[[1,3-bis(ben zyloxy)-2-p r op oxy]m eth -
yl]ben zim id a zole (19a ). Compound 19a was prepared from
8a (1.0 g, 4.5 mmol), CH3CN (200 mL), NaH (0.21 g, 5.2 mmol,
60% oil dispersion), and [1,3-bis(benzyloxy)-2-propoxy]methyl
chloride (18)34 (2.2 g, 6.7 mmol) in CH3CN (25 mL) by the
method described for 10a . The resulting oil was purified by
flash column chromatography (2 × 28 cm) 230-400 mesh),
prepared with wet SiO2 in hexane. Elution with hexane:EtOAc
(8:2, v/v) and evaporation of the appropriate fractions gave 19a
(2.77 g) as an oil. Although the 1H NMR spectra revealed a
small amount of an impurity (18), it was used without further
purification for the next step.
2,5,6-Tr ich lor o-1-[(1,3-d ih yd r oxy-2-p r op oxy)m et h yl]-
ben zim id a zole (20a ). Compound 20a (0.62 g, 41%) was
prepared from 19a (2.36 g, 4.6 mmol), BCl3 (5 M solution in
CH2Cl2, 21 mL), CH2Cl2 (50 mL), and MeOH (20 mL) by the
method described for 11a . 20a : mp 142-144 °C (EtOAc); 1H
NMR (DMSO-d6) δ 8.05 and 7.93 (2 s, 2 H, H-7, H-4), 5.74 (s,
2 H, H-1′). Anal. (C11H11N2Cl3O3) C, H, N.
2-Am in o-5,6-d ich lor o-1-[(1,3-d ih yd r oxy-2-p r op oxy)-
m eth yl]ben zim id a zole (21a ). Compound 21a was prepared
from 20a (0.1 g, 0.3 mmol) and liquid NH3 (10 mL) by the
method described for 12a to give 0.069 g (74%) of 21a : mp
159-161 °C (MeOH-H2O); 1H NMR (DMSO-d6) δ 7.49 and
7.29 (2 s, 2 H, H-7, C-4), 6.83 (s, 2 H, exchanges with D2O,
NH2), 5.49 (s, 2 H, H-1′). Anal. (C11H13N3Cl2O3) C, H, N.
5,6-Dich lor o-2-(m eth yla m in o)-1-[(1,3-d ih yd r oxy-2-p r o-
p oxy)m eth yl]ben zim id a zole (21b). Compound 21b was
prepared from 20a (0.1 g, 0.3 mmol) and NH2CH3 (33%
solution in absolute ethanol, 10 mL) by the method described
for 12b to give 0.087 g (85%) of 21b: mp 185-186 °C (MeOH-
4,6-Dich lor o-1-[(2-h yd r oxyeth oxy)m eth yl]ben zim id a -
zole-2-th ion e (16). Compound 16 (0.41 g, 79%) was prepared
from 11b (0.53 g, 1.8 mmol), EtOH (80 mL), and thiourea (0.26
g, 3.3 mmol) by the method described for 15. 16: mp 181-
1
182 °C; H NMR (DMSO-d6) δ 13.60 (bs, 1 H, NH), 7.50 (d, 1
H, J ) 1.42 Hz, H-7), 7.41 (d, 1 H, J ) 1.37 Hz, H-5), 5.68 (s,
2 H, H-1′). Anal. (C10H10N2Cl2O2S) C, H, N.
2-(Ben zylt h io)-4,6-d ich lor o-1-[(2-h yd r oxyet h oxy)m e-
th yl]ben zim id a zole (13d ). Compound 13d (0.09 g, 80%) was
prepared from 16 (0.09 g, 0.3 mmol), CH3CN:H2O (1:1), NH4-
OH (aqueous, 0.01 mL), and benzyl chloride (0.08 mL) by the
method described for 12d . 13d : mp 84-85 °C; 1H NMR
(DMSO-d6) δ 7.76 (d, 1 H, J ) 1.8 Hz, H-7), 7.50-7.47 (m, 2
H, C6H5), 7.40 (d, 1 H, J ) 1.7 Hz, H-5), 7.33-7.23 (m, 3 H,
C6H5), 5.50 (s, 2 H, H-1′). Anal. (C17H16N2Cl2O2S), C, H, N.
4,6-Dich lor o-1-[(2-h yd r oxyeth oxy)m eth yl]ben zim id a -
zole (13e). Compound 13e (0.04 g, 49%) was prepared from
16 (0.09 g, 0.3 mmol), Raney Ni (0.2 g, wet), and EtOH (25
mL) by the method described for 12e. 13e: mp 112-113 °C
(hexane-EtOAc); 1H NMR (DMSO-d6) δ 8.51 (s, 2 H, H-2), 7.82
(d, 1 H, J ) 1.8 Hz, H-7), 7.45 (d, 1 H, J ) 1.8 Hz, H-5), 5.69
(s, 2 H, H-1′). Anal. (C10H10N2Cl2O2) C, H, N.
2,4,5-Tr ich lor o-1-[[2-(ben zyloxy)eth oxy]m eth yl]ben z-
im id a zole (10c). Compound 10c was prepared from 7a (1.5
g, 6.7 mmol) using NaH (0.35 g, 8.8 mmol, 60% oil dispersion),
CH3CN (120 mL), and 9 (1.6 g, 8.1 mmol) in CH3CN (20 mL)
by the method described for 10a . Compound 10c (4.10 g) was
used as such without further purification.
2,4,5-Tr ich lor o-1-[(2-h yd r oxyeth oxy)m eth yl]ben zim i-
d a zole (11c). Compound 11c was prepared from 10c (4.10
g, 11.0 mmol), BCl3 (5 M solution in CH2Cl2, 30 mL), CH2Cl2
(50 mL), and MeOH (25 mL) by the method described for 11a
1
to give 0.90 g (45%) of 11c: mp 82-85 °C; H NMR (DMSO-
d6) δ 7.74 (d, 1 H, J ) 8.65 Hz, H-7), 7.57 (d, 1 H, J ) 8.65 Hz,
H-6), 5.70 (s, 2 H, H-1′). Anal. (C10H9N2Cl3O2) C, H, N.
2-Am in o-4,5-dich lor o-1-[(2-h ydr oxyeth oxy)m eth yl]ben -
zim id a zole (14a ). Compound 14a (0.081 g, 87%) was pre-

888 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 4
Saluja et al.
H2O); 1H NMR (DMSO-d6) δ 7.51 and 7.36 (2 s, 2 H, H-7, H-4),
6.97 (d, 1 H, exchanges with D2O, NH), 5.48 (s, 2 H, H-1′),
2.89 (d, 3 H, NHCH3). Anal. (C12H15N3Cl2O3) C, H, N.
5,6-Dich lor o-2-(d im et h yla m in o)-1-[(1,3-d ih yd r oxy-2-
pr opoxy)m eth yl]ben zim idazole (21c). Compound 21c (0.098
g, 94%) was prepared from 20a (0.1 g, 0.3 mmol) and NH-
(CH3)2 (33% solution in absolute ethanol, 10 mL) by the method
described for 12b. 21c: mp 175-176 °C (MeOH-H2O); 1H
NMR (DMSO-d6) δ 7.68 and 7.50 (2 s, 2 H, H-7, H-4), 5.50 (s,
2 H, H-1′), 3.15 (d, 3 H, N(CH3)2). Anal. (C13H17N3Cl2O3) C,
H, N.
5,6-Dich lor o-1-[(1,3-d ih yd r oxy-2-p r op oxy)m eth yl]ben -
zim id a zole-2-th ion e (24). Compound 24 was prepared from
20a (0.05 g, 0.15 mmol), EtOH (10 mL), and thiourea (0.034
g, 3.3 mmol) by the method described for 15 to give 0.04 g
(76%) of 24: mp 175-176 °C; 1H NMR (DMSO-d6) δ 13.20 (bs,
1 H, exchanges with D2O, NH), 7.69 and 7.36 (2 s, 2 H, H-7,
H-4), 5.70 (s, 2 H, H-1′). Anal. (C11H12N2Cl2O3S) C, H, N.
2-(Ben zylt h io)-5,6-d ich lor o-1-[(1,3-d ih yd r oxy-2-p r o-
p oxy)m eth yl]ben zim id a zole (21d ). Compound 21d was
prepared from 24 (0.09 g, 0.3 mmol) using CH3CN:H2O (1:1),
NH4OH (aqueous, 0.01 mL), and benzyl chloride (0.05 mL) by
the method described for 12d to give 0.10 g (87%) of 21d : mp
128-129 °C (MeOH-H2O); 1H NMR (DMSO-d6) δ 7.90 and
7.86 (2 s, 2 H, H-7, H-4), 7.45 (d, 2 H, C6H5), 7.33-7.25 (m, 3
H, C6H5), 5.60 (s, 2 H, H-1′), 4.60 (s, 2 H, CH2C6H5). Anal.
(C18H18N2Cl2O3S) C, H, N.
20b (0.35 g, 1.0 mmol), EtOH (70 mL), and thiourea (0.51 g,
6.8 mmol) by the method described for 15 to give 0.29 g (84%)
of 25: mp 218-220 °C; H NMR (DMSO-d6) δ 13.55 (bs, 1 H,
exchanges with D2O, NH), 7.49 (d, J ) 1.5 Hz, 1 H, H-7), 7.40
(d, J ) 1.4 Hz, 1 H, H-5), 5.74 (s, 2 H, H-1′), 4.55 (t, 2 H,
exchanges with D2O, 2 × OH), 3.66-3.60 (m, 1 H, H-3′), 3.48-
3.42 (m, 2 H, H-4′), 3.34-3.32 (m, 2 H, H-5′). Anal. (C11H12N2-
Cl2O3S) C, H, N.
1
2-(Ben zylt h io)-4,6-d ich lor o-1-[(1,3-d ih yd r oxy-2-p r o-
p oxy)m eth yl]ben zim id a zole (22d ). Compound 22d was
prepared from 25 (0.09 g, 0.3 mmol) using CH3CN:H2O (1:1),
NH4OH (aqueous, 0.01 mL), and benzyl chloride (0.05 mL) by
the method described for 12d to give 0.086 g (75%) of 22e:
1
mp 117 °C; H NMR (DMSO-d6) δ 7.70 (bs, 1 H, H-7), 7.50-
7.37 (m, 2 H, C6H5), 7.34 (s, 1 H, H-5), 7.31-7.24 (m, 3 H,
C6H5), 5.61 (s, 2 H, H-1′), 4.62 (bs, 4 H, exchanges with D2O,
2 × OH, CH2C6H5), 3.48-3.38 (m, 3 H, H-3′, H-4′), 3.30-3.26
(m, 2 H, H-5′). Anal. (C18H18N2Cl2O3S) C, H, N.
2,4,5-Tr ich lor o-1-[[1,3-bis(ben zyloxy)-2-p r op oxy]m eth -
yl]ben zim id a zole (19c). Compound 19c (1.6 g) was prepared
as an oil from 7a (0.6 g, 2.7 mmol), NaH (0.13 g, 3.2 mmol,
60% oil dispersion), CH3CN (200 mL), and 18 (1.04 g, 3.2
mmol) in CH3CN (20 mL) by the method described for 10a .
1
The H NMR spectrum showed a small impurity (18), but the
oil was used without further purification for the next step.
2,4,5-Tr ich lor o-1-[[1,3-d ih yd r oxy-2-p r op oxy]m et h yl]-
ben zim id a zole (20c). Compound 20c was prepared as an
oil from 19c (1.56 g, 3.0 mmol) using (5 M solution in CH2Cl2,
14 mL), CH2Cl2 (30 mL), and MeOH (14 mL) by the method
described for 11a to give 0.32 g (32%) of 20c: mp 162-164 °C
(EtOAc); 1H NMR (DMSO-d6) δ 7.74 (d, 1 H, J ) 8.7 Hz, H-7),
7.57 (d, 1 H, J ) 8.7 Hz, H-6), 5.70 (s, 2 H, H-1′). Anal.
(C11H11N2Cl3O3) C, H, N.
5,6-Dich lor o-1-[(1,3-d ih yd r oxy-2-p r op oxy)m eth yl]ben -
zim id a zole (21e). Compound 21e was prepared from 24 (0.15
g, 0.46 mmol) using Raney Ni (0.2 g, wet) and EtOH (30 mL)
by the method described for 12e to give 0.093 g (69%) of 21e:
mp 160-162 °C (hexane-EtOAc); 1H NMR (DMSO-d6) δ 8.47
(bs, 1 H, H-2), 8.01 and 7.95 (2 s, 2 H, H-7, H-4), 5.75 (s, 2 H,
H-1′). Anal. (C11H12N2Cl2O3) C, H, N.
2-Am in o-4,5-d ich lor o-1-[(1,3-d ih yd r oxy-2-p r op oxy)-
m eth yl]ben zim id a zole (23a ). Compound 23a (0.073 g, 90%)
was prepared from 20c (0.088 g, 0.27 mmol) and liquid
ammonia (10 mL) by the method described for 12a . 23a : mp
2,4,6-Tr ich lor o-1-[[1,3-bis(ben zyloxy)-2-p r op oxy]m eth -
yl]ben zim id a zole (19b). Compound 19b (2.73 g) was pre-
pared from 2a (0.59 g, 2.69 mmol), NaH (0.11 g, 2.7 mmol,
60% oil dispersion), CH3CN (72 mL), and 18 (1.03 g, 3.2 mmol)
in CH3CN (10 mL) by the method described for 19a . 19b: oil.
1
181-183 °C; H NMR (DMSO-d6) δ 7.20 (d, 1 H, J ) 8.2 Hz,
H-7), 7.08 (d, 1 H, J ) 8.23 Hz, H-6), 6.96 (bs, 2 H, exchanges
with D2O, NH2), 5.51 (s, 2 H, H-1′). Anal. (C11H13N3Cl2O3) C,
H, N.
1
The H NMR spectrum showed a small impurity (18), but the
mixture was used without further purification for the next
step.
4,5-Dich lor o-2-(m eth yla m in o)-1-[(1,3-d ih yd r oxy-2-p r o-
p oxy)m eth yl]ben zim id a zole (23b). Compound 23b (0.068
g, 93%) was prepared from 20c (0.08 g, 0.23 mmol), EtOH (5
mL), and NH2CH3 (33% solution in absolute ethanol, 6 mL)
by the method described for 12b. 23b: mp 164-165 °C
(hexane-EtOAc); 1H NMR (DMSO-d6) δ 7.21 (d, 1 H, J ) 8.4
Hz, H-7), 7.10 (d, 1 H, J ) 8.3 Hz, H-6), 7.01 (d, 1 H, exchanges
with D2O, NH), 5.49 (s, 2 H, H-1′), 2.93 (d, 3 H, NHCH3). Anal.
(C12H15N3Cl2O3) C, H, N.
2,4,6-Tr ich lor o-1-[(1,3-d ih yd r oxy-2-p r op oxy)m et h yl]-
ben zim id a zole (20b). Compound 20b was prepared from
19b (2.53 g, 5.0 mmol) using BCl3 (5 M solution in CH2Cl2, 23
mL), CH2Cl2 (49 mL), and MeOH (20 mL) by the method
described for 11a to give 0.22 g (14%) of 20b: mp 135-137 °C
(EtOAc); 1H NMR (DMSO-d6) δ 7.84 (bs, 1 H, H-7), 7.49 (bs, 1
H, H-5), 5.75 (s, 2 H, H-1′). Anal. (C11H11N2Cl3O3) C, H, N.
2-Am in o-4,6-d ich lor o-1-[(1,3-d ih yd r oxy-2-p r op oxy)-
m eth yl]ben zim id a zole (22a ). Compound 22a was prepared
from 20b (0.27 g, 0.83 mmol) and liquid NH3 (20 mL) by the
method described for 12a to give 0.24 g (95%) of 22a : mp 181-
4,5-Dich lor o-2-(d im et h yla m in o)-1-[(1,3-d ih yd r oxy-2-
p r op oxy)m eth yl]ben zim id a zole (23c). Compound 23c was
prepared from 20c (0.076 g, 0.23 mmol), EtOH (5 mL), and
NH(CH3)2 (33% solution in absolute ethanol, 6 mL) by the
method described for 12b. 23c (0.07 g, 91%): mp 149-150
1
183 °C (MeOH); H NMR (DMSO-d6) δ 7.32 (d, J ) 1.4 Hz, 1
H, H-7), 7.09 (d, J ) 1.4 Hz, 1 H, H-5), 6.98 (bs, 2 H, exchanges
with D2O, NH2), 5.50 (s, 2 H, H-1′). Anal. (C11H13N3Cl2O3) C,
H, N.
1
°C (hexane-EtOAc); H NMR (DMSO-d6) δ 7.38 (d, 1 H, J )
8.40 Hz, H-7), 7.22 (d, 1 H, J ) 8.34 Hz, H-6), 5.53 (s, 2 H,
H-1′), 3.08 (d, 6 H, N(CH3)2). Anal. (C13H17N3Cl2O3) C, H, N.
4,6-Dich lor o-2-(m eth yla m in o)-1-[(1,3-d ih yd r oxy-2-p r o-
p oxy)m eth yl]ben zim id a zole (22b). Compound 22b was
prepared from 20b (0.11 g, 0.34 mmol) and NH2CH3 (33%
solution in absolute ethanol, 15 mL) by the method described
for 12b to give 0.11 g (80%) of 22b: mp 152 °C (MeOH-H2O);
1H NMR (DMSO-d6) δ 7.33 (d, J ) 1.5 Hz, 1 H, H-7), 7.09 (d,
J ) 1.2 Hz, 1 H, H-5), 6.97 (d, 1 H, exchanges with D2O, NH),
5.48 (s, 2 H, H-1′), 2.89 (d, 3 H, NHCH3). Anal. (C12H15N3-
Cl2O3‚0.25H20) C, H, N.
4,6-Dich lor o-2-(d im et h yla m in o)-1-[(1,3-d ih yd r oxy-2-
pr opoxy)m eth yl]ben zim idazole (22c). Compound 22c (0.068
g, 88%) was prepared from 20b (0.076 g, 0.23 mmol) and NH-
(CH3)2 (33% solution in absolute ethanol, 10 mL) by the method
described for 12b. 22c: mp 156-158 °C (EtOH); 1H NMR
(DMSO-d6) δ 7.50 (d, J ) 0.9 Hz, 1 H, H-7), 7.21 (d, J ) 1.2
Hz, 1 H, H-5), 5.51 (s, 2 H, H-1′), 3.06 (d, 6 H, N(CH3)2). Anal.
(C13H17N3Cl2O3) C, H, N.
4,5-Dich lor o-1-[(1,3-d ih yd r oxy-2-p r op oxy)m eth yl]ben -
zim id a zole-2-th ion e (26). Compound 26 (0.081 g, 83%) was
prepared from 20c (0.1 g, 0.3 mmol), EtOH (15 mL), and
thiourea (0.069 g, 0.9 mmol) by the method described for 15.
26: mp 155-156 °C; 1H NMR (DMSO-d6) δ 13.57 (bs, 1 H,
exchanges with D2O, NH), 7.43 and 7.37 (dd, 2 H, J ) 9.5 Hz,
H-6, H-7), 5.76 (s, 2 H, H-1′). Anal. (C11H12N2Cl2O3S) C, H,
N.
2-(Ben zylt h io)-4,5-d ich lor o-1-[(1,3-d ih yd r oxy-2-p r o-
p oxy)m eth yl]ben zim id a zole (23d ). Compound 23d was
prepared from 26 (0.09 g, 0.3 mmol), CH3CN:H2O (1:1), NH4-
OH (aqueous, 0.01 mL), and benzyl chloride (0.05 mL) by the
method described for 12d . 23d (0.10 g, 89%): mp 118-120
°C; 1H NMR (DMSO-d6) δ 7.56 (d, 1 H, J ) 8.5 Hz, H-7), 7.49
(d, 1 H, J ) 8.7 Hz, H-6), 7.42 (d, 2 H, C6H5), 7.33-7.25 (m, 3
H, C6H5), 5.62 (s, 2 H, H-1′). Anal. (C18H18N2Cl2O3S) C, H,
N.
4,6-Dich lor o-1-[(1,3-d ih yd r oxy-2-p r op oxy)m eth yl]ben -
zim id a zole-2-th ion e (25). Compound 25 was prepared from

SAR of 2-Substituted Benzimidazoles
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 4 889
4,5-Dich lor o-1-[(1,3-d ih yd r oxy-2-p r op oxy)m eth yl]ben -
zim id a zole (23e). Compound 23e was prepared from 26 (0.14
g, 0.43 mmol) using Raney Ni (0.1 g, wet) and EtOH (15 mL)
by the method described for 12e to give 0.08 g (64%) of 23e:
mp 156-158 °C (MeOH-H2O); 1H NMR (DMSO-d6) δ 8.50 (s,
1 H, H-2), 7.67 (d, 1 H, J ) 8.6 Hz, H-7), 7.49 (d, 1 H, J ) 8.6,
1 Hz, H-6), 5.77 (s, 2 H, H-1′). Anal. (C11H12N2Cl2O3) C, H,
N.
was prepared from 8b (0.33 g, 1.23 mmol), NaH (0.048 g, 1.2
mmol, 60% oil dispersion), CH3CN (40 mL), and 30 (0.49 g,
1.85 mmol) in CH3CN (10 mL) by the method described for
28a . 31a : mp 110-112 °C; H NMR (DMSO-d6) δ 8.10 and
7.96 (2 s, 2 H, H-7, H-4), 5.74 (s, 2 H, H-1′). Anal. (C15H15N2-
Cl2O5Br) C, H, N.
1
2-Br om o-5,6-d ich lor o-1-[(1,3-d ih yd r oxy-2-p r op oxy)-
m eth yl]ben zim id a zole (32a ). A mixture of 31a (0.2 g, 0.44
mmol), KCN (0.086 g, 2.8 mmol), and EtOH (10% aqueous, 18
mL) was stirred at room temperature for 4 h or until the
reaction was complete. The excess ethanol was removed under
reduced pressure to dryness. The resulting mixture was
diluted with H2O (50 mL), extracted with EtOAc (50 mL),
washed with H2O (50 mL), and dried (anhydrous Na2SO4) and
the solvent removed under reduced pressure to dryness. The
resulting solid was dissolved in CHCl3 (20 mL) and filtered.
The residue was recrystallized with MeOH-H2O to afford
0.087 g (47%) of 32a : mp 149-150 °C; 1H NMR (DMSO-d6) δ
8.05 and 7.93 (2 s, 2 H, H-7, H-4), 5.73 (s, 2 H, H-1′). Anal.
(C11H11N2Cl2O3Br) C, H, N.
2-Br om o-4,6-d ich lor o-1-[(1,3-d ia ce t oxy-2-p r op oxy)-
m eth yl]ben zim id a zole (31b). Compound 31b was prepared
from 2b (0.31 g, 1.1 mmol), NaH (0.49 g, 1.1 mmol, 60% oil
dispersion), CH3CN (40 mL), and 30 (0.62 g, 2.3 mmol) in CH3-
CN (10 mL) by the method described for 28a . 31b (0.34 g,
64%): mp 125 °C; 1H NMR (DMSO-d6) δ 7.89 (d, 1 H, J )
1.77 Hz, H-7), 7.50 (d, 1 H, J ) 1.77 Hz, H-5), 5.75 (s, 2 H,
H-1′). Anal. (C15H15N2Cl2O5Br) C, H, N.
2-Br om o-5,6-d ich lor o-1-[(2-a cetoxyeth oxy)m eth yl]ben -
zim id a zole (28a ). To a stirred suspension of 2-bromo-5,6-
dichlorobenzimidazole20a (8b) (0.3 g, 1.1 mmol) in dry CH3CN
(60 mL) was added NaH (0.066 g, 60% oil dispersion, 1.6 mmol)
under a N2 atmosphere. The solution was stirred until H2
evolution had ceased and a clear solution was obtained (20
min). At that time, (2-acetoxyethoxy)methyl bromide39 (27)
(0.26 g, 1.3 mmol) in CH3CN (10 mL) was added dropwise.
The reaction mixture was stirred for an additional 5 h. The
resulting mixture was concentrated under reduced pressure,
diluted with H2O (100 mL), extracted with EtOAc (150 mL),
washed with H2O (50 mL), and dried (anhydrous Na2SO4) and
the solvent removed under reduced pressure. The resulting
oil was purified by flash column chromatography (2 × 20 cm)
(230-400 mesh), prepared with wet SiO2 in hexane. Elution
with hexane:EtOAc (8:2, v/v) gave the desired product which
was recrystallized from MeOH to afford 0.32 g (75%) of 28a
which was used as such without further purification: mp 110-
111 °C; 1H NMR (DMSO-d6) δ 8.14 and 7.96 (2s, 2 H, H-7,
H-4), 5.67 (s, 2 H, H-1′).
2-Br om o-5,6-dich lor o-1-[(2-h ydr oxyeth oxy)m eth yl]ben -
zim id a zole (29a ). A mixture of 28a (0.48 g, 1.2 mmol), Na2-
CO3 (0.3 g, 2.8 mmol), and EtOH (10% aqueous, 100 mL) was
stirred at room temperature for 12 h or until the reaction was
complete as determined by TLC. The excess ethanol was
removed under reduced pressure to dryness. The resulting
mixture was diluted with H2O (100 mL), extracted with EtOAc
(250 mL), washed with H2O (50 mL), and dried (anhydrous
Na2SO4) and the solvent removed under reduced pressure. The
resulting product was purified by flash column chromatogra-
phy (2 × 20 cm) (230-400 mesh), prepared with wet SiO2 in
CHCl3. Elution of the column with CHCl3:MeOH (95:5, v/v)
gave the desired product which was recrystallized from a
mixture of hexane:EtOAc to afford 0.26 g (62%) of 29a : mp
154-155 °C; 1H NMR (DMSO-d6) δ 8.12 and 7.95 (2, 2 H, H-7,
H-4), 5.67 (s, 2 H, H-1′). Anal. (C10H9N2Cl2O2Br) C, H, N.
2-Br om o-4,6-d ich lor o-1-[(2-a cetoxyeth oxy)m eth yl]ben -
zim id a zole (28b). Compound 28b was prepared from 2b
(0.53 g, 1.9 mmol), NaH (0.12 g, 2.9 mmol, 60% oil dispersion),
CH3CN (100 mL), and 27 (0.46 g, 2.3 mmol) in CH3CN (20
mL) by the method described for 28a . 28b (0.56 g, 75%): mp
2-Br om o-4,6-d ich lor o-1-[(1,3-d ih yd r oxy-2-p r op oxy)-
m eth yl]ben zim id a zole (32b). Compound 32b was prepared
from 31b (0.19 g, 0.34 mmol), KCN (0.083 g, 1.3 mmol), and
EtOH (10% aqueous, 12 mL) by the method described for 32a .
32b (0.70 g, 55%): mp 148-150 °C; 1H NMR (DMSO-d6) δ 7.84
(d, 1 H, J ) 1.7 Hz, H-6), 7.47 (d, 1 H, J ) 1.8 Hz, H-4), 5.74
(s, 2 H, H-1′). Anal. (C11H11N2Cl2O2Br) C, H, N.
2-Br om o-4,5-d ich lor o-1-[(1,3-d ia ce t oxy-2-p r op oxy)-
m eth yl]ben zim id a zole (31c). Compound 31c (0.47 g, 69%)
was prepared from 7b (0.4 g, 1.5 mmol), NaH (0.072 g, 1.8
mmol, 60% oil dispersion), CH3CN (60 mL), and 30 (0.67 g,
1.8 mmol) in CH3CN (10 mL) by the method described for 28a .
31c: mp 135-137 °C; 1H NMR (DMSO-d6) δ 7.72 (d, 1 H, J )
8.2 Hz, H-7), 7.53 (d, 1 H, J ) 8.3 Hz, H-6), 5.76 (s, 2 H, H-1′).
Anal. (C15H15N2Cl2O5Br) C, H, N.
2-Br om o-4,5-d ich lor o-1-[(1,3-d ih yd r oxy-2-p r op oxy)-
m eth yl]ben zim id a zole (32c). Compound 32c was prepared
from 31c (0.3 g, 0.66 mmol), KCN (0.128, 1.9 mmol), and EtOH
(10% aqueous, 18 mL) by the method described for 32a . 32c
(0.094 g, 38%): mp 148-150 °C (MeOH); 1H NMR (DMSO-d6)
δ 7.69 (d, 1 H, J ) 8.5 Hz, H-7), 7.53 (d, 1 H, J ) 8.7 Hz, H-6),
5.75 (s, 2 H, H-1′). Anal. (C11H11N2Cl2O3Br) C, H, N.
Cell Cu ltu r e P r oced u r es. The routine growth and pas-
sage of KB, BSC-1, and HFF cells was performed in monolayer
cultures using minimal essential medium (MEM) with either
Hanks salts [MEM(H)] or Earle salts [MEM(E)] supplemented
with 10% calf serum or 10% fetal bovine serum (HFF cells).
The sodium bicarbonate concentration was varied to meet the
buffering capacity required. Cells were passaged at 1:2-1:10
dilutions according to conventional procedures by using 0.05%
trypsin plus 0.02% EDTA in a HEPES-buffered salt solution.
Vir ologica l P r oced u r es. The Towne strain, plaque-puri-
fied isolate PO, of HCMV was kindly provided by Dr. Mark
Stinski, University of Iowa. The KOS strain of HSV-1 was
used in most experiments and was provided by Dr. Sandra K.
Weller, University of Connecticut. Stock HCMV was prepared
by infecting HFF cells at a multiplicity of infection (moi) of
<0.01 plaque-forming units (PFU)/cell as detailed previously.43
High-titer HSV-1 stocks were prepared by infecting KB cells
at an moi of <0.1 also as detailed previously.43 Virus titers
were determined using monolayer cultures of HFF cells for
HCMV and monolayer cultures of BSC-1 cells for HSV-1 as
described earlier.43 Briefly, HFF or BSC-1 cells were planted
as described above in 96-well cluster dishes and incubated
overnight at 37 °C. The next day cultures were inoculated
with HCMV or HSV-1 and serially diluted 1:3 across the
remaining 11 columns of the 96-well plate. After virus
adsorption the inoculum was replaced with fresh medium, and
1
103-105 °C; H NMR (DMSO-d6) δ 7.85 (d, 1 H, J ) 1.7 Hz,
H-5), 7.48 (d, 1 H, J ) 1.8 Hz, H-7), 5.75 (s, 2 H, H-1′). Anal.
(C12H11N2Cl2O3Br) C, H, N.
2-Br om o-4,6-dich lor o-1-[(2-h ydr oxyeth oxy)m eth yl]ben -
zim id a zole (29b). Compound 29b was prepared from 28b
(0.49 g, 1.2 mmol) using Na2CO3 (0.3 g, 2.8 mmol) and EtOH
(10% aqueous, 100 mL) by the method described for 29a to
1
give 0.24 g (55%) of 29b: mp 128-130 °C; H NMR (DMSO-
d6) δ 7.91 (d, H, J ) 1.7 Hz, H-7), 7.48 (d, 1 H, J ) 1.7 Hz,
H-5), 5.67 (s, 2 H, H-1′). Anal. (C10H9N2Cl2O2Br) C, H, N.
2-Br om o-4,5-d ich lor o-1-[(2-a cetoxyeth oxy)m eth yl]ben -
zim id a zole (28c). Compound 28c was prepared from 7b (0.53
g, 1.9 mmol), NaH (0.12 g, 2.9 mmol, 60% oil dispersion), CH3-
CN (100 mL), and 27 (0.46 g, 2.3 mmol) in CH3CN (10 mL) by
the method described for 28a . 28c (0.63 g, 83%): mp 123-
1
125 °C; H NMR (DMSO-d6) δ 7.75 (d, H, J ) 8.8 Hz, H-7),
7.56 (d, 1 H, J ) 8.8 Hz, H-6), 5.70 (s, 2 H, H-1′). Anal.
(C12H11N2Cl2O3Br) C, H, N.
2-Br om o-4,5-dich lor o-1-[(2-h ydr oxyeth oxy)m eth yl]ben -
zim id a zole (29c). Compound 29c was prepared from 28c
(0.39 g, 1.0 mmol), Na2CO3 (0.21 g, 2.0 mmol), and EtOH (10%
aqueous, 100 mL) by the method described for 29a . 29c (0.24
g, 69%): mp 128-130 °C; 1H NMR (DMSO-d6) δ 7.74 (d, 1 H,
J ) 8.7 Hz, H-7), 7.55 (d, 1 H, J ) 8.6 Hz, H-6), 5.69 (s, 2 H,
H-1′). Anal. (C10H9N2Cl2O2Br) C, H, N.
2-Br om o-5,6-d ich lor o-1-[(1,3-d ia ce t oxy-2-p r op oxy)-
m eth yl]ben zim id a zole (31a ). Compound 31a (0.34 g, 61%)

890 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 4
Saluja et al.
cultures were incubated at 7 days for HCMV, 2 or 3 days for
HSV-1. Plaques were enumerated under 20-fold magnification
in wells having the dilution which gave 5-20 plaques/well.
Virus titers were calculated according to the following for-
mula: titer (PFU/mL) ) no. of plaques × 5 × 3n, where n
represents the nth dilution of the virus used to infect the well
in which plaques were enumerated.
HCMV P la qu e Red u ction Assa y. HFF cells in 24-well
cluster dishes were infected with ca. 100 PFU of HCMV/cm2
cell sheet using the procedures detailed above. Following virus
adsorption, compounds dissolved in growth medium were
added to duplicate wells in four to eight selected concentra-
tions. After incubation at 37 °C for 7 days, cell sheets were
fixed and stained with crystal violet and microscopic plaques
enumerated as described above. Drug effects were calculated
as a percentage of reduction in the number of plaques in the
presence of each drug concentration compared to the number
observed in the absence of drug.
were calculated from the regression lines. Samples containing
positive controls (ACV for HSV-1, GCV for HCMV, and
2-acetylpyridine thiosemicarbazone for cytotoxicity) were used
in all assays.
Ack n ow led gm en t. These studies were supported
with federal funds from NIAID Grant U01-AI-31718
from the Department of Health and Human Services,
research contracts N01-AI42554 and N01-AI72641, and
Research Agreement DRDA 942921 with Glaxo-
Wellcome. The authors acknowledge Dr. J . C. Drach’s
research group for the antiviral evaluations and the
many contributions of Dr. V. D. Patil and J . Hinkley.
We thank Ms. Patti Compton and Ms. Marina Savic for
preparation of the manuscript.
HCMV Yield Assa y. HFF cells were planted as described
above in 96-well cluster dishes and incubated overnight,
medium was removed, and the cultures were inoculated with
HCMV at a moi of 0.5-1 PFU/cell as reported44 elsewhere.
After virus adsorption, inoculum was replaced with 0.2 mL of
fresh medium containing test compounds. The first row of 12
wells was left undisturbed and served as virus controls. Each
well in the second row received an additional 0.1 mL of
medium with test compound at 3 times the desired final
concentration. The contents of the 12 wells were mixed by
repeated pipetting and then serially diluted 1:3 along the
remaining wells. In this manner, six compounds could be
tested in duplicate on a single plate with concentrations from
100 to 0.14 µM. Plates were incubated at 37 °C for 7 days
and subjected to one cycle of freezing and thawing; aliquots
from each of the eight wells of a given column were transferred
to the first column of a fresh 96-well monolayer culture of HFF
cells. Contents were mixed and serially diluted 1:3 across the
remaining 11 columns of the secondary plate. Each column
of the original primary plate was diluted across a separate
plate in this manner. Cultures were incubated, plaques were
enumerated, and titers were calculated as described above.
HSV-1 ELISA An ELISA was employed45 to detect HSV-
1. Ninety-six-well cluster dishes were planted with 10 000
BSC-1 cells/well in 200 µL/well of MEM(E) plus 10% calf
serum. After overnight incubation at 37 °C, selected drug
concentrations in quadruplicate and HSV-1 at a concentration
of 100 PFU/well were added. Following a 3 day incubation at
37 °C, medium was removed, plates were blocked and rinsed,
and horse radish peroxidase-conjugated rabbit anti-HSV-1
antibody was added. Following removal of the antibody-
containing solution, plates were rinsed and then developed by
adding 150 µL/well of a solution of tetramethylbenzidine as
substrate. The reaction was stopped with H2SO4, and absor-
bance was read at 450 and 570 nm. Drug effects were
calculated as a percentage of the reduction in absorbance in
the presence of each drug concentration compared to absor-
bance obtained with virus in the absence of drug.
Cytotoxicity Assa ys. Two different assays were used to
explore cytotoxicity of selected compounds using methods we
have detailed previously. (i) Cytotoxicity produced in station-
ary HFF cells was determined by microscopic inspection of cells
not affected by the virus used in plaque assays.43 (ii) The effect
of compounds during two population doublings of KB cells was
determined by crystal violet staining and spectrophotometric
quantitation of dye eluted from stained cells as described
earlier.46 Briefly, 96-well cluster dishes were planted with KB
cells at 3000-5000 cells/well. After overnight incubation at
37 °C, test compound was added in quadruplicate at six to
eight concentrations. Plates were incubated at 37 °C for 48 h
in a CO2 incubator, rinsed, fixed with 95% ethanol, and stained
with 0.1% crystal violet. Acidified ethanol was added, and
plates were read at 570 nm in a spectrophotometer designed
to read 96-well ELISA assay plates.
Refer en ces
(1) MacCoss, M.; Tolman, R. L.; Ashton, W. T.; Wagner, A. F.;
Hannah, J .; Field, A. K.; Karkas, J . D.; Germershausen, J . I.
Synthetic, Biochemical and Antiviral Aspects of Selected Acy-
clonucleosides and Their Derivatives. Chem. Scr. 1986, 26, 113-
121.
(2) Schaeffer, H. J .; Beauchamp, L.; De Miranda, P.; Elion, G. B.;
Bauer, D. J .; Collins, P. 9-(2-Hydroxyethoxymethyl)guanine
Activity Against Viruses of the Herpes Group. Nature 1978, 272,
583-589.
(3) Field, A. K.; Davies, M. E.; Dewitt, C.; Perry, H. C.; Liou, R.;
Germershausen, J .; Karkas, J . D.; Ashton, W. T.; J ohnston, D.
B.; Tolman, R. L. 9-([2-Hydroxy-1-hydroxymethyl)ethoxy]-
methyl)-guanine: A Selective Inhibitor of Herpes Group Virus
Replication. Proc. Natl. Acad. Sci. U.S.A. 1983, 80, 4139-4143.
(4) Drach, J . P. Purine Nucleosides as an Antiviral Agents. In
Targets for the Design of Antiviral Agents; De Clercq, E., Walker,
R. T., Eds.; Plenum Press: New York, 1984; pp 231-257.
(5) De Clercq, E.; Descamps, J .; De Somer, P.; Barr, P. J .; J ones, A.
S.; Walker, R. T. (E)-5-(2-Bromovinyl)-2′-deoxyuridines: A Po-
tent and Selective Antiherpes Agent. Proc. Natl. Acad. Sci.
U.S.A. 1979, 76, 2947-2951.
(6) Watanabe, K. A.; Reichman, V.; Hirota, K.; Lopez, C.; Fox, J . J .
Nucleosides. 110. Synthesis and Antiherpes Virus Activity of
Some 2′-Fluoro-2′-deoxyarabinofuranosylpyrimidine Nucleosides.
J . Med. Chem. 1979, 22, 21-24.
(7) Faulds, D.; Heel, R. C. Ganciclovir. A Review of its Antiviral
Activity, Pharmacokinetic Properties and Therapeutic Efficacy
in Cytomegalovirus Infections. Drugs 1990, 39, 597-638.
(8) Chrisp, P.; Clissold, S. P. Foscarnet. A Review of its Antiviral
Activity, Pharmacokinetic Properties and Therapeutic use in
Immunocompromised Patients with Cytomegalovirus Retinitis.
Drugs 1991, 41, 104-129.
(9) Gozlan, J .; Salford, J . M.; Roullet, E.; Baudrimont, M.; Caburet,
F.; Picard, O.; Meyohas, M. C.; Duvivier, C.; J acomet, C.; Petit,
J . C. Rapid Detection of Cytomegalovirus DNA in Cerebrospinal
Fluid of AIDS Patients with Neurologic Disorders. J . Infect. Dis.
1992, 166, 1416-1421.
(10) (a) Germershausen, J .; Bostedor, R.; Field, A. K.; Perry, H.; Liou,
R.; Bull, H.; Tolman, R. L.; Karkas, J . D. A Comparison of the
Antiviral agents 2′-nor-2′-deoxyguanosine And Acyclovir: Up-
take and Phosphorylation in Tissue Culture and Kinetics of in
vitro inhibition of Viral and Cellular DNA Polymerase by their
respective Triphosphates. Biochem. Biophys. Res. Commun.
1983, 116, 360-367. (b) Biron, K. K.; Stanat, S. C.; Sorrell, J .
B.; Fyfe, J . A.; Keller, P. M.; Lambe, C. U.; Nelson, D. J .
Metabolic Activation of the Nucleoside Analog 9-[(2-Hydroxy-1-
(hydroxymethyl)ethoxy]methyl)guanine in Human Diploid Fi-
broblasts Infected with Human Cytomegalovirus. Proc. Natl.
Acad. Sci. U.S.A. 1985, 82, 2473-2477.
(11) Crumpacker, C. S.; Schnipper, L. E.; Zaia, J . A.; Levin, M. J .
Growth Inhibition by Acycloguanosine of Herpesviruses Isolated
from Human Infections. Antimicrob. Agents Chemother. 1979,
15, 642-645.
(12) Sullivan, V. C.; Talarico, C. L.; Stanat, S. C.; Davis, M.; Coen,
D. M.; Biron, K. K. A. Protein Kinase Homolog Controls
Phosphorylation of Ganciclovir in Human Cytomegalovirus-
Infected Cells. Nature (London) 1992, 358, 162-164.
(13) Biron, K. K.; Fyfe, J . A.; Stanat, S. C.; Leslie, L. K.; Sorrell, J .
B.; Lambe, C. U.; Coen, D. M. A Human Cytomegalovirus
Mutant Resistant to the Nucleoside Analog 9-([2-Hydroxy-1-
(hydroxymethyl)ethoxy}methyl)guanine (BW B759u) Induces
Reduced Levels of BW B759 Triphosphates. Proc. Natl. Acad.
Sci. U.S.A 1986, 83, 8769-8773.
Da ta An a lysis. Dose-response relationships were con-
structed by linearly regressing the percent inhibition of
parameters derived in the preceding sections against log drug
concentrations. Fifty percent inhibitory (IC50) concentrations
(14) Field, A. K.; Biron, K. K. “The End of Innocene” Revisited:
Resistance of Herpesviruses to Antiviral Drugs. Clin. Microbiol.
Rev. 1994, 7, 1-13.

SAR of 2-Substituted Benzimidazoles
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 4 891
(15) (a) Reardon, J . E.; Spector, T. Herpes simplex virus type 1 DNA
polymerase. Mechanism of Inhibition by Acyclovir Triphosphate.
J . Biol. Chem. 1989, 264, 7405-7411. (b) Reardon, J . E. Herpes
Simplex Virus Type 1 and Human DNA Polymerase Interactions
with 2′-Deoxyguanosine-5′-Triphosphate Analogues. J . Biol.
Chem. 1989, 264, 19039-19044.
(16) Datema, R.; Ericson, A. C.; Field, H. J .; Larson, A.; Stenberg,
K. Critical Determinants of Antiherpes Efficacy of Buciclovir and
Related Acyclic Guanosine Analogs. Antiviral Res. 1987, 7, 303-
316.
(17) Chu, C. K.; Cutler, S. J . Chemistry and Antiviral Activities of
Acyclonucleosides. J . Heterocycl. Chem. 1986, 23, 289-319.
(18) Tamm, I.; Folkers, K.; Shunk, C. H.; Horsfall, F. L. Inhibition
of Influenza Virus Multiplication by N-Glycosides of Benzimi-
dazoles. J . Exp. Med. 1954, 99, 227-250.
(19) Tamm, I.; Sehgal, P. B. Halobenzimidazole Ribosides and RNA
Synthesis of Cells and Viruses. Adv. Virus Res. 1978, 22, 187-
258.
DNA Does Not Properly Mature in the Presence of 2-Bromo-
5,6-dichloro-1-â-D-ribofuranosylbenzimidazole (BDCRB). Her-
pesvirus Workshop, Pittsburgh, PA, J uly 1993. (b) Underwood,
M. R.; Stanat, S. C.; Drach, J . C.; Harvey, R. J .; Biron, K. K.
Inhibition of HCMV DNA Processing by a New Class of Anti-
HCMV Compounds is Mediated Through the UL89 Gene Prod-
uct. Herpesvirus Workshop, Vancouver, BC, August 1994.
(29) Mandel, L. R.; Porter, C. C., J r.; Kuehl, F. A.; J ensen, N. P.;
Schmitt, S. M.; Windholz, T.; Beattie, T. R.; Carty, J . A.;
Christensen, B. G.; Shen, T. Y. Inhibitions of Adrenal Phenetha-
nolamine N-Methyltransferase by Substituted Benzimidazoles.
J . Med. Chem. 1970, 13, 1043-1047.
(30) Kazimierczuk, Z.; Cottam, H. B.; Revankar, G. R.; Robins, R. K.
Synthesis of 2′-Deoxy tubercidin, 2′-Deoxyadenosine, and Re-
lated 2′-Deoxynucleosides via
a Novel Direct Stereospecific
Sodium Salt Glycosylation Procedure. J . Am. Chem. Soc. 1984,
106, 6379-6382.
(31) Kawashima, E.; Gupta, P. K.; Devivar, R. V.; Townsend, L. B.
2,5,6-Trichlorobenzimidazole. In Nucleic Acid Chemistry;
Townsend, L. B., Tipson, R. S., Eds.; J ohn Wiley and Sons: New
York, 1991; Part 4, pp 24-26.
(32) Zou, R.; Townsend, L. B. Unpublished results.
(33) (a) Chloromethylation of 2-(benzyloxy)ethanol (Aldrich) with
p-formaldehyde and HCl (gas) gave 2-(benzyloxy)-1-(chloro-
methoxy)ethane. (b) Butler, C. L.; Renfrew, A. G.; Clapps, M.
The Preparation of Benzyloxyalkyl p-toluenesulfonates. J . Am.
Chem. Soc. 1938, 60, 1472-1473.
(34) Martin, J . C.; Dvorak, C. A.; Smee, D. F.; Matthews, T. R.;
Verheyden, J . P. 9-[(1,3-Dihydroxy-2-propoxy)methyl]guanine:
A New Potent and Selective Antiherpes Agent. J . Med. Chem.
1983, 26, 759-761.
(35) Oglivie, K. K.; Nguyen, BA.N.; Hamilton, R. G. A Trihydroxy
Acyclonucleoside Series. Can. J . Chem. 1984, 62, 1622-1627.
(36) Rosemeyer, H.; Toth, G.; Seela, F. Assignment of Anomeric
Configuration of D-Ribo-Arabino-2′-Deoxyribo-, and 2′,3′-
Dideoxyribonucleosides by NOE Difference Spectroscopy. Nu-
cleosides Nucleotides 1989, 8, 587-597.
(37) Harrison, D.; Ralph, J . T. Nucleophilic Substitution Reaction of
2-Chlorobenzimidazoles. Part I. Formation of Benzimidazolin-
2-ones and 2-Alkoxybenzimidazoles. J . Chem. Soc. 1965, 236-
239.
(38) Silverstein, R. M.; Bassler, G. C. Infrared Spectrometry “Spec-
trometric Identification of Organic Compounds” 2nd ed.; J ohn
Wiley and Sons, Inc.: New York, 1976; pp 95-105.
(39) Robins, M. J .; Hatfield, P. W. Nucleic Acid Related Compounds.
37. Convenient and High-yield Syntheses of N-[(2-Hydroxy-
ethoxy)methyl]heterocycles as “Acyclic Nucleoside” Analogues.
Can. J . Chem. 1982, 60, 547-533.
(20) (a) Tamm, I.; Overman, J . R. Relationship Between Structure
and Benzimidazole Derivatives and Inhibitory Activity on Vac-
cinia Virus Multiplication. Virology 1957, 3, 185-196. (b)
Pothier, P.; Dru, A.; Beaud, G. The Inhibition of Vaccinia Virus
Replication by 5,6-Dichloro-1-â-D-Ribofuranosylbenzimidazole
(DRB): an Effect at the Assembly Stage. J . Gen. Virol. 1981,
55, 87-94.
(21) (a) Tamm, I. Ribonucleic Acid Synthesis and Influenza Virus
Multiplication. Science 1957, 126, 1235-1236. (b) Tamm, I.;
Nemes, M. M.; Osterhout, S. On the Role of Ribonucleic Acid in
Animal Virus Synthesis. I. Studies with 5,6-Dichloro-1-â-D-
ribofuranosylbenzimidazole. J . Exp. Med. 1960, 111, 339-349.
(c) Sehgal, P. B.; Fraser, N. W.; Darnell, J . E. Early Ad-2
Transcription Units: Only Promoter-Proximal RNA Continues
to be Made in the presence of DRB. Virology 1979, 94, 185-
191. (d) Fraser, N. W.; Sehgal, P. B.; Darnell, J . E. Multiple
Discrete Sites for Premature RNA-Chain Termination Late in
Adenovirus-2 Infection: Enhancement by 5,6-Dichloro-1-â-D-
ribofuranosylbenzimidazole. Proc. Natl. Acad. Sci. U.S.A. 1979,
76, 2571-2575.
(22) (a) Harlow, P.; Molloy, G. Effect of 5,6-dichloro-1-â-D-ribofura-
noyslbenzimidazole on Ribonucleotide Metabolism and Ac-
cumulation of Mitochondrial Rna and Low-Molecular-Weight
Cytoplasmic Rna in Hela Cells. Arch. Biochem. Biophys. 1980,
203, 764-773. (b) Tamm, I.; Kikuchi, J . E.; Salditt-Georgieff,
M. Short Capped hnRNA Precursor Chains in Hela Cells:
Continued Synthesis in the Presence of 5,6-dichloro-1-â-D-
ribofuranosylbenzimidazole. Biochemistry 1980, 19, 2743-2748.
(23) Chodosh, L. A.; Fire, A.; Samuels, M.; Sharp, P. A. 5,6-Dichloro-
1-â-D-ribofuranosylbenzimidazole Inhibits Transcription Elon-
gation by RNA Polymerase II in vitro. J . Biol. Chem. 1989, 264,
2250-2257.
(24) Bucknall, R. A. The Effects of Substituted Benzimidazoles on
the Growth of Viruses and the Nucleic Acid Metabolism of Host
Cells. J . Gen. Virol. 1967, 1, 89-99.
(25) Townsend, L. B.; Revankar, G. R. Benzimidazole Nucleosides,
Nucleotides, And Related Derivatives. Chem. Rev. 1970, 70,
389-438.
(40) Beauchamp, L. M.; Serling, B. L.; Kelsey, J . E.; Biron, K. K.;
Collins, P.; Selway, J .; Lin, J . C.; Schaeffer, H. J . Effect of Acyclic
Pyrimidines Related to 9-[(1,3-Dihydroxy-2-propoxy]methyl]-
guanine on Herpesviruses. J . Med. Chem. 1988, 31, 144-149.
(41) Devivar, R. V.; Kawashima, E.; Revankar, G. R.; Breitenbach,
J . M.; Drach, J . C.; Townsend, L. B. Benzimidazole Ribonucleo-
sides: Design, Synthesis and Antiviral Evaluation of Certain
2-Alkylthio-5,6-dichloro-1-(â-D-ribofuranosyl)benzimidazoles. J .
Med. Chem. 1994, 37, 2942-2949.
(26) (a) Smith, C. M.; Zombor, G.; Henderson, J . F. Inhibitors of
Hypoxanthine Metabolism in Ehrlich Ascites Tumor Cells in
vitro. Cancer Treat. Rep. 1976, 60, 1567-1583. (b) Drug
Research and Development Chemotherapy, National Cancer
Institute, report of March 1, 1972, to L. B. Townsend.
(27) (a) Townsend, L. B.; Devivar, R. V.; Turk, S. R.; Nassiri, M. R.;
Drach, J . C. Design, Synthesis and Antiviral Activity of Certain
2,5,6-trihalo-1-(â-D-ribofuranosyl)benzimidazoles. J . Med. Chem.
1995, 38, 4098-4105. (b) Townsend, L. B. Benzimidazole Ribo-
nucleosides: Design, Synthesis, and Evaluation of 2,5,6-Trichloro-
1-(â-D-ribofuranosyl) benzimidazole (TCRB), 2-Bromo-5,6-dichloro-
1-(â-D-ribofuranosyl) benzimidazole (BDCRB), and Some Struc-
turally Related Analogs as Agents for Human Cytomegalovirus
Infections. Fifth International Conference on Antiviral Re-
search, Vancouver, BC, Canada, March 8-13, 1992. (c) Drach,
J . C.; Townsend, L. B.; Nassiri, M. R.; Turk, S. R.; Coleman, L.
A.; Devivar, R. V.; Genzlinger, G.; Kreske, E. D.; Renau, T. E.;
Westerman, A. C.; Shipman, C., J r.; Biron, K. K.; Dornsife, R.;
Kern, E. R. Benzimidazole Ribonucleosides: A New Class of
Antivirals with Potent and Selective Activity Against Human
Cytomegalovirus. Fifth International Conference on Antiviral
Research, Vancouver, BC, Canada, March 8-13, 1992.
(28) (a) Underwood, M. R.; Biron, K. K.; Hemphill, M. L.; Miller, T.
L.; Stanat, S. C.; Dornsife, R. E.; Drach, J . C.; Townsend, L. B.;
Edwards, C. A.; Harvey, R. J . High Molecular Weight HCMV
(42) The solvent system in parentheses next to the melting point is
solvent of crystallization and/or recrystallization.
(43) Turk, S. R.; Shipman, C., J r.; Nassiri, M. R.; Genzingler, G.;
Krawczyk, S. H.; Townsend, L. B.; Drach, J . C. Pyrrolo[2,3-d]-
pyrimidine Nucleosides as Inhibitors of Human Cytomegalovi-
rus. Antimicrob. Agents Chemother. 1987, 31, 544-550.
(44) Prichard, M. N.; Turk, S. R.; Coleman, L. A.; Engelhardt, S. L.;
Shipman, C., J r.; Drach, J . C. A. Microtiter Virus Yield Reduc-
tion Assay for The Evaluation of Antiviral Compounds Against
Human Cytomegalovirus and Herpes Simplex Virus. J . Virol.
Methods 1990, 28, 101-106.
(45) Prichard, M. N.; Shipman, C., J r. A. Three-Dimensional Model
To Analyze Drug-Drug Interactions. Antiviral Res. 1990, 14,
181-206.
(46) Prichard, M. N.; Prichard, L. E.; Baguley, W. A.; Nassiri, M. R.;
Shipman, C., J r. Three-Dimensional Analysis of the Synergistic
Cytotoxicity of Ganciclovir and Zidovudine. Antimicrob. Agents
Chemother. 1991, 35, 1060-1065.
J M950556A