6-Nitrobenzimidazole derivatives: Potential phosphodiesterase inhibitors: Synthesis and structure-activity relationship

Article abstract of DOI:10.1016/j.bmc.2011.12.041

6-Nitrobenzimidazole derivatives (1-30) synthesized and their phosphodiesterase inhibitory activities determined. Out of thirty tested compounds, ten showed a varying degrees of phosphodiesterase inhibition with IC₅₀ values between 1.5 ± 0.043 and 294.0 ± 16.7 μM. Compounds 30 (IC₅₀ = 1.5 ± 0.043 μM), 1 (IC₅₀ = 2.4 ± 0.049 μM), 11 (IC₅₀ = 5.7 ± 0.113 μM), 13 (IC₅₀ = 6.4 ± 0.148 μM), 14 (IC₅₀ = 10.5 ± 0.51 μM), 9 (IC₅₀ = 11.49 ± 0.08 μM), 3 (IC₅₀ = 63.1 ± 1.48 μM), 10 (IC₅₀ = 120.0 ± 4.47 μM), and 6 (IC₅₀ = 153.2 ± 5.6 μM) showed excellent phosphodiesterase inhibitory activity, much superior to the standard EDTA (IC₅₀ = 274 ± 0.007 μM), and thus are potential molecules for the development of a new class of phosphodiesterase inhibitors. A structure-activity relationship is evaluated. All compounds are characterized by spectroscopic parameters.

Full text of DOI:10.1016/j.bmc.2011.12.041

Bioorganic & Medicinal Chemistry 20 (2012) 1521–1526
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
6-Nitrobenzimidazole derivatives: Potential phosphodiesterase inhibitors:
Synthesis and structure–activity relationship
K.M. Khan a, , Zarbad Shah a, V.U. Ahmad a, N. Ambreen a, M. Khan a, M. Taha a, F. Rahim a, S. Noreen a,
⇑
S. Perveen b, M.I. Choudhary a, W. Voelter c
a H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan
b PCSIR Laboratories Complex, Karachi, Shahrah-e-Dr. Salimuzzaman Siddiqui, Karachi 75280, Pakistan
c Interfakultäres Institut für Biochemie der Universität Tübingen, Hoppe-Seyler Straße 4, D-72076 Tübingen, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
6-Nitrobenzimidazole derivatives (1–30) synthesized and their phosphodiesterase inhibitory activities
Received 5 November 2011
Revised 19 December 2011
Accepted 19 December 2011
Available online 27 December 2011
determined. Out of thirty tested compounds, ten showed a varying degrees of phosphodiesterase inhibition
with IC50 values between 1.5 0.043 and 294.0 16.7
(IC50 = 2.4 0.049 M), 11 (IC50 = 5.7 0.113 M), 13 (IC50 = 6.4 0.148
9 (IC50 = 11.49 0.08 M), 3 (IC50 = 63.1 1.48 M), 10 (IC50 = 120.0 4.47
5.6 M) showed excellent phosphodiesterase inhibitory activity, much superior to the standard EDTA
(IC50 = 274 0.007 M), and thus are potential molecules for the development of a new class of phosphodi-
l
M. Compounds 30 (IC50 = 1.5 0.043
M), 14 (IC50 = 10.5 0.51
M), and 6 (IC50 = 153.2
l
M), 1
l
l
l
l
M),
l
l
l
l
Keywords:
l
6-Nitrobenzimidazole derivatives
Potential phosphodiesterase inhibitors
Structure–activity relationship
esterase inhibitors. A structure–activity relationship is evaluated. All compounds are characterized by spec-
troscopic parameters.
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
di-p-nitrophenyl phosphate, and p-nitrophenyl ester of TMP).34
The NPP family comprises of three members known as NPP-1,
Benzimidazole derivatives find application in the treatment of
several diseases like epilepsy, diabetes, anti-fertility, etc.1,2 Recently
several researches elucidated that biological profiles of benzimid-
azole analogscan suitablybe modified bytheintroduction of different
heterocyclicmoieties to exhibita broadspectrum offurtherbiological
activities, that is, anti-cancer and antifungal3,4 antiviral,5–8 antibacte-
rial,9–15 antihelmintic,16,17 antiinflammatory,18 antihistaminic,19 pro-
ton pump inhibiting,20,21 antioxidant,22–25 antihypertensive,26
anticoagulant,27 antileukaemic28 or anti-ulcer.29
Benzimidazole derivatives reveal also considerable biological
activity against important viruses such as HIV, herpes (HSV-1),
RNA influenza, and human cytomegalovirus (HCMV).30,31 A num-
ber of benzimidazole displayed good antitumor activity.32 The
nitroimidazoles, in particular metronidazole is most commonly
used and accepted as the drug of choice for the chemotherapy of
anaerobic bacteria, protozoal disease and as radio sensitizer for
hypoxic tumors.33
NPP-2, and NPP-3. They are widely distributed in mammalian
intestinal mucosa, liver cell, and serum, snake venom and in vari-
ous plants. They have distinct patterns of distribution in different
cells types and even within the same types of cells.35 NPP-1 has
been localized in cells of the distal convoluted tubules of the kid-
ney, in epididymis, chondrocytes, osteoblasts, and hepatocytes.
NPP1 or PC1 (plasma cell membrane glycoprotein) is a key regula-
tor of calcification of bone and other tissues. Over-expression of
NPP1 has been associated with chondrocalcinosis,36 while under-
expression causes severe periarticular calcification in mice37 and
the syndrome of idiopathic infantile arterial calcification in
human.38
As our group is working on the lead molecules and in recent
past we published our paper on the enzyme inhibition.39 We car-
ried out the preliminary studies on several classes of molecules
randomly and 6-nitrobenzimidazole showed encouraging results
therefore these molecules chose to synthesize and screened for
NPPs inhibiting activities. All the synthetic compounds are charac-
terized by spectroscopic analyses including 1H NMR and EI MS. All
compounds gave satisfactory elemental analysis.
Nucleotide pyrophosphatases/phosphodiesterases (NPPs) (EC
3.1.4.1) are hydrolases that act on diesters of phosphoric acid. They
catalyze the release of nucleoside-50-monophosphates from
various pyrophosphate bonds (e.g., nucleoside diphosphates and
triphosphates, NAD, FAD, and UDP-glucose) and phospho
diester bonds (in oligonucleotides and exogenous substrates like
2. Results and discussion
2.1. Chemistry
The syntheses of the 6-nitrobenzimidazoles derivatives
1–30 were carried out by reacting commercially available
⇑
Corresponding author. Tel.: +00922134824910; fax: +00922134819018.
E-mail addresses: hassaan2@super.net.pk, khalid.khan@iccs.edu (K.M. Khan).
0968-0896/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2011.12.041

1522
K. M. Khan et al. / Bioorg. Med. Chem. 20 (2012) 1521–1526
as compared to 30 caused by the change in position of the hydroxyl
NH2
NH2
N
RCHO, Na2S2O5
DMSO, reflux 4 h
R
groups. However, again compound 11 with neighboring hydroxyl
substitution in the phenyl ring is far most active than compound
9 with 2,4-dihydroxyl substitution in the phenyl ring.
N
O2N
O2N
H
1-30
Compound 1, (IC50 = 2.4 0.049 lM), the 4-hydroxyphenyl ana-
log is the second most active compound of the series, however, the
2-hydroxyphenyl analog 18 was found to be completely inactive
suggesting that the hydroxyl group at position 4 of the phenyl res-
idue provides a sterically-favored orientation for a fruitful and sig-
nificant interaction with the enzyme.
Scheme 1. Synthesis of 6-nitrobenzimidazole derivatives 1–30.
4-nitrophenylenediamine with a variety of aromatic aldehydes in
DMSO in high yields (Scheme 1). In a typical reaction, sodium
metabisulfite (Na2S2O5) (3 mmol) was added to a stirring solution
of 4-nitrophenylenediamine (3.12 equiv) and the corresponding
substituted aromatic aldehydes (3.16 equiv) in DMSO and refluxed
to the completion of reaction. The progress of the reaction was
monitored by TLC. After completion of the reaction it was allowed
to cool to room temperature. Addition of water (30 mL) resulted in
precipitation of a solid residue which was then column-chromato-
graphed yielding the corresponding 6-nitrobenzimidazole deriva-
tive in high yields. The structures of these compounds were
determined by 1H NMR and EI mass spectroscopy.
Compound 13, (IC50 = 6.4 0.148
lM), a 2,4,6-trihydroxyphenyl
analog, is the fourth most active structure of the series and the
2,3,4-trihydroxyl analog 14 (IC50 = 10.5 0.51 lM) was found to
be slightly less active.
3. Materials and methods
Phosphodiesterase from Bothrops atrox crude dried venom
(P4631), substrate bis(p-nitrophenyl) phosphate sodium salt (N-
3002), and magnesium acetate were purchased from Sigma, while
ammonium acetate was from Merck. Tris buffer was a product
from Scharlau (TR 0423). The standard inhibitor EDTA was pur-
chased from Avon Chem limited.
2.2. In vitro phosphodiesterase activity
All synthetic compounds 1–30 were screened for their in vitro
phosphodiesterase activity. Out of thirty tested compounds, ten
showed a varying degree of phosphodiesterase inhibition with IC50
3.1. In vitro phosphodiesterase assay
values between 1.5 0.043 and 294.0 16.7
(IC50 = 1.5 0.043 M), 1 (IC50 = 2.4 0.049
0.113 M), 13 (IC50 = 6.4 0.148 M), 14 (IC50 = 10.5 0.51
(IC50 = 11.49 0.08 M), 3 (IC50 = 63.1 1.48 M), 10 (IC50 = 120.0
4.47 M), and 6 (IC50 = 153.2 5.6 M) showed IC50 values supe-
rior to the standard EDTA (IC50 = 274 0.007 M) and thus are
considered excellent inhibitors against phosphodiesterase. Only
compound 5 (IC50 = 294.0 16.7 M) showed a slightly less IC50 va-
lue than the standard (EDTA). Compounds 2, 4, 7, 8, 12, and 15–29
had less than 50% inhibition power, therefore, were not further eval-
uated for their IC50 values.
Some preliminary conclusions concerning the SAR of the 6-
nitrobenzimidazole series and their phosphodiesterase inhibiting
activity can be drawn from the data collected in Table 1.
l
l
M. Compounds 30
M), 11 (IC50 = 5.7
M), 9
The phosphodiesterase I inhibition assay was performed using
snake venom according to the previously reported method40 with
minute variations. Briefly, 33 mM tris–HC1 buffer (pH 8.8), 30 mM
magnesium acetate with enzyme concentration of 0.000742 U/well,
and 0.33 mM bis(p-nitropheny1) phosphate (Sigma N-3002) were
l
l
l
l
l
l
l
l
l
taken as substrate. EDTA with IC50 SEM = 274 0.007
lM was
used as positive control.41,42
l
After a pre-incubation period of 30 min, the enzyme with the
test samples was observed spectrophotometrically for the enzyme
activity on a microtitre plate reader at 37 °C by following release of
p-nitrophenol from p-nitrophenyl phosphate registering the O.D/
min at 410 nm. The assay was processed in triplicate.43
4. Experimental
Compound 30 (IC50 = 1.5 0.043 lM) showed the remarkably
highest inhibitory activity presumably caused by the presence of
two hydroxyl groups at positions 2 and 3 of the phenyl residue.
Surprisingly, compound 16 where the hydroxyl group at position
3 is replaced by an ethoxy residue was found to be completely
inactive suggesting that the activity in 30 results from the com-
bined effect of the two neighboring hydroxyls and/or the sterically
less hindered orientation of one of the hydroxyl groups needed for
interaction with the enzyme. In fact this hypothesis is further sup-
ported by the inactivity of compound 12 in which the ethoxy res-
idue of compound 16 is replaced by a methoxy moiety at the same
position. The supporting effect of the two neighboring hydroxyls in
compound 30 is further confirmed by the inactivity of compounds
18, bearing a 2-hydroxyphenyl, 28, substituted by a 2,5-dihydroxy-
phenyl, 17 with an attached 2-hydroxy-5-chloro, and 2, substi-
tuted by a 2-hydroxy-3,5-dibromophenyl residue.
4.1. General experimental
Melting points were determined on a Büchi 434 melting point
apparatus and are uncorrected. NMR experiments were performed
on Avance Bruker AM 300, 400, and 500 MHz instruments. Electron
impact mass spectra (EI MS) were recorded on a Finnigan MAT-
311A, Germany. Thin layer chromatography (TLC) was performed
on pre-coated silica gel aluminum plates (Kieselgel 60, 254, E.
Merck, Germany). Chromatograms were visualized by UV at 254
and 365 nm.
4.2. Synthetic procedure of compounds 1–30
6-Nitrobenzimidazole derivatives were synthesized by refluxing
4-nitrophenylenediamine (3.12 equiv) and substituted aromatic
aldehydes (3.16 equiv) in 15 mL DMSO in a round bottom flask
(100 mL). Sodium metabisulfite (Na2S2O5) (3 mmol) was added to
the stirring solutions. The reaction mixture was heated until the
reaction completion and the progress was observed by TLC. When
the reactions were completed they were cooled to room tempera-
ture. Addition of water (30 mL) resulted in the precipitation of crude
solid residues. The crude mixtures were chromatographed on silica
gel columns to afford the 6-nitrobenzimidazole derivatives 1–30 in
high yields. The structures of the synthesized compounds 1–30
were confirmed by 1H NMR and EI mass spectroscopy.
Surprisingly compound 5 (IC50 = 294 16.7
droxy-3,5-dicholrophenyl residue showed comparable activity to
the standard EDTA (IC50 = 274 0.007 M). This enhancement in
lM) with a 2-hy-
l
activity of compound 5 may be due to 3-chloro-residue which
might provide assistance to the neighboring hydroxyl group for a
significant interaction with the enzyme being smaller in size as
compared to the dibromo substitution at same position as in com-
pound 2.
Compounds 11 (IC50 = 5.7 0.113
lM) and 9 (IC50 = 11.49
0.08 M), 3,4- and 2,4-dihydroxy analogs exhibited less activity
l

K. M. Khan et al. / Bioorg. Med. Chem. 20 (2012) 1521–1526
1523
Table 1
Phosphodiesterase activity of 6-nitrobenzimidazole derivatives 1–30
N
R
N
H
O2N
1-30
Compound No.
R
IC50
(lM
SEM)a
Compound No.
R
IC50
NAb
(l
M
SEM)a
1'
1'
OH
2'
3'
6'
3'
5'
1
2.4 0.049
16
5'
OEt
4'
OH
1'
1'
OH
Br
OH
6'
6'
4'
2
3
NAb
17
18
NAb
NAb
3'
Br
Cl
4'
4'
1'
1'
OH
6'
5'
2'
6'
5'
63.1 1.48
3'
OMe
OMe
1'
1'
Cl
Cl
6'
5'
6'
5'
4
5
NAb
19
20
NAb
NAb
3'
3'
4'
Cl
1'
1'
OH
Cl
Cl
6'
6'
294.0 16.7
153.2 5.6
3'
Cl
O2N
4'
4'
1'
1'
F
6'
5'
2'
3'
6'
5'
6
7
8
21
22
23
NAb
NAb
NAb
3'
4'
NO2
1'
1'
2'
3'
6'
5'
6'
5'
2'
3'
NAb
Me
Br
2'
1'
6'
5'
2'
3'
1'
S
NAb
4'
5'
Cl
Cl
10'
1'
OH
9'
6'
5'
2'
3'
9
11.49 0.08
24
NAb
8'
7'
4'
OH
1'
5'
6'
1'
6'
5'
6'
5'
2'
2'
3'
10
11
120.0 4.47
25
26
NAb
3'
4'
Cl
1'
1'
6'
5'
2'
3'
2'
6'
5'
5.7 0.113
NAb
OH
OH
SMe
(continued on next page)

1524
K. M. Khan et al. / Bioorg. Med. Chem. 20 (2012) 1521–1526
Table 1 (continued)
Compound No.
R
IC50
NAb
(
l
M
SEM)a
Compound No.
R
IC50
NAb
(
l
M
SEM)a
1'
OH
5'
6'
2'
3'
6'
12
13
27
5'
N
OMe
4'
1'
1'
1'
HO
OH
OH
6'
6.4 0.148
10.5 0.51
NAb
28
29
30
NAb
3'
3'
5'
HO
4'
OH
9'
10'
1'
OH
OH
3'
5'
2'
3'
8'
7'
14
15
NAb
4'
6'
5'
OH
1'
OH
OH
6'
5'
5'
6'
3'
2'
NMe2
1.5 0.043
4'
EDTAc
274 0.007
a
SEM is the standard error of the mean.
NA–not active.
EDTA standard inhibitor for phosphodiesterease activity.
b
c
4.2.1. 4-(6-Nitro-1H-benzimidazol-2-yl)phenol (1)
C13H7Cl2N3O3: C, 48.17; H, 2.18, N, 12.96; Found: C, 48.12, H,
2.14, N, 12.93.
Yield: 0.65 g (81%); 1H NMR: (300 MHz, DMSO-d6): dH 8.38 (d,
1H, J7,5 = 2.0 Hz, H-7), 8.10 (dd, 1H, J5,7 = 2.0, J5,4 = 9.0 Hz, H-5),
8.04 (d, 2H, J2 ,3 /6 ,5 = 8.7 Hz, H-20/60), 7.69 (d, 1H, J4,5 = 9.0 Hz, H-
4.2.6. 6-Nitro-2-(4-nitrophenyl)-1H-benzimidazole (6)
0
0
0
0
4), 6.94 (d, 2H, J3 ,2 /5 ,6 = 8.7 Hz, H-30/50); MS: m/z (rel. abund.%),
255 (M+, 100), 209 (37), 182 (25). Anal. Calcd for C13H9N3O3: C,
61.18; H, 3.55, N, 16.46; Found: C, 60.83, H, 3.34, N, 16.73.
Yield: 0.71 g (80%); 1H NMR: (300 MHz, MeOD): dH 8.59 (d, 1H,
0
0
0
0
J7,5 = 2.0 Hz, H-7), 8.44 (d, 2H, J3 ,2 /5 ,6 = 9.0 Hz, H-30/50), 8.38, (d,
0
0
0
0
2H, J2 ,3 /6 ,5 = 9.0 Hz, H-20/60), 8.25 (dd, 1H, J5,7 = 2.0, J5,4 = 9.0 Hz,
H-5), 7.79 (d, 1H, J4,5 = 9.0 Hz, H-4); MS: m/z (rel. abund.%), 284
(M+, 100), 238 (15), 192 (15). Anal. Calcd for C13H8N4O4: C,
54.93; H, 2.84, N, 19.71; Found: C, 53.98, H, 2.82, N, 19.72.
0
0
0
0
4.2.2. 2,4-Dibromo-6-(6-nitro-1H-benzimidazol-2-yl)phenol (2)
Yield: 0.82 g (82%); 1H NMR: (300 MHz, DMSO-d6): dH 8.59 (br s,
1H, H-7), 8.34 (d, 1H, J4 ,6 = 2.5 Hz, H-40), 8.21 (dd, 1H, J5,7 = 2.5,
0
0
J5,4 = 9.0 Hz, H-5), 7.98 (d, 1H, J6 ,4 = 2.5 Hz, H-60), 7.88 (d, 1H,
J4,5 = 9.0 Hz, H-4); MS: m/z (rel. abund.%), 412 (M+, 100), 367
(36), 169 (10). Anal. Calcd for C13H7Br2N3O3: C, 37.80; H, 1.71, N,
10.17; Found: C, 37.83, H, 1.14, N, 10.13.
4.2.7. 2-(4-Methylphenyl)-6-nitro-1H-benzimidazole (7)
Yield: 0.61 g (81%); 1H NMR: (300 MHz, DMSO-d6): dH 8.44 (d,
1H, J7,5 = 2.0 Hz, H-7), 8.12 (m, 3H, H-5/20/60), 7.72 (d, 1H,
0
0
J4,5 = 9.0 Hz, H-4), 7.40 (d, 2H, J3 ,2 /5 ,6 = 8.0 Hz, H-30/50); MS: m/z
0
0
0
0
(rel. abund.%), 253 (M+, 100), 209 (23), 180 (13). Anal. Calcd for
4.2.3. 2-(3,4-Dimethoxyphenyl)-6-nitro-1H-benzimidazole (3)
Yield: 0.79 g (85%); 1H NMR: (300 MHz, MeOD): dH 8.47 (d, 1H,
J7,5 = 2.0 Hz, H-7), 8.18 (dd, 1H, J5,7 = 2.5, J5,4 = 9.0 Hz, H-5), 7.70 (m,
C13H8N4O4: C, 66.40; H, 4.38, N, 16.59; Found: C, 66.38, H, 4.32,
N, 16.42.
3H, H-4/20/60), 7.15 (d, 1H, J5 ,6 = 8.5 Hz, H-50), 3.96 (s, 3H, –OMe),
3.92 (s, 3H, –OMe); MS: m/z (rel. abund.%), 299 (M+, 100), 253
(30), 210 (49). Anal. Calcd for C15H13N3O4: C, 60.20; H, 4.35, N,
14.04; Found: C, 61.02, H, 4.44, N, 13.53.
4.2.8. 4.10.2-(3,4-Dichlorophenyl)-6-nitro-1H-benzimidazole
(8)
0
0
Yield: 0.76 g (79%); 1H NMR: (300 MHz, MeOD): dH 8.58 (d, 1H,
J7,5 = 2.0 Hz, H-7), 8.25 (dd, 1H, J5,7 = 2.5, J5,4 = 9.0 Hz, H-5), 7.90 (d,
1H, J5 ,6 = 8.4 Hz, H-50), 7.78 (d, 1H, J4,5 = 9.0 Hz, H-4), 7.74 (d, 1H,
0
0
J2 ,6 = 2.0 Hz, H-20), 7.56 (dd, 1H, J6 ,2 = 2.0, J6 ,5 = 8.4 Hz, H-60);
MS: m/z (rel. abund.%), 307 (M+, 100), 277 (33), 261 (33). Anal.
Calcd for C13H7Cl2N3O2: C, 50.67; H, 2.29, N, 13.64; Found: C,
50.90, H, 2.27, N, 13.62.
0
0
0
0
0
0
4.2.4. 2-(2-Chlorophenyl)-6-nitro-1H-benzimidazole (4)
Yield: 0.688 g (80%); 1H NMR: (400 MHz, DMSO-d6): dH 8.54 (br
0
0
s, 1H, H-7), 8.16 (d, 1H, J5,4 = 8.5 Hz, H-5), 7.94 (d, 1H, J6 ,5 = 7.0 Hz,
H-60), 7.81 (d, 1H, J4,5 = 8.5 Hz, H-4), 7.70 (d, 1H, J3 ,4 = 7.0 Hz, H-30),
7.70 (m, 2H, H-40/50); MS: m/z (rel. abund.%), 273 (M+, 100), 243
(28), 227 (29). Anal. Calcd for C13H8ClN3O2: C, 57.05; H, 2.95, N,
15.35; Found: C, 56.92, H, 3.04, N, 15.33.
0
0
4.2.9. 4.11.4-(6-Nitro-1H-benzimidazol-2-yl)-1,3-benzenediol
(9)
Yield: 0.69 g (81%); 1H NMR: (300 MHz, DMSO-d6): dH 8.44 (br s,
1H, H-7), 8.12 (dd, 1H, J5,7 = 2.0, J5,4 = 9.0 Hz, H-5), 7.92 (d, 1H,
4.2.5. 2,4-Dichloro-6-(6-nitro-1H-benzimidazol-2-yl)phenol (5)
Yield: 0.83 g (83%); 1H NMR: (300 MHz, DMSO-d6): dH 8.58 (d,
1H, J7,5 = 1.5 Hz, H-7), 8.18 (m, 2H, H-5/60), 7.84 (d, 1H,
J6 ,5 = 8.7 Hz, H-60), 7.74 (d, 1H, J4,5 = 9.0 Hz, H-4), 6.45 (m, 2H, H-
0
0
30/50), 7.56 (dd, 1H, J6 ,2 = 2.0, J6 ,5 = 8.4 Hz, H-60); MS: m/z (rel.
abund.%), 271 (M+, 100), 225 (88). Anal. Calcd for C13H8N3O4: C,
57.57; H, 3.34, N, 15.49; Found: C, 57.68, H, 3.82, N, 15.42.
0
0
0
0
J4,5 = 9.0 Hz, H-4), 7.72 (d, 1H, J4 ,6 = 2.0 Hz, H-40); MS: m/z (rel.
0
0
abund.%), 323 (M+, 100), 293 (23), 277 (47). Anal. Calcd for

K. M. Khan et al. / Bioorg. Med. Chem. 20 (2012) 1521–1526
1525
+
(d, 1H, J5 ,4 = 8.7 Hz, H-50); MS: m/z (rel. abund.%), 289 (M , 100),
243 (53), 179 (09). Anal. Calcd for C13H8ClN3O3: C, 53.90; H, 2.78,
N, 14.15; Found: C, 53.91, H, 2.77, N, 14.52.
0
0
4.2.10. 2-(4-Chlorophenyl)-6-nitro-1H-benzimidazole (10)
Yield: 0.73 g (85%); 1H NMR: (300 MHz, DMSO-d6): dH 8.47 (br s,
1H, H-7), 8.21 (d, 2H, J3 ,2 /5 ,6 = 8.5 Hz, H-30/50), 8.13 (dd, 1H,
0
0
0
0
J5,7 = 2.5, J5,4 = 9.0 Hz, H-5), 7.76 (d, 1H, J4,5 = 9.0 Hz, H-4), 7.69 (d,
+
2H, J2 ,3 /6 ,5 = 8.5 Hz, H-20/60); MS: m/z (rel. abund.%), 273 (M ,
100), 227 (70), 200 (33). Anal. Calcd for C13H8ClN3O2: C, 57.05; H,
2.95, N, 15.35; Found: C, 57.08, H, 2.92, N, 15.36.
4.2.18. 2-(6-Nitro-1H-benzimidazol-2-yl)phenol (18)
0
0
0
0
Yield: 0.66 g (82%); 1H NMR: (300 MHz, DMSO-d6): dH 8.53 (br s,
1H, H-7), 8.16 (m, 2H, H-5/60), 7.82 (d, 1H, J4,5 = 9.0 Hz, H-4), 7.43 (t,
1H, J4 /5 ,6 = 7.5 Hz, H-40), 7.06 (m, 2H, H-30/50); MS: m/z (rel. abund.%),
255 (M+, 100), 209 (94), 182 (12). Anal. Calcd for C13H9N3O4: C, 61.18;
H, 4.38, N, 14.04; Found: C, 61.19, H, 4.37, N, 14.06.
0
0
0
4.2.11. 4-(6-Nitro-1H-benzimidazol-2-yl)-1,2-benzenediol (11)
Yield: 0.69 g (81%); 1H NMR: (300 MHz, DMSO-d6): dH 8.37 (d,
1H, J7,5 = 2.0 Hz, H-7), 8.08 (dd, 1H, J5,7 = 2.0, J5,4 = 9.0 Hz, H-5),
7.66 (d, 1H, J5 ,6 = 8.7 Hz, H-50), 7.63 (d, 1H, J2 ,6 = 2.0 Hz, H-20),
4.2.19. 2-(2,4-Dichlorophenyl)-6-nitro-1H-benzimidazole (19)
Yield: 0.78 g (81%); 1H NMR: (300 MHz, DMSO-d6): dH 8.55 (d,
1H, J7,5 = 1.5 Hz, H-7), 8.18 (dd, 1H, J5,7 = 2.5, J5,4 = 9.0 Hz, H-5),
0
0
0
0
7.50 (dd, 1H, J6 ,2 = 2.0, J6 ,5 = 8.0 Hz, H-60), 6.90 (d, 1H,
J4,5 = 9.0 Hz, H-4); MS: m/z (rel. abund.%), 271 (M+, 100), 241
(38), 225 (83). Anal. Calcd for C13H9N3O4: C, 57.57; H, 3.34, N,
15.49; Found: C, 57.58, H, 3.33, N, 15.46.
0
0
0
0
7.98 (d, 1H, J6 ,5 = 8.5 Hz, H-60), 7.90 (d, 1H, J3 ,5 = 2.0 Hz, H-30),
0
0
0
0
0
0
0
0
7.41 (d, 1H, J4,5 = 9.0 Hz, H-4), 7.73 (d, 1H, J5 ,3 = 2.0, J5 ,6 = 8.5 Hz,
H-50); MS: m/z (rel. abund.%), 307 (M+, 100), 261 (49), 159 (42).
Anal. Calcd for C13H7Cl2N3O3: C, 50.67; H, 2.29, N, 13.64; Found:
C, 50.66, H, 2.27, N, 13.62.
4.2.12. 2-Methoxy-6-(6-nitro-1H-benzimidazol-2-yl)phenol (12)
Yield: 0.68 g (77%); 1H NMR: (300 MHz, DMSO-d6): dH 8.46 (d,
1H, J7,5 = 2.0 Hz, H-7), 8.05 (dd, 1H, J5,7 = 2.0, J5,4 = 9.0 Hz, H-5),
7.73 (d, 1H, J4 ,5 = 8.0 Hz, H-40), 7.70 (d, 1H, J4,5 = 9.0 Hz, H-4),
4.2.20. 2-(2-Chloro-5-nitrophenyl)-6-nitro-1H-benzimidazole
(20)
0
0
7.06 (d, 1H, J6 ,5 = 8.0 Hz, H-60), 7.50 (t, 1H, J5 /4 ,6 = 8.0 Hz, H-50),
3.82 (s, 3H, -OMe); MS: m/z (rel. abund.%), 285 (M+, 100), 267
(82), 196 (57). Anal. Calcd for C14H11N3O2: C, 58.95; H, 3.85, N,
14.73; Found: C, 58.98, H, 3.82, N, 14.76.
0
0
0
0
0
Yield: 0.77 g (77%); 1H NMR: (300 MHz, DMSO-d6): dH 8.79 (d,
1H, J6 ,4 = 2.5, H-60), 8.60 (d, 1H, J7,5 = 1.5 Hz, H-7), 8.41 (dd, 1H,
0
0
0
0
0
0
J5,7 = 2.5, J5,4 = 9.0 Hz, H-5), 7.73 (dd, 1H, J4 ,6 = 2.0, J4 ,3 = 8.5 Hz,
H-40), 8.01 (d, 1H, J3 ,4 = 8.5 Hz, H-30), 7.88 (d, 1H, J4,5 = 9.0 Hz, H-
4); MS: m/z (rel. abund.%), 318 (M+, 100), 272 (75), 226 (47). Anal.
Calcd for C13H7ClN4O4: C, 49.00; H, 2.21, N, 17.58; Found: C, 48.91,
H, 2.27, N, 17.52.
0
0
4.2.13. 2-(6-Nitro-1H-benzimidazol-2-yl)-1,3,5-benzenetriol (13)
Yield: 0.72 g (81%); 1H NMR: (300 MHz, MeOD): dH 8.37 (d, 1H,
J7,5 = 2.0 Hz, H-7), 8.14 (dd, 1H, J5,7 = 2.0, J5,4 = 9.0 Hz, H-5), 7.68 (d,
1H, J4,5 = 9.0 Hz, H-4), 6.00 (s, 2H, H-30/50); MS: m/z (rel. abund.%),
287 (M+, 100), 241 (26), 203 (30). Anal. Calcd for C13H9N3O5: C,
54.36; H, 3.16, N, 14.63; Found: C, 54.35, H, 3.12, N, 14.66.
4.2.21. 2-(2-Fluorophenyl)-6-nitro-1H-benzimidazole (21)
Yield: 0.645 g (79%); 1H NMR: (400 MHz, DMSO-d6): dH 8.52 (d,
1H, J7,5 = 2.0 Hz, H-7), 8.27 (td, 1H, J4 ,6 = 1.5, J4 /3 ,5 = 8.5 Hz, H-40),
8.14 (dd, 1H, J5,7 = 2.5, J5,4 = 9.0 Hz, H-5), 7.81 (d, 1H, J4,5 = 9.0 Hz,
H-4); 7.62 (m, 1H, H-30), 7.48 (m, 2H, H-50/60); MS: m/z (rel. abund.%),
257 (M+, 100), 211 (57), 184 (34). Anal. Calcd for C13H8FN3O2: C,
60.70; H, 3.13, N, 16.34; Found: C, 60.60, H, 3.14, N, 16.32.
0
0
0
0
0
4.2.14. 4-(6-Nitro-1H-benzimidazol-2-yl)-1,2,3-benzenetriol
(14)
Yield: 0.75 g (84%); 1H NMR: (400 MHz, DMSO-d6): dH 8.45 (br s,
1H, H-7), 8.13 (dd, 1H, J5,7 = 2.5, J5,4 = 9.0 Hz, H-5), 7.73 (d, 1H,
J6 ,5 = 8.5 Hz, H-60), 7.41 (d, 1H, J4,5 = 9.0 Hz, H-4), 7.73 (d, 1H,
0
0
+
J5 ,6 = 8.5 Hz, H-50); MS: m/z (rel. abund.%), 287 (M , 100), 241
(69), 212 (13). Anal. Calcd for C13H9N3O5: C, 54.36; H, 3.16, N,
14.63; Found: C, 54.35, H, 3.12, N, 14.66.
4.2.22. 2-(4-Bromophenyl)-6-nitro-1H-benzimidazole (22)
Yield: 0.79 g (80%); 1H NMR: (300 MHz, DMSO-d6): dH 8.47 (br s,
0
0
1H, H-7), 8.15 (d, 2H, J3 ,2 /5 ,6 = 8.5 Hz, H-30/50), 8.13 (dd, 1H,
0
0
0
0
J5,7 = 2.5, J5,4 = 9.0 Hz, H-5), 7.80 (d, 2H, J2 ,3 /6 ,5 = 8.5 Hz, H-20/60),
7.76 (d, 1H, J4,5 = 9.0 Hz, H-4); MS: m/z (rel. abund.%), 317 (M+,
100), 289 (29), 192 (21). Anal. Calcd for C13H8BrN3O2: C, 49.08;
H, 2.53, N, 13.21; Found: C, 49.01, H, 2.51, N, 13.22.
0
0
0
0
4.2.15. N,N-Dimethyl-4-(6-nitro-1H-benzimidazol-2-yl)aniline
(15)
Yield: 0.37 g (82%); 1H NMR: (400 MHz, DMSO-d6): dH 8.33 (br s,
1H, H-7), 8.06 (dd, 1H, J5,7 = 2.0, J5,4 = 9.0 Hz, H-5), 8.04 (d, 2H,
J2 ,3 /6 ,5 = 8.8 Hz, H-20/60), 7.63 (d, 1H, J4,5 = 9.0 Hz, H-4), 6.94 (d,
4.2.23. 6-Nitro-2-(3-thienyl)-1H-benzimidazole (23)
0
0
0
0
2H, J3 ,2 /5 ,6 = 8.8 Hz, H-30/50), 3.26 (s, 3H, NCH3), 3.01 (s, 3H,
NCH3); MS: m/z (rel. abund.%), 282 (M+, 100), 236 (73). Anal. Calcd
for C15H14N4O2: C, 63.82; H, 5.00, N, 19.85; Found: C, 64.01, H,
4.97, N, 19.86.
Yield: 0.65 g (84%); 1H NMR: (300 MHz, DMSO-d6): dH 8.44 (d,
1H, J7,5 = 2.1, H-7), 8.38 (m, 1H, H-20), 8.12 (dd, 1H, J5,7 = 2.1,
J5,4 = 8.7 Hz, H-5), 7.79 (m, 3H, H-4/40/50);MS: m/z (rel. abund.%),
245 (M+, 100), 199 (61), 172 (37). Anal. Calcd for C11H7N3O2S: C,
53.87; H, 2.88, N, 17.13; Found: C, 53.91, H, 2.77, N, 14.52.
0
0
0
0
4.2.16. 2-Ethoxy-6-(6-nitro-1H-benzimidazol-2-yl)phenol (16)
Yield: 0.73 g (78%); 1H NMR: (400 MHz, DMSO-d6): dH 8.53 (br s,
1H, H-7), 8.16 (dd, 1H, J5,7 = 2.5, J5,4 = 9.0 Hz, H-5), 7.81 (d, 1H,
4.2.24. 6-Nitro-2-(1-phenanthryl)-1H-benzimidazole (24)
Yield: 0.85 g (86%); 1H NMR: (300 MHz, DMSO-d6): dH 8.98 (d,
J4,5 = 9.0 Hz, H-4), 7.68 (d, 1H, J6 ,5 = 8.0 Hz, H-60),7.14 (d, 1H,
2H, J4 ,3 /5 ,6 = 8.1, Hz, H-40/50), 8.95 (d, 1H, J2 ,3 = 8.4 Hz, H-20),
8.60 (br s, 1H, H-7), 8.44 (m, 1H, H-100), 8.20 (dd, 1H, J5,7 = 2.1,
0
0
0
0
0
0
0
0
J4 ,5 = 8.0 Hz, H-40), 6.97 (t, 1H, J5 /4 ,6 = 8.0 Hz, H-50), 4.10 (q, 2H,
J = 7.0 Hz, -OCH2), 1.37 (t, 3H, J = 7.0 Hz, -CH3); MS: m/z (rel.
abund.%), 299 (M+, 78), 284 (100), 196 (48). Anal. Calcd for
C15H13N3O4: C, 60.20; H, 4.38, N, 14.04; Found: C, 60.21, H, 4.37,
N, 14.06.
0
0
0
0
0
J5,4 = 8.7 Hz, H-5), 8.15 (d, 1H, J9 ,10 = 8.2 Hz, H-90), 7.78 (m, 5H,
H-4/30/60/70/80); MS: m/z (rel. abund.%), 339 (M+, 100), 292 (86),
203 (25). Anal. Calcd for C21H13N3O2: C, 74.33; H, 3.86, N, 12.38;
Found: C, 73.98, H, 3.87, N, 12.36.
0
0
4.2.17. 4-Chloro-2-(6-nitro-1H-benzimidazol-2-yl)phenol (17)
Yield: 0.73 g (81%); 1H NMR: (300 MHz, DMSO-d6): dH 8.53 (d,
1H, J7,5 = 2.0 Hz, H-7), 8.16 (m, 2H, H-5/60), 7.82 (d, 1H,
4.2.25. 6-Nitro-2-phenyl-1H-benzimidazole (25)
Yield: 0.57 g (76%); 1H NMR: (400 MHz, DMSO-d6): dH 8.46 (d,
0
0
0
0
1H, J7,5 = 2.0, H-7), 8.21 (dd, 2H, J5,7/2 ,4 = 2.0, J5,4/2 ,3 = 8.0 Hz,
J4,5 = 9.0 Hz, H-4), 7.66 (dd, 1H, J4 ,6 = 2.5, J4 ,5 = 8.7 Hz, H-40), 7.11
H-5/20), 8.12 (dd, 1H, J6 ,4 = 2.4, J6 ,5 = 9.0 Hz, H-60), 7.75 (d, 1H,
0
0
0
0
0
0
0
0

1526
K. M. Khan et al. / Bioorg. Med. Chem. 20 (2012) 1521–1526
J4,5 = 9.0 Hz, H-4), 7.58 (m, 3H, H-30/40/50);MS: m/z (rel. abund.%),
239 (M+, 100), 209 (38), 166 (19). Anal. Calcd for C13H9N3O2: C,
65.27; H, 3.79, N, 17.56; Found: C, 64.97, H, 3.77, N, 17.55.
References and notes
1. Orjales, A.; Mosquera, R.; Labeaga, L.; Rodes, R. J. Med. Chem. 1997, 40, 586.
2. Grimmett, M. In Comprehensive Heterocyclic Chemistry: The Structure, Reactions,
Synthesis and Uses of Heterocyclic Compounds; Pergamon: Oxford, 1996; Vol. 3,
pp 77–260.
4.2.26. Methyl 4-(6-nitro-1H-benzimidazol-2-yl)phenyl sulfide
(26)
3. Wank, S. A. Am. J. Physiol. 1998, 274, G607.
4. Arjmand, F.; Mohani, B.; Ahmad, S. Eur. J. Med. Chem. 2005, 40, 1103.
5. Budow, S.; Kozlowska, M.; Gorska, A.; Kazimierczuk, Z.; Eickmeier, H.; Colla, P.
L.; Gosselin, G.; Seela, F. Arkivoc 2009, 3, 225.
Yield: 0.74 g (74%); 1H NMR: (400 MHz, DMSO-d6): dH 8.43 (d,
1H, J7,5 = 2.0 Hz, H-7), 8.13(d, 2H, J2 ,3 /6 ,5 = 8.5 Hz, H-20/60), 8.10
(dd, 1H, J5,7 = 2.0, J5,4 = 9.0 Hz, H-5), 7.74 (d, 1H, J4,5 = 9.0 Hz, H-4),
0
0
0
0
6. Ishida, T.; Suzuki, T.; Hirashima, S.; Mizutani, K.; Yoshida, A.; Ando, I.; Ikeda, S.;
Adachi, T.; Hashimoto, H. Bioorg. Med. Chem. Lett. 2006, 16, 1859.
7. Garuti, L.; Roberti, M.; Gentilomi, G. Farmaco 2001, 56, 815.
8. Biron, K. K.; Harvey, R. J.; Chamberlain, S. C.; Godd, S. S.; Smith, A. A., III; Davis,
M. G.; Talarico, C. L.; Miller, W. H.; Rerris, R.; Dornsife, R. E.; Stanat, S. C.; Drach,
J. C.; Townsend, L. B.; Koszalka, G. W. Anti. Agents Chemother. 2002, 46, 2365.
9. Kazimierczuk, Z.; Upcroft, J. A.; Upcroft, P.; Górska, A.; Starooeciak, B.; Laudy, A.
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10. Elnima, E. I.; Zubair, M. U.; Al-Badr, A. A. Agents Chemother. 1981, 19, 29.
11. Goker, H.; Tunçbilek, M.; Ayhan, G.; Altanlar, N. Il Farmaco 1998, 53, 415.
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2005, 20, 93.
13. Boiani, M.; Gonzalez, M. Mini-Rev. Med. Chem. 2005, 5, 409.
14. Özden, S.; Atabey, D.; Yildiz, S.; Göker, H. Med. Chem. 2005, 13, 1587.
15. Göker, H.; Ozden, S.; Yıldız, S.; Boykin, D. W. Eur. J. Med. Chem. 2005, 40, 1062.
16. Veerakumari, L.; Munuswamy, N. Vet. Parasitol. 2000, 91, 129.
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I.; Schinkel, A. H. Drug Metab. Dis. 2005, 33, 614.
18. Achar, K. C. S.; Hosamani, K. M.; Seetharamareddy, H. R. Eur. J. Med. Chem. 2010,
45, 2048.
19. Iemura, R.; Kawashima, T.; Fukuda, T.; Ito, K.; Tsukamoto, G. J. Med. Chem. 1986,
29, 1178.
20. Kuhler, T. C.; Swanson, M.; Shcherbuchin, V.; Larsson, H.; Mellgard, B.;
Sjostrom, J. E. J. Med. Chem. 1998, 41, 1777.
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22. Cole, E. R.; Crank, G.; Salam-Sheikh, A. J. Agric. Food Chem. 1974, 22, 918.
23. Kus, C.; Ayhan-KIlcIgil, G.; Eke, B. C.; Iscan, M. Arch. Pharm. Res. 2004, 27, 156.
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Sener, E.; Yalcin, I.; Iscan, M. Acta Biol. Hung. 2006, 57, 201.
25. Ates-Alagoz, Z.; Kus, C.; Coban, T. J. Enzyme Inhib. Med. Chem. 2005, 20, 325.
26. Kumar, J. R.; Jat, J. L.; Pathak, D. P. E-J. Chem. 2006, 3, 278.
27. Zhao, Z.; Arnaiz, D. O.; Griedel, B.; Sakata, S.; Dallas, J. L.; Whitlow, M.; Trinh, L.;
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28. Kamal, A.; Kumar, P. P.; Sreekanth, K.; Seshadri, B. N.; Ramulu, P. Bioorg. Med.
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29. Mason, J. S.; Morize, I.; Menard, P. R.; Cheney, D. L.; Hume, C.; Labaudiniere, R.
F. J. Med. Chem. 1999, 42, 3251.
7.46 (d, 2H, J3 ,2 /5 ,6 = 8.5 Hz, H-30/50); MS: m/z (rel. abund.%), 285
(M+, 100), 239 (80), 212 (41). Anal. Calcd for C14H11N3O2S: C,
58.93; H, 3.89, N, 14.73; Found: C, 58.92, H, 3.87, N, 14.72.
0
0
0
0
4.2.27. 6-Nitro-2-(4-pyridinyl)-1H-benzimidazole (27)
Yield: 0.61 g (81%); 1H NMR: (400 MHz, DMSO-d6): dH 8.81 (d,
2H, J2 ,3 /6 ,5 = 8.5 Hz, H-20/60), 8.55 (br s, 1H, H-7), 8.16 (dd, 1H,
0
0
0
0
J5,7 = 2.0, J5,4 = 8.8 Hz, H-5), 8.12 (d, 2H, J3 ,2 /5 ,6 = 8.5 Hz, H-30/50),
7.83 (d, 1H, J4,5 = 8.8 Hz, H-4); MS: m/z (rel. abund.%), 240 (M+,
100), 194 (48), 63 (24). Anal. Calcd for C12H8N4O2: C, 60.00; H,
3.36, N, 23.32; Found: C, 60.01, H, 3.37, N, 22.82.
0
0
0
0
4.2.28. 2-(6-Nitro-1H-benzimidazol-2-yl)-1,4-benzenediol (28)
Yield: 0.71 g (83%); 1H NMR: (400 MHz, DMSO-d6): dH 9.17 (br s,
1H, NH), 8.51 (br s, 1H, H-7), 8.13 (dd, 1H, J5,7 = 2.5, J5,4 = 9.0 Hz, H-
5), 7.79 (d, 1H, J4,5 = 9.0 Hz, H-4), 7.53 (d, 1H, J6 ,4 = 2.5 Hz, H-60),
6.88 (m, 2H, H-30/40);MS: m/z (rel. abund.%), 271 (M+, 100), 225
(65). Anal. Calcd for C13H8N3O4: C, 57.57; H, 3.34, N, 15.49; Found:
C, 57.68, H, 3.82, N, 15.42.
0
0
4.2.29. 2-(9-Anthryl)-6-nitro-1H-benzimidazole (29)
Yield: 0.83 g (84%); 1H NMR: (300 MHz, DMSO-d6): dH 8.90 (s,
1H, H-60), 8.64 (br s, 1H, H-7), 8.24 (m, 3H, H-5/20/100), 7.88 (d,
0
0
0
0
1H, J4,5 = 8.7 Hz, H-4), 7.67 (d, 2H, J5 ,4 /7
,
= 8.7 Hz, H-50/70), 7.57
8
(m, 4H, H-30/40/80/90); MS: m/z (rel. abund.%), 339 (M+, 100), 292
(57), 146 (10). Anal. Calcd for C21H13N3O2: C, 74.33; H, 3.86, N,
12.38; Found: C, 73.98, H, 3.87, N, 12.36.
30. Valdez, J.; Cedillo, R.; Hernandez-Campos, A.; Yepez, L.; Hernandez-Luis, F.;
Navarrete-Vazquez, G.; Tapia, A.; Cortes, R.; Hermandezc, M.; Castilloa, R.
Bioorg. Med. Chem. Lett. 2002, 12, 2221.
31. Tiwaria, A. K.; Mishrab, A. K.; Bajpai, A.; Mishra, P.; Singh, S.; Sinha, D.; Singh, V.
K. Bioorg. Med. Chem. Lett. 2007, 17, 2749.
32. LaPlante, S. R.; Jakalian, A.; Aubry, N.; Bousquet, Y.; Ferland, J. M.; Gillard, J.;
Lefebvre, S.; Poirier, M.; Tsantrizos, Y. S.; Kukolj, G.; Beaulieu, P. L. Angew.
Chem., Int. Ed. 2004, 43, 4306.
4.2.30. 3-(6-Nitro-1H-benzimidazol-2-yl)-1,2-benzenediol (30)
Yield: 0.73 g (86%); 1H NMR: (300 MHz, DMSO-d6): dH 8.53 (br s,
1H, H-7), 8.17 (m, 1H, H-5), 7.80 (d, 1H, J4,5 = 8.7 Hz, H-4), 7.53 (t,
1H, J5 /4 ,6 = 8.0 Hz, H-50), 6.93 (m, 2H, H-40/60); MS: m/z (rel. abund.%),
271 (M+, 100), 225 (53), 196 (8). Anal. Calcd for C13H8N3O4: C, 57.57;
H, 3.34, N, 15.49; Found: C, 57.68, H, 3.82, N, 15.42.
0
0
0
33. Benakli, K.; Terme, T.; Maldonado, J.; Vanelle, P. Heterocycles 2002, 57, 1689.
34. Razzell, W. E. Methods Enzymol. 1963, 6, 236.
35. Goding, J. W.; Terkeltaub, R.; Maurice, M.; Deterre, P.; Sali, A.; Belli, S. A.
Immunol. Rev. 1998, 161, 11.
5. Conclusion
36. Johnson, K.; Hashimoto, S.; Lotz, M.; Pritzker, K.; Goding, J.; Terkeeltaub, R.
Arthritis Rheum. 2001, 44, 1071.
37. Okawa, A.; Nakamura, I.; Goto, S.; Moriya, H.; Nakamura, Y.; Ikegawa, S. Nat.
Genet. 1998, 19, 271.
38. Rutsch, F.; Vaingankar, S.; Johnson, K.; Golgfine, I.; Maddux, B.; Chauerte, P.;
Kalhoff, H.; Sano, K.; Boisvert, W. A. Am. J. Pathol. 2001, 158, 543.
39. Khan, K. M.; Fatima, N.; Rasheed, M.; Jalil, S.; Ambreen, N.; Perveen, S.;
Choudhary, M. I. Bioorg. Med. Chem. 2009, 17, 7816.
40. Boswell-Smith, V.; Spina, D.; Page, C. P. Br. J. Pharmacol. 2006, 147, 252.
41. Hans, F. H.; Sverre, S. Clin. Chem. 1977, 23, 1531.
From these SAR considerations it can be concluded that the 6-
nitrobenzimidazoles with the utmost phosphodiesterase inhibitory
activities bear a substituted or unsubstituted 4-hydroxyphenyl or a
2,3-dihydroxyphenyl residue. From the present study it is con-
cluded that 6-nitrobenzimidazole derivatives are a new class of
compounds with an outstanding phosphodiesterase inhibitory po-
tential. Compounds 1, 3, 6, 9, 10, 11, 13, 14, and 30, demonstrated
excellent phosphodiesterase inhibitory activities which are supe-
rior to the standard EDTA and thus are potential lead molecules
for further research.
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