Synthesis and antistaphylococcal activity of N-substituted-1H- benzimidazole-sulphonamides

Article abstract of DOI:10.1002/ardp.200900199

A series of N-substituted-1H-benzimidazole-5(6)-sulfonamides and 3-(5,6-dichloro-1H-benzimidazol-2-yl)-N-substituted benzensulfonamides were synthesized and evaluated for antibacterial activity against Staphylococcus aureus and methicillin-resistant S. aureus (MRSA). Certain compounds inhibit bacterial growth with low MIC (μg/mL) values. The most active compounds 30, 31, and 32 have the lowest MIC values with 0.39 to 0.19 μg/mL. Among the compounds having sulfonamido moities, 16, 23, and 24 exhibited the strongest antibacterial activity with 1.56 μg/mL MIC values.

Full text of DOI:10.1002/ardp.200900199

Arch. Pharm. Chem. Life Sci. 2010, 343, 31–39
M. O. Pꢀskꢀllꢀ et al.
31
Full Paper
Synthesis and Antistaphylococcal Activity of N-Substituted-
1H-benzimidazole-sulphonamides
M. Orhan Pꢀskꢀllꢀ1, Sulhiye Yıldız2, and Hakan Gꢁker1
1 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ankara University, Tandogan, Ankara-
Turkey
2 Department of Microbiology, Faculty of Pharmacy, Ankara University, Tandogan, Ankara-Turkey
A series of N-substituted-1H-benzimidazole-5(6)-sulfonamides and 3-(5,6-dichloro-1H-benzimida-
zol-2-yl)-N-substituted benzensulfonamides were synthesized and evaluated for antibacterial
activity against Staphylococcus aureus and methicillin-resistant S. aureus (MRSA). Certain com-
pounds inhibit bacterial growth with low MIC (lg/mL) values. The most active compounds 30,
31, and 32 have the lowest MIC values with 0.39 to 0.19 lg/mL. Among the compounds having
sulfonamido moities, 16, 23, and 24 exhibited the strongest antibacterial activity with 1.56 lg/
mL MIC values.
Keywords: Anti-staphylococcal activity / 1H-Benzimidazolesulphonamide / Methicillin-resistant Staphylococcus aur-
eus / Tautomerism /
Received: May 28, 2009; accepted: August 20, 2009
DOI 10.1002/ardp.200900199
Introduction
Multiple drug-resistant organisms such as MRSA (Methi-
cillin-resistant Staphylococcus aureus), VRE (Vancomycin
resistant enterococci), MRSE (Methicillin-resistant Staphy-
lococcus epidermidis) are becoming common causes of
infections in the acute and long-term care units in hospi-
tals. The emergence of these resistant bacteria has cre-
ated a major concern and an urgent need of antibacterial
agent in structural classes distinct from known antibac-
terial agents [1].
In our previous papers [2, 3], we have reported the syn-
thesis of benzimidazoles I and II (Fig. 1) possessing amide
functions at different positions; also, their promising
antimicrobial activity results have been reported.
Recently, two new benzimidazoles [4] having 3,5-di-tert-
butyl-2-hydroxy-2-phenyl compounds III and 30 (Fig. 1)
have been reported as inhibitors of histidine protein kin-
ases from a bacterial two-component system, which
Figure 1. Structures of compounds I, II, III, and 30.
showed very good antibacterial activity, in particular,
against Gram-positive bacteria. These results prompted
us to continue an investigation on a series of new N1-sub-
stituted-1H-benzimidazole-5(6)-sulphonamides
11–35
and sulfonamides carrying 5,6-dichloro-N1-substituted-
1H-benzimidazoles 37–40, which should be the bio-iso-
sters of the potent compounds in Fig. 1. Herein, we report
the synthesis of some N-sulphonylbenzimidazoles and
the results concerning their potent anti-staphylococcal
activity.
Correspondence: Hakan Gꢁker, Department of Pharmaceutical Chemis-
try, Faculty of Pharmacy, Ankara University, 06100 Tandogan, Ankara-
Turkey.
E-mail: goker@pharmacy.ankara.edu.tr
Fax: +90 312 213-1081
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32
M. O. Pꢀskꢀllꢀ et al.
Arch. Pharm. Chem. Life Sci. 2010, 343, 31–39
Reagents and conditions: (a) N,N-Dimethylethylenediamine; (b) NH3 gas or benzyl amine; (c) H2, Pd/C; (d) NH4OH; (e) EtOH/H2O;
(f) Na2S2O5 adduct of 3-formylbenzenesulfonic acid; (g) SOCl2 and several amines.
Scheme 1. Synthesis of some intermediates and new benzimidazoles 11–35 and 37–40.
nucleophilic substitution reaction. The Pd/C-catalyzed
Results and discussion
reduction of 2, 3, and 6 gave the 3,4-diaminobenzene-
5(6)-sulphonamides 4, 5, and 7. 4-Chloro-3-nitrobenzen-
sulphonyl chloride was hydrolyzed to sulfonic acid,
then, the chlorine atom was transformed into amine.
The Pd/C-catalyzed reduction of 9 gave 3,4-diaminoben-
zene-5(6)-sulfonic acid 10. The final compounds 11–35
were obtained by the condensation of substituted o-phe-
Chemistry
As depicted in Scheme 1, uncommercial starting materi-
als, N-substituted benzensulfonamides 2, 3, were pre-
pared by reaction of 4-chloro-3-nitrobenzensulphonyl
chloride and the corresponding amines. Then, chlorine
atoms were converted to amines by using the aromatic
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Arch. Pharm. Chem. Life Sci. 2010, 343, 31–39
N-Substituted 1H-Benzimidazole-sulphonamides
33
Table 1. In-vitro antistaphylococcal activity and formulas of compounds 11–40.
No
R9
R
R1
R2
R3
R4
R5
Anti-staphylococcal activities
MIC (lg/mL)
S. aureus*
MRSA**
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
37
38
39
40
(Me)2NCH2CH2NHO2S-
(Me)2NCH2CH2NHO2S-
(Me)2NCH2CH2NHO2S-
(Me)2NCH2CH2NHO2S-
(Me)2NCH2CH2NHO2S-
(Me)2NCH2CH2NHO2S-
(Me)2NCH2CH2NHO2S- benzyl
(Me)2NCH2CH2NHO2S- benzyl
(Me)2NCH2CH2NHO2S- benzyl
(Me)2NCH2CH2NHO2S- benzyl
(Me)2NCH2CH2NHO2S- benzyl
H2NO2S
H2NO2S
H2NO2S
HO3S
HO3S
HO3S
HO3S
HOOC
HOOC
NC
H
H
H
H
H
H
H
H
H
H
OH
OH
H
H
Cl
H
H
H
OH
OH
H
Cl
CF3
Cl
H
H
CF3
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Cl
H
H
H
H
H
H
H
H
H
A25
A25
A25
12.5
3.12
1.56
25
A25
A25
A25
12.5
3.12
0.78
A25
A25
A25
A25
A25
A25
1.56
0.78
A25
A25
A25
12.5
6.25
0.78
0.39
0.19
A25
3.12
3.12
A25
6.25
6.25
A25
25
benzyloxy
H
C(CH3)3
C(CH3)3
Cl
CF3
Cl
Br
H
benzyloxy
p-chloro-phenoxy
H
H
Cl
H
H
F
H
C(CH3)3
H
CF3
Cl
H
H
H
H
C(CH3)3
H
H
H
C(CH3)3
H
C(CH3)3
H
C(CH3)3
C(CH3)3
H
A25
A25
A25
A25
A25
1.56
1.56
A25
A25
A25
12.5
3.12
0.39
0.39
0.39
A25
3.12
1.56
>25
3.12
6.25
A25
0.78
0.78
p-chloro-phenoxy
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Cl
Cl
H
H
Cl
H
H
H
H
H
H
H
H
H
H
C(CH3)3
C(CH3)3
Cl
Cl
H
OH
OH
OH
OH
OH
OH
OH
OH
OH
C(CH3)3
C(CH3)3
C(CH3)3
C(CH3)3
C(CH3)3
C(CH3)3
C(CH3)3
C(CH3)3
C(CH3)3
NC
O2N
F3C
H
H
Ampicillin
Sultamicillin
25
MIC: minimum inhibitory concentration (lg/mL).
Staphyloccocus aureus (ATCC 25923).
** Methicillin-resistant Staphylococcus aureus (MRSA; ATCC 43300).
*
nylendiamines 4, 5, 7, 10 and other corresponding start- listed in Table 1. The synthesized compounds and refer-
ing materials with the Na2S2O5-adduct of arylaldehydes ence drugs were dissolved in DMSO/H2O (50%), at a con-
in DMF [5]. Compound 36 (Scheme 1) was published centration of 400 lg/mL. The concentration was adjusted
before [3]. Compound 37 was activated with thionyl to 100 lg/mL by fourfold dilution with media culture
chloride, then, acyl chlorides were amidified to yield the and bacteria solution. Data were not taken for the initial
targeted sulphonamide derivatives 38–40.
solution because of the high DMSO concentration
(12.5%). Some of the compounds exhibited more potent
inhibitory activity against the selected bacteria than the
reference compounds Ampicillin and Sultamicillin. The
Microbiological studies
All described benzimidazoles 11–40 were tested in vitro most active compounds having a COOH- and a CN-group
for antibacterial activity against Gram-positive S. aureus, on position C-5(6), were 30 and 31, 32, respectively, hav-
methicillin-resistant S. aureus (MRSA, clinical isolate), ing the lowest MIC values with 0.39 lg/mL. When these
and other bacteria, and for antifungal activity against groups were exchanged with sulfonic acid, the activity
Candida albicans by diffusion method. While some of the was highly decreased (28 with 12.5 lg/mL). However,
compounds exhibit very good potencies against Gram- replacement of the same group by sulphonamide
positive bacteria (S. aureus and MRSA), none of the com- resulted in an increased activity (16, 23, 24 with 1.56 lg/
pounds was active against Escherichia coli; unimportant mL value). In our previous studies, we have reported that
activity has been observed against C. albicans. Therefore, benzyl substitution and chlorine substitution at posi-
all benzimidazoles were further tested by the macro- tions N1 and C-5(6), respectively, enhance the antibacte-
broth dilution assay [6] to determine the MIC's that are rial activities against. Thus, compounds 38–40 were
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34
M. O. Pꢀskꢀllꢀ et al.
Arch. Pharm. Chem. Life Sci. 2010, 343, 31–39
3.06–3.12 (s, 4H), 7.18 (d, 1H, Jo = 8.4 Hz), 7.74 (dd, 1H, Jo = 7.6 Hz),
8.1 (br.s, 2H), 8.37 (s, 1H), 10.6 (br.s, 1H); 13C-NMR (DMSO-d6) d
ppm: 149, 133.1, 129.5, 126.61, 125.8, 121.03, 56.18, 42.94,
38.16; MS m/e: 289 [M + 1] (100%).
designed, and the best result was obtained with 38 (3.12
lg/mL).
Experimental
3-Nitro-4-benzylamino-N-[2-
(dimethylamino)ethyl]benzenesulfonamide 3
Chemistry
A mixture of 1 (0.6 g, 0.18 mmol) and benzyl amine (1 mL) in
DMF (1 mL) was heated under reflux for 5 h at 1108C. The mix-
ture was allowed to cool and water was added. The resultant yel-
low precipitate was filtered, washed with water and crystallized
from ethanol. Yield: 0.5 g (79%); m.p.: 166–1688C; 1H-NMR
(CDCl3) d [ppm]: 2.09 (s, 6H), 2.34 (t, 2H, J = 5.2 Hz), 2.96 (t, 2H, J =
5.2 Hz), 4.6 (d, 2H, J = 5.6 Hz), 6.91 (d, 1H, J = 9.2 Hz), 7.32–7.41
(m, 4H), 7.81 (dd, 1H, Jo = 8.8 Hz, Jm = 2 Hz), 8.71–8.75 (m, 2H);13C-
NMR (CDCl3) d [ppm]: 147.24, 136.27, 133.98, 131.33, 129.39,
128.39, 127.47, 127.28, 126.85, 115.16, 57.12, 47.56, 44.97, 40.21;
MS m/e: 379 [M + 1] (100%).
Uncorrected melting points were measured on an Bꢀchi B-540
capillary melting point apparatus (Bꢀchi Labortechnik, Flawil,
Switzerland). 1H (400 MHz) and 13C (100 MHz) -NMR spectra were
recorded employing a Varian Mercury 400 MHz FT spectrometer
(Varian Inc., Palo Alto, CA, USA), chemical shifts (d) are in ppm
relative to TMS, and coupling constants (J) are reported in Hertz.
Mass spectra were taken on a Waters Micromass ZQ connected
with Waters Alliance HPLC (Waters Corporation, Milford, MA,
USA), using ESI(+) method, with a C-18 column. Elemental analy-
ses were performed by Leco CHNS-932 (Leco, St. Joseph, MI, USA).
The compounds reported as salts were frequently analyzed cor-
rectly for fractional moles of water and / or ethanol from solva-
tion. All chemical and solvents were purchased from Aldrich
Chemical Co. or Fischer Scientific.
3,4-Diamino-N-[2-
(dimethylamino)ethyl]benzenesulfonamide 4
Compound 2 (0.289 g, 1 mmol) in ethanol (30 mL) was subjected
to hydrogenation using 40 psi of H2 and 10% Pd/C until uptake of
H2 ceased. The catalyst was filtered on a bed of Celite, washed
with ethanol, and concentrated in vacuo. The oily residue was
Compound 36 [3], 4-(4-chlorophenoxy)benzaldehyde [7], 4-(3,4-
dimethoxyphenoxy)-benzaldehyde [7], 3-formylbenzensulfonic
acid [8] were published earlier. For the HCl salts of the synthe-
sized compounds, the free bases were dissolved in ethanol and
dry HCl gas was passed through the solution. Because of the tau-
tomeric effect of the imidazole ring in compounds 23–28 and
1
used for the subsequent steps without crystallization. H-NMR
(DMSO-d6) d [ppm]: 2.70 (s, 6H), 2.93 (2H), 3.05 (2H), 6.56 (d, 1H,
Jo = 8 Hz), 6.87 (dd, 1H), 6.93 (s, 1H, Jm = 1.7 Hz), 7.40 (t, 1H); MS
m/e: 259 [M + 1] (100%).
1
30–34, the H-NMR spectra of some compounds are not clear
enough under standard conditions. In order to prevent the tau-
tomeric effects, the compounds were dissolved in DMSO-d6, fol-
lowed by a tiny amount of dry NaH, and 2–3 drops of D2O were
added to the NMR tube and stirred well. As it is reported below
for compounds 23–28 and 30–34, now very clear NMR spectra
were observed.
3-Amino-4-benzylamino-N-[2-
(dimethylamino)ethyl]benzenesulfonamide 5
It was obtained in the manner as described for 4 with compound
3 (0.45 g, 1.19 mmol). 1H-NMR (CDCl3) d [ppm]: 2.09 (s, 6H), 2.34 (t,
2H, J = 5.2 Hz), 2.93 (t, 2H, J = 5.2 Hz), 4.36 (d, 2H), 6.61 (d, 1H, J =
8.4 Hz), 7.25–7.81 (m, 7H); 13C-NMR (CDCl3) d [ppm]: 142.13,
138.42, 133.4, 129, 127.82, 127.6, 121.55, 115.44, 110.2, 57.3,
48.26, 44.9, 40.22; MS m/e: 349 [M + 1] (100%).
4-Chloro-N-[2-(dimethylamino)ethyl]-3-
nitrobenzenesulfonamide N HCl 1
A mixture of N,N-dimethylethylenediamine (1.1 mL, 10 mmol)
and triethylamine (1.39 mL) in dichloromethane (10 mL) was
added dropwise to a solution of 4-chloro-3-nitro-benzenesulfonyl
chloride (2.56 g, 10 mmol) in dichloromethane (25 mL). The mix-
ture was stirred at room temperature for 25 h. The solvent was
removed by rotary evaporation, leaving a yellow powder which
was taken up in ethyl acetate, washed with water, and dried
(Na2SO4), and the solvent was removed in vacuo. Crystallization
of the crude product from ethanolic HCl gave pure, light yellow
colored 1, 3.2 g (92%). M.p.: 175–1778C; 1H-NMR (DMSO-d6) d
[ppm]: 2.78 (s, 6H), 3.12–3.20 (m, 4H), 8.06 (d, 1H, Jo = 8.4 Hz),
8.12 (dd, 1H, Jo = 6.8 Hz, Jm = 1.6 Hz), 8.49 (d, 1H, Jm = 1.6 Hz); 13C-
NMR (DMSO-d6) d [ppm]: 148.18, 140.5, 133.9, 131.21, 130.29,
124.84, 56.22, 38.22, 43.02, 41.24; MS m/e: 308 [M + 1] (100%), 310
[M + 1 + 2] (35%).
3-Nitro-4-aminobenzenesulfonamide 6
A mixture of 4-chloro-3-nitro-benzenesulfonyl chloride (1 g, 0.39
mmol) and dioxane (5 mL) and ethyl acetate (5 mL) was heated in
a sealed tube for 10 h at 1108C. The mixture was allowed to cool
and was evaporated, and the residue was washed with water and
dried. Yield: 0.78 g (91%); m.p.: 207–2088C, lit.: [9]: 2098C.
3,4-Diaminobenzenesulfonamide 7
It was obtained in the manner as described for 4 with compound
6 (0.5 g, 1.19 mmol). Yield: 0.4 g (93%), black colored powder;
m.p.: 170–1728C, lit.: [10] 174–1758C.
4-Amino-N-[2-(dimethylamino)ethyl]-3-
nitrobenzenesulfonamide 2
A mixture of 1 (0.6 g, 0.18 mmol) and saturated ethanolic ammo-
nia (30 mL) was heated in sealed tube for 4 h at 1108C. The mix-
ture was allowed to cool and was then evaporated, the residue
was washed with water and dried. Yield: 0.42 g (84%), yellow col-
ored; m.p.: 250–2528C; 1H-NMR (DMSO-d6) d [ppm]: 2.73 (s, 6H),
4-Chloro-3-nitrobenzenesulfonic acid 8
A mixture of 4-chloro-3-nitro-benzenesulfonyl chloride (0.5 g,
0.195 mmol) and ethanol (85–90%, 30 mL) was heated under
reflux for 1 h. The mixture was allowed to cool, evaporated, and
the solid residue was collected. Yield: 0.4 g, (86%); 1H-NMR
(DMSO-d6) d [ppm]: 7.77 (d, 1H, Jo = 8.4 Hz), 7.88 (dd, 1H, Jo = 8.4
Hz, Jm = 2 Hz), 8.16 (d, 1H, Jm = 2 Hz); 13C-NMR (DMSO-d6) d [ppm]:
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Arch. Pharm. Chem. Life Sci. 2010, 343, 31–39
N-Substituted 1H-Benzimidazole-sulphonamides
35
149.05, 147.5, 132.33, 131.42, 125.82, 123.23; MS ESI(–) m/e: 236
[M – 1] (100%).
(q, J = 33.5 Hz, CF3), 127.69, 125.11, 124.21, 122.4, 121.95, 116.15,
58.49, 45.49, 41.1; MS m/e: 481 [M + 1] (100%). Anal. calcd. for
C19H18F6N4O2S N 0.1 C3H8O: C, 47.65; H, 3.90; N, 11.52; S, 6.59.
Found: C, 47.52; H, 3.94; N, 11.69; S, 6.80.
4-Amino-3-nitrobenzenesulfonic acid 9
A mixture of 8 (0.4 g, 1.7 mmol), ammonium hydroxide solution
(25%, 10 mL) and ethanol (10 mL) was heated in a sealed tube for
6 h at 1008C. The mixture was allowed to cool and was evapo-
rated, the residue was stirred with diluted HCl, washed with
water and dried, heated and stirred in isopropanol, cooled and
filtered. Yield: 0.34 g (93%), yellow colored powder; m.p.: A3008C;
1H-NMR (DMSO-d6) d [ppm]: 6.94 (d, 1H, Jo = 8.8 Hz), 7.52 (dd, 1H, Jo
= 8.8 Hz, Jm = 2 Hz), 7.56 (br.s, D2O exchangable), 8.14 (d, 1H, Jm = 2
Hz); 13C-NMR (DMSO-d6) d [ppm]: 146.93, 136.5, 133.96, 129.12,
122.91, 119.44; MS ESI(–) m/e: 217 [M – 1] (100%).
2-(3,4-Dibenzyloxyphenyl)-N-[2-(dimethylamino)ethyl]-
1H-benzimidazol-5(6)-sulfonamide N HCl 13
It was purified by column chromatography (dichloromethane/
isopropanol/ammonium hydroxide, 12:2:0.1). Yield: 25.5%, m.p.:
1
245–2468C; H-NMR (DMSO-d6) d [ppm]: 2.75 (d, 6H, J = 4 Hz)*,
3.10 (4H)*, 5.32 (s, 2H), 5.35 (s, 2H), 7.32–7.56 (m, 11H), 7.92 (d,
1H, Jo = 9.2 Hz), 7.97 (d, 1H, Jo = 8.4 Hz), 8.10 (d, 1H, Jo = 8 Hz), 8.21
(s, 1H), 8.36 (t, 1H), 8.42 (s, 1H), 10.43 (s, 1H); * D2O exchangable:
2.76 (s, 6H), 3.10 (t, 2H), 3.14 (t, 2H); 13C-NMR (DMSO-d6) d [ppm]:
152.96, 152.69, 149.14, 137.34, 137.21, 136.81, 136.31, 134.12,
129.18, 129.13, 128.69, 128.54, 128.27, 123.76, 123.04, 117.27,
115.4, 114.98, 114.3, 113.94, 71.13, 70.72, 56.27, 43.03, 38.31; MS
m/e: 557 [M + 1] (100%). Anal. calcd. for C31H32N4O4S N 2.3 H2O N 2
HCl: C, 55.48; H, 5.80; N, 8.35; S, 4.78. Found: C, 55.44; H, 5.89; N,
8.44; S, 4.87.
3,4-Diaminobenzenesulfonic acid 10
It was obtained as described for 4 with compound 9 (0.3 g, 1.4
mmol). Yield: 0.2 g, (81%), cream-colored powder; m.p.: >3008C;
1H-NMR (DMSO-d6) d [ppm]: 4.7 (br.s), 6.35 (d, 1H, Jo = 7.6 Hz), 6.65
(dd, 1H, Jo = 8 Hz, Jm = 2 Hz), 7.68 (d, 1H, Jm = 2 Hz); 1H-NMR (D2O) d
[ppm]: 6.70 (d, 1H, Jo = 8.4 Hz), 7.01 (dd, 1H, Jo = 8 Hz, Jm = 2 Hz),
7.044 (d, 1H, Jm = 2 Hz); 13C-NMR (DMSO-d6) d [ppm]: 137.57,
136.23, 134.22. 115.87, 113.26, 113.12; 13C-NMR (D2O) d [ppm]:
137.99, 133.69, 132.89, 118.79, 116.66, 114.7; MS m/e: 189 [M + 1]
(100%).
2-(4-(4-Chlorophenoxy)phenyl)-N-[2-(dimethylamino)-
ethyl]-1H-benzimidazol-5(6)-sulfonamide 14
It was purified by column chromatography (dichloromethane/
isopropanol/ammonium hydroxide, 12:2:0.1). Yield: 12.6%; m.p.:
68–698C; 1H-NMR (DMSO-d6 + 3 drops D2O) d [ppm]: 1.99 (s, 6H),
2.21 (t, 2H), 2.77 (t, 2H), 7.10–7.46 (m, 6H), 7.62 (dd, 1H, Jo = 8.8
Hz, Jm = 1.6 Hz), 7.72 (d, 1H, Jo = 8 Hz), 7.98 (s, 1H), 8.16 (d, 2H); 13C-
NMR (DMSO-d6) d [ppm]: 159.33, 155.21, 154.28, 134.64, 130.82,
129.58, 128.81, 125.41, 121.94, 121.26, 119.3, 58.71, 45.7, 41.4.
MS m/e: 471 [M + 1] (100%), 473 [M + 1 + 2] (33%). Anal. calcd. for
C23H23ClN4O3S N 0.5 C2H6O N 0.5 H2O: C, 57.31; H, 5.41; N, 11.13; S,
6.37. Found: C, 57.49; H, 5.52; N, 11.07; S, 6.40.
General procedure for the synthesis of 11–35 and 37
The corresponding benzaldehydes (6 mmol) were dissolved in
EtOH (20 mL), and sodium metabisulfite (0.64 g) in H2O (3 mL)
was added in portions. The reaction mixture was stirred vigo-
rously and more EtOH was added. The mixture was kept in a
refrigerator for several hours. The precipitate was filtered and
dried. The mixture of these salts (1 mmol) and 4, 5, 7, 10 and
other corresponding o-phenylenediamines (1 mmol) in DMF (1–
2 mL) was heated at 1108C for 4 h. The reaction mixture was
cooled, poured into water, and the solid was filtered. If it was
not solid, it was extracted with chloroform.
2-(3-tert-Butyl-2-hydroxyphenyl)-N-[2-(dimethyl-
amino)ethyl]-1H-benzimidazol-5(6)-sulfonamide 15
It was purified by column chromatography (dichloromethane/
isopropanol/ammonium hydroxide, 20:2:0.05). Yield: 40.4%;
m.p.: 182–1838C; 1H-NMR (DMSO-d6 + 3 drops D2O) d [ppm]: 1.44
(s, 9H), 2.08 (s, 6H), 2.31 (t, 2H), 2.87 (t, 2H), 7.00 (t, 1H, Jo = 8 Hz),
7.42 (d, 1H, Jo = 7.2 Hz), 7.74 (dd, 1H, Jo = 8.4 Hz), 7.84 (d, 1H), 7.90
(d, 1H, Jo = 7.6 Hz), 8.10 (s, 1H); 13C-NMR (DMSO-d6) d [ppm]:
157.76, 155.99, 137.94, 134.79, 130.09, 125.04, 121.80, 119.54,
112.60, 58.30, 45.32, 40.90, 35.30, 29.84; MS m/e: 417 [M + 1]
(100%). Anal. calcd. for C21H28N4O3S: C, 60.55; H, 6.78; N, 13.45; S,
7.70. Found: C, 60.57; H, 6.70; N, 13.37; S, 7.66.
2-(3,4-Dichlorophenyl)-N-[2-(dimethylamino)ethyl]-1H-
benzimidazol-5(6)-sulfonamide 11
It was purified by column chromatography (dichloromethane/
isopropanol/ammonium hydroxide, 12:2:0.1). Yield: 17.5%; m.p.:
196–1978C; 1H-NMR (DMSO-d6) d [ppm]: 2.05 (s, 6H), 2.26 (t, 2H),
2.82 (t, 2H), 7.70 (dd, 1H, Jo = 8.4 Hz, Jm = 1.6 Hz), 7.81 (d, 1H, Jo =
8.4 Hz), 7.88 (d, 1H, Jo = 8.8 Hz), 8.06 (s, 1H), 8.18 (dd, 1H, Jo = 8.4
Hz, Jm = 2 Hz), 8.42 (d, 1H, Jm = 2 Hz); 13C-NMR (DMSO-d6 + NaH + 3
drops D2O) d [ppm]: 159.2, 148.17, 146.5, 138.58, 136.9, 131.4,
130.86, 129.4, 128.4, 127.03, 118.14, 115.94, 115.56, 62.16, 45.77,
44.2; MS m/e: 413 [M + 1] (100%), 415 [M + 1 + 2] (67%), 417 [M + 1 +
4] (11%). Anal. calcd. for C17H18Cl2N4O2S: C, 49.4; H, 4.39; N, 13.56;
S, 7.76. Found: C, 49.03; H, 4.60; N, 13.58; S, 7.70.
2-(3,5-Di-tert-butyl-2-hydroxyphenyl)-N-[2-(dimethyl-
amino)ethyl]-1H-benzimidazol-5(6)-sulfonamide 16
It was purified by column chromatography (dichloromethane/
isopropanol/ammonium hydroxide, 20:2:0.05). Yield: 32.4%;
m.p.: 112–1148C; 1H-NMR (DMSO-d6) d [ppm]: 1.20 (s, 9H), 1.30 (s,
9H), 1.90 (s, 6H), 2.11 (t, 2H), 2.70 (t, 2H), 7.25 (d, 1H, Jm = 2 Hz),
7.58 (d, 1H, Jo = 8.4 Hz), 7.68 (s, 1H), 7.81 (d, 1H), 7.96 (s, 1H), 13.39
(s, 1H); 13C-NMR (DMSO-d6) d [ppm]: 156.22, 155.95, 141.12,
137.06, 135.39, 127.08, 121.66, 111.82, 98.06, 58.71, 45.68, 41.39,
35.54, 34.93, 32.08, 30.0; MS m/e: 473 [M + 1] (100%). Anal. calcd.
for C25H36N4O3S N 0.5 C3H8O: C, 63.31; H, 8.02; N, 11.15; S, 6.38.
Found: C, 63.16; H, 7.89; N, 11.36; S, 6.47.
2-[3,5-Bis(trifluoromethyl)phenyl]-N-[2-(dimethylamino)-
ethyl]-1H-benzimidazol-5(6)-sulfonamide 12
It was purified by column chromatography (dichloromethane/
isopropanol/ammonium hydroxide, 12:2:0.1). Yield: 22.5%; m.p.:
215–2168C; 1H-NMR (DMSO-d6) d [ppm]: 2.04 (s, 6H), 2.24 (t, 2H),
2.81 (t, 2H), 7.70 (dd, 1H, Jo = 8.8 Hz, Jm = 2 Hz), 7.84 (d, 1H, Jo = 8.4
Hz), 8.09 (d, 1H, Jm = 1.2 Hz), 8.30 (s, 1H), 8.82 (s, 2H); 13C-NMR
(DMSO-d6) d [ppm]: 151.9, 141.67, 140.06, 135.28, 132.64, 131.86
i 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

36
M. O. Pꢀskꢀllꢀ et al.
Arch. Pharm. Chem. Life Sci. 2010, 343, 31–39
1-Benzyl-2-(3,4-dichlorophenyl)-N-[2-(dimethylamino)-
1-Benzyl-2-[4-(4-chlorophenoxy)phenyl]-N-[2-
ethyl]-1H-benzimidazol-5-sulfonamide 17
(dimethylamino)ethyl]-1H-benzimidazol-5-sulfonamide 21
It was purified by column chromatography (dichloromethane/
isopropanol/ammonium hydroxide, 12:2:0.1). Yield: 41%; m.p.:
153–1548C; 1H-NMR (DMSO-d6) d [ppm]: 2.05 (s, 6H), 2.25 (t, 2H),
2.85 (t, 2H), 5.65 (s, 2H), 7.01 (d, 2H), 7.12–7.16 (m, 4H), 7.24–
7.28 (m, 3H), 7.45–7.49 (m, 2H), 7.66 (d, 1H, Jo = 8.8 Hz), 7.69 (dd,
1H, Jo = 8.4 Hz, Jm = 1.6 Hz), 7.76–7.79 (m, 2H), 8.15 (d, 1H, Jm = 1.2
Hz); 13C-NMR (DMSO-d6) d [ppm]: 158.91, 155.90, 155.27, 142.61,
138.93, 137.07, 135.31, 131.86, 130.77, 129.54, 128.81, 128.32,
126.80, 125.22, 121.86, 121.66, 119.08, 118.84, 112.44, 58.72,
48.47, 45.69, 41.41; MS m/e: 561 [M + 1] (100%), 563 [M + 1 + 2]
(35%). Anal. calcd. for C30H29ClN4O3S N 0.1 H2O: C, 64.01; H, 5.22;
N, 9.98; S, 5.70. Found: C, 63.94; H, 4.81; N, 10.11; S, 5.83.
It was purified by column chromatography (dichloromethane/
isopropanol/ammonium hydroxide, 12:2:0.1). Yield: 22%; m.p.:
124–1268C; 1H-NMR (CDCl3) d [ppm]: 2.05 (s, 6H), 2.32 (t, 2H), 3.00
(t, 2H), 5.48 (s, 2H), 7.03–7.05 (m, 2H), 7.34–7.36 (m, 4H), 7.48
(dd, 1H, Jo = 8.8 Hz, Jm = 1.6 Hz), 7.55 (d, 1H, Jo = 8 Hz), 7.79 (dd, 1H,
Jo = 8.4 Hz, Jm = 1.6 Hz), 7.83 (d, 1H, Jm = 2 Hz), 8.39 (d, 1H, Jm = 2
Hz); MS m/e: 503 [M + 1] (100%), 505 [M + 1 + 2] (65%), 507 [M + 1 +
4] (11%). Anal. calcd. for C24H24Cl2N4O2S N 0.1 C3H8O N 1.1
CH2Cl2 N 1.5 H2O: C, 48.43; H, 4.80; N, 8.90; S, 5.09. Found: C,
48.22; H, 4.75; N, 9.32; S, 5.45.
2-[3,5-Bis(trifluoromethyl)phenyl]-1-benzyl-N-[2-
(dimethylamino)ethyl]-1H-benzimidazol-5-sulfonamide 18
It was purified by column chromatography (dichloromethane/
isopropanol/ammonium hydroxide, 12:2:0.1). Yield: 31%; m.p.:
174–1758C; 1H-NMR (DMSO-d6) d [ppm]: 2.05 (s, 6H), 2.25 (t, 2H),
2.85 (t, 2H), 5.71 (s, 2H), 7.02 (m, 2H), 7.25–7.31 (m, 3H), 7.79 (dd,
2-(3,4-Dichlorophenyl)-1H-benzimidazol-5(6)-
sulfonamide 22
It was purified by column chromatography (dichloromethane/
isopropanol/ammonium hydroxide, 20:2:0.05). Yield: 20.6%;
m.p.: 254–2568C; 1H-NMR (DMSO-d6 + 3 drops D2O) d [ppm]:
7.67–7.76 (m, 3H), 8.03–8.06 (m, 2H), 8.28 (d, 1H, Jm = 2 Hz); MS
m/e: 342 [M + 1] (100%), 344 [M + 1 + 2] (66%), 346 [M + 1 + 4] (11%).
Anal. calcd. for C13H9Cl2N3O2S N 0.25 C3H8O N 0.5 C2H6O: C, 46.59;
H, 3.71; N, 11.05; S, 8.43. Found: C, 46.78; H, 3.59; N, 11.29; S,
8.41.
1H, Jo = 8.4 Hz, Jm = 2 Hz), 7.87 (d, 1H, Jo = 8.8 Hz), 8.20 (d, 1H, Jm
=
1.6 Hz), 8.29 ve 8.31 (s, s, 3H); 13C-NMR (DMSO-d6) d [ppm]: 153.33,
142.29, 139.28, 136.95, 135.88, 132.69, 131.51 (q, CF3), 130.44,
129.59, 128.44, 126.80, 124.94, 124.55, 122.50, 122.23, 119.40,
112.80, 58.74, 48.68, 45.71, 41.46; 19F-NMR (DMSO-d6) d [ppm]:
–61.873; MS m/e: 571 [M
+ 1] (100%). Anal. calcd. for
C26H24F6N4O2S N 0.2 C2H6O N 0.1 H2O: C, 54.52; H, 4.40; N, 9.63; S,
5.51. Found: C, 54.26; H, 4.01; N, 9.85; S, 5.68.
2-(3-tert-Butyl-2-hydroxyphenyl)-1H-benzimidazol-5(6)-
sulfonamide 23
It was purified by column chromatography (dichloromethane/
isopropanol/ammonium hydroxide, 20:2:0.05). Yield: 49.3%;
m.p.: 234–2358C; 1H-NMR (DMSO-d6 + NaH + 3 drops D2O) d
[ppm]: 1.41 (s, 9H), 6.71 (t, 1H, Jo = 8 Hz), 7.10 (d, 1H, Jo = 7.2 Hz),
7.35 (dd, 1H, Jo = 8 Hz, Jm = 1.6 Hz), 7.45 (d, 1H, Jo = 8.4 Hz), 7.88 (s,
1H), 8.05 (d, 1H, Jo = 7.2 Hz); 13C-NMR (DMSO-d6) d [ppm]: 158.13,
158.07, 155.75, 155.42, 143.26, 140.57, 139.72, 139.35, 137.96,
137.89, 135.87, 133.10, 130.05, 129.96, 125.11, 121.69, 120.87,
119.33, 118.69, 116.36, 112.58, 112.49, 112.44, 110.23, 35.38,
29.93; 13C-NMR (DMSO-d6 + NaH + 3 drops D2O) d [ppm]: 163.87,
158.14, 147.02, 143.92, 136.49, 135.25, 126.52, 125.91, 119.34,
117.72, 116.79, 115.27, 113.95, 35.13, 30.12; MS m/e: 346 [M + 1]
(100%). Anal. calcd. for C17H19N3O3S N 0.1 C4H8O2 N 0.1 H2O: C,
58.69; H, 5.66; N, 11.8; S, 9.00. Found: C, 58.22; H, 5.18; N, 11.51;
S, 8.91.
1-Benzyl-N-[2-(dimethylamino)ethyl]-2-(2,3,5-
trichlorophenyl)-1H-benzimidazol-5-sulfonamide 19
It was purified by column chromatography (dichloromethane/
isopropanol/ammonium hydroxide, 12:2:0.1). Yield: 29.85%;
m.p.: 170–1718C; 1H-NMR (DMSO-d6) d [ppm]: 2.01 (s, 6H), 2.21 (t,
2H), 2.79 (t, 2H), 5.40 (s, 2H), 6.94–7.77(m, 8H), 8.08 (d, 1H, Jm = 2
Hz), 8.16 (s, 1H); 13C-NMR (DMSO-d6) d [ppm]: 151.93, 142.36,
137.69, 136.34, 135.59, 134.25, 133.16, 132.91, 132.71, 131.55,
131.34, 129.28, 128.47, 127.62, 122.21, 119.42, 112.81, 58.76,
48.41, 45.70, 41.45; MS m/e: 537 [M + 1] (98%), 539 [M + 1 + 2]
(100%), 541 [M + 1 + 4] (35%). Anal. calcd. for C24H23Cl3N4O2S: C,
53.59; H, 4.31; N, 10.42; S, 5.96. Found: C, 53.28; H, 4.18; N, 10.41;
S, 6.02.
1-Benzyl-2-(3-bromo-4-fluorophenyl)-N-[2-
2-(3,5-Di-tert-butyl-2-hydroxyphenyl)-1H-benzimidazol-
(dimethylamino)ethyl]-1H-benzimidazol-5-sulfonamide 20 5(6)-sulfonamide 24
It was purified by column chromatography (dichloromethane/
isopropanol/ammonium hydroxide, 12:2:0.1). Yield: 22.7%; m.p.:
142–1438C; 1H-NMR (DMSO-d6) d [ppm]: 2.01 (s, 6H), 2.21 (t, 2H),
2.80 (t, 2H), 5.65 (s, 2H), 6.98 (d, 2H, Jo = 7.6 Hz), 7.24–7.30 (m,
3H), 7.55 (t, 1H, Jo = 8.4 Hz), 7.70–7.79 (m, 3H), 8.05 (dd, 1H, Jo =
6.4 Hz, Jm = 1.6 Hz), 8.15 (s, 1H); 13C-NMR (DMSO-d6) d [ppm]:
160.09 (d, J = 247 Hz), 154.17, 142.40, 138.96, 136.99, 135.57,
134.96, 131.48 (d, J = 8.3 Hz), 129.60, 128.43, 128.26 (d, J = 7.2 Hz),
126.88, 122.05, 119.10, 118.02 (d, J = 22.8 Hz), 112.67, 109.34 (d, J
= 21.3 Hz), 58.75, 48.53, 45.73, 41.46; 19F-NMR (DMSO-d6) d [ppm]:
–85.00; MS m/e: 531 [M + 1] (98%), 533 [M + 1 + 2] (100%). Anal.
calcd. for C24H24BrFN4O2S N 0.1 H2O N 0.1 C3H8O: C, 54.12; H, 4.67;
N, 10.39; S, 5.95. Found: C, 53.97; H, 4.26; N, 10.55; S, 6.15.
It was purified by column chromatography (dichloromethane/
isopropanol/ammonium hydroxide, 20:2:0.05). Yield: 16%; m.p.:
263–2658C; 1H-NMR (DMSO-d6) d [ppm]: 1.21 (s, 9H), 1.30 (s, 9H),
1
7.23–7.28 (m, 3H), 7.60–8.02 (m, 4H), 13.18 ve 13.22 (2H); H-
NMR (DMSO-d6 + NaH + 3 drops D2O) d [ppm]: 1.29 (s, 9H), 1.42 (s,
9H), 7.04 (s, 1H), 7.24 (m, 2H), 7.78 (s, 1H), 8.08 (br.s, 1H); 13C-NMR
(DMSO-d6) d [ppm]: 155.85, 155.67, 155.57, 155.51, 143.08,
140.85, 140.39, 139.31, 138.95, 136.84, 136.74, 135.60, 132.80,
126.82, 126.69, 121.32, 121.30, 120.51, 118.32, 115.99, 112.05,
111.53, 111.44, 109.77, 35.24, 34.64, 31.78, 29.70; 13C-NMR
(DMSO-d6 + NaH + 3 drops D2O) d [ppm]: 163.01, 155.97, 145.35,
143.53, 140.92, 138.93, 135.56, 123.10, 122.37, 118.56, 116.99,
114.53, 113.11, 35.70, 34.82, 32.14, 30.18; MS m/e: 402 [M + 1]
i 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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Arch. Pharm. Chem. Life Sci. 2010, 343, 31–39
N-Substituted 1H-Benzimidazole-sulphonamides
37
(100%). Anal. calcd. for C21H27N3O3S N H2O: C, 60.11; H, 6.96; N,
10.01; S, 7.64. Found: C, 60.1; H, 6.64; N, 10.11; S, 7.66.
117.18, 114.73, 113.56, 35.21, 34.62, 31.81, 29.71; MS m/e: 401 [M
+ 1] (100%).
2-(3-tert-Butyl-2-hydroxyphenyl)-1H-benzimidazole-5(6)-
carboxylic acid 29
2-(3,4-Dichlorophenyl)-1H-benzimidazol-5(6)-sulfonic
acid 25
It was purified by column chromatography (dichloromethane/
methanol/acetic acid, 10:1:0.1). Yield: 24.2%; m.p.: 165–1668C;
1H-NMR (DMSO-d6 + 518C) d [ppm]: 1.37 (s, 9H), 6.93 (t, 1H, Jo = 8
Hz), 7.35 (dd, 1H, Jo = 7.6 Hz, Jm = 1.6 Hz), 7.68 (d, 1H, Jo = 8.4 Hz),
7.9 (dd, 1H, Jo = 8.8 Hz, Jm = 1.6 Hz), 7.94 (d, 1H, Jo = 8 Hz, Jm = 1.6
Hz), 8.22 (s, 1H); 13C-NMR (DMSO-d6 + NaH + 3 drops D2O) d [ppm]:
174.28, 161.69, 159.80, 145.69, 143.17, 136.94, 129.82, 126.21,
125.74, 121.64, 119.17, 117.35, 116.48, 113.98, 35.11, 30.14; MS
m/e: 311 [M + 1] (100%). Anal. calcd. for C18H18N2O3 . H2O: C, 65.83;
H, 6.14; N, 8.53. Found: C, 65.75; H, 6.46; N, 8.84.
It was purified by column chromatography (dichloromethane/
1
ethanol, 10:1). Yield: 29.2%; m.p.: A3008C; H-NMR (DMSO-d6) d
[ppm]: 7.47–8.14 (5H), 8.36 (d, 1H), 13.15 (s, s); 1H-NMR (DMSO-d6
+ NaH + 3 drops D2O) d [ppm]: 7.18 (dd, 1H, Jo = 8 Hz, Jm = 2 Hz),
7.32 (d, 1H, Jo = 8.4 Hz), 7.54 (d, 1H, Jo = 8 Hz), 7.75 (d, 1H), 8.16 (dd,
1H, Jo = 8.4 Hz, Jm = 2 Hz), 8.37 (d, 1H, Jm = 2 Hz); 13C-NMR (DMSO-d6)
d [ppm]: 150.64, 150.53, 144.34, 144.08, 143.31, 143.22, 135.79,
134.73, 133.07, 132.54, 131.99, 131.25, 128.71, 127.21, 122.18,
121.10, 118.74, 116.94, 111.36, 109.76; 13C-NMR (DMSO-d6 + NaH
+ 3 drops D2O) d [ppm]: 159.42, 148.25, 146.45, 138.55, 137.74,
131.47, 130.86, 129.49, 128.50, 127.08, 117.16, 115.53, 114.76;
MS m/e: 343 [M + 1] (100%), 345 [M + 1 + 2] (67%), 347 (11%) [M + 1 +
4]. Anal. calcd. for C13H8Cl2N2O3S N 1.25 CH4O N CH2Cl2 N 0.1
C2H6O: C, 39.25; H, 3.32; N, 5.92; S, 6.78. Found: C, 39.16; H, 3.18;
N, 6.40; S, 6.29.
2-(3,5-Di-tert-butyl-2-hydroxyphenyl)-1H-benzimidazol-
5(6)-carboxylic acid 30
It was purified by column chromatography (dichloromethane/
methanol/acetic acid, 10:1:0.1). Yield: 19.7%; m.p.: 273–2758C;
1H-NMR (DMSO-d6 + NaH + 3 drops D2O) d [ppm]: 1.27 (s, 9H), 1.39
(s, 9H), 7.08 (d, 1H, Jm = 2.8 Hz), 7.27 (d, 1H, Jo = 8 Hz), 7.52 (dd, 1H,
Jo = 8 Hz, Jm = 1.6 Hz), 7.98 (d, 1H, Jm = 1.2 Hz), 8.11 (d, 1H, Jm = 2.4
Hz); 13C-NMR (DMSO-d6 + NaH + 3 drops D2O) d [ppm]: 210.63,
174.10, 162.34, 156.56, 138.43, 135.59, 129.79, 122.92, 122.37,
121.39, 118.63, 117.45, 113.93, 35.29, 34.55, 32.32, 30.23; MS m/
e: 367 [M + 1] (100%). Anal. calcd. for C22H26N2O3: C, 72.11; H, 7.15;
N, 7.64. Found: C, 72.17; H, 7.20; N, 7.99.
2-(2,6-Dichlorophenyl)-1H-benzimidazol-5(6)-sulfonic
acid 26
It was purified by column chromatography (dichloromethane/
methanol/acetic acid, 10:1:0.1). Yield: 24.9%; m.p.: 288–2908C;
1H-NMR (DMSO-d6 + NaH + 3 drops D2O) d [ppm]: 7.19 (dd, 1H, Jo =
8.4 Hz, Jm = 2 Hz), 7.31–7.42 (m, 4H), 7.74 (d, 1H, Jm = 1.6 Hz); 13C-
NMR (DMSO-d6 + NaH + 3 drops D2O) d [ppm]: 158.76, 147.45,
145.51, 138.29, 136.57, 135.72, 130.12, 128.24, 116.13, 115.36,
114.61; MS m/e: 343 [M + 1] (100%), 345 [M + 1 + 2] (66%), 347 [M +
1 + 4] (11%).
2-(3-tert-Butyl-2-hydroxyphenyl)-1H-benzimidazol-5(6)-
carbonitrile 31
It was purified by column chromatography (n-hexane/ethyl ace-
tate, 10:1). Yield: 26%; m.p.: 283–2848C; 1H-NMR (CD3OD + NaH +
3 drops D2O) d [ppm]: 1.45 (s, 9H), 6.76 (t, 1H, Jo = 7.6 Hz), 7.2 (dd,
1H, Jo = 8.2 Hz, Jm = 1.8 Hz), 7.24 (dd, 1H, Jo = 8 Hz, Jm = 1.6 Hz), 7.58
(d, 1H, Jo = 8 Hz), 7.84 (d, Jm = 1.2 Hz, 1H), 8.07 (dd, 1H, Jo = 8 Hz,
Jm = 1.2 Hz); 13C-NMR (CD3OD + NaH + 3 drops D2O) d [ppm]: 165.1,
158.6, 148.3, 144.1, 136.7, 126.7, 125.5, 122.3, 121.9, 119.7,
118.2, 117.1, 115.9, 99.7, 34.6, 29; MS m/e: 292 [M + 1] (100%).
Anal. calcd. for C18H17N3O: C, 74.20; H, 5.88; N, 14.42. Found: C,
73.76; H, 5.51; N, 14.2.
2-(3-tert-Butyl-2-hydroxyphenyl)-1H-benzimidazol-5(6)-
sulfonic acid 27
It was purified by column chromatography (dichloromethane/
ethanol, 10:1). Yield: 29.5%; m.p.: A3008C; 1H-NMR (DMSO-d6 +
NaH + 3 drops D2O) d [ppm]: 1.38 (s, 9H), 6.65 (t, 1H, Jo = 7.6 Hz),
7.04 (d, 1H, Jo = 7.6 Hz), 7.21 (dd, 1H, Jo = 8 Hz, Jm = 1.2 Hz), 7.32 (d,
1H, Jo = 8.4 Hz), 7.71 (s, 1H), 7.99 (dd, 1H, Jo = 7.2 Hz, Jm = 1.2 Hz);
13C-NMR (DMSO-d6) d [ppm]: 157.92, 154.07, 154.01, 144.36,
143.63, 141.24, 140.31, 137.77, 137.75, 133.87, 132.85, 129.45,
124.86, 122.31, 121.39, 119.14, 117.44, 115.62, 112.95, 112.89,
111.19, 109.56, 35.82, 30.08; 13C-NMR (DMSO-d6 + NaH + 3 drops
D2O) d [ppm]: 162.51, 158.63, 145.30, 143.45, 137.59, 136.53,
126.13, 125.78, 119.53, 117.22, 117.16, 114.53, 113.58, 35.82,
30.08; MS m/e: 347 [M + 1] (100%).
2-(3,5-Di-tert-butyl-2-hydroxyphenyl)-1H-benzimidazol-
5(6)-carbonitrile 32 [4]
It was purified by column chromatography (n-hexane/ethyl ace-
tate, 10:1). Yield: 24%; m.p.: 265–2678C; 1H-NMR (DMSO-d6 + NaH
+ 3 drops D2O) d [ppm]: 1.25 (s, 9H), 1.3 (s, 9H), 7.13 (d, 1H, Jm = 2.4
Hz), 7.16 (dd, 1H, Jo = 8.4 Hz, Jm = 1.6 Hz), 7.49 (d, 1H, Jo = 8.4 Hz),
7.80 (d, 1H), 8.12 (d, 1H, Jm = 2.4 Hz); 13C-NMR (DMSO-d6 + NaH + 3
drops D2O) d [ppm]: 165.52, 156.01, 149.08, 145.02, 139.09,
135.62, 123.75, 122.97, 122.87, 122.00, 120.17, 118.41, 116.71,
98.80, 35.31, 34.56, 32.25, 30.18; MS m/e: 348 [M + 1] (100%). Anal.
calcd. for C22H25N3O N 0.1 C4H8O2 N 0.1 C6H14: C, 75.71; H, 7.51; N,
11.51. Found: C, 75.95; H, 7.61; N, 11.30.
2-(3,5-Di-tert-butyl-2-hydroxyphenyl)-1H-benzimidazol-
5(6)-sulfonic acid 28
It was purified by column chromatography (dichloromethane/
1
ethanol, 10:1). Yield: 17.3%; m.p.: A3008C; H-NMR (DMSO-d6
+
NaH + 3 drops D2O) d [ppm]: 1.24 (s, 9H), 1.36 (s, 9H), 7.09 (s, 1H),
7.21 (d, 1H, Jo = 8 Hz), 7.34 (d, 1H, Jo = 8.4 Hz), 7.72 (s, 1H), 8.08 (s,
1H); 13C-NMR (DMSO-d6) d [ppm]: 155.40, 155.35, 154.11, 154.06,
144.03, 143.29, 140.99, 140.62, 140.08, 136.57, 136.52, 133.53,
132.50, 126.13, 126.07, 121.88, 121.12, 121.04, 121.00, 117.04,
115.23, 111.89, 111.83, 110.74, 109.06, 35.21, 34.62, 31.81, 29.71;
13C-NMR (DMSO-d6 + NaH + 3 drops D2O) d [ppm]: 163.20, 155.96,
145.65, 143.59, 139.15, 136.86, 135.70, 123.32, 122.44, 118.47,
2-(3,5-Di-tert-butyl-2-hydroxyphenyl)-5(6)-nitro-1H-
benzimidazole 33
It was purified by column chromatography (n-hexane/ethyl ace-
1
tate, 10:1). Yield: 28.9%; m.p.: 264–2668C; H-NMR (DMSO-d6 +
i 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

38
M. O. Pꢀskꢀllꢀ et al.
Arch. Pharm. Chem. Life Sci. 2010, 343, 31–39
NaH + 3 drops D2O) d [ppm]: 1.22 (s, 9H), 1.38 (s, 9H), 7.16 (d, 1H,
Jm = 2.4 Hz), 7.46 (d, 1H, Jo = 8.8 Hz), 7.82 (dd, 1H, Jo = 8.4 Hz, Jm = 2
Hz), 8.13 (d, 1H, Jm = 2 Hz), 8.29 (d, 1H, Jm = 2 Hz);13C-NMR (DMSO-
d6 + NaH + 3 drops D2O) d [ppm]: 167.39, 155.69, 151.41, 144.44,
139.88, 139.74, 135.79, 124.33, 122.85, 117.94, 115.49, 115.25,
112.13, 35.29, 34.57, 32.17, 30.11; MS m/e: 368 [M + 1] (100%).
Anal. calcd. for C21H25N3O3: C, 68.64; H, 6.86; N, 11.44. Found: C,
68.37; H, 6.92; N, 11.49.
+ 1 + 2] (100%), 569 [M + 1 + 4] (35%). Anal. calcd. for
C26H27Cl3N4O2S N 2.1 HCl N 1.9 H2O N 0.1 C2H6O: C, 46.19; H, 4.96;
N, 8.23; S, 4.71. Found: C, 45.7; H, 5.01; N, 8.70; S, 4.85.
3-(1-(4-Chlorobenzyl)-5,6-dichloro-1H-benzimidazol-
2-yl)-N-(2-(isopropylamino)ethyl)
benzenesulfonamide N HCl 39
It was purified by column chromatography (dichloromethane/
isopropanol/ammonium hydroxide, 10:1:0.1). Yield: 21%; m.p.:
153–1548C; 1H-NMR (DMSO-d6) d [ppm]: 1.17 (d, 6H), 2.92 (t, 2H),
3.07 (t, 2H), 3.21 (m, 1H), 5.69 (s, 2H), 6.99 (d, 2H, Jo = 8.4 Hz), 7.33
(d, 2H, Jo = 8.8 Hz), 7.76 (t, 1H, Jo = 8 Hz), 7.94 (d, 1H, Jo = 8 Hz), 7.99
(d, 1H, Jo = 8 Hz), 8.07 (d, 2H), 8.20 (s, 1H), 9.07 (s, 2H); 13C-NMR
(DMSO-d6) d [ppm]: 154.34, 141.79, 141.06, 136.08, 135.63,
133.58, 133.02, 130.98, 130.38, 129.55, 129.20, 128.81, 127.98,
126.78, 126.38, 121.06, 113.84, 56.73, 50.32, 48.01, 44.02, 19.06;
MS m/e: 551 [M + 1] (98%), 553 [M + 1 + 2] (100%), 555 [M + 1 + 4]
(35%). Anal. calcd. for C25H25Cl3N4O2S N 2 HCl N 0.5 H2O N 0.1
C2H6O: C, 47.4; H, 4.51; N, 8.78; S, 5.02. Found: C, 47.02; H, 4.59;
N, 9.24; S, 5.05.
2-(3,5-Di-tert-butyl-2-hydroxyphenyl)-5(6)-trifluoromethyl-
1H-benzimidazole 34
It was purified by column chromatography (n-hexane/ethyl ace-
tate, 10:1). Yield: 28.9%; m.p.: 82–848C (bubbling); 1H-NMR
(CD3OD + NaH + 3 drops D2O) d [ppm]: 1.25 (s, 9H), 1.36 (s, 9H),
7.35 (m, 2H), 7.65 (d, 1H, Jo = 8.8 Hz), 7.84 (s, 1H), 8.02 (d, 1H, Jm =
2.4 Hz); MS m/e: 391 [M
+ 1] (100%). Anal. calcd. for
C22H25F3N2O N 0.2 H2O: C, 67.06; H, 6.50; N, 7.11. Found: C, 67.1;
H, 6.36; N, 7.00.
2-(3-tert-Butyl-2-hydroxyphenyl)-1H-benzimidazole 35
It was purified by column chromatography (n-hexane/ethyl ace-
1
tate, 10:3). Yield: 41.4%; m.p.: 136–1378C; H-NMR (DMSO-d6, at
1-(4-Chlorobenzyl)-5,6-dichloro-2-(3-(4-methylpiperazin-
0.068 M conc.)* d [ppm]: 1.41 (s, 9H), 6.92 (t, 1H, Jo = 8 Hz), 7.23–
7.28 (m, 2H), 7.32 (dd, 1H, Jo = 7.4 Hz, Jm = 1.6 Hz), 7.57 (dd, 1H, Jo =
8.4 Hz, Jm = 1.2 Hz), 7.70 (dd, 1H, Jo = 7.2 Hz, Jm = 1.2 Hz), 7.90 (dd,
1H, Jo = 8 Hz, Jm = 1.6 Hz), 13.20 ve 14.03 (s, s, 2H);13C-NMR (DMSO-
d6, at 0.068 M conc.) d [ppm]: 158.04, 153.16, 141.27, 137.71,
133.80, 129.20, 124.77, 123.89, 123.01, 118.97, 118.43, 113.01,
112.03, 29.95, 22.05; MS m/e: 267 [M + 1] (100%). Anal. calcd. for
C17H18N2O: C, 76.66; H, 6.81; N, 10.52. Found: C, 76.23; H, 6.80; N,
10.71.
1-yl-sulphonyl)phenyl)-1H-benzimidazole 40
It was purified by column chromatography (dichloromethane/
isopropanol/ammonium hydroxide, 10:1:0.1). Yield: 29.4%; m.p.:
192–1938C; 1H-NMR (DMSO-d6) d [ppm]: 2.11 (s, 3H), 2.30 (s, 4H),
2.74 (s, 4H), 5.64 (s, 2H), 6.93 (d, 2H, Jo = 8 Hz), 7.32 (d, 2H, Jo = 8.8
Hz), 7.80 (t, 1H, Jo = 7.6 Hz), 7.86 (d, 1H, Jo = 8 Hz), 7.89 (s, 1H),
8.06–8.11 (m, 3H); 13C-NMR (DMSO-d6) d [ppm]: 154.40, 142.64,
136.43, 136.26, 135.86, 134.11, 132.96, 131.06, 130.95, 129.83,
129.57, 128.59, 128.37, 126.53, 126.02, 121.48, 113.60, 54.02,
47.83, 46.34, 45.86; MS m/e: 549 [M + 1] (98%), 551 [M + 1 + 2]
(100%), 553 [M + 1 + 4] (35%). Anal. calcd. for C25H23Cl3N4O2S: C,
54.6; H, 4.22; N, 10.19; S, 5.83. Found: C, 54.12; H, 4.11; N, 9.99; S,
5.92.
3-[5,6-Dichloro-1-(4-chlorobenzyl)-1H-benzimidazol-2-yl]
benzenesulfonic acid 37
It was purified by crystallization from ethanol. Yield: 40.1%;
m.p.: 124–1258C; 1H-NMR (DMSO-d6) d [ppm]: 5.63 (s, 2H), 6.99–
7.01 (d, 2H, Jo = 8.4 Hz), 7.34–7.36 (d, 2H, Jo = 8 Hz), 7.48 (q, 1H),
7.62 (d, 1H, Jo = 8 Hz), 7.78 (d, 1H, Jo = 7.6 Hz), 7.91 (s, 1H), 8.04 (s,
1H), 8.06 (s, 1H); MS m/e: 464 [M + 1] (98%), 466 [M + 1 + 2] (100%),
468 [M + 1 + 4] (35%).
Microbiological studies
Activity tests were performed in Mueller–Hinton broth (MHB)
(Difco, Difco Laboratories, Detroit, MI, USA). Four or five S. aureus
colonies from overnight growth on Tryptic Soy Agar (Merck,
Darmstadt, Germany) were suspended in 5 mL saline and the
turbidity was adjusted to match that of a 0.5 McFarland Stand-
art. Then, a portion of the standardized suspension was diluted
1:100 (106 CFU/mL) with MHB. One mL of this dilution was added
to each tube containing 1 mL of the compound diluted in MHB.
All tubes were incubated at 358C for 18 h and MIC's were deter-
mined.
General procedure for the synthesis of 38–40
Compound 37 (0.5 mmol) was refluxed in benzene (3 mL) with
SOCl2 (1 mL) for 2 h at 808C. Then, the solvent and excess SOCl2
were evaporated completely and the residue was dissolved in
dichloromethane (2 mL). Corresponding amine derivatives were
added in excess and the mixture was stirred for 2 h while heated
at 508C. Chloroform was evaporated.
Central Laboratory of Pharmacy Faculty of Ankara University pro-
vided support for the acquisition of the NMR, mass spectrometer, and
elemental analyzer used in this work.
3-(1-(4-Chlorobenzyl)-5,6-dichloro-1H-benzimidazol-2-yl)-
N-(2-(diethylamino)ethyl) benzenesulfonamide N HCl 38
It was purified by column chromatography (dichloromethane/
isopropanol/ammonium hydroxide 10:1:0.1). Yield: 26.6%; m.p.:
The authors have declared no conflict of interest.
1
125–1268C; H-NMR (CDCl3) d [ppm]: 0.90 (t, 6H), 2.39 (q, 4H),
2.48 (t, 2H), 2.90 (t, 2H), 5.39 (s, 2H), 6.98 (d, 2H, Jo = 8 Hz), 7.32 (d,
2H), 7.35 (s, 1H), 7.63 (t, 1H), 7.85 (d, 1H), 7.93 (s, 1H), 7.99 (d, 1H,
Jo = 8 Hz), 8.16 (d, 1H, Jm = 1.6 Hz);13C-NMR (CDCl3) d [ppm]: 153.86,
142.31, 141.14, 135.25, 134.37, 133.51, 132.96, 130.32, 129.90,
129.60, 128.67, 127.90, 127.63, 127.45, 127.30, 121.51, 111.76,
51.04, 48.12, 46.32, 40.19, 11.50; MS m/e: 565 [M + 1] (98%), 567 [M
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