Benzimidazole-1,2,3-triazole hybrid molecules: Synthesis and evaluation for antibacterial/antifungal activity

Article abstract of DOI:10.1002/ardp.201400142

A novel series of hybrid molecules 4a-i and 5a-i were prepared by condensation of 4-(trimethylsilylethynyl)benzaldehyde 1 with substituted o-phenylenediamines. These in turn were reacted with 2-(azidomethoxy)ethyl acetate in a Cu alkyne-azide cycloaddition (CuAAC) to generate the 1,2,3-triazole pharmacophore under microwave assistance. The newly synthesized compounds were examined for their in vitro antimicrobial activities against Gram-positive and Gram-negative bacteria and the phytopathogenic fungi Verticillium dahliae and Fusarium oxysporum f. sp. albedinis. 2-((4-(4-(5-Trifluoromethyl benzimidazol-2-yl)phenyl)-1,2,3-triazol-1-yl)methoxy)ethanol 5e showed a moderate inhibition of 30% in the Foa sporulation test. Hybrid molecules including benzimidazole, benzene, and triazole rings were synthesized and characterized. The compounds were assessed for their in vitro antimicrobial activities against Gram-positive and Gram-negative bacteria and phytopathogenic fungi. 2-((4-(4-(5-Trifluoromethyl benzimidazol-2-yl)phenyl)-1,2,3-triazol-1-yl)-methoxy)ethanol 5e was found to achieve moderate inhibition of 30% in the Foa sporulation test.

Full text of DOI:10.1002/ardp.201400142

Arch. Pharm. Chem. Life Sci. 2014, 347, 1–8
1
Full Paper
Benzimidazole-1,2,3-triazole Hybrid Molecules: Synthesis and
Evaluation for Antibacterial/Antifungal Activity
Abdelaaziz Ouahrouch1,2,3, Hana Ighachane2,4, Moha Taourirte1*, Joachim W. Engels3,
My Hassan Sedra4, and Hassan B. Lazrek2*
1
Laboratory of Bioorganic and Macromolecular Chemistry, Department of Chemistry, Faculty of Sciences and
Technology Gueliz (FSTG), Marrakesh, Morocco
Laboratory of Biomolecular and Medicinal Chemistry, Department of Chemistry, Faculty of Sciences Semlalia,
2
Marrakesh, Morocco
3
Institute for Organic Chemistry and Chemical Biology, Goethe-University Frankfurt am Main, Frankfurt am
Main, Germany
4
Laboratory of Genetic Phytopathology and Microbial Control, INRA, Marrakesh, Morocco
A novel series of hybrid molecules 4a–i and 5a–i were prepared by condensation of 4-
(trimethylsilylethynyl)benzaldehyde 1 with substituted o-phenylenediamines. These in turn were
reacted with 2-(azidomethoxy)ethyl acetate in a Cu alkyne–azide cycloaddition (CuAAC) to generate
the 1,2,3-triazole pharmacophore under microwave assistance. The newly synthesized compounds
were examined for their in vitro antimicrobial activities against Gram-positive and Gram-negative
bacteria and the phytopathogenic fungi Verticillium dahliae and Fusarium oxysporum f. sp. albedinis. 2-((4-(4-
(5-Trifluoromethyl benzimidazol-2-yl)phenyl)-1,2,3-triazol-1-yl)methoxy)ethanol 5e showed a moderate
inhibition of 30% in the Foa sporulation test.
Keywords: Antibacterial activity / Antifungal activity / Hybrid molecules
Received: April 8, 2014; Revised: June 10, 2014; Accepted: June 13, 2014
DOI 10.1002/ardp.201400142
Introduction
The principal way to prepare benzimidazole derivatives is
the condensation of 1,2-phenylenediamines and carbonyl
compounds such as aldehydes [6–11] or acid derivatives [12–
15]. Quite often this reaction is run using the aldehyde route
under mild oxidative conditions.
The 1,2,3-triazole core has been applied in many synthetic
organic chemistry approaches. This heterocycle exhibited a
broad range of efficient biological activities. Moreover, 1,2,3-
triazole derivatives are shown to possess a diversity of
interesting biological activities, including anti-HIV and
hepatitis C [16–18], anti-allergic [19], antifungal [20–23],
anti-tubercular [24, 25], anti-inflammatory agents [26], and
antimicrobial [27].
Infectious diseases have been a serious and growing threat to
human health during the past few decades. The decrease of
sensitivity to anti-microbial agents in current use has also
been increasing for a great variety of pathogens and the
resistance to multiple drugs is more and more prevalent for
several microorganisms, especially for Gram-positive bacteria
and some intractable fungi. The benzimidazole ring is an
important nitrogen-containing heterocyclic compound,
found in several pharmaceutical, synthetic, and natural
products. Benzimidazole-based compounds can exhibit a
broad range of biological activities; i.e., they are efficient
structures against the human cytomegalovirus (HCMV) [1],
they have also been used as antihistaminic [2], antimicrobi-
al [3], antifungal [4], and anti-herpes (HSV-1) [5] agents.
One of the most popular methods to prepare 1,2,3-triazoles
is the cycloaddition of alkyl azides with terminal alkynes via
1,3-dipolar cycloaddition reaction – the Huisgen reaction – as
Correspondence: Prof. Joachim W. Engels, Institute for Organic
Chemistry and Chemical Biology, Goethe-University Frankfurt am Main,
Max-von-Laue-Strasse 7, 60438 Frankfurt am Main, Germany.
E-mail: joachim.engels@chemie.uni-frankfurt.de
ꢀAdditional correspondence: Prof. Moha Taourirte,
E-mail: taourirte@gmail.com; Prof. Hassan B. Lazrek,
E-mail: hblazrek50@gmail.com
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A. Ouahrouch et al.
Arch. Pharm. Chem. Life Sci. 2014, 347, 1–8
a regioisomeric mixture of the 1,4- and 1,5-disubstituted
ones [28]. This reaction was further developed by Meldal and
Sharpless. They discovered that the use of copper(I) as catalyst
guarantees a high regioselectivity and excellent yield allowing
exclusively the 1,4-regioisomer. The copper-catalyzed azide–
alkyne cycloaddition (CuAAC) has thus attracted attention for
use in a variety of applications [29–32].
Syntheses of heterocycles have seen impressive improve-
ments in using different synthetic methods. Especially,
microwave ovens as the heating source have become a very
helpful procedure in their preparation. Microwave irradiation
in general is a powerful tool for fast and efficient synthesis of a
diversity of organic products [33].
Combining preferred heterocyclic entities to construct
hybrid molecules have emerged as an interesting exploratory
concept for developing new pharmaceutical compounds.
They may provide scaffolds on which pharmacophores can be
arranged to yield potent and hopefully selective drugs. The
increase in bacterial resistance has attracted considerable
interest in the discovery and development of new classes of
anti-bacterial agents. The new agents should preferably have
chemical characteristics that clearly differ from those of
existing agents. The search for efficient antibiotics is growing
for the reason that most of antibiotic agents develop
resistance in clinical applications. Hybrid molecules remain
an active area of research despite their extensive
investigation.
In the second step, the trimethylsilyl group was removed by
reacting the products 2a–i with tetrabutylammonium
fluoride in tetrahydrofuran at room temperature [36, 37] to
obtain the terminal acetylene linked to the benzimidazole
core 3a–i (Scheme 2).
Next, the resulting compounds 3a–i with terminal acety-
lene and the azido substrate were condensed using the Cu
alkyne–azide cycloaddition (CuAAC) and triethylamine under
microwave irradiation to achieve the new ring 1-substituted
1,2,3-triazole connected via benzene to the benzimidazole
nucleus 4a–i with excellent yields (Table 1, Scheme 3) and in
very short reaction time. The next step is cleavage of the acetyl
group using potassium carbonate (K2CO3) in methanol [38, 39]
in order to liberate the hydroxy group of the corresponding
hybrid triazolides 5a–h. The latter were obtained in almost
quantitative yields (Table 1, Scheme 3).
The structures of all compounds were characterized by
1H NMR, 13C NMR, mass spectrometry, and HRMS spectra.
The structure of 5a was also confirmed by X-ray diffraction
analysis. This structure contains three planar parts: the
benzimidazole, the benzene, and the triazole ring. Further-
more, various intermolecular hydrogen bond interactions
between the molecules form a three-dimensional network
(the hydrogen at N1 with the nitrogens at N4 and N5 as well
as the hydrogen at O2 with the nitrogen at N2). The
molecular structure of single crystal 5a is shown in
Fig. 1 [40].
Following this concept, we report the synthesis, antibacte-
rial and antifungal evaluation of novel hybrid molecules that
covalently connect 1,2,3-triazolide and benzimidazoles via a
benzene connector.
Antibacterial in vitro screening of compounds 4a–i and
5a–h
All described compounds (4a–i, 5a–h) were evaluated in vitro
for their antibacterial activity against the following bacterial
strains: Staphylococcus aureus (ATCC 13709 in vivo, ATCC 25923,
Oxford and MRSA in vivo), Enterococcus faecalis (ATCC 29212
VanS), Enterococcus faecium (Van A), Streptococcus pneumoniae
(VanA, ATCC49619, PenR and Blood effect), Haemophilus
influenzae (ATCC 31517 MMSA), Escherichia coli (ATCC 25922),
and Pseudomonas aeruginosa (ATCC 27853), using standard
techniques and the minimum inhibitory concentration
values (MICs) [41]. All products were dissolved in DMSO to
have a concentration of 2.56 mg/mL. The MIC of synthesized
compounds against Gram-negative and Gram-positive
Results and discussion
Chemistry
In this report, the hybrid molecules were prepared as
illustrated in the schemes below. In the first step, the 4-
(trimethylsilylethynyl)benzaldehyde 1 was condensed with o-
phenylenediamine derivatives in the presence of Na2S2O5 [34,
35] in dioxane under microwave irradiation to get 2-(4-(2-
(trimethylsilyl)ethynyl)phenyl)benzimidazole derivatives 2a–i
in good yields (Scheme 1).
R
R
N
H2N
Na2S2O5
Si
Si
CHO
1,4-Dioxane
MWI
N
H
X
R'
H2N
R'
X
_
1
2a i
X = C, R = Me, R' = H
b:
c:
X = C, R = Me, R' = Me
a: X = C, R = H, R' = H
e: X = C, R = CF3, R' = H f: X = C, R = F, R' = H
X = N, R = H, R' = H
i: X = C, R = Cl, R' = Cl
d: X = C, R = OMe, R' = H
g:
X = C, R = NO2, R' = H
h:
Scheme 1. Condensation reaction to 2a–i of 4-(trimethylsilylethynyl)benzaldehyde 1 with substituted o-phenylenediamines.
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Arch. Pharm. Chem. Life Sci. 2014, 347, 1–8
Benzimidazole-1,2,3-triazole Hybrid Molecules
3
R
R
N
N
N
(C4H9)4N+ F-
THF
r. t
Si
N
R'
X
R'
X
H
H
_
_
3a i
2a i
X = C, R = Me, R' = H
b:
c:
X = C, R = Me, R' = Me
a: X = C, R = H, R' = H
e: X = C, R = CF3, R' = H f: X = C, R = F, R' = H
X = N, R = H, R' = H
i: X = C, R = Cl, R' = Cl
d: X = C, R = OMe, R' = H
g:
X = C, R = NO2, R' = H
h:
Scheme 2. Deprotection of 2a–i to obtain the free acetylenic compounds 3a–i.
Table 1. Results of 1,2,3-triazole-benzimidazole hybrids.
Entry
Product
Yielda) (%)
Product
Yielda) (%)
1
2
3
4
5
6
7
8
9
4a
4b
4c
4d
4e
4f
4g
4h
4i
93
82
75
86
70
80
60
65
67
5a
5b
5c
5d
5e
5f
5g
5h
–
99
98
98
99
95
98
98
95
–
a)
Isolated yields.
R
N
N
N
N
R
N
CuI / Et3N
MWI
O
N3
O
AcO
N
H
R'
X
R''O
N
H
R'
X
_
_
3a i
4a i, R'' = Ac
Deprotection:
MeOH / K2CO3
_
5a h, R'' = H
X = C, R = Me, R' = H
b:
e: X = C, R = CF3, R' = H f: X = C, R = F, R' = H
h:
c:
a: X = C, R = H, R' = H
X = C, R = Me, R' = Me
d: X = C, R = OMe, R' = H
g:
X = N, R = H, R' = H
X = C, R = NO2, R' = H
i: X = C, R = Cl, R' = Cl
Scheme 3. Microwave assisted Cu alkyne–azide cycloaddition to 4a–i followed by deprotection to 5a–h.
Figure 1. X-ray crystal structure of compound 5a; displacement ellipsoids are drawn at the 50% probability level.
bacteria were tested using ciprofloxacin and linezolid as
standard drugs for comparison. All compounds lacked
antibacterial activity with MICs greater than 64 mg/mL, only
5d showed an activity against H. influenza Hi4 at 32 mg/mL.
Screening of antifungal activity in vitro
The newly synthesized compounds 5a–h were screened for
antifungal activities in vitro against two phytopathogenic
fungi Verticillium dahliae Kleb (VD) and Fusarium oxysporum f. sp.
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Arch. Pharm. Chem. Life Sci. 2014, 347, 1–8
Table 2. Antifungal activities of compounds 5a–h at 20 mg/mL.
Table 3. Title compounds and their sporulation medium.
Linear growth inhibitory rates (%)a)
Sporulation inhibitory rates (means %)a)
Compounds
VD
Foa
Compounds
VD
Foa
PELT
5a
5b
5c
5d
5e
5f
100 ꢁ 0.1
11.29 ꢁ 0.3
13.76 ꢁ 0.6
10.64 ꢁ 0.41
7.21 ꢁ 0.84
29.76 ꢁ 0.2
ꢂ1.69 ꢁ 0.03
ꢂ7.72 ꢁ 1.03
1.56 ꢁ 0.07
100 ꢁ 0.14
3.02 ꢁ 0.96
ꢂ1.59 ꢁ 0.05
2.7 ꢁ 0.16
PELT
5a
5b
5c
5d
5e
5f
100 ꢁ 0.02
ꢂ1.88 ꢁ 0.03
ꢂ18.87 ꢁ 1.9
ꢂ2.13 ꢁ 0.83
ꢂ14.82 ꢁ 0.97
22.04 ꢁ 1.02
ꢂ0.31 ꢁ 0.4
ꢂ12.92 ꢁ 0.6
5.59 ꢁ 0.4
100 ꢁ 0.2
ꢂ5.85 ꢁ 0.04
16.36 ꢁ 0.2
ꢂ34.79 ꢁ 0.72
21.94 ꢁ 0.26
30.62 ꢁ 0.5
ꢂ0.16 ꢁ 0.02
17.01 ꢁ 0.96
2.3 ꢁ 0.29
ꢂ77.59 ꢁ 2.64
ꢂ61.05 ꢁ 1.34
ꢂ48.72 ꢁ 2.35
5g
5h
ꢂ1.41 ꢁ 0.3
ꢂ1.14 ꢁ 0.05
5g
5h
a)
a)
Linear growth inhibitory rates, showing as mean ꢁ standard
Shown as mean ꢁ standard error.
error.
albedinis (Foa) by using the mycelia linear growth rate method
followed by sporulation test (Table 2). The two tests were
carried out as described [42, 43]. All compounds were tested at
a concentration of 20 mg/mL (H. B. Lazrek, unpublished
results). A positive control is Pelt, which is a systemic
was evaluated in the aim to know their fungicidal or
fungistatic effect (Table 2, 3). The structure of this molecule
uniquely holds a CF3 group fixed to the benzimidazole core.
Since the trifluoromethyl group due to their lipophilicity
is known to modulate absorption and metabolism, it may
explain the enhanced activity.
fungicide,
a benzimidazole precursor (70% of methyl
thiophanate). The trial was established as a completely
randomized experimental design with five replicates. Data
were subjected to analysis of variance using SPSS software
V17.0. The mean values among treatments were compared by
As shown in Table 3, benzimidazole derivatives 5b, 5d, and
5e exhibited a weak inhibition effect on the growth of Foa
sporulation.
Duncan’s multiple range tests at a 5% (p < 0.05) level to Conclusion
determine significant difference between the inhibition rates
of various compounds at the same concentration.
In summary, we have described the synthesis of a series of
The result of the mycelia linear growth rate indicates that
some of the compounds show a weak inhibition against the
two fungi, the only compound that shows a significantly
increased rate is compound 5e with (29.76%) (p < 0.05) against
Verticillium dahliae (Fig. 2). On the other hand, the sporulation
hybrid molecules, which combined two “privileged pharma-
cophore” heterocycles (benzimidazole and 1,2,3-triazole) in
excellent yields using simple, efficient, and fast routes. These
benzimidazole/triazoles 5a–h were tested against Gram-
negative and Gram-positive bacteria and as antifungal agents,
Figure 2. Comparison of the inhibition rate (%) of compounds 5a–h at the 8th day against VD and Foa at 20 mg/mL.
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Arch. Pharm. Chem. Life Sci. 2014, 347, 1–8
Benzimidazole-1,2,3-triazole Hybrid Molecules
5
only very modest inhibition against sporulation of F.
oxysporum f. sp. albedinis (Foa) was observed for some of these
analogs and a modest inhibition was found for the CF3
substituted 5e.
CH-triazole), 8.02 (d, 2H, Ar–H, J ¼ 7.6 Hz), 8.19 (d, 2H, Ar–H,
J ¼ 7.2 Hz), 8.71 (s, 1H, NH). 13C NMR (100 MHz, CDCl3) d (ppm):
59.71, 67.28 (CH2), 78.35 (CH2), 114.96, 122.38 (Bzm-CH), 122.94,
125.94 (phenyl-CH), 127.15 (phenyl-C), 128.79 (triazole-CH), 131.57
(Bzm-C), 146.18 (triazole-C), 151.77 (Bzm-C), 171.12 (CO). ESI-MS
m/z calcd. for C20H19N5O3 (MþH): 378.40, found: 378.50.
Experimental
2-((4-(4-(5-Methyl benzimidazol-2-yl)phenyl)-1,2,3-triazol-
1-yl)methoxy)ethyl acetate (4b)
General methods
Yield: 82%; Rf: 0.63; eluent: CH2Cl2/MeOH, 95:5 v/v; 1H NMR
(400 MHz, DMSO-d6) d (ppm): 1.89 (s, 3H, –CH3), 2.38 (s, 3H,
Ar–CH3), 3.74 (m, 4H, –CH2–), 5.77 (s, 2H, –CH2–), 7.07 (d, 2H,
Ar–H, J ¼ 8.0 Hz), 7.43 (s, 1H, CH-triazole), 7.54 (d, 1H, Ar–H,
J ¼ 7.2 Hz), 7.99 (d, 2H, Ar–H, J ¼ 8.00 Hz), 8.17 (d, 2H, Ar–H,
J ¼ 7.6 Hz), 8.69 (s, 1H, NH). 13C NMR (100 MHz, CDCl3) d (ppm):
20.36 (CH3), 21.08 (Bzm-CH3), 62.74, 67.33 (CH2), 78.46 (CH2),
114.17, 114.97, 122.29 (Bzm-CH), 124.44, 125.82 (phenyl-CH),
126.97 (phenyl-C), 127.16 (triazole-CH), 131.57, 132.67 (Bzm-C),
146.13 (triazole-C), 153.91 (Bzm-C), 171.09 (CO). ESI-MS m/z calcd.
for C21H21N5O3 (MþH): 392.42, found: 392.40.
All starting materials for synthesis were purchased from Alfa
Aesar, Fluka, or Sigma–Aldrich; thin-layer chromatography (TLC):
aluminum sheets, silica gel 60 F254. Melting points were
measured using
a Stuart Scientific melting point (SMP1)
apparatus. NMR spectra were recorded with a Bruker AC-
300 MHz and AC-400 MHz in CDCl3 and DMSO-d6 with SiMe4 as
an internal standard. Chemical shifts are given in ppm and the
spin–spin coupling constants, J, are given in Hz (s, singlet; d,
doublet; t, triplet; m, multiplet, and br, broad); Bzm ¼ benzimid-
azole and Imzp ¼ imidazo[4,5-b]pyridine.
All microwave-assisted syntheses were carried out in
a
dedicated CEM-Discover mono-mode microwave apparatus. ESI-
mass spectrometry was performed on a Fisons instrument
equipped with a VG platform II with quadrupole analyzer.
High-resolution mass spectrometry (HRMS) was performed with a
MALDI Orbitrap LTQ XL instrument (Thermo Fisher).
2-((4-(4-(5,6-Dimethyl benzimidazol-2-yl)phenyl)-1,2,3-
triazol-1-yl)methoxy)ethyl acetate (4c)
Yield: 75%; Rf: 0.64; eluent: CH2Cl2/MeOH, 95:5 v/v; 1H NMR
(400 MHz, DMSO-d6) d (ppm): 1.89 (s, 3H, –CH3), 2.27 (s, 6H, Ar–
CH3), 3.74 (m, 4H, –CH2–), 5.77 (s, 2H, –CH2–), 7.38 (s, 1H, CH-
triazole), 7.99 (m, 3H, Ar–H), 8.13 (m, 3H, Ar–H), 8.68 (s, 1H, NH).
13C NMR (100 MHz, CDCl3) d (ppm): 19.83 (Bzm-CH3), 20.37 (CH3),
62.70, 67.27 (CH2), 78.33 (CH2), 114.94 (Bzm-CH), 125.84, 126.71
(phenyl-CH), 129.09 (triazole-CH), 131.12 (phenyl-C), 131.61 (Bzm-
C), 146.25 (triazole-C), 151.92 (Bzm-C), 171.16 (CO). ESI-MS m/z
calcd. for C22H23N5O3 (MꢂH): 404.45, found: 404.27.
General procedure for the synthesis of compounds 4a–h
A
mixture of 4-(trimethylsilylethynyl)benzaldehyde (150 mg,
0.74 mmol), 2 equivalents of the appropriate ortho-phenylenedi-
amine and 1.01 equivalents of sodium metabisulfite were
dissolved in 1 mL of dioxane and reacted under microwave
irradiation for 2 min. The residue was poured in water and
extracted with ethyl acetate (3 ꢃ 20 mL). The organic extract was
dried over Na2SO4 and evaporated under reduced pressure. The
crude products were purified by column chromatography using a
methylene chloride and methanol mixture in 98:2 ratio.
The benzimidazole compounds 2a–i were obtained in good
yields (84–95%).
The trimethylsilyl group was cleaved by reaction of tetrabu-
tylammonium fluoride (1 equivalent) with the compounds 2a–i
in tetrahydrofuran (2.5 mL), the reaction was monitored by TLC
analysis until complete consumption of the protected product
(20–30 min). The resulting products 3a–i were purified by
column chromatography eluting with methylene chloride/
methanol (95:5). This reaction is characterized by giving
excellent yields.
2-((4-(4-(5-Methoxy benzimidazol-2-yl)phenyl)-1,2,3-
triazol-1-yl)methoxy)ethyl acetate (4d)
Yield: 86%; Rf: 0.60; eluent: CH2Cl2/MeOH, 95:5 v/v; 1H NMR
(300 MHz, DMSO-d6) d (ppm): 1.88 (s, 3H, –CH3), 3.72 (m, 4H,
–CH2–), 3.74 (s, 3H, –OCH3), 5.75 (s, 2H, –CH2–), 6.83 (dd, 2H, Ar–H,
J ¼ 8.0 Hz), 7.12 (s, 1H, CH-triazole), 7.54 (d, 1H, Ar–H, J ¼ 8.0 Hz),
7.90 (d, 2H, Ar–H, J ¼ 8.4 Hz), 8.12 (d, 2H, Ar–H, J ¼ 8.4 Hz), 8.61
(s, 1H, NH). 13C NMR (75 MHz, CDCl3) d (ppm): 20.35 (CH3), 55.42
(–OCH3), 62.74, 67.28 (CH2), 78.33 (CH2), 97.22, 112.52, 116.15
(Bzm-CH), 125.76, 125.90 (phenyl-CH), 126.82 (triazole-CH), 128.67
(phenyl-C), 131.29 (Bzm-C), 146.14 (triazole-C), 156.13 (Bzm-C),
171.16 (CO). ESI-MS m/z calcd. for C21H21N5O4 (MþH): 408.42,
found: 408.40.
The terminal alkynes 3a–i, ethanol 2-(azidomethoxy)acetate
(2.5 equivalents), triethylamine (1 equivalent), and copper(I)
iodide (0.1 equivalents) were irradiated in a microwave oven
using 300 W as power level for 2 min. The crude products 4a–i
were then purified on silica gel column using methylene chloride/
methanol (95:5) as eluent to afford the expected compounds.
2-((4-(4-(5-Trifluoromethyl benzimidazol-2-yl)phenyl)-
1,2,3-triazol-1-yl)methoxy)ethyl acetate (4e)
Yield: 70%; Rf: 0.50; eluent: CH2Cl2/MeOH, 95:5 v/v; 1H NMR
(400 MHz, DMSO-d6) d (ppm): 1.90 (s, 3H, –CH3), 3.74 (m, 4H,
–CH2–), 5.77 (s, 2H, –CH2–), 7.51 (d, 1H, Ar–H, J ¼ 8.4 Hz), 7.76
(d, 1H, Ar–H, J ¼ 8.4 Hz), 7.94 (s, 1H, CH-triazole), 8.01 (d, 2H, Ar–H,
J ¼ 8.4 Hz), 8.17 (m, 3H, Ar–H), 8.70 (s, 1H, NH). 13C NMR (75 MHz,
CDCl3) d (ppm): 20.35 (CH3), 62.73, 67.25 (CH2), 78.32 (CH2), 119.20,
122.40, 123.43 (Bzm-CH), 123.01 (–CF3), 125.70, 125.92 (phenyl-
CH), 127.57 (triazole-CH), 128.30 (phenyl-C), 132.05 (Bzm-C),
146.05 (triazole-C), 153.45 (Bzm-C), 171.09 (CO). ESI-MS m/z calcd.
for C21H18F3N5O3 (MþH): 446.39, found: 446.35.
Spectral data for selected compounds 4a–h
2-((4-(4-(Benzimidazol-2-yl)phenyl)-1,2,3-triazol-1-yl)-
methoxy)ethyl acetate (4a)
Yield: 93%; Rf: 0.63; eluent: CH2Cl2/MeOH, 95:5 v/v; 1H NMR
(400 MHz, DMSO-d6) d (ppm): 1.90 (s, 3H, –CH3), 3.75 (m, 4H,
–CH2–), 5.78 (s, 2H, –CH2–), 7.26 (m, 2H, Ar–H), 7.64 (m, 3H, Ar–H,
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Arch. Pharm. Chem. Life Sci. 2014, 347, 1–8
2-((4-(4-(5-Fluoro benzimidazol-2-yl)phenyl)-1,2,3-triazol-
Spectral data for selected compounds 5a–h
1-yl)methoxy)ethyl acetate (4f)
Yield : 80%; Rf: 0.50; eluent: CH2Cl2/MeOH, 95:5 v/v; 1H NMR
(300 MHz, DMSO-d6) d (ppm): 1.89 (s, 3H, –CH3), 3.74 (m, 4H,
–CH2–), 5.76 (s, 2H, –CH2–), 7.02 (m, 1H, Ar–H), 7.36 (d, 1H, Ar–H,
J ¼ 11.6 Hz), 7.58 (s, 1H, CH-triazole), 7.98 (d, 2H, Ar–H, J ¼ 8.4 Hz),
8.12 (m, 3H, Ar–H, J ¼ 8.4 Hz), 8.67 (s, 1H, NH). 13C NMR (75 MHz,
CDCl3) d (ppm): 20.34 (CH3), 62.73, 67.24 (CH2), 78.31 (CH2), 115.64,
122.34 (Bzm-CH), 125.71, 125.99 (phenyl-CH), 127.14 (triazole-CH),
128.55 (phenyl-C), 131.60 (Bzm-C), 146.11 (triazole-C), 157.22,
160.35 (Bzm-C), 171.16 (CO). ESI-MS m/z calcd. for C20H18FN5O3
(MꢂH): 394.39, found: 394.45.
2-((4-(4-(Benzimidazol-2-yl)phenyl)-1,2,3-triazol-1-yl)-
methoxy)ethanol (5a)
M.p. 229–230°C; yield: 99%; Rf: 0.40; eluent: CH2Cl2/MeOH, 9:1 v/v;
1H NMR (400 MHz, DMSO-d6) d (ppm): 3.52 (t, 2H, –CH2–,
J ¼ 4.0 Hz), 3.55 (t, 2H, –CH2–, J ¼ 4.0 Hz), 5.19 (bs, 1H, –OH),
5.76 (s, 2H, –CH2–), 7.21–7.33 (m, 2H, Ar–H), 7.60–7.69 (m, 3H, Ar–
H, CH-triazole), 8.01 (d, 2H, Ar–H, J ¼ 8.4 Hz), 8.17 (d, 2H, Ar–H,
J ¼ 8.4 Hz), 8.64 (s, 1H, NH). 13C NMR (100 MHz, CDCl3) d (ppm):
59.71, 70.90 (CH2), 78.56 (CH2), 122.25, 122.77 (Bzm-CH), 125.90
(phenyl-CH), 127.07 (phenyl-C), 128.94 (triazole-CH), 131.46 (Bzm-
C), 146.15 (triazole-C), 151.73 (Bzm-C). ESI-MS m/z calcd. for
2-((4-(4-(6-Nitrobenzimidazol-2-yl)phenyl)-1H-1,2,3-
triazol-1-yl)methoxy)ethyl acetate (4g)
C
18H17N5O2 (MþH): 336.36, found: 336.4. HRMS (MþH): calcd. for
C18H17N5O2 : 336.14550, found: 336.14574.
Yield: 60%; Rf: 0.50; eluent: CH2Cl2/MeOH, 95:5 v/v; 1H NMR
(300 MHz, DMSO-d6) d (ppm): 1.90 (s, 3H, –CH3), 3.73 (m, 4H,
–CH2–), 5.73 (s, 2H, –CH2–), 7.60 (d, 1H, Ar–H, J ¼ 8.4 Hz), 7.86–7.89
(m, 2H, Ar–H, 8.2 Hz), 7.95–8.03 (m, 4H, Ar–H, J ¼ 8.0 Hz), 8.30 (s,
1H, CH-triazole), 8.62 (s, 1H, NH). 13C NMR (75 MHz, CDCl3) d
(ppm): 20.38 (CH3), 62.75, 67.29 (CH2), 78.39 (CH2), 104.51, 114.13,
118.22 (Bzm-CH), 125.82, 127.52 (phenyl-CH), 128.63 (triazole-CH),
132.25, 133.15 (phenyl-C), 145.99, 142.71 (Bzm-C), 150.68 (triazole-
C), 155.25 (Bzm-C), 171.12 (CO). ESI-MS m/z calcd. for C20H18N6O5
(MꢂH): 421.39, found: 421.44.
2-((4-(4-(5-Methyl benzimidazol-2-yl)phenyl)-1,2,3-triazol-
1-yl)methoxy)ethanol (5b)
M.p. 203–204°C; yield: 98%; Rf: 0.40; eluent: CH2Cl2/MeOH, 9:1 v/v;
1H NMR (400 MHz,DMSO-d6) d (ppm): 2.34 (s, 3H, Ar–CH3), 3.52 (t,
2H, –CH2–, J ¼ 3.6 Hz), 3.54 (t, 2H, –CH2–, J ¼ 3.6 Hz), 5.26 (bs, 1H,
–OH), 5.75 (s, 2H, –CH2–), 7.00 (d, 2H, Ar–H, J ¼ 8.0 Hz), 7.37 (s, 1H,
CH-triazole), 7.49 (d, 1H, Ar–H, J ¼ 7.6 Hz), 7.95 (d, 2H, Ar–H,
J ¼ 8.00 Hz), 8.14 (d, 2H, Ar–H, J ¼ 6.4 Hz), 8.64 (s, 1H, NH). 13C NMR
(100 MHz, CDCl3) d (ppm): 21.08 (Bzm-CH3), 59.71, 70.89 (CH2),
78.54 (CH2), 114.21, 122.15, 124.17 (Bzm-CH), 125.83 (phenyl-CH),
126.88 (phenyl-C), 129.04 (triazole-CH), 131.25, 132.21 (Bzm-C),
146.18 (triazole-C), 150.44 (Bzm-C). ESI-MS m/z calcd. for
C19H19N5O2 (MþH): 350.39, found: 350.1. HRMS (MþH): calcd.
for C19H19N5O2: 350.16115, found: 350.16114.
2-((4-(4-(Imidazo[4,5-b]pyridin-2-yl)phenyl)-1,2,3-triazol-1-
yl)methoxy)ethyl acetate (4h)
Yield: 65%; Rf: 0.60; eluent: CH2Cl2/MeOH, 95:5 v/v; 1H NMR
(300 MHz, DMSO-d6) d (ppm): 1.90 (s, 3H, –CH3), 3.75 (m, 4H,
–CH2–), 5.78 (s, 2H, –CH2–), 7.29 (dd, 1H, Ar–H, J ¼ 12 Hz), 8.00–
8.05 (m, 4H, Ar–H), 8.23 (d, 2H, Ar–H, J ¼ 12.4 Hz), 8.33 (s, 1H, CH-
triazole), 8.71 (s, 1H, NH). 13C NMR (75 MHz, CDCl3) d (ppm): 20.37
(CH3), 62.74, 67.27 (CH2), 78.35 (CH2), 118.70, 122.49 (Imzp-CH),
125.92, 126.02 (phenyl-CH), 127.58 (phenyl-C), 128.49 (triazole-
CH), 132.08 (Imzp-CH), 144.07 (Imzp-C), 146.09 (triazole-C), 152.65
(Imzp-C), 171.11 (CO). ESI-MS m/z calcd. for C19H18N6O3 (MþH):
379.38, found: 379.50.
2-((4-(4-(5,6-Dimethyl benzimidazol-2-yl)phenyl)-1,2,3-
triazol-1-yl)methoxy)ethanol (5c)
M.p. 233–234°C; yield: 98%; Rf: 0.45; eluent: CH2Cl2/MeOH, 9:1 v/v;
1H NMR (400 MHz, DMSO-d6) d (ppm): 2.26 (s, 6H, Ar–CH3), 3.51 (t,
2H, –CH2–, J ¼ 3.6 Hz), 3.55 (t, 2H, –CH2–, J ¼ 3.6 Hz), 5.19 (bs, 1H,
–OH), 5.76 (s, 2H, –CH2–), 7.36 (s, 1H, CH-triazole), 7.96–7.99 (m,
3H, Ar–H), 8.11–8.14 (m, 3H, Ar–H), 8.66 (s, 1H, NH). 13C NMR
(100 MHz, CDCl3) d (ppm): 19.83 (Bzm-CH3), 59.70, 70.89 (CH2),
78.55 (CH2), 122.17 (Bzm-CH), 126.79 (phenyl-CH), 129.18 (phenyl-
C), 131.09 (triazole-CH), 131.50 (Bzm-C), 146.21 (triazole-C), 149.87
(Bzm-C). ESI-MS m/z calcd. for C20H21N5O2 (MþH): 364.41, found:
364.5. HRMS (MþH): calcd. for C20H21N5O2: 364.17680, found:
364.17704.
2-((4-(4-(5,6-Dichlorobenzimidazol-2-yl)phenyl)-1,2,3-
triazol-1-yl)methoxy)ethyl acetate (4i)
Yield: 67%; Rf: 0.65; eluent: CH2Cl2/MeOH, 95:5 v/v; 1H NMR
(300 MHz, DMSO-d6) d (ppm): 1.89 (s, 3H, –CH3), 3.74 (m, 4H,
–CH2–), 5.76 (s, 2H, –CH2–), 7.77 (m, 2H, Ar–H), 7.95 (s, 1H, CH-
triazole), 8.07 (m, 2H, Ar–H, 8.4 Hz), 8.13 (d, 2H, Ar–H, J ¼ 8.0 Hz),
8.67 (s, 1H, NH). 13C NMR (75 MHz, CDCl3) d (ppm): 20.36 (CH3),
62.73, 67.24 (CH2), 78.30 (CH2), 122.29, 124.86 (Bzm-CH), 125.70,
127.08 (phenyl-CH), 128.10 (Bzm-C), 128.89 (triazole-CH), 131.80,
133.35 (phenyl-C), 137.48 (Bzm-C), 146.03 (triazole-C), 153.15
(Bzm-C), 171.07 (CO). ESI-MS (MꢂH), m/z calcd. for C20H18N6O5:
446.29, found: 445.40.
2-((4-(4-(5-Methoxy benzimidazol-2-yl)phenyl)-1,2,3-
triazol-1-yl)methoxy)ethanol (5d)
M.p. 172–173°C; yield: 99%; Rf: 0.40; eluent: CH2Cl2/MeOH, 9:1 v/v;
1H NMR (300 MHz, DMSO-d6) d (ppm): 3.48 (t, 2H, –CH2–,
J ¼ 3.6 Hz), 3.52 (t, 2H, –CH2–, J ¼ 4 Hz), 3.74 (s, 3H, –OCH3),
5.16 (bs, 1H, –OH), 5.74 (s, 2H, –CH2–), 6.81–6.84 (dd, 2H, Ar–H,
J ¼ 11.6 Hz), 7.09 (s, 1H, CH-triazole), 7.47 (d, 1H, Ar–H, J ¼ 11.6
Hz), 7.96 (d, 2H, Ar–H, J ¼ 11.2 Hz), 8.08 (d, 2H, Ar–H, J ¼ 10.8 Hz),
8.64 (s, 1H, NH). 13C NMR (75 MHz, CDCl3) d (ppm): 55.39 (–OCH3),
59.68, 70.86 (CH2), 78.33 (CH2), 112.29, 122.16 (Bzm-CH), 125.84,
125.91 (phenyl-CH), 126.70 (phenyl-C), 129.05 (triazole-CH), 131.14
(Bzm-C), 146.16 (triazole-C), 155.99 (Bzm-C). ESI-MS m/z calcd. for
C19H19N5O3 (MþH): 366.39, found: 366.3. HRMS (MþH): calcd. for
General procedure for the synthesis of compounds 5a–h
The compounds 4a–h were reacted at room temperature with K2CO3
(2 equivalents) in methanol 2.5 mL. The mixture was stirred for
30 min. The reaction was monitored by TLC analysis. The solvent was
evaporated under reduced pressure. Then, the crude compounds
5a–h were purified by passing through a flash chromatography
column using methylene chloride/methanol (95:5) as eluent.
C19H19N5O3: 366.15607, found: 366.15583.
ß 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

Arch. Pharm. Chem. Life Sci. 2014, 347, 1–8
Benzimidazole-1,2,3-triazole Hybrid Molecules
7
2-((4-(4-(5-Trifluoromethyl benzimidazol-2-yl)phenyl)-
1,2,3-triazol-1-yl)methoxy)ethanol (5e)
project. We would like to thank all members of the instrumental
laboratory (Goethe-University Frankfurt am Main) for their help (NMR
and mass analysis). We gratefully acknowledge the experimental help
in testing the compounds by Phil Dudfield VP, Alliances and Informatics
Galapagos NV, 102 avenue Gaston Roussel, 93230 Romainville.
M.p. 150–151°C; yield: 95%; Rf: 0.30; eluent: CH2Cl2/MeOH, 9:1 v/v;
1H NMR (300 MHz, DMSO-d6) d (ppm): 3.52 (m, 4H, –CH2–), 5.16 (bs,
1H, –OH), 5.72 (s, 2H, –CH2–), 7.41 (d, 1H, Ar–H, J ¼ 11.2 Hz), 7.70
(d, 1H, Ar–H, J ¼ 11.2 Hz), 7.86 (s, 1H, CH-triazole), 7.94 (d, 2H, Ar–
H, J ¼ 10.0 Hz), 8.10 (m, 3H, Ar–H), 8.63 (s, 1H, NH). 13C NMR
(75 MHz, CDCl3) d (ppm): 59.68, 62.46 (CH2), 78.52 (CH2), 119.08,
122.26, 122.90 (Bzm-CH), 123.32 (–CF3) 125.64, 125.84 (phenyl-
CH), 127.30 (triazole-CH), 128.16 (phenyl-C), 131.96 (Bzm-C),
145.99 (triazole-C), 153.33 (Bzm-C). ESI-MS m/z calcd. for
C19H16F3N5O2 (MþH): 404.36, found: 404.5. HRMS (MþH): calcd.
for C19H16F3N5O2: 404.13289, found: 404.13232.
The authors have declared no conflict of interest.
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