Catechol-bearing imidazolium and benzimidazolium chlorides as promising antimicrobial agents

Article abstract of DOI:10.1002/ardp.202000013

Catechol-containing imidazolium (four) and benzimidazolium chlorides (eight) were synthesized to evaluate their antimicrobial properties. All the compounds were fully characterized using ¹H and ¹³C nuclear magnetic resonance, liquid

Full text of DOI:10.1002/ardp.202000013

Received: 12 January 2020
Revised: 26 March 2020
Accepted: 27 March 2020
|
|
DOI: 10.1002/ardp.202000013
F U L L P A P E R
Catechol‐bearingimidazoliumandbenzimidazoliumchlorides
as promising antimicrobial agents
1
2
2
1
Mert O. Karataş
| Selami Günal | Ahmet Mansur | Bülent Alıcı
|
1
,3
İsmail Özdemir
1
Department of Chemistry, Faculty of Science,
İnönü University, Malatya, Turkey
Abstract
2
Department of Microbiology, Faculty of
Catechol‐containing imidazolium (four) and benzimidazolium chlorides (eight) were
Pharmacy, İnönü University, Malatya, Turkey
3
synthesized to evaluate their antimicrobial properties. All the compounds were fully
Catalysis Research and Application Centre,
1
13
İnönü University, Malatya, Turkey
characterized using H and C nuclear magnetic resonance, liquid chromatography–mass
spectrometry, infrared spectroscopic methods, and elemental analyses. Antimicrobial
activities of the compounds were tested against the bacteria Escherichia coli,
Pseudomonas aeruginosa, Acinetobacter baumannii, Klebsiella pneumoniae, Staphylococcus
aureus, methicillin‐resistant S. aureus (MRSA), Enterococcus faecalis, and the fungal strains
Candida albicans and Candida glabrata , and promising results were achieved. The two
most important benzyl‐substituted benzimidazolium chlorides, 3l and 3k, showed com-
parable activity to vancomycin against MRSA.
Correspondence
Mert O. Karataş and İsmail Özdemir,
Department of Chemistry, Faculty of Science,
İnönü University, 9044280 Malatya, Turkey.
Email: mert.karatas@inonu.edu.tr (M. O. K.)
and ismail.ozdemir@inonu.edu.tr (İ. Ö.)
K E Y W O R D S
antibacterial, antifungal, benzimidazolium, catechol, imidazolium
1
| INTRODUCTION
Imidazolium and benzimidazolium salts are ionic compounds
which have been mainly synthesized as N‐heterocyclic carbene
[
5]
The emergence of microorganisms which have resistance against
pharmaceutical and agrochemical antimicrobial agents forced
scientists to develop more effective antimicrobial agents with low
(NHC) precursors in organometallic chemistry.
The biological
properties of imidazolium and benzimidazolium salts have been less
frequently investigated compared with their neutral derivatives.
As natural products, two imidazolium salts (Figure 1), which have
remarkable cytotoxic effects, were isolated from the roots of
[
1]
toxicity. For this purpose, many classes of compounds are being
investigated owing to their presence in the structure of natural
products and demonstrated pharmaceutical properties, hetero-
cyclic compounds are indispensable building blocks in drug
design. Additionally, it was reported that conformationally re-
stricted structures of heterocyclics may provide them with
more bioactivity and selectivity compared with their acyclic
[6]
Lepidium meyenii. However, early studies in this area may be traced
[
7]
back to the 1980s. In 1989, Dominianni and Yen reported that
[7]
phenacylimidazolium salts have hypoglycemic activity. In the fol-
[
8]
[9]
lowing studies, Pernak et al. and Çetinkaya et al. reported that
imidazolium salts have antimicrobial activity. After the pioneering
study of Youngs et al. in 2004, in which silver–NHC complexes were
[
2]
analogues.
Imidazole and its benzene‐fused derivative,
[
10]
benzimidazole, are nitrogen heterocycles that can be found
in the structures of biologically important compounds. For
example, imidazole is found in the structures of histidine,
reported as a new class of antimicrobial agents,
many imidazolium
and benzimidazolium chlorides were synthesized to prepare their
silver–NHC complexes. However, in most of these studies, imidazo-
[
3]
purine, and biotin,
while N‐ribosyl‐dimethylbenzimidazole
lium and benzimidazolium salts were not tested or reported as
[11–13]
[
4]
acts as a ligand in the structure of vitamin B12
.
Moreover,
inactive against bacterial and fungal strains.
More recently,
many clinically used drugs were developed thanks to their
Schmitzer and colleagues reported that benzimidazolium salt causes
electrolyte imbalance and disrupts the integrity and the potential
of bacterial membranes. In addition, the same benzimidazolium
anticancer, antimicrobial, antiulcer, and other therapeutic
[
3]
properties.
Arch Pharm. 2020;e2000013.
wileyonlinelibrary.com/journal/ardp
© 2020 Deutsche Pharmazeutische Gesellschaft
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https://doi.org/10.1002/ardp.202000013

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KARATAŞ ET AL.
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FIGURE 1 General structure of the target compounds
salt presents low toxicity to human cells in bacteriostatic range
facilitated the purification step. The synthesis and structures of
compounds are given in Scheme 1 and some physical and spectral
data of compounds are given in Table 1. Additionally, N‐butyl‐N‐
[
14]
concentrations.
In contrast, enzyme inhibitory and anticancer
properties of these compounds were also reported. Many studies
showed that these compounds have a significant inhibitory effect on
benzylbenzimidazolium chloride (4) was synthesized according to
[28,29]
[
15]
[16]
the activities of prolyl oligopeptidase,
carbonic anhydrase,
[19]
the literature
(Figure 2) to compare its antimicrobial activity
[
17]
[18]
paraoxonase 1,
tyrosinase,
and acetylcholinesterase.
In
with catechol‐substituted analogues.
2
009, Yang et al. reported that phenacyl‐substituted imidazolium
The compounds were fully characterized by a combination of
13
[
20]
1
bromide (Figure 1) exhibits remarkable anticancer activity.
Later,
H
and
C
nuclear magnetic resonance (NMR), liquid
in the following studies, they showed that attaching biologically re-
levant groups to the imidazolium or benzimidazolium scaffold may
chromatography–mass spectrometry (LC–MS) and infrared (IR)
spectra and elemental analyses (see Supporting Information for all
[
21–25]
1
render these compounds as highly potent anticancer agents.
spectra). In
H NMR spectra of compounds, the signals of
Catechol (1,2‐dihydroxybenzene) and its derivatives are
acidic –NCHN– hydrogens were observed in the range
9.09–9.97 ppm except for 3b which has a methyl group instead of
hydrogen at 2‐position of the imidazole ring. Signals of hydroxy
hydrogens were observed as broad signals as expected. Other
signals were observed in accordance with the expected integral
ubiquitous in nature and display various chemical and physical
[
26]
properties.
For example, catecholamine derivatives dopamine,
epinephrine (adrenaline), and norepinephrine (Figure 1) are hor-
mones synthesized by adrenal glands. These compounds have
well‐defined biochemical roles such as raising blood pressure,
sending more blood to major organs, and increasing the blood
1
3
values and coupling patterns. In C NMR spectra of compounds,
signals of carbonyl carbons were observed in the range
189.4–189.8 ppm. The signals of –NCHN– imino carbons were
observed in the range 137.2–138.2 ppm for imidazolium chlorides
and 142.8–144.3 ppm for benzimidazolium chlorides. The signal for
[
27]
glucose level.
Additionally, these compounds are water soluble
and bound to plasma proteins.
Based on the above information, with the aim of enhancing the
biological properties of imidazolium and benzimidazolium salts with
biologically relevant molecules, we synthesized catechol bearing
four imidazolium and eight benzimidazolium chlorides (Figure 1).
The antimicrobial properties of the compounds were evaluated
against four Gram‐negative and three Gram‐positive bacteria, and
two fungal strains.
3
–NC(CH )N– imino carbon of 3b was observed at 146.2 ppm. Other
signals were observed in accordance with the proposed structures.
In LC–MS spectra of compounds, maximal peak intensities were
attributed to the cationic part of salts (see characterization data).
In IR spectra, the broad signals of hydroxy groups and sharp signals
of carbonyl groups were observed as expected. Additionally, ele-
mental analyses also support the proposed structures.
2
2
| RESULTS AND DISCUSSION
2
.2 | Antimicrobial studies
.1 | Synthesis and spectral characterization
In drug design, solubility and bioconjugation of compounds are highly
important parameters. Therefore, solubilities of all compounds were
tested in physiological saline solution (containing 2.5% ethanol and
The target compounds were synthesized by a reaction between
‐chloro‐3′,4′‐dihydroxyacetophenone (1) and N‐alkylimidazole or
2
[30]
N‐alkylbenzimidazole derivatives (2a–l). The reaction was carried
out in acetonitrile under open‐air conditions and target compounds
were obtained in good yields between 58% and 91%. After
completion of the reaction, the precipitation of target compounds
2.5% Tween‐80) according to the literature.
As seen in Table 1,
9 of 12 compounds are soluble in physiological saline solution at
room temperature, while 1 compound (3k) is soluble at 37°C and
2 compounds (3j,l) are not soluble even at 37°C. In addition, the

KARATAŞ ET AL.
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SCHEME 1 Synthesis and structures of the imidazolium and benzimidazolium chlorides
synthesized salts have structural similarity with catecholamines such
as dopamine, epinephrine, and norepinephrine which are biologically
fungal strains. This result can be attributed to the outer membrane of
Gram‐negative bacteria that render them more resistant against
[27]
[31]
synthesized and water‐soluble hormones.
antimicrobial agents.
Minimal inhibitory concentrations (MICs) of all compounds were
determined against four Gram‐negative (Escherichia coli, Pseudomonas
aeruginosa, Acinetobacter baumannii, Klebsiella pneumoniae) and three
Gram‐positive (Staphylococcus aureus, methicillin‐resistant S. aureus,
Enterococcus faecalis) bacteria and two fungal (Candida albicans, Can-
dida glabrata) strains. The results are listed in Table 2. Ampicillin,
amikacin, vancomycin, and fluconazole were used as standard drugs
for comparison.
The antimicrobial properties of 2‐chloro‐3′,4′‐dihydroxyacetop
henone (1), N‐benzylbenzimidazole (2j), and N‐butyl‐N‐benzylbenzim
idazolium chloride (4) were also tested against the same bacterial and
fungal strains to control whether a combination of catechol and
imidazolium scaffolds confer an advantage. These results are also
listed in Table 2. As shown in Table 2, 3j exhibited much stronger
activity than its starting materials (1 and 2j). Moreover, the activity of
benzimidazolium salt without catechol (4) can be compared with 3h
and 3j which contain the same groups except catechol. As seen
from the results, benzimidazolium salts containing catechol
displayed stronger activity against all bacterial and fungal strains
than their noncatechol analogue. This result clearly revealed that
introducing the catechol group into the imidazolium scaffold in-
creased the antimicrobial activity significantly.
As seen in Table 2, all compounds inhibited the growth of all
bacterial and fungal strains. If we evaluate the results, first, we must
point out that benzimidazolium salts exhibited stronger inhibitory
effect than imidazolium salts against all bacterial and fungal strains.
If we compare the benzimidazolium salts, it can be said that
methyl‐ (3e,f) and benzyl‐ (3j–l) containing salts are more active than
allyl‐ (3g), butyl‐ (3h) and decyl‐ (3i) containing derivatives. Especially,
the activities of benzyl‐containing derivatives are comparable
with standard drugs. For example, compounds 3j and 3l exhibited
the same activity as fluconazole against C. albicans. In contrast,
all compounds exhibited lower or equal inhibitory effect against
Gram‐negative bacterial strains compared with Gram‐positive and
Vancomycin is one of the most widely used antibiotics against
methicillin‐resistant S. aureus (MRSA); however, emergence of
vancomycin‐resistant S. aureus necessitated the development of
[
32]
new antibiotics.
In recent years, it was shown that cationic
small molecules have a different mechanism of action such as
[
33]
depolarizing and disturbing the bacterial membrane.
Schmitzer

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KARATAŞ ET AL.
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TABLE 1 Some physical and spectral data of the compounds
1
13
H NMR (ppm)
–OH
10.39, 9.73
C NMR (ppm)
a
Compound
Yield (%)
89
Melting point (°C)
250–251
245–247
220–222
166–168
252–253
290–292
177–178
250–252
169–172
276–277
Solubility
–NCHN–
9.15
–c
–C═O
189.8
189.6
189.4
189.7
189.7
189.7
189.6
189.6
189.6
189.6
–NCHN–
3
3
3
3
3
3
3
3
3
3
a
b
c
d
e
f
+
+
+
+
+
+
+
+
+
−
138.2
c
c
78
9.92 (2 × OH)
10.46, 9.73
10.42, 9.76
10.48, 9.71
10.48, 9.71
10.41, 9.65
10.47, 9.71
10.48, 9.71
9.00–11.00
146.2
71
9.60
9.27
9.80
9.64
9.80
9.90
9.91
9.97
137.2
137.9
144.3
143.0
144.1
143.9
143.9
144.2
90
75
69
g
h
i
64
83
58
j
91
(
2 × OH)
b
3
k
l
83
80
227–230
248–249
+
10.48, 9.74
10.46, 9.72
9.74
9.09
189.7
189.7
144.3
142.8
3
−
Abbreviations: +, completely dissolved; −, not all dissolved.
a
One milligram of compound dissolved in 1.0 ml of physiological saline (containing 2.5% ethanol and 2.5% Tween‐80) at room temperature.
Completely dissolved at 37°C.
b
c
Compound has a methyl group instead of hydrogen at 2‐position.
et al. showed that benzimidazolium salts also follow a similar
benzimidazolium salts exhibited remarkable inhibitory activity against
the growth of bacterial and fungal strains. We believe that some of the
reported compounds deserve further mechanistic and clinical in-
vestigation due to their advantages such as facile synthesis, low cost,
and high solubility in addition to remarkable antimicrobial activity.
[
14]
mechanism of action.
Therefore, quaternization of currently
used antimicrobial drugs is one of the new strategies. For example,
excellent antibacterial activity was obtained against some drug‐
resistant bacterial strains by the lipophilic quaternization of
vancomycin. Additionally, it was also reported that permanent
positive charge instead of secondary amines is essential for
[
34]
activity.
the most promising ones are the comparable inhibitory effects of
k and 3l with vancomycin against MRSA. Although detailed
Therefore, among the results obtained in this study,
4 | EXPERIMENTAL
4.1 | Chemistry
3
mechanistic studies are necessary, in light of the above informa-
tion, we think that the compounds exhibit their antimicrobial
activity by disturbing the bacterial membrane.
4.1.1 | General
The synthesis of imidazolium and benzimidazolium chlorides were
carried out under open‐air conditions. 1‐Alkylbenzimidazole
[
35]
3
| CONCLUSION
derivatives were synthesized according to the literature.
Alkyl
chlorides, benzyl chloride derivatives, 1‐methylimidazole, 1,
2‐dimethylimidazole, 1‐vinylimidazole, 1‐butylimidazole, 2‐chloro‐3′,
4′‐dihydroxyacetophenone, and solvents were commercially pro-
vided by Sigma‐Aldrich (Iİstanbul, Turkey) and used without further
purification. Melting points were determined in open capillary tubes
by Electrothermal 9200 melting point apparatus. IR spectra were
recorded in attenuated total reflection sampling accessory with
PerkinElmer Spectrum 100 spectrophotometer. The C, H, and N
elemental analyses were determined by LECO CHNS‐932 elemental
In conclusion, catechol containing four imidazolium and eight benzimi-
dazolium salts were synthesized and fully characterized by appropriate
spectroscopic and physical techniques. Antimicrobial activities of all
compounds were evaluated against four Gram‐negative and three
Gram‐positive bacteria and two fungal strains. Especially, some of the
analyzer. LC–MS spectra were recorded in an Agilent 1100 LC/MSD
1
SL mass spectrometer equipped with an electrospray ion source.
H
1
3
and C NMR spectra were recorded using Bruker Ascend™ 400
FIGURE 2 Structure of N‐butyl‐N‐benzylbenzimidazolium
chloride. DMF, dimethylformamide
1
13
Avance III HD operating at 400 MHz ( H) and 100 MHz ( C). NMR

KARATAŞ ET AL.
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|
TABLE 2 Minimal inhibitory concentrations (µg/ml) of compounds
Bacteria
Gram negative
Gram positive
Fungi
Escherichia Pseudomonas Acinetobacter Klebsiella
Staphylococcus
Staphylococcus
Enterococcus
faecalis
Candida
albicans
Candida
glabrata
Compound
1
coli
200
200
200
200
100
100
25
aeruginosa
400
400
200
200
100
100
50
baumannii
400
400
100
100
100
100
25
pneumoniae aureus
aureus (MRSA)
200
200
100
100
100
100
12.5
25
200
400
100
100
50
200
400
25
200
400
100
100
50
200
200
50
100
100
50
2
3
3
3
3
3
3
3
3
3
3
3
3
4
j
a
b
c
d
e
f
50
100
50
100
50
50
50
50
25
50
50
12.5
25
25
12.5
12.5
50
12.5
12.5
50
6.25
12.5
50
25
25
25
25
g
h
i
50
100
100
100
25
100
100
100
25
50
50
50
50
50
50
50
50
50
50
100
25
100
25
50
50
25
50
50
j
6.25
12.5
6.25
200
1.56
–
25
6.25
12.5
6.25
100
1.56
–
6.25
12.5
6.25
100
–
6.25
12.5
6.25
100
–
k
l
50
50
25
25
12.5
12.5
200
–
25
25
25
25
200
3.12
–
200
–
200
–
100
1.56
1.56
–
Ampicillin
Amikacin
1.56
–
3.12
–
–
–
–
Vancomycin
Fluconazole
–
–
3.12
–
–
–
–
–
–
–
–
–
–
6.25
3.12
Abbreviation: MRSA, methicillin‐resistant Staphylococcus aureus.
multiplicities were abbreviated as follows: br, broad; s, singlet; d,
doublet; t, triplet; quin, quintet; sex, sextet; m, multiplet.
The original spectra of the investigated compounds are provided
as Supporting Information, as are their InChI keys together with
some biological activity data.
53.93, H: 5.09, N: 10.17. LC–MS, calculated for cationic part,
−1
C
12
H
13
N
2
O
3
, m/z: 233.1; found: 233.1. IR (ʋmax, cm ): 3,322 (O–H),
1
3,080 (Ar–H), 1,678 (C═O), 1,524 (C═N). H NMR (400 MHz, dimethyl
sulfoxide (DMSO)‐d
OH), 9.15 (s, 1H, –NCH N–), 7.78 (s, 1H, ArH), 7.72 (s, 1H, ArH), 7.47
m, 2H, ArH and Himidazole), 7.01–6.99 (m, 1H, Himidazole), 5.96
6
, 298 K): δ 10.39 (br, 1H, –OH), 9.73 (br, 1H, –
(
1
3
(
s, 2H, –NCH
2
CO–), 3.95 (s, 3H, –NCH
, 298 K): δ 189.8 (C═O), 152.6, 146.1, 138.2 (–NCHN–), 125.8, 124.4,
CO–), 36.4 (–NCH ).
3
). C NMR (100 MHz, DMSO‐
4
.1.2 | General procedure for the synthesis of the
d
6
imidazolium and benzimidazolium chlorides 3a–l
123.6, 122.1, 116.0, 115.4, 55.2 (–NCH
2
3
A solution of 2‐chloro‐3′,4′‐acetophenone (5 mmol) and corresponding
1‐Methyl‐2‐methyl‐3‐{[1‐(3,4‐dihydroxyphenyl)ethan‐1‐one]‐2‐
yl}imidazolium chloride (3b)
3
N‐alkylimidazole or N‐alkylbenzimidazole (5 mmol) in 10 ml of CH CN
was stirred at 82°C for 48 hr. After this period of time, the mixture
was allowed to cool to ambient temperature and the precipitated
crude product was collected by filtration, washed with diethyl ether
White solid, yield: 1.1 g (78%), m.p.: 245–247°C. Elemental analysis,
calculated for C13
2 3
H15ClN O : C: 55.23, H: 5.35, N: 9.91; found: C:
55.47, H: 5.51, N: 9.63. LC–MS, calculated for cationic part,
−
1
(3 × 10 ml), and dried under vacuum.
C
13
H
15
N
2
O
3
, m/z: 247.1; found: 247.1. IR (ʋmax, cm ): 3,511 (O–H),
1
2
,953 (C–H), 1,679 (C═O), 1,520 (C═N). H NMR (400 MHz, DMSO‐
1
‐Methyl‐3‐{[1‐(3,4‐dihydroxyphenyl)ethan‐1‐one]‐2‐yl}imidazolium
d
6
, 298 K): δ 9.92 (br, 2H, 2 × OH), 7.72 (s, 1H, ArH), 7.62 (s, 1H,
ArH), 7.48 (m, 2H, ArH and Himidazole), 7.03–7.01 (m, 1H, Himidazole),
5.97 (s, 2H, –NCH CO–), 3.86 (s, 3H, –NCH ), 2.52 (–NC(CH )N–).
C NMR (100 MHz, DMSO‐d , 298 K): δ 189.6 (C═O), 152.6, 146.2
chloride (3a)
White solid, yield: 1.2 g (89%), m.p.: 250–251°C. Elemental analysis,
2
3
3
1
3
calculated for C12
2 3
H13ClN O : C: 53.64, H: 4.88, N: 10.43; found: C:
6

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KARATAŞ ET AL.
|
(
(
–NC(CH
3
)N–), 146.1, 125.8, 122.8, 122.6, 122.3, 115.9, 115.7, 54.3
), 9.7 (–NC(CH )N–).
62.57, H: 5.60, N: 7.82. LC–MS, calculated for cationic part,
−1
–NCH CO–), 35.4 (–NCH
2
3
3
C H N O
18 19 2 3
, m/z: 311.1; found: 311.2. IR (ʋmax, cm ): 3,143 (O–H),
1
3
,037 (Ar–H), 1,676 (C═O), 1,519 (C═N). H NMR (400 MHz, DMSO‐
1
‐Vinyl‐3‐{[1‐(3,4‐dihydroxyphenyl)ethan‐1‐one]‐2‐yl}imidazolium
chloride (3c)
White solid, yield: 1.0 g (71%), m.p.: 220–222°C. Elemental analysis,
calculated for C13 13ClN : C: 55.62, H: 4.67, N: 9.98; found:
C: 55.86, H: 4.87, N: 9.66. LC–MS, calculated for cationic part,
d
6
, 298 K): δ 10.48 (br, 1H, –OH), 9.71 (br, 1H, –OH), 9.64 (s, 1H, –
NCHN–), 7.84–7.81 (m, 2H, ArH), 7.57–7.51 (m, 3H, ArH), 7.06–7.03
(m, 1H, ArH), 6.25 (s, 2H, –NCH CO–), 4.14 (s, –NCH ), 2.44 (s, 3H,
). C NMR (100 MHz, DMSO‐d , 298 K): δ
189.7 (C═O), 152.7, 146.1, 143.0 (–NCHN–), 136.8, 136.0, 130.8,
130.4, 125.9, 122.4, 116.0, 115.7, 113.7, 113.5, 52.9 (–NCH CO), 33.8
(–NCH ), 20.4 (ArCH ).
2
3
1
3
H
2
O
3
ArCH
3
), 2.38 (s, 3H, ArCH
3
6
−
1
C
13
H
13
N
2
O
3
, m/z: 245.1; found: 245.0. IR (ʋmax, cm ): 3,337 (O–H),
2
1
2
,999 (C–H), 1,677 (C═O), 1,517 (C═N). H NMR (400 MHz,
3
3
DMSO‐d
H, –NCHN–), 8.35 (s, 1H, ArH), 7.89 (s, 1H, ArH), 7.51–7.47 (m, 3H,
ArH, Himidazole, and –NCH═CH ), 7.02–7.00 (m, 1H, Himidazole),
CO– and –NCH═CH ), 5.46 (d, 1H,
). C NMR (100 MHz, DMSO‐d , 298 K): δ
6
, 298 K): δ 10.46 (br, 1H, –OH), 9.73 (br, 1H, –OH), 9.60 (s,
1
1‐Allyl‐3‐{[1‐(3,4‐dihydroxyphenyl)ethan‐1‐one]‐2‐yl}benz‐
imidazolium chloride (3g)
2
6
.07–6.02 (m, 3H, –NCH
2
2
White solid, yield: 1.1 g (64%), m.p.: 177–178°C. Elemental analysis,
calculated for C18 17ClN : C: 62.70, H: 4.97, N: 8.12; found: C:
62.93, H: 5.19, N: 7.90. LC–MS, calculated for cationic part,
1
3
J = 8.0 Hz, NCH═CH
2
6
H
2 3
O
1
1
89.4 (C═O), 152.7, 146.2, 137.2 (–NCHN–), 129.3, 125.7, 125.4,
22.1, 118.9, 116.0, 115.5, 109.4, 55.6 (–NCH CO–).
−
1
2
C H
18 17
N O
2
3
, m/z: 309.1; found: 309.1. IR (ʋmax, cm ): 3,360 (O–H),
1
3
,064 (Ar–H), 1,669 (C═O), 1,533 (C═N). H NMR (400 MHz, DMSO‐
1
‐Butyl‐3‐{[1‐(3,4‐dihydroxyphenyl)ethan‐1‐one]‐2‐yl}imidazolium
d
6
, 298 K): δ 10.41 (br, 1H, –OH), 9.80 (s, 1H, –NCHN–), 9.65 (br,
1H, –OH), 8.00–7.97 (m, 2H, ArH), 7.63–7.57 (m, 2H, ArH), 7.49–7.44
(m, 2H, ArH), 6.98–6.95 (m, 1H, ArH), 6.26 (s, 2H, –NCH CO–), 6.09
(m, 1H, –NCH CH═CH ), 5.36–5.30 (m, 2H, –NCH CH═CH ),
5.26–5.24 (m, 2H, –NCH ). C NMR (100 MHz, DMSO‐d
chloride (3d)
White solid, yield: 1.4 g (90%), m.p.: 166–168°C. Elemental analysis,
2
calculated for C15
2
H19ClN O
3
: C: 57.97, H: 6.16, N: 9.01; found: C:
2
2
2
2
1
3
58.25, H: 6.22, N: 8.72. LC–MS, calculated for cationic part,
2
CH═CH
2
6
,
−1
C
15
H N
19 2
O
3
, m/z: 275.1; found: 275.1. IR (ʋmax, cm ): 3,295 (O–H),
298 K): δ 189.6 (C═O), 152.7, 146.1, 144.1 (–NCHN–), 132.6, 131.6,
1
2
,871 (C–H), 1,677 (C═O), 1,518 (C═N).
DMSO‐d
H, –NCHN–), 7.90 (s, 1H, ArH), 7.75 (s, 1H, ArH), 7.47–7.45
m, 2H, ArH and Himidazole), 7.02–7.00 (m, 1H, Himidazole), 5.96 (s, 2H, –
NCH CO–), 4.29 (t, 2H, J = 6.6 Hz, –NCH CH –), 1.81 (quin, 2H,
J = 6.9 Hz, –NCH CH –), 1.29 (sex, 2H, J = 7.1 Hz, –CH CH ), 0.92 (t,
H, J = 7.1 Hz, –CH CH ). C NMR (100 MHz, DMSO‐d , 298 K): δ
89.7 (C═O), 152.6, 146.2, 137.9 (–NCHN–), 125.8, 124.6, 122.4,
22.0, 116.0, 115.5, 55.3 (–NCH CO–), 49.1 (–NCH CH –), 31.9
CH –), 19.2 (–CH CH ), 13.8 (–CH CH ).
H
NMR (400 MHz,
131.1, 127.3, 127.1, 125.8, 122.4, 120.8, 116.0, 115.8, 114.5, 114.3,
6
, 298 K): δ 10.42 (br, 1H, –OH), 9.76 (br, 1H, –OH), 9.27 (s,
2 2 2
53.1 (–NCH CO–), 49.3 (–NCH CH═CH ).
1
(
1‐Butyl‐3‐{[1‐(3,4‐dihydroxyphenyl)ethan‐1‐one]‐2‐yl}benz‐
imidazolium chloride (3h)
2
2
2
2
2
2
3
White solid, yield: 1.5 g (83%), m.p.: 250–252°C. Elemental analysis,
1
3
3
1
1
2
3
6
calculated for C19
2 3
H21ClN O : C: 63.24, H: 5.87, N: 7.76; found: C:
63.56, H: 5.97, N: 7.60. LC–MS, calculated for cationic part,
−
1
2
2
2
C
19
H
21
N
2
O
3
, m/z: 325.2; found: 325.1. IR (ʋmax, cm ): 3,244 (O–H),
1
(–NCH
2
2
2
3
2
3
2,934 (C–H), 1,677 (C═O), 1,521 (C═N). H NMR (400 MHz,
6
DMSO‐d , 298 K): δ 10.47 (br, 1H, –OH), 9.90 (s, 1H, –NCHN–), 9.71
1
‐Methyl‐3‐{[1‐(3,4‐dihydroxyphenyl)ethan‐1‐one]‐2‐
(br, 1H, –OH), 8.16 (d, 1H, J = 8.2 Hz, ArH), 8.05 (d, 1H, J = 8.2 Hz,
ArH), 7.73–7.65 (m, 2H, ArH), 7.58–7.52 (m, 2H, ArH), 7.04 (d, 1H,
yl}benzimidazolium chloride (3e)
White solid, yield: 1.2 g (75%), m.p.: 252–253°C. Elemental analysis,
calculated for C16 15ClN : C: 60.29, H: 4.74, N: 8.79; found: C:
0.62, H: 4.92, N: 8.70. LC–MS, calculated for cationic part,
J = 8.2 Hz, ArH), 6.31 (s, 2H, –NCH
NCH CH –), 1.92 (quin, 2H, J = 7.4 Hz, –NCH
J = 7.5 Hz, –CH CH ), 0.94 (t, 3H, J = 7.3 Hz, –CH
(100 MHz, DMSO‐d , 298 K): δ 189.6 (C═O), 152.7, 146.1, 143.9
(–NCHN–), 132.5, 131.2, 127.2, 127.0, 125.8, 122.4, 116.0, 115.7,
114.4, 114.2, 53.0 (–NCH CO–), 47.0 (–NCH CH –), 31.0
(–NCH CH –), 19.5 (–CH CH ), 13.8 (–CH CH ).
2
CO–), 4.63 (t, 2H, J = 7.1 Hz, –
H
O
2 3
2
2
2
CH –), 1.36 (sex, 2H,
2
1
3
6
2
3
2 3
CH ). C NMR
−1
C
16
H
15
N
2
O
3
, m/z: 283.1; found: 283.1. IR (ʋmax, cm ): 3,152 (O–H),
6
1
3,113 (Ar–H), 1,701 (C═O), 1,513 (C═N). H NMR (400 MHz, DMSO‐
d
6
, 298 K): δ 10.48 (br, 1H, –OH), 9.80 (s, 1H, –NCHN–), 9.71 (br, 1H, –
OH), 8.08–8.01 (m, 2H, ArH), 7.73–7.65 (m, 2H, ArH), 7.58–7.52 (m,
H, ArH), 7.05 (d, 1H, J = 8.3 Hz, ArH), 6.33 (s, 2H, –NCH CO–), 4.20
, 298 K): δ 189.7 (C═O),
52.7, 146.1, 144.3 (–NCHN–), 132.3, 131.9, 127.1, 126.9, 125.9,
22.4, 116.0, 115.7, 114.3, 114.1, 53.0 (–NCH CO–), 33.9 (–NCH ).
2
2
2
2
2
2
3
2
3
2
2
13
(s, 3H, –NCH
3
). C NMR (100 MHz, DMSO‐d
6
1‐Decyl‐3‐{[1‐(3,4‐dihydroxyphenyl)ethan‐1‐one]‐2‐yl}benz‐
imidazolium chloride (3i)
1
1
2
3
White solid, yield: 1.3 g (58%), m.p.: 169–172°C. Elemental analysis,
calculated for C25 33ClN : C: 67.48, H: 7.48, N: 6.30; found: C: 67.70,
H: 7.66, N: 6.13. LC–MS, calculated for cationic part, C25 , m/z:
H
2 3
O
1
‐Methyl‐3‐{[1‐(3,4‐dihydroxyphenyl)ethan‐1‐one]‐2‐yl}‐
,6‐dimethylbenzimidazolium chloride (3f)
33 2 3
H N O
−1
5
409.2; found: 409.3. IR (ʋmax, cm ): 3,204 (O–H), 3,061 (Ar–H), 2,920
1
White solid, yield: 1.2 g (69%), m.p.: 290–292°C. Elemental analysis,
calculated for C18 19ClN : C: 62.34, H: 5.52, N: 8.08; found: C:
(C–H), 1,676 (C═O), 1,520 (C═N). H NMR (400 MHz, DMSO‐d
6
,
H
O
2 3
298 K): δ 10.48 (br, 1H, –OH), 9.91 (s, 1H, –NCHN–), 9.71 (br, 1H, –OH),

KARATAŞ ET AL.
7 of 8
|
8
2
2
.16 (d, 1H, J = 8.0 Hz, ArH), 8.05 (d, 1H, J = 8.0 Hz, ArH), 7.72–7.65 (m,
(m, 1H, ArH), 6.19 (s, 2H, –NCH
NCH H–(CH ), 2.26 (s, 6H, ArCH ), 2.20 (s, 6H, ArCH
NMR (100 MHz, DMSO‐d
142.8 (–NCHN–), 134.9, 134.7, 133.4, 132.9, 131.6, 128.8, 127.4,
127.1, 125.8, 122.2, 116.0, 115.7, 114.5, 114.4, 53.1 (–NCH CO–),
46.4 (–NCH H–(CH ), 20.6 (ArCH ), 15.8 (ArCH ).
2
CO–), 5.83 (s, 2H,
–
13
H, ArH), 7.58–7.52 (m, 2H, ArH), 7.05 (d, 1H, J = 8.2 Hz, ArH), 6.32 (s,
2
C
6
3
)
4
3
3
).
C
H, –NCH
CH –), 1.33–1.23 (m, 14H, –NCH
J = 7.0 Hz, –N(CH
2
CO–), 4.62 (t, 2H, J = 7.0 Hz, –NCH
CH (CH
). C NMR (100 MHz, DMSO‐d
89.6 (C═O), 152.7, 146.2, 143.9 (–NCHN–), 132.5, 131.2, 127.2, 127.0,
25.8, 122.4, 116.0, 115.8, 114.4, 114.2, 53.0 (–NCH CO–), 10 carbons
2
–), 1.93 (m, 2H, –
–), 0.85 (t, 3H,
, 298 K): δ
6
, 298 K): δ 189.7 (C═O), 152.6, 146.1,
NCH
2
2
2
2
2 7
)
13
2
)
9
CH
3
6
2
1
1
2
C
6
)
3 4
3
3
2
of decyl chain are as follows: 47.3, 31.8, 29.33, 29.31, 29.1, 29.0, 28.9,
6.1, 22.6, 14.4.
2
4.2 | Biological assays
1
‐Benzyl‐3‐{[1‐(3,4‐dihydroxyphenyl)ethan‐1‐one]‐2‐yl}benz‐
4.2.1 | Determination of the antimicrobial activities
imdazolium chloride (3j)
of the imidazolium and benzimidazolium chlorides
White solid, yield: 1.8 g (91%), m.p.: 276–277°C. Elemental analysis,
calculated for C22
H
19ClN
2
O
3
: C: 66.92, H: 4.85, N: 7.09; found: C:
All the compounds were tested at a concentration of 1,000–1.56 µg/ml
against the standard culture collections of the most frequently isolated
strains (listed below) among the society and hospital‐acquired infectious
agents depending on the suggestions of Clinical Laboratory Standards
Institute (CLSI) with the method of serial dilution using sterile 96‐well
67.17, H: 5.07, N: 6.90. LC–MS, calculated for cationic part,
−1
22 19 2 3
C H N O , m/z: 359.1; found: 359.1. IR (ʋmax, cm ): 3,198 (O–H),
1
3,003 (Ar–H), 1,676 (C═O), 1,520 (C═N). H NMR (400 MHz, DMSO‐
d
7
4
2
6
, 298 K): δ 11.00–9.00 (br, 2H, 2 × OH), 9.97 (s, 1H, –NCHN–),
.99–7.96 (m, 2H, ArH), 7.59–7.55 (m, 2H, ArH), 7.49–7.45 (m,
H, ArH), 7.38–7.29 (m, 3H, ArH), 6.99–6.96 (m, 1H, ArH), 6.27 (s,
[36]
microplate readers (PLT microtiter plate; ESP).
Ten milligrams of the
compound was dissolved in 1,000 µl of DMSO to obtain a stock solution.
Hundred microliters of the Müller–Hinton Broth (Merck 110293) was
loaded to the test wells. Hundred microliters of the stock solution of our
material was taken, and starting from the 1st to 10th well, serial dilu-
tions were performed and the last two wells were used as control
groups. Ten microliters of bacterial suspensions which were prepared
according to the McFarland 0.5 turbidity threshold, were distributed to
1
3
H, –NCH
, 298 K): δ 189.6 (C═O), 152.8, 146.2, 144.2 (–NCHN–),
34.5, 132.7, 130.4, 129.5, 129.3, 128.8, 127.3, 127.1, 125.8, 122.4,
16.0, 115.8, 114.6, 114.3, 53.2 (–NCH CO–), 50.4 (–NCH ).
2 2 6 5
CO–), 5.85 (s, 2H, –NCH C H ). C NMR (100 MHz,
DMSO‐d
6
1
1
2
2 6 5
C H
1
‐(3‐Methylbenzyl)‐3‐{[1‐(3,4‐dihydroxyphenyl)ethan‐1‐one]‐2‐yl}
bezimidazolium chloride (3k)
White solid, yield: 1.7 g (83%), m.p.: 227–230°C. Elemental ana-
lysis, calculated for C23 21ClN : C: 67.56, H: 5.18, N: 6.85;
found: C: 67.66, H: 5.30, N: 6.73. LC–MS, calculated for cationic
[37]
all samples including the control wells.
Orbital shaker (PST 60HL
Thermo) was used for 5 min to mix bacteria and our compounds. The lid
of the microplate was closed and it was incubated at 35°C for 18–20 hr.
To check bacterial growth, culture from each well was streaked on
Müller–Hinton Agar plate using a sterile plastic loop and incubated
under the same conditions. A predilution of the concentration in which
H
2 3
O
−
1
part, C23
H
21
N
2
O
3
, m/z: 373.2; found: 373.2. IR (ʋmax, cm ): 3,172
1
(
(
O–H), 2,909 (C–H), 1,675 (C═O), 1,520 (C═N).
400 MHz, DMSO‐d
H NMR
[38–40]
6
, 298 K): δ 10.48 (s, 1H, –OH), 9.74 (s,
growth was observed was determined as MIC of that substance .
2
1
7
H, –OH and –NCHN–), 8.11–8.08 (m, 1H, ArH), 8.04–8.01 (m,
Antifungal activity was determined using Sabouraud Dextrose Broth
[41]
H, ArH), 7.70–7.67 (m, 2H, ArH), 7.56–7.51 (m, 2H, ArH),
.35–7.24 (m, 4H, ArH), 7.06–7.03 (m, 1H, ArH), 6.32 (s, 2H, –
and Agar (CM0147, CM0041; Oxoid) under the same conditions.
In
addition to this, in our study, reference drugs for each group of bacteria
and fungi were tested under the same conditions in which the com-
pounds were tested.
NCH
2
CO–), 5.92 (s, 2H, –NCH
2
C
6
H
4
–CH
3 3
), 2.37 (s, 3H, ArCH ).
1
3
C NMR (100 MHz, DMSO‐d
6
, 298 K): δ 189.7 (C═O), 152.7,
1
1
1
46.1, 144.3 (–NCHN–), 137.3, 132.7, 132.2, 131.4, 131.3, 129.5,
29.1, 127.4, 127.1, 127.0, 125.8, 122.4, 116.0, 115.7, 114.6,
14.4, 53.2 (–NCH
2
CO–), 49.1 (–NCH
2
C
6
H
4
–CH
3
), 19.2 (ArCH
3
).
4.2.2 | Bacterial strains
1
‐(2,3,5,6‐Tetramethylbenzyl)‐3‐{[1‐(3,4‐dihydroxyphenyl)ethan‐1‐
The bacterial strains used in this study were S. aureus ATCC 29213,
E. faecalis ATCC 29212, S. aureus MRSA ATCC 43300, E. coli ATCC
25922, K. pneumoniae ATCC 700603, P. aeruginosa ATCC 27853,
A. baumannii ATCC 19606.
one]‐2‐yl}benzimidazolium chloride (3l)
White solid, yield: 1.8 g (80%), m.p.: 248–249°C. Elemental analysis,
calculated for C26 27ClN : C: 69.56, H: 5.61, N: 6.24; found: C:
9.77, H: 5.83, N: 6.10. LC–MS, calculated for cationic part,
H
2 3
O
6
−1
C
26
H N
27 2
O
3
, m/z: 413.2; found: 412.3. IR (ʋmax, cm ): 3,241 (O–H),
1
2
,948 (C–H), 1,669 (C═O), 1,518 (C═N). H NMR (400 MHz, DMSO‐
4.2.3 | Fungal strains
d
6
, 298 K): δ 10.46 (br, 1H, –OH), 9.72 (br, 1H, –OH), 9.09 (s, 1H, –
NCHN–), 8.30–8.26 (m, 1H, ArH), 8.08–8.06 (m, 1H, ArH), 7.80–7.69
m, 2H, ArH), 7.51–7.47 (m, 2H, ArH), 7.15 (s, 1H, ArH), 7.04–7.01
C. glabrata ATCC 90030 and C. albicans ATCC 14053 were the fungal
(
strains used in this study.

8
of 8
KARATAŞ ET AL.
|
CONFLICT OF INTERESTS
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The authors declare that there are no conflicts of interests.
[
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ORCID
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Struct. 2020, 1206, 178668. https://doi.org/10.1016/j.molstruc.2019.
Mert O. Karataş
İsmail Özdemir
http://orcid.org/0000-0001-8500-2088
http://orcid.org/0000-0001-6325-0216
1
27668
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How to cite this article: Karataş MO, Günal S, Mansur A,
Alıcı B, Özdemir İ. Catechol‐bearing imidazolium and
benzimidazolium chlorides as promising antimicrobial agents.
Arch Pharm. 2020;e2000013.
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