Gold(I) and Gold(III) N-Heterocyclic Carbene Complexes as Antibacterial Agents and Inhibitors of Bacterial Thioredoxin Reductase

Article abstract of DOI:10.1002/cmdc.202100381

A series of (NHC)Au(I)Cl monocarbene complexes and their gold(III) analogues (NHC)Au(III)Cl₃ were prepared and investigated as antibacterial agents and inhibitors of bacterial TrxR. The complexes showed stronger antibacterial effects against the Gram-positive MRSA and E. faecium strains than against several Gram-negative bacteria. All complexes were efficient inhibitors of bacterial thioredoxin reductase, indicating that inhibition of this enzyme might be involved in their mechanism of action. The efficacy of gold(I) and gold(III) analogues was comparable in most of the assays. The cytotoxicity of the gold NHC compounds against cancer and human cells was overall weaker than the activity against the Gram-positive bacteria, suggesting that their optimization as antibacterials warrants further investigation.

Full text of DOI:10.1002/cmdc.202100381

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Gold(I) and Gold(III) N-Heterocyclic Carbene Complexes as
Antibacterial Agents and Inhibitors of Bacterial Thioredoxin
Reductase
[a]
[b]
[a]
[c]
[b]
Rolf Büssing, Bianka Karge, Petra Lippmann, Peter G. Jones, Mark Brönstrup, and
Ingo Ott*
[a]
A series of (NHC)Au(I)Cl monocarbene complexes and their gold
III) analogues (NHC)Au(III)Cl were prepared and investigated as
this enzyme might be involved in their mechanism of action.
The efficacy of gold(I) and gold(III) analogues was comparable
in most of the assays. The cytotoxicity of the gold NHC
compounds against cancer and human cells was overall weaker
than the activity against the Gram-positive bacteria, suggesting
that their optimization as antibacterials warrants further inves-
tigation.
(
3
antibacterial agents and inhibitors of bacterial TrxR. The
complexes showed stronger antibacterial effects against the
Gram-positive MRSA and E. faecium strains than against several
Gram-negative bacteria. All complexes were efficient inhibitors
of bacterial thioredoxin reductase, indicating that inhibition of
Introduction
application of gold compounds as a new type of antibacterials,
and this has been substantiated by recent studies.
[5]
With increasing numbers of drug-resistant bacteria, the need
for new and improved antibiotics has been growing rapidly.
Besides the identification of new molecular targets, novel
chemical structures are of the utmost interest for medicinal
chemistry and drug development. The majority of registered
antibiotics, however, belong to only a few chemical classes,
such as penicillins or tetracyclines. In this context, metal-based
compounds offer a pool of relatively unexplored chemical
We have recently reported on gold(I) complexes with N-
heterocyclic carbene (NHC) ligands with antibacterial and
[6–8]
anticancer activity.
NHC ligands offer the advantage of a
wide variability and adaptability of the properties of the
complexes. This makes a modular synthetic approach possible,
allowing a broad spectrum of modifications to be evaluated
[9]
and analysed.
With regard to the application of gold compounds as
antibacterial agents, their generally high activity as inhibitors of
thioredoxin reductase (TrxR) offers an unconventional molecular
mechanism of drug action. Notably, many Gram-positive
pathogenic bacteria, including S. aureus, lack sufficient levels of
glutathione, thus making their metabolism highly dependent
on the activity of TrxR, which reduces oxidized thioredoxin
[1]
scaffolds for antibacterial drug design projects.
Over the last 10–15 years, gold complexes have attracted
major attention in inorganic medicinal chemistry, leading to
very promising experimental drugs, in particular for anticancer
[2,3]
indications.
Ever since an early report by Robert Koch on
antimicrobial activity displayed by gold cyanide salts against M.
[4]
[10]
tuberculosis, there has been evidence for the possible
(Trx). In consequence, a functional Trx/TrxR system is critical
for growth and survival of bacteria with low glutathione levels.
In our recent report we were able to confirm the effective
inhibition of bacterial TrxR by gold complexes of the type (NHC)
Au(I)Cl in combination with high activity against several Gram-
[
[
[
a] R. Büssing, P. Lippmann, Prof. Dr. I. Ott
Institute of Medicinal and Pharmaceutical Chemistry
Technische Universität Braunschweig
Beethovenstrasse 55, 38106 Braunschweig (Germany)
E-mail: ingo.ott@tu-bs.de
b] B. Karge, Prof. Dr. M. Brönstrup
Department of Chemical Biology
Helmholtz Centre for Infection Research and
German Centre for Infection Research (DZIF)
Inhoffenstrasse 7, 38124 Braunschweig (Germany)
c] Prof. Dr. P. G. Jones
Institute of Inorganic and Analytical Chemistry
Technische Universität Braunschweig
[6]
positive pathogenic bacteria. Initial structure-activity-relation-
ships indicated that monocarbene (NHC)Au(I)Cl complexes
triggered much stronger inhibition of bacterial TrxR than
+
cationic biscarbene complexes of the type Au(I)(NHC)2 , which
were also less active as antibacterial agents, but on the other
hand triggered substantially higher antiproliferative activity
[7,8]
against cancer cell lines.
The antibacterial activity of gold
NHC biscarbene complexes was also decreased or lost when the
[
11]
organometallics were incorporated in macrocyclic structures.
Hagenring 30, 38106 Braunschweig (Germany)
Here we report on the extension of our efforts in developing
antibacterial monocarbene gold NHC complexes by comparing
a series of (NHC)Au(I)Cl complexes with the respective gold(III)
This article belongs to the joint Special Collection with the European Journal
of Inorganic Chemistry, “Metals in Medicine”.
©
2021 The Authors. ChemMedChem published by Wiley-VCH GmbH. This is
an open access article under the terms of the Creative Commons Attribution
Non-Commercial License, which permits use, distribution and reproduction
in any medium, provided the original work is properly cited and is not used
for commercial purposes.
derivatives of the type (NHC)Au(III)Cl . The structures of the
3
carbene ligands contain ethyl groups on the nitrogen side
chains, in continuation of our previous work with this type of
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[
6–8]
complexes.
The possible release of the carbene ligands
tained, confirming the structures of 1c, 2c, 3b and 3c (Figure 1;
ellipsoids are shown at the 50% level).
would result in benzimidazolium cations that are probably non-
toxic. The synthesis and characterization of the complexes are
presented, together with a biological investigation as antibacte-
rial TrxR inhibitors. Experiments with cancer cell lines were
added to assess the selectivity of the compounds.
Molecular dimensions (Table 1) may be regarded as normal,
with only small deviations from ideal bond angles at the gold
atoms. The carbene ligands and the CAuCl3 units are all
effectively planar (max. r.m.s. deviation 0.018 Å) and mutually
perpendicular (but less so for 1c). A slight but consistent trans
influence of the carbene ligand on the Au1À Cl1 bond is
observed, making it longer than the cis AuÀ Cl bonds. A search
Results and Discussion
[17]
of the Cambridge Database, Version 5.41, gave 38 hits (47
Chemistry
molecules) for the fragment C(carbene)À AuCl , whereby we
3
deleted one serious outlier; the trans AuÀ Cl bond length then
averaged 2.313(9) and the cis bond length 2.279(12) Å, with an
average AuÀ C bond length of 2.002(12) Å.
The target compounds were synthesised using established
procedures with minor modifications (Scheme 1).
[6,12–15]
In the
first step, the (benz)imidazolium salts 1a–4a were formed via
alkylation of the respective (benz)imidazoles 1–4 with iodo-
ethane in the presence of potassium carbonate. The gold(I)
NHC complexes 1b–4b were synthesised in a two-step reaction
via a silver intermediate, which was reacted with chlorido-
The crystal packing of 1c involves short intermolecular
contacts between chlorine atoms [Cl1···Cl1’ 3.6447(8) Å, oper-
ator -x, 1-y, 1-z, and Cl2···Cl2’ 3.4945(9) Å, operator -x, 1-y, -z].
These combine to form zigzag chains of molecules parallel to
the c axis (Figure 2). Such short halogen-halogen contacts are a
[18]
(dimethylsulfide)gold(I). The gold(III) compounds 1c–4c were
special case of “halogen bonds”. We have drawn attention to
–
obtained by oxidation of 1b–4b using dichlorophenyliodane.
the presence of such interactions between [AuX ] anions (X=
4
1
13
[19]
The products were characterized by H- and C-NMR, mass
spectroscopy, and elemental analysis. These data were in good
agreement with the proposed structures. The transformation of
the (benz)imidazolium salts 1a–4a to the gold(I) complexes
Cl, Br).
Molecules of 4c are linked to form inversion-symmetric
pairs by aurophilic interactions [Au1···Au1’ 3.3537(3) Å, operator
1-x, 1-y, -z). Such contacts are frequently observed for gold(I)
[20]
1
b–4b was confirmed by the absence of the C2-hydrogen
compounds. A further short, linear contact C7À H7···Cl1 [H···Cl
2.68 Å, angle 170°, operator x, 1+y, z] may reasonably be
signal in the spectra of the products; the metal-free precursors
1
1
1
a–4a show a signal for this hydrogen in the range 10.1-
1.3 ppm. Whereas the H-NMR spectra of the gold(I) complexes
b–4b are very similar to those of the respective gold(III)
1
analogues 1c–4c, there is a notable downfield shift (ranging
1
3
from 25.6 ppm for 4b/4c to 31.7 ppm for 1b/1c) in the C-
NMR signal of C2 upon complex formation, an effect previously
[16]
reported by Sivaram et al. For the gold(III) complexes, mass
spectrometry confirmed the presence of multiple chlorido
+
+
ligands ([2 M-5Cl] and [2MÀ Cl] signals for 1c, [MÀ Cl+
+
+
MeOH] for 2c and [M+Na] signals for 3c and 4c). Elemental
analyses confirmed the high purity of all target compounds
with deviations below 0.41% from the calculated values.
Additionally, crystal structures for four complexes were ob-
Figure 1. Molecular structures of 1c (top left), 2c (top right), 3b (bottom
left) and 4c (bottom right).
Table 1. Selected molecular dimensions (Å or °).
Compound
1c
2c
3b
4c
Au1-Cl1
Au1-Cl2
Au1-Cl3
Au1-C1
2.3199(4)
2.2791(4)
2.2814(4)
2.3151(3)
2.2767(3)
2.2757(3)
2.2852(8) 2.3054(5)
–
–
2.2820(6)
2.2868(5)
2.004(2)
1.9974(16) 2.0087(11) 1.978(3)
C1-Au1-Cl1
C1-Au1-Cl2
C1-Au1-Cl3
Interpl. angle carbene/
178.28(5)
89.34(5)
88.06(5)
77.2(1)
178.20(3)
90.52(3)
87.29(3)
86.79(2)
179.41(9) 179.01(6)
–
–
–
88.18(6)
88.43(6)
89.75(3)
Scheme 1. Synthesis of the target compounds.
AuCl
3
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Antibacterial effects
The averaged minimal inhibitory concentration (MIC) was
determined in two Gram-positive (E. faecium, methicillin
resistant S. aureus, MRSA) and in four Gram-negative (A.
baumannii, E. coli, K. pneumoniae, P. aeruginosa) pathogenic
bacteria strains by a curve-fitting procedure (Table 2). Auranofin
and various antibiotics served as references.
The gold NHC complexes displayed the highest activity
against the Gram-positive strains MRSA (MIC values in the range
of 0.8–2.8 μM) and E. faecium (MIC values in the range 1.2–
1
1.5 μM) and were less active against the Gram-negative strains
E. Coli (MIC values >18 μM), P. aeruginosa (MIC values >30 μM),
A. baumannii (MIC values 3.5–17.2 μM) and K. pneumoniae (MIC
values >18 μM). We have already observed such a preference
for Gram-positive strains, although in the current study a
substantially stronger activity against the Gram-negative A.
baumannii was registered.
Figure 2. Packing diagram of compound 1c, viewed perpendicular to the ac
plane. Thick dashed lines indicate short Cl···Cl contacts. Hydrogen atoms are
omitted for clarity.
[6]
The results in the two most sensitive strains, MRSA and E.
faecium, show no clear trend concerning the oxidation state of
gold. Compound 2b was the most active gold NHC complex
against Gram-positive pathogens; however, it remained less
active than the gold-containing reference drug auranofin.
Interestingly, in the two Gram-negative strains A. baumannii
and K. pneumoniae a consistently higher inhibition of bacterial
cell growth was noted for the gold(III) NHC complexes,
compared to the respective gold(I) analogues. For example,
against K. pneumoniae the gold(III) NHC complex 2c, with an
MIC value of 16.8 μM, was approximately four times as active as
the gold(I) analogue 2b (MIC value of 65.6 μM).
regarded as a hydrogen bond. The net effect is to form ribbons
of dimers parallel to the b axis (Figure 3). Molecules of 4c are
linked by the hydrogen bond C5À H5···O1 [H···O 2.35 Å, angle
1
48°, operator 2-x, 1-y, 1-z] to form inversion-symmetric pairs.
Inhibition of bacterial TrxR
The inhibition of isolated bacterial E. coli TrxR was determined
in an enzymatic assay (Table 3). The gold complexes 1b–4b
and 1c–4c and the reference compound K[Au(CN) ] inhibited
2
the enzyme efficiently, with IC50 values in a narrow range of 0.2
to 0.6 μM, suggesting TrxR inhibition as a possible mechanism
of antibacterial activity. The most active compounds were
auranofin and 2b. Comparing gold(I) with gold(III) complexes,
no clear trend could be observed.
Figure 3. Packing diagram of compound 3b viewed perpendicular to the ac
plane. Thin and thick dashed lines indicate H···Cl or Au···Au contacts
respectively. All hydrogen atoms except H7 are omitted for clarity.
Table 2. Mean MIC values [μM] � standard error (n=3-13); MRSA=methicillin-resistant S. aureus; amikacin (P. aeruginosa), linezolid (S. aureus) and
ciprofloxacin (E. faecium, E. coli, A. baumannii, K. pneumoniae) were used as antibiotic references.
MRSA
E. faecium
E. coli
P. aeruginosa
A. baumannii
K. pneumoniae
antibiotic
auranofin
2.8�1.0
<0.2
n.d.
0.3�0.1
>30
22.4�0.0
18.7�0.0
39.3�0.0
39.1�25.6
>30
34.9�8.6
50.1�16.7
53.4�8.4
6.9�7.3
>30
85.1�20.1
74.9�0.0
118.0�43.1
>30
2.3�1.5
7.8�7.1
3.8�2.4
2.3�0.0
8.4�2.4
3.5�1.2
17.2�0.0
7.5�0.0
16.7�0.0
7.3�0.0
2.9�3.4
0.6�0.2
1.4�0.0
2.3�0.0
1.2�0.0
4.2�0.0
11.5�5.0
3.7�0.0
5.6�2.4
3.6�0.0
>30
1
1
2
2
3
3
4
4
b
c
b
c
b
c
2.8�0.0
1.6�0.7
0.8�0.4
1.1�0.0
2.2�0.0
1.6�0.5
18.7�9.2
18.7�0.0
65.6�32.1
16.8�0.0
91.8�39.7
24.9�8.6
66.8�0.0
29.1�0.0
>60
59.8�0.0
�
1
b
c
2.4 .6
>30
1.8�0.0
58.2�0.0
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general stronger than the growth-inhibiting effects against
human cell lines.
Table 3. Inhibition of bacterial TrxR as IC50 values � standard deviation
n=3).
(
Compound
IC50 [μM]
TrK(Au(CN)
auranofin
2
)
0.310�0.112
0.210�0.030
0.243�0.032
0.550�0.211
0.183�0.018
0.270�0.156
0.267�0.077
0.252�0.060
0.450�0.121
0.332�0.179
Conclusion
Et
2
Et
2
Et
2
Et
2
Et
2
Et
2
Et
2
Et
2
ImAuCl
ImAuCl
BIAuCl
1b
1c
2b
2c
3b
3c
4b
4c
3
A series of (NHC)Au(I)Cl monocarbene complexes and their gold
(III) analogues (NHC)Au(III)Cl were prepared, analytically charac-
3
BIAuCl
3
BICO
BICO
BICO
BICO
2
2
2
2
MeAuCl
MeAuCl
EtAuCl
terized, and investigated as organometallic antibacterial drugs.
Whereas the anticancer activity of gold NHC complexes has
been intensively studied over the last years, the possible
application of gold NHC complexes as anti-infectives has been
explored to a much smaller extent. However, antitrypanosomal,
antileishmanial or antimalarial effects have also been confirmed
3
EtAuCl
3
[3,21]
Antiproliferative effects
for this type of organometallics.
The complexes triggered higher antibacterial effects against
the Gram-positive MRSA and E. faecium than against the Gram-
negative strains (A. baumannii, E. coli, K. pneumoniae, P.
aeruginosa). Such preference for Gram-positive bacteria by
monocarbene gold(I) complexes had already been observed in
The antiproliferative potential of gold NHC complexes is well
known and was studied here in reference to the antibacterial
effects.
The cell growth inhibitory effects were determined in A549
lung carcinoma cells, MDA-MB-231 breast adenocarcinoma cells
[6]
our previous study and a screening of the literature indicates
that some other complexes of this type had shown similar
and RC-124 kidney epithelial cells (Table 4). K[Au(CN) ] and
2
[22]
auranofin were used as references.
effects.
Whereas the metal free ligands 1a–4a were inactive or only
marginally active, all the gold complexes exhibited good to
moderate cytotoxicity. However, the gold reference compounds
All target complexes were efficient inhibitors of bacterial
TrxR, suggesting that inhibition of this enzyme might be
involved in the mechanism of the antibacterial activity and
[6]
auranofin and K[Au(CN) ] remained the most cytotoxic com-
confirming our previous results. Interestingly, inhibition of
bacterial TrxR has been recently confirmed also for a antimicro-
2
plexes in this study. The antiproliferative effects of the gold(I/III)
NHC complexes were generally stronger in MDA-MB-231 and
RC-124 cells (IC50 values in the range 4–11 μM for 1b/1c–4b/
[23]
bial silver NHC complex (K =10.8 nM).
i
The IC50 values for the antiproliferative activity against
cancer and human cells were generally higher than the MIC
values against the Gram-positive bacteria and were dependent
on the individual cell line, indicating that monocarbene gold
NHC complexes have a selectivity index in principle, which
however needs to be increased by structurally optimized
analogues. Notably, some of the complexes reported here have
been studied in different cell lines in an assay that uses almost
confluent cell layers, and afforded lower cytotoxicity under
these experimental conditions (unpublished results).
In summary, this report confirms for the first time the
antibacterial effects of gold(III) NHC species and their efficient
inhibition of bacterial TrxR. With the exception of the activity
against some Gram-negative bacteria, the efficacy of the
studied gold(I) and gold(III) analogues was comparable. Further
investigation of monocarbene gold NHC complexes for the
development of novel antibiotics is worthwhile.
4
c) than in in A549 cells, where the complexes reached
activities of 10–24 μM. The efficient toxicity against RC-124 cells
showed that there was no relevant selectivity for tumor tissue.
Complex 1b was the only example of a gold(I) complex that
triggered higher cytotoxicity than the respective gold(III)
analogue (1c). In the case of the pairs 2b/2c, 3b/3c and 4b/4c
the differences were not significant. The antiproliferative activity
of 1b and 2b had been studied in a previous report and had
afforded comparable values, confirming the appropriate repro-
[6]
ducibility of the assay procedure. Notably, the antibacterial
effects against Gram-positive strains (see Table 2) were in
Table 4. Antiproliferative activity as IC50 values (μM) � standard deviation
(
n=2-4).
Compound
K(Au(CN)
A549
MDA-MB-231
RC-124
2
)
1.0�0.2
4.2�0.6
>100
13.5�1.3
23.6�0.6
>50
10.0�0.4
11.6�0.8
51.4�4.8
24.0�0.8
19.3�0.6
50.8�2.5
11.6�0.5
13.2�0.5
0.3�0.1
1.2�0.3
>100
6.2�0.8
10.6�0.0
>100
8.8�0.6
6.7�0.5
>100
9.5�1.0
9.1�0.5
>100
0.1�0.0
0.4�0.3
>100
6.1�2.6
7.0�2.4
57.0�8.9
4.7�1.1
6.3�2.0
>100
auranofin
1
1
1
2
2
2
3
3
3
4
4
4
a
b
c
a
b
c
a
b
c
a
b
c
Experimental Section
General
The reagents were purchased from Sigma-Aldrich, Alfa Aesar or TCI
and used without additional purification steps. All reactions were
7.2�3.7
6.4�1.9
>100
1
performed without precautions to exclude air or moisture. H and
13
C NMR were recorded on a DRX-400 AS, AVIIIHD 500 or AVII 600.
A Finnigan LCQDeca or a Finnigan MAT 95 was used to record the
ESI mass spectra. The elemental analyses were performed using a
5.2�0.4
4.0�2.6
4.7�0.2
5.5�0.9
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Flash EA 1112 (Thermo Quest CE Instruments). Absorption measure-
ments for TrxR inhibition and antiproliferative activity were
1,3-Diethyl-5-ethoxycarbonyl-benzimidazolium iodide 4a
TM
The compound was prepared from ethyl-1H-benzimiazole-5-carbox-
performed on a Perkin-Elmer 2030 Multilabel Reader VICTOR X4.
[6]
[12]
[13]
[14]
ylate (897 mg, 4.716 mmol); yield: 1307 mg (3.493 mmol, 74%), pale
Compounds 1a, 1b, 2a, 2b, 2c and PhICl2 were prepared
1
brown powder; H NMR (500.3 MHz, CDCl ) δ (ppm)=11.27 (s, 1H,
3
as described in the literature.
C(2)H), 8.42 (dd, J=1.4, 0.7 Hz, 1H, C(4)H), 8.35 (dd, J=8.7, 1.4 Hz,
1
4
9
H, C(6)H), 7.84 (dd, J=8.7, 0.7 Hz, 1H, C(7)H), 4.76 (qd, J=7.3,
.2 Hz, 4H, NCH CH ), 4.48 (q, J=7.1 Hz, 2H, OCH CH ), 1.82 (dt, J=
Synthesis
2
3
2
3
1
3
.2, 7.4 Hz, 6H, NCH CH ), 1.46 (t, J=7.1 Hz, 3H, OCH CH ); C-NMR
2
3
2
3
(125.8 MHz, CDCl ) δ (ppm)=164.7 (1 C, COO), 143.6 (1 C, NCHN,
3
Ethyl-1H-benzimiazole-5-carboxylate BICOOEt
C(2)H), 133.8 (1 C, C(Ar)), 131.1 (1 C, C(Ar)), 129.8 (1 C, C(Ar)), 128.2
1 C, C(Ar)H), 114.9 (1 C, C(Ar)H), 113.1 (1 C, C(Ar)H), 62.1 (1 C,
OCH CH ), 43.5 (2 C, NCH CH ), 14.8(2 C, NCH CH ), 14.3 (1 C,
(
This compound was prepared according to a modified version of a
[24]
published procedure. Benzimidazole-5-carboxylic acid (650 mg,
.009 mmol) was suspended in absolute ethanol (10 mL),
conc.H SO (0.25 mL, cat.) was added and the solution was stirred
2
3
2
3
2
3
+
OCH CH ); MS (ESI): m/z: 247.1 [MÀ I] ; CHN (calc./found) C (44.93/
4
2
3
44.95), H (5.12/5.09), N (7.49/7.31).
2
4
under reflux for 26 h. The reaction mixture was poured onto ice/
water, made alkaline with NaOH solution (5 N) and extracted with
ethyl acetate (EtOAc, 3×50 mL). The combined organic layers were
General procedure for synthesis of (NHC)Au(I)Cl complexes 3b
and 4b
dried over anhydrous Na SO4 and the solvent was removed in
2
vacuo to yield the product. When necessary, the product was
redissolved in EtOAc and washed with saturated Na CO solution.
2
3
The aqueous phase was once more extracted with EtOAc and the
combined organic layers were dried over anhydrous Na SO . The
2
4
solvent was again removed in vacuo to isolate the purified product;
1
yield: 453 mg (2.382 mmol, 59%), brown or pale brown powder; H-
NMR (500.3 MHz, CDCl ): δ (ppm)=8.44 (dd, J=1.58, 0.68 Hz, 1 H,
3
C(4)H), 8.25 (s, 1 H, C(2)H), 8.03 (dd, J=8.51, 1.58 Hz, 1 H, C(6)H),
7
.69 (dd, J=8.51, 0.68 Hz, 1 H, C(7)H), 4.41 (q, J=7.10 Hz, 2 H,
13
OCH CH ), 1.41 (t, J=7.10 Hz, 3 H, OCH CH ); C-NMR (100.7 MHz,
2
3
2
3
CDCl ): δ (ppm)=167.2 (1 C, COO), 142.8 (1 C, NCHN), 140.7 (1 C,
C(Ar)), 137.5 (1 C, C(Ar)), 125.4 (1 C, C(Ar)), 124.4 (1 C, C(Ar)H), 118.1
3
Chlorido(1,3-diethyl-5-methoxycarbonyl-benzimidazol-2--
ylidene)gold(I) 3b
(
1 C, C(Ar)H), 115.0 (1 C, C(Ar)H), 61.1 (1 C, OCH CH ), 14.3 (1 C,
2 3
+ +
OCH CH ); MS (ESI): m/z: 162.9 [M+HÀ Et] , 190.9 [M+H] ; CHN
The compound was prepared from 1,3-diethyl-5-methoxycarbonyl-
2
3
(
calc./found) C (63.15/62.97), H (5.30/5.37), N (14.73/14.36).
benzimidazolium iodide 3a (500 mg, 1.388 mmol); yield: 317 mg
1
(
0.682 mmol, 49%), light yellow powder; H-NMR (600.1 MHz, CDCl )
3
δ (ppm)=8.21 (dd, J=1.4, 0.7 Hz, 1H, C(4)H), 8.16 (dd, J=8.6,
1.4 Hz, 1H, C(6)H), 7.53 (dd, J=8.6, 0.7 Hz, 1H, C(7)H), 4.58 (m 4H,
Procedure for synthesis of (benz-)imidazolium iodides 3a and
1
3
4
a
NCH
CH ), 4.00 (s, 3H, OCH ), 1.57 (m, 6H, NCH CH ); C-NMR
2 3 3 2 3
(
150.9 MHz, CDCl ) δ (ppm)=180.3 (1 C, NCAuN, C(2)), 166.1 (1 C,
3
The appropriate benzimidazole (1 eq.) and K CO3 (1 eq.) were
2
COO), 135.6 (1 C, C(Ar)), 132.6 (1 C, C(Ar)), 126.7 (1 C, C(Ar)), 126.0
1 C, C(Ar)H), 113.3 (1 C, C(Ar)H), 111.1 (1 C, C(Ar)H), 52.7 (1 C, OCH ),
suspended in acetonitrile (15 mL), ethyl iodide (5 eq.) was added,
and the reaction mixture was stirred under reflux for 24 h. The
solvent was removed in vacuo, the residue was suspended in
dichloromethane (20 mL) and the solution filtered. The solvent was
removed again and the residue was washed three times with
tetrahydrofuran/n-hexane (2/5).
(
3
+
4
4
5
4.3 (2 C, NCH CH ), 15.5 (2 C, NCH CH ); MS (EI): m/z: 429.0 [MÀ Cl] ,
2
3
2
3
+
64.0 [M] ; CHN (calc./found) C (33.60/33.51), H (3.47/3.36), N (6.03/
.85).
Chlorido(1,3-diethyl-5-ethoxycarbonyl-benzimidazol-2-ylidene)
gold(I) 4b
1
,3-Diethyl-5-methoxycarbonyl-benzimidazolium iodide 3a
The compound was prepared from 1,3-diethyl-5-ethoxycarbonyl-
The compound was prepared from methyl-1H-benzimiazole-5-
carboxylate (580 mg, 3.292 mmol); yield: 688 mg (1.910 mmol,
benzimidazolium iodide 4a (300 mg, 0.794 mmol); yield: 176.5 mg
1
(
0.369 mmol, 46%), grey-white powder; H-NMR (500.3 MHz, CDCl )
1
3
5
1
8
8%), pale brown powder; H-NMR (400.4 MHz, CDCl ) δ (ppm)=
1.27 (s, 1H, C(2)H), 8.44 (dd, J=1.4, 0.7 Hz, 1H, C(4)H), 8.35 (dd, J=
.8, 1.4 Hz, 1H, C(6)H), 7.85 (dd, J=8.8, 0.7 Hz, 1H, C(7)H), 4.76 (qd,
3
δ (ppm)=8.20 (dd, J=1.4, 0.6 Hz, 1H, C(4)H), 8.16 (dd, J=8.6,
.4 Hz, 1H, C(6)H), 7.52 (dd, J=8.6, 0.6 Hz, 1H, C(7)H), 4.58 (m, 4H,
NCH CH ), 4.46 (q, J=7.1 Hz, 2H, OCH CH ), 1.57 (m, 6H, NCH CH ),
1
2
3
2
3
2
3
J=7.4, 2.3 Hz, 4H, CH CH ), 4.02 (s, 3H, OCH ), 1.82 (td, J=7.4,
13
2
3
3
1
.45 (t, J=7.1 Hz, 3H, OCH CH ); C NMR (125.8 MHz, CDCl ) δ
13
2
3
3
5
.7 Hz, 6H, CH CH ); C-NMR (100.7 MHz, CDCl ) δ (ppm)=165.1
2
3
3
(
1
ppm)=180.2 (1 C, NCAuN, C(2)), 165.7 (1 C, COO), 135.5 (1 C, C(Ar)),
32.6 (1 C, C(Ar)), 127.1 (1 C, C(Ar)), 125.9 (1 C, C(Ar)H), 113.2 (1 C,
C(Ar)H), 111.0 (1 C, C(Ar)H), 61.7 (1 C, OCH CH ), 44.2 (2 C, NCH CH ),
(
1 C, COO), 143.7 (1 C, NCHN, C(2)), 133.9 (1 C, C(Ar)), 131.1 (1 C,
C(Ar)), 129.4 (1 C, C(Ar)), 128.2 (1 C, C(Ar)H), 115.0 (1 C, C(Ar)H),
13.2 (1 C, C(Ar)H), 53.0 (1 C, OCH ), 43.5 (1 C, CH CH ), 43.4 (1 C,
2
3
2
3
1
3
2
3
1
5.5 (2 C, NCH CH ), 14.4 (1 C, OCH CH ); MS (EI): m/z: 415.0 [MÀ Et-
2
3
+ + +
2
3
CH CH ), 14.9 (1 C, CH CH ), 14.8 (1 C, CH CH ); MS (ESI): m/z: 233.1
2
3
2
3
2
3
Cl] , 431.0 [MÀ Cl] , 478.0 [M] ; CHN (calc./found) C (35.13/35.36), H
3.79/3.75), N (5.85/5.72).
+
+
[
4
MÀ I] , 593.1 [2MÀ I] ; CHN (calc./found) C (43.35/43.35), H (4.76/
(
.75), N (7.78/7.71).
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General procedure for synthesis of (NHC)Au(III)Cl complexes
radiation. Absorption corrections were implemented on the basis of
3
2
1
c, 3c, 4c
multi-scans. The structures were refined anisotropically on F using
[
25]
the programs SHELXL-2017 or À 2018.
Hydrogen atoms were
(
NHC)Au(III)Cl complexes were prepared according to a modified
3
included using rigid methyl groups or a riding model starting from
calculated positions.
[16]
reported procedure. The respective (NHC)Au(I)Cl complex (1 eq.)
was dissolved in dichloromethane (4 mL) and stirred at room
temperature with protection from light. Dichlorophenyliodane
Crystallographic data are summarized in Table 5. Additionally,
complete data have been deposited with the Cambridge Crystallo-
graphic Data Centre under the numbers CCDC 2085400–3. Copies
of the data can be obtained free of charge from –www.ccdc.cam.a-
c.uk/data_request/cif.
(
1.4 eq.) was added and the mixture was stirred for 24 h. The
solvent was removed and the residue was washed with n-hexane
3x), diethyl ether (3x) and cold chloroform (2x). The obtained solid
(
was dried in vacuo at 40°C.
Trichlorido(1,3-diethyl-imidazol-2-ylidene)gold(III) 1c
Antibacterial screening
The following strains were used and maintained at 37
°
C in MHB
The compound was prepared from chlorido(1,3-diethyl-imidazol-2-
ylidene)gold(I) 1b (100.0 mg, 0.280 mmol) yield: 69.2 mg
(21 g/L Müller Hinton, pH 7.4) or TSY (30 g/L trypticase soy broth,
3 g/L yeast extract, pH 7.0–7.2) medium. Acinetobacter baumannii
(DSM 30007, ATCC 19606) in MHB, Escherichia coli (DSM1116, ATCC
9637) in TSY, Klebsiella pneumoniae (DSM 11678, ATCC33495) in
MHB, Pseudomonas aeruginosa PA7 (DSM 24068) in MHB, Enter-
ococcus faecium (DSM 20477, ATCC 19434) in TSY, Staphylococcus
aureus MRSA (DSM 11822, ICB 25701) in TSY). Minimum inhibitory
concentration (MIC) values were determined following a stand-
ardized protocol in broth dilution assays. The compounds and
auranofin were serially diluted starting from 64 μg/ml using a
pipetting robot (epMotion, Eppendorf, Germany). Starting inocula
1
(
0.162 mmol, 58%) pale yellow powder; H-NMR (500.3 MHz, DMSO-
3
d ) δ (ppm)=8.20 (s, 2H, CH), 4.29 (m, J=7.3 Hz, 4H, NCH CH ),
.45 (m, J=7.3 Hz, 6H, NCH CH ); C-NMR (125.8 MHz, DMSO-d6)
6
2
3
3
13
1
2 3
δ=135.2 (NCAuN, C2), 124.2 (CH), 45.3 (NCH CH ), 15.4 (NCH CH );
2
3
2
3
+
+
+
MS (ESI): m/z: 677.1 [2 M-5Cl] , 819.0 [2MÀ Cl] , 876.9 [2 M+Na] ;
CHN (calc./found) C (19.67/19.48), H (2.83/2.90), N (6.55/6.37).
Trichlorido(1,3-diethyl-5-methoxycarbonyl-benzimidazol--
2
-ylidene)gold(III) 3c
5
of 2–8×10 colony-forming units per ml in MHB or TSY media at
The compound was prepared from chlorido(1,3-diethyl-5-meth-
3
7°C were used, and serial dilutions were carried out in 384-well
oxycarbonyl-benzimidazol-2-ylidene)gold(I) 3b (118.7 mg,
.250 mmol); yield: 130 mg (0.243 mmol, 97%), yellow powder; H-
NMR (600.1 MHz, CDCl ) δ (ppm)=8.35 (d, J=1.5 Hz, 1H, C(4)H),
microtiter plates in duplicate. After incubation of the plates for 20 h
1
0
at 37°C, the absorbance at 600 nm was measured to determine the
3
MIC value (Enspire Multimode Microplate Reader, Perkin Elmer Inc.).
The MIC values for the tested compounds were determined in three
independent experiments by a curve-fitting procedure using the
GraphPad Prism software (GraphPad Software, Inc.). Amikacin (P.
aeruginosa), Linezolid (S. aureus), and Ciprofloxacin (all other strains)
served as positive controls.
8
.26 (dd, J=8.7, 1.4 Hz, 1H, C(6)H), 7.71–7.67 (m, 1H, C(7)H), 4.71 (m,
J=7.4 Hz, 4H, NCH CH ), 4.03 (s, 3H, OCH ), 1.70 (m, J=7.4 Hz, 6H,
NCH CH ); C-NMR (150.9 MHz, CDCl ) δ (ppm)=165.3 (1 C, COO),
2
3
3
13
2
3
3
1
(
54.6 (1 C, NCAuN, C(2)), 136.0 (1 C, C(Ar)), 133.2 (1 C, C(Ar)), 128.1
1 C, C(Ar)), 127.1 (1 C, C(Ar)H), 114.1 (1 C, C(Ar)H), 112.0 (1 C, C(Ar)
H), 53.0 (1 C, OCH ), 44.3 (2 C, NCH CH ), 14.7 (2 C, NCH CH ) ; MS
3
2
3
2
3
+
+
+
(
ESI): m/z: 557.0 [M+Na] , 1035.0 [2MÀ Cl] , 1093.0 [2 M+Na] ;
CHN (calc./found) C (29.15/29.56), H (3.01/3.24), N (5.23/5.02).
Inhibition of bacterial TrxR (E.coli)
The TrxR (E.coli) inhibition assay was performed according to a
[
6]
Trichlorido(1,3-diethyl-5-ethoxycarbonyl-benzimidazol-2-
previously published procedure. It is partly based on the
[26]
-ylidene)gold(III) 4c
procedure developed by Lu et al. and detects the formation of 5-
TNB (5-thionitrobenzoic acid). Solutions of E. coli TrxR (35.4 U/mL)
and of its substrate thioredoxin (Trx) E.coli (156 μg/mL) (both
purchased from Sigma-Aldrich and diluted with distilled water) and
fresh stock solutions of the test compounds (in DMF) were
prepared. TE buffer (Tris-HCl 50 mM, EDTA 1 mM, pH 7.5) containing
graded concentrations of the respective compounds (20 μL) or
buffer without compounds (20 μL, as control) were mixed with TrxR
solution (10 μL), Trx solution (10 μL), and a solution of NADPH
(200 μM) in TE buffer (100 μL) in a well on a 96-well plate. As blank
solution, 200 μM NADPH in TE buffer (100 μL) mixed with a DMF/
buffer mixture (40 μL) was used (final concentrations of DMF: 0.5%
v/v). The solutions on the 96-well plate were incubated for 75 min
at 25°C with moderate shaking. A volume of 100 μL of a reaction
The compound was prepared from chlorido(1,3-diethyl-5-eth-
oxycarbonyl-benzimidazol-2-ylidene)gold(I) 4b (125 mg,
.261 mmol); yield: 106 mg (0.193 mmol, 74%), pale yellow to pale
0
1
orange powder; H-NMR (500.3 MHz, CDCl ) δ (ppm)=8.33 (dd, J=
3
1
.4, 0.7 Hz, 1H, C(4)H), 8.26 (dd, J=8.7, 1.4 Hz, 1H, C(6)H), 7.68 (dd,
J=8.7, 0.7 Hz, 1H, C(7)H), 4.71 (m, J=7.3 Hz, 4H, NCH CH ), 4.49 (q,
2
3
J=7.2 Hz, 2H, OCH CH ), 1.70 (m, J=7.3 Hz, 6H, NCH CH ), 1.46 (t,
2
3
2
3
13
J=7.2 Hz, 3H, OCH CH ); C-NMR (100.7 MHz, CDCl ) δ (ppm)=
2
3
3
1
(
1
64.9 (1 C, COO), 154.6 (1 C, NCAuN, C(2)), 135.9 (1 C, C(Ar)), 133.2
1 C, C(Ar)), 128.6 (1 C, C(Ar)), 127.1 (1 C, C(Ar)H), 114.0 (1 C, C(Ar)H),
11.9 (1 C, C(Ar)H), 60.1 (1 C, OCH CH ), 44.3 (2 C, NCH CH ), 14.8
2
3
2
3
(
1 C, NCH CH ), 14.6 (1 C, NCH CH ), 14.3 (1 C, OCH CH ); MS (ESI):
2 3 2 3 2 3
+ + +
m/z: 571.0 [M+Na] , 1063.1 [2MÀ Cl] , 1121.0 [2 M+Na] ; CHN
mixture (TE buffer containing 200 μM NADPH and 5 mM DTNB) was
added to each well to initiate the reaction. After thorough mixing,
the formation of 5-TNB was monitored by a microplate reader at
(calc./found): C (30.59/30.25), H (3.30/3.39), N (5.10/4.88).
4
05 nm in 35 s intervals (10 measurements). The values were
Crystal Structure Determinations
corrected by subtraction of the values for the blank solution. The
2
increase in concentration of 5-TNB followed a linear trend (r ꢀ
For compound 3b, the crystal was mounted in inert oil on a glass
fibre and transferred to an Oxford Diffraction Xcalibur E diffrac-
tometer; intensity data were recorded using monochromated Mo-
Kα radiation. Other crystals were mounted in inert oil on nylon
loops and transferred to a Rigaku/Oxford XtaLAB Synergy diffrac-
tometer; intensity data were recorded using mirror-focussed Mo-Kα
0
.990) and the enzymatic activities were calculated as the gradients
(increase in absorbance per second) thereof. Absence of interfer-
ence with the assay components was confirmed by a negative
control experiment for each test compound. The highest test
compound concentration was used and the enzyme solution was
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6
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Table 5. Crystallographic data and structure refinement details.
1
c
2c
3b
4c
CCDC number
Formula
2085400
12AuCl
427.50
2085401
2085402
2085403
C
7
H
3
N
2
C
11
H
14AuCl
3
N
2
C
13
H16AuClN
2
O
2
C
14
H18AuCl
3 2 2
N O
M
r
477.56
464.69
549.62
Cryst. size (mm)
Crystal system
Space group
0.2×0.15×0.10
monoclinic
0.16×0.14×0.10
orthorhombic
Pbca
0.20×0.10×0.04
triclinic
P(-1)
0.10×0.03×0.03
monoclinic
P2 /c
1
P2
1
/n
Temperature (°C)
À 173
À 173
À 173
À 173
a (Å)
b (Å)
c (Å)
α (°)
β (°)
γ (°)
8.31009(18)
14.8691(3)
10.1260(2)
90
13.38840(17)
14.21271(16)
14.49339(17)
90
9.0249(4)
9.3241(7)
10.1589(6)
114.783(6)
93.470(5)
111.503(6)
698.52
2
7.7709(2)
14.8464(4)
15.3816(4)
90
103.407(2)
90
1217.11
4
2.333
90
90
2757.88
8
2.300
101.737(3)
90
1737.48
4
2.101
3
V (Å )
Z
D
À 3
x
(Mg m
)
2.209
λ (Å)
μ (mm
0.71073
12.7
0.71073
11.2
0.71073
10.7
0.71073
8.9
À 1
)
Transmissions
F(000)
0.542–1.000
792
0.511–1.000
1792
0.524–1.000
440
0.534–1.000
1048
2
θ
max
76.7
120169
6607
104.3
613091
15837
59
31317
3586
68
82892
6595
Refl. measured
Refl. indep.
R
int
0.61
120
0.042
0.074
156
0.039
0.051
175
0.041
0.041
202
0.048
Parameters
wR(F , all refl.)
2
R(F, >4σ(F))
S
Max. Δp (e Å
0.019
1.03
1.6, À 2.1
0.026
1.15
1.8, À 2.6
0.021
1.05
1.3, À 0.95
0.023
1.09
3.2, À 0.83
À 3
)
replaced by TE buffer for this purpose. The IC50 values were
calculated as the concentration of the compound decreasing the
enzymatic activity of the positive control by 50% and are presented
as the means and standard deviations of three repeated experi-
ments.
respective cell medium to obtain various concentrations (final
concentration of DMF: 0.1% v/v). After 72 h (A549) or 96 h (MDA-
MB-231, RC-124) of exposure, the biomass of the cells was
determined via crystal violet staining and the IC50 value was
determined as the concentration that caused 50% inhibition of cell
proliferation relative to an untreated control. The results were
calculated as the mean values of three independent experiments,
unless stated otherwise.
Cell culture
A549 lung carcinoma cells and MDA-MB-231 breast cancer cells
were maintained in Dulbecco’s modified Eagle’s medium (DMEM;
4
.5 g/L D-glucose, L-glutamine, pyruvate), supplemented with fetal
Acknowledgements
bovine serum superior, standardized (Biochrom GmbH, Berlin, 10%
v/v) and gentamycin (50 mg/L) with a weekly passage. RC-124
healthy human kidney cells were maintained in McCoy’s 5 A
medium (modified with L-glutamine) supplemented with fetal
bovine serum superior, standardized (Biochrom GmbH, Berlin) and
gentamycin (50 mg/L) (10% v/v), and were also passaged weekly.
For experiments with RC-124 cells, microtiter plates were pretreated
as follows: sterilized gelatine solution (1.5%; 30 μL) was added to
each well of a flat-bottomed 96-well plate and incubated for 1 h at
Financial support by the DFG (Deutsche Forschungsgemeinschaft,
bilateral grant 382040922 for TU-BS and HZI) and the Lower
Saxony Ministry for Science and Culture for the doctoral program
“
Drug Discovery and Cheminformatics for New Anti-Infectives
(iCA)” are gratefully acknowledged. Open access funding enabled
and organized by Projekt DEAL.
3
7°C while covered with the lid. The excess solution was removed
and the wells were washed with PBS (pH 7.4). The new cell culture
medium was immediately added.
Conflict of Interest
The authors declare no conflict of interest.
Antiproliferative assay in tumorigenic and non-tumorgenic cells
The antiproliferative effects were determined according to a
[
6]
Keywords: antibacterial · gold · N-heterocyclic carbene ·
thioredoxin reductase
previously published procedure. A volume of 100 μL of A549 cells
710000 cells/mL), MDA-MB-231 cells (830000 cells/mL) and RC-124
(
cells (610000 cells/mL) was transferred into the wells of a 96-well
plate (plates for RC-124 were pretreated as mentioned above) and
incubated at 37°C under 5% CO for 72 h (MDA-MB-231, RC-124) or
2
4
8 h (A549). Stock solutions of the compounds were freshly
prepared in dimethylformamide (DMF) and diluted with the
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ChemMedChem
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Manuscript received: May 28, 2021
Revised manuscript received: July 10, 2021
Accepted manuscript online: July 16, 2021
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ChemMedChem 2021, 16, 1–9
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FULL PAPERS
Worth their weight: A series of
R. Büssing, B. Karge, P. Lippmann,
Prof. Dr. P. G. Jones, Prof. Dr. M.
Brönstrup, Prof. Dr. I. Ott*
(NHC)Au(I)Cl monocarbene
complexes and their gold(III)
analogues (NHC)Au(III)Cl were
3
1
– 9
prepared, analytically characterized,
and investigated as organometallic
antibacterial drugs. This report is the
first confirmation of the antibacterial
effects of gold(III) NHC species and
their efficient inhibition of bacterial
thioredoxin reductase (TrxR).
Gold(I) and Gold(III) N-Heterocyclic
Carbene Complexes as Antibacterial
Agents and Inhibitors of Bacterial
Thioredoxin Reductase