Antimicrobial Properties of Mono-and Di-fac-rhenium Tricarbonyl 2-Pyridyl-1,2,3-triazole Complexes

Article abstract of DOI:10.1071/CH15433

A family of mono-and di-fac-rhenium tricarbonyl 2-pyridyl-1,2,3-triazole complexes with different aliphatic and aromatic substituents was synthesized in good-to-excellent yields (46-99%). The complexes were characterized by ¹H and ¹³

Full text of DOI:10.1071/CH15433

RESEARCH FRONT
CSIRO PUBLISHING
Aust. J. Chem.
Full Paper
http://dx.doi.org/10.1071/CH15433
Antimicrobial Properties of Mono- and Di-fac-rhenium
Tricarbonyl 2-Pyridyl-1,2,3-triazole Complexes†
A B
,
A
B
Sreedhar V. Kumar,
Warrick K. C. Lo, Heather J. L. Brooks,
A
A C
,
Lyall R. Hanton, and James D. Crowley
A
Department of Chemistry, University of Otago, PO Box 56, Dunedin, New Zealand.
Department of Microbiology and Immunology, Otago School of Medical Sciences,
University of Otago, Dunedin, New Zealand.
B
C
Corresponding author. Email: jcrowley@chemistry.otago.ac.nz
A family of mono- and di-fac-rhenium tricarbonyl 2-pyridyl-1,2,3-triazole complexes with different aliphatic and
aromatic substituents was synthesized in good-to-excellent yields (46–99 %). The complexes were characterized by
1H and 13C NMR spectroscopy, infrared spectroscopy, electronic (UV-visible) spectroscopy, high-resolution electrospray
mass spectrometry, and elemental analyses. In four examples, the solid-state structures of the rhenium(I) complexes were
confirmed by X-ray crystallography. The family of the mono- and di-rhenium(I) complexes and the corresponding
2-pyridyl-1,2,3-triazole was tested for antimicrobial activity in vitro against both Gram-positive (Staphylococcus aureus)
and Gram-negative (Escherichia coli) microorganisms. Agar-based disk diffusion assays indicated that most of the
rhenium(I) complexes were active against Staphylococcus aureus and that the cationic rhenium(I) complexes were more
active than the related neutral systems. However, in all cases, the minimum inhibitory concentrations for all the complexes
were modest (i.e. 16–1024 mg mLꢀ1).
Manuscript received: 18 July 2015.
Manuscript accepted: 25 August 2015.
Published online: 9 October 2015.
inspired by Dwyer and coworkers,[5] considerable effort has
focussed on systems containing inert hydrophobic cations of the
type [Ru(phen)2(N–N)]2þ (where N–N ¼ diimine ligand).[9]
Though these mono-metallic complexes have proved effective
against resistant bacterial strains such as MRSA, Keene and
coworkers have shown that related di-metallic systems linked
by alkyl spacer units (2a, Fig. 1) display improved activity.[9b]
Subsequent studies[10] by the same group have suggested that the
antibacterial activity of these inert di-metallic ruthenium(II)
complexes is related to the cellular uptake. Complexes having
longer alkyl chain spacers exhibited the greatest cellular accumu-
lation and activity. Thus, it appears that the lipophilicity of
complexes is an important parameter for activity. Furthermore,
Keene and coworkers have shown that a subtle interplay among
the overall charge on the complex, spacing between the charges,
and lipophilicity leads to high activity. Mono- and di-iridium(III)
complexes (1b and 2b, Fig. 1) that are structurally analogous to
the active ruthenium(II) complexes but display a higher 3þ charge
at the metal centres are not active antimicrobial agents.[10d,10e]
Additionally, related tri- and tetra-ruthenium(II) complexes that
have the same or a higher overall charge than the iridium(III)
complexes are active, presumably because the charge distribution
in these systems is different. Though the exact biological mode of
action for these systems is still not well defined, the above results
suggest that inert hydrophobic cationic metal complexes hold
great potential as antibacterial agents.
Introduction
Bacteria have built up resistance to a wide variety of organic
antibacterial agents that are commonly used to kill such patho-
genic microbes.[1] This is in part due to the widespread overuse
of antibacterial agents.[2] Additionally, there has been a lack of
interest in the development of new antibacterial drugs.[3] These
factors have led to the assertion by the World Health Organi-
zation (WHO) in 2014 that the human race is on the verge of a
‘post-antibiotic era’.[4] As such, there is an urgent need for the
development of new antimicrobial agents that display novel
modes of biological activity.
In 1952, Dwyer and coworkers showed that hydrophobic
cationic metal complexes of the formula [M(phen/bipy)3]2þ
(where M ¼ Ni2þ, Fe2þ, Ru2þ, Os2þ, phen ¼ 1,10-phenanthro-
line, and bipy ¼ 2,20-bipyridine) displayed antibacterial activity
against Gram-positive, Gram-negative, and acid-fast bacterial
strains.[5] Inert hydrophobic complexes containing the [Ru
(phen)3]2þ unit (1a, Fig. 1) proved to be the most effective.[5]
Six decades after this landmark discovery, interest in these types
of systems has re-emerged, in the hope that metal-based anti-
microbial agents will have different modes of action compared
with traditional organic systems and provide new weapons
to fight resistant bacteria.[6] A wide range of cationic mono-[7]
and di-metallic[8] complexes display promising antibacterial
properties against different bacterial strains including methicil-
lin-resistant Staphylococcus aureus (MRSA). However,
†This paper is dedicated to Prof. Brice Bosnich (FRS, 1936–2015), a gifted scientist and a superb mentor.
Journal compilation Ó CSIRO 2015
www.publish.csiro.au/journals/ajc

B
S. V. Kumar et al.
nꢀ
nꢀ
N
M
N
N
M
N
N
M
N
N
N
N
N
N
N
N
N
N
N
N
N
y
1a (M ꢁ Ru, n ꢁ 2)
1b (M ꢁ Ir, n ꢁ 3)
2a (M ꢁ Ru, n ꢁ 4, y ꢁ 12)
2b (M ꢁ Ir, n ꢁ 6, y ꢁ 12)
ꢀ
ꢀ
N
N
N
OC
CO
N
Re
N
N
N
N
CO
N
N
N
N
O
O
N
O
Re(CO)3
4
O
O
N
N
H
H
O
3
OH
Fig. 1. Selected inert metal complexes that display antimicrobial activity.
fac-Rhenium(I) tricarbonyl complexes are a well-studied
at 1258C for 3 h. After cooling the reaction mixture to room
temperature (RT), copper sulfate pentahydrate (CuSO4ꢁ5H2O;
0.4 equiv.), sodium ascorbate (0.5 equiv.) and 2-ethynylpyridine
(2 equiv.) were added to the in situ generated diazides, and the
resulting suspensions were stirred for 12 h, providing the new
ligands (6c and 6d) as colourless solids in good yields (79–85 %)
after workup (Supplementary Material). The 1H and 13C NMR
and high-resolution electrospray ionization mass spectra and
elemental analysis data were all consistent with the expected
formulation of the ligands.
class of inert hydrophobic metal complexes. Due to the inertness
and photo-activity of these complexes, they have found use
in biological systems as luminescent probes.[11] Additionally, it
has been shown that some fac-rhenium(I) tricarbonyl complexes
have potential as anticancer agents.[12] Despite these biological
applications, there has been little interest in examining the
antimicrobial activity of these inert lipophilic metal complexes.
Very recently, Metzler-Nolte and coworkers reported that tri-
metallic complexes containing a fac-rhenium(I) tricarbonyl unit
display potent bactericidal activity against MRSA.[13] Subse-
quent work showed that the fac-rhenium(I) tricarbonyl motif
(3, Fig. 1) was essential for the activity.[14] We have shown that
cationic fac-rhenium(I) tricarbonyl complexes of readily func-
tionalized ‘click’ macrocycles (4, Fig. 1) display modest anti-
microbial activity.[15]
As part of our[16] interest in readily functionalized 2-pyridyl-
1,2,3-triazole ‘click’ ligands,[17] generated using the functional
group tolerant Cu(I)-catalyzed 1,3-cycloaddition of organic
azides with terminal alkynes (the CuAAC reaction),[18] and
biologically active metal complexes,[19] we herein report the
syntheses and antibacterial properties of a series of mono- and
di-fac-rhenium(I) complexes generated from mono- and di-2-
pyridyl-1,2,3-triazole ‘click’ ligands.
We have reported the synthesis of fac-rhenium tricarbonyl
2-pyridyl-1,2,3-triazole chloride complexes (7aCl and 7bCl)
previously.[20] The mono-bromide (7aBr and 7bBr) and
the di-chloride and di-bromide (8aCl–8dCl and 8aBr–8dBr
)
complexes were synthesized using similar procedures
(Scheme 1).[20,21] One of the ligands (5a, 5b, 6a, 6b, 6c or 6d)
and either pentacarbonylrhenium(I) chloride [Re(CO)5Cl] or
pentacarbonylrhenium(I) bromide [Re(CO)5Br] were suspended
in ethanol, and the resulting mixture was refluxed for 24 h.
The neutral chloride (8aCl–8dCl) and bromide (7aBr, 7bBr and
8aBr–8dBr) complexes were isolated as off-white solids in
good-to-excellent yields (83–99 %). These neutral compounds
were converted into the cationic 4-(N,N0-dimethylamino)
pyridine (DMAP)[22] complexes (7aDMAP, 7bDMAP and
8aDMAP–8dDMAP) using a modification of the procedure devel-
oped by Benoist and coworkers (Scheme 1).[21b] One of the
Results and Discussion
neutral rhenium bromide complexes (7aBr, 7bBr, 8aBr or 8bBr
;
Synthesis and Characterization of the 2-Pyridyl-
1,2,3-triazole Ligands and Complexes
1 equiv.) and silver triflate (AgOTf, 1 or 2 equiv.) were dissolved
in dry dichloromethane and stirred at room temperature in the
absence of light for 12 h. The silver bromide precipitate was
removed and the in situ generated triflate complexes were
added to DMAP (1 or 2 equiv.) in THF and irradiated for
1 h at 1008C in a pressurized microwave reactor. The mono-
metallic complexes (7aDMAP and 7bDMAP) were isolated in
good yields (73–78 %), whereas the yields of the di-metallic
systems (8aDMAP–8dDMAP) were more modest (46–53 %).
Initial attempts to use the chloride complexes (7aCl, 7bCl, 8aCl
and 8bCl) as the synthetic precursors were not as successful.
A small library of mono- (5a and 5b) and di- (6a and 6b)
2-pyridyl-1,2,3-triazole ligands substituted with aliphatic and
aromatic spacer units were synthesized using our previously
reported procedure (Supplementary Material).[16g] The proce-
dure was slightly modified to generate the di-(2-pyridyl-1,2,3-
triazole) ligands 6c and 6d. The dibromoalkyl precursor (either
1,6-dibromohexane or 1,8-dibromooctane; 1 equiv.) and sodium
azide (3 equiv.) were dissolved in DMF/water (4 : 1), and the
resulting solution was irradiated in a microwave reactor (200 W)

Antimicrobial Rhenium(I) 2-Pyridyl-1,2,3-triazole Complexes
C
8
7
6
5
4
3
2
1
0
ꢀ (Xꢂ)
c
d
e
R
R
(i)
N
N
N
N
b
L
N
N
N
N
8bCl
8bBr
8bDMAP
a
Re
CO
OC
CO
(R ꢁ Bn, L ꢁ X ꢁ CIꢂ)
(R ꢁ Bn, L ꢁ X ꢁ Brꢂ)
5a (R ꢁ Bn)
5b (R ꢁ C8H17
7aCI
7aBr
7aDMAP
7bCI
)
(ii)
(ii)
(R ꢁ Bn, L ꢁ DMAP, X ꢁ OTfꢂ)
(R ꢁ C8H17, L ꢁ X ꢁ CIꢂ)
(R ꢁ C8H17, L ꢁ X ꢁ Brꢂ)
7bBr
7bDMAP (R ꢁ C8H17, L ꢁ DMAP, X ꢁ OTfꢂ)
c
d
e
N
N
N
Spacer
Spacer ꢁ
b
N
N
N
N
N
a
a
6a–6d
300
400
(i)
2ꢀ (Xꢂ)2
Wavelength [nm]
b
c
d
4
N
N
N
N
Spacer
Fig. 2. Electronic absorption spectra (DMF, 10ꢀ5 M) of the neutral (8bCl
and 8bBr) and cationic (8bDMAP) di-rhenium(I) complexes.
6
L
L
N
N
N
N
Re
Re
10
OC
CO
OC
CO
CO
CO
Supplementary Material). The cationic mono- and di-rhenium
(I) DMAP complexes are very similar, and each feature a
well-defined peak at ,290 nm and a shoulder in the range of
330–340 nm (Fig. 2 and Supplementary Material). The higher
energy, more intense absorptions are ascribed to intraligand
p–p* transitions, whereas the lower energy bands are attributed
to metal-to-ligand charge transfer transitions on the basis of
previous density functional theory calculations.[20]
8aCI or Br (L ꢁ X ꢁ Clꢂ or Brꢂ)
8bCI or Br (L ꢁ X ꢁ Clꢂ or Brꢂ)
8cCI or Br (L ꢁ X ꢁ Clꢂ or Brꢂ)
8dCI or Br (L ꢁ X ꢁ Clꢂ or Brꢂ)
8aDMAP (L ꢁ DMAP, X ꢁ OTfꢂ)
8bDMAP (L ꢁ DMAP, X ꢁ OTfꢂ)
8cDMAP (L ꢁ DMAP, X ꢁ OTfꢂ)
8dDMAP (L ꢁ DMAP, X ꢁ OTfꢂ)
(ii)
Scheme 1. Synthesis of mono- and di-rhenium(I) tricarbonyl 2-pyridyl-
1,2,3-triazole complexes. Reaction conditions: (i), either [Re(CO)5Cl] or
[Re(CO)5Br], ethanol, reflux, 24 h; (ii) (a) silver triflate (AgOTf), CH2Cl2,
RT, 12h, (b) DMAP, THF, microwave irradiation (200 W), 1008C, 1 h.
1
The H NMR spectra (recorded in d6-DMSO at 298 K) of
the fac-rhenium(I) tricarbonyl complexes displayed large down-
field shifts of pyridyl (Ha) and triazolyl (He) proton signals
relative to the ligands, indicative of metal complexation
Intractable mixtures containing very low yields of the desired
DMAP complexes along with unreacted starting material and
partially reacted mono-substituted complexes, in the case of the
di-metallic systems, were obtained.
All complexes were characterized using a combination of
1H and 13C NMR, infrared (IR), and UV-visible spectroscopies,
high-resolution electrospray mass spectrometry (HR-ESMS)
and elemental analyses. IR spectra of the complexes (7aCl,
1
(Fig. 3 and Supplementary Material). The H NMR spectra of
the cationic rhenium complexes (7aDMAP and 7bDMAP and
8aDMAP–8dDMAP) contained three additional resonances, two
aromatic (between 7.70 and 6.40 ppm) and one alkyl (2.90 ppm),
confirming the presence of the coordinated DMAP ligands to the
rhenium ions (Fig. 3c and Supplementary Material).
The molecular structures of the mono- (7aBr and 7aDMAP
)
7bCl, 7aBr, 7bBr, 7aDMAP, 7bDMAP, 8aCl–8dCl, 8aBr–8dBr
,
and di- (8aCl and 8aDMAP) rhenium(I) complexes (Fig. 4,
Table 1, and Supplementary Material) were unambiguously
confirmed by X-ray crystallography. X-ray-quality single crys-
tals were obtained by vapour diffusion of either diethyl ether or
diisopropyl ether into an acetonitrile (or DMF) solution of the
complexes. The neutral rhenium(I) complexes (7aBr and 8aCl)
crystallized in the orthorhombic space groups Pbcn and Pbca,
respectively, whereas the cationic systems (7aDMAP and
and 8aDMAP–8dDMAP) displayed bands consistent with the
presence of the aromatic units of the ligands (3100–2900 cmꢀ1
and 1600–1400 cmꢀ1) and carbonyl ligands (three strong n(CO)
stretching bands in the range of 2020–1885 cmꢀ1), indicative
of the presence of the fac-[Re(CO)3]þ core. The elemental
analysis data were consistent with the expected formulation
of the complexes and this was further supported by the
HR-ESMS data. The mass spectra of the neutral mono-chloride
ꢀ
8aDMAP) were found to form in the triclinic space group P1.
and mono-bromide complexes (7aCl, 7bCl, 7aBr and 7bBr
)
As expected, the pyridyltriazole ‘click’ ligands are coordinated
to the rhenium(I) ions in a bidentate fashion through the triazole
(trz) and pyridyl (py) nitrogen atoms. The three carbonyl ligands
are also bound to the rhenium ions in the expected facial array,
leading to a distorted octahedral coordination environment at the
metal centre. The final coordination site is occupied by either a
chlorido, bromido, or DMAP ligand. The bidentate pyridyltria-
zole ligands form five-membered chelate rings and the bite
angle of the ligands varies slightly in the complexes, ranging
from 74.4(2)8 to 74.9(1)8. In addition, the Npy–Re bonds (2.175
showed major ions due to [(L)Re(CO)3X þ Na]þ (L ¼ 5a or
5b, X ¼ Brꢀ or Clꢀ) and [(L)Re(CO)3]þ, whereas the di-rhenium
complexes (8aCl–8dCl and 8aBr–8dBr) each displayed a promi-
nent peak consistent with [(L0)Re2(CO)6X]þ (L0 ¼ 6a or 6b or 6c
or 6d, X ¼ Brꢀ or Clꢀ). Similarly, the mass spectra of the cationic
DMAP complexes, 7aDMAP and 7bDMAP and 8aDMAP–8dDMAP
,
showed major ions due to either [(L)Re(CO)3(DMAP)]þ or
[(L0)Re2(CO)6(DMAP)2]2þ. All the mass spectra displayed the
expected 185/187Re isotope patterns (Supplementary Material).
The UV-visible spectra (recorded in DMF) of the neutral
˚
(7)–2.204(3) A) are consistently longer than the Ntrz–Re bonds
˚
(2.127(6)–2.153(9) A), suggesting that the triazolyl nitrogens
mono- and di-rhenium(I) complexes (7aCl, 7bCl, 7aBr and 7bBr
,
8aCl–8dCl, and 8aBr–8dBr) each display an intense shoulder
at ,290 nm and a weaker band at 330 nm (Fig. 2 and
coordinate more strongly to the Re centre than the pyridyl
nitrogens of the ligands; this behaviour has been observed in

D
S. V. Kumar et al.
other metal complexes of these ‘click’ ligands.[16] The Re–Br
crystallize as a racemic mixture of both the L and D enantio-
mers. The di-rhenium complexes can form either syn or anti
stereoisomers (Supplementary Material). In the solid-state
structures of 8aCl and 8aDMAP, the syn isomers are observed.
This is consistent with the H NMR spectra, which show only
one set of resonances, suggesting the selective formation of a
single diastereomer. However, we cannot rule out that a mixture
1
of the syn and anti diastereomers (which display identical H
˚
bond length (2.617(1) A) of complex 7aBr is considerably longer
[21m]
˚
than the Re–Cl distance (2.471(2) A) reported for 7aCl,
suggesting, as expected, that the Re–Br bond is weaker than the
Re–Cl bond and providing a reason for the more facile activation
of the bromido complexes. Somewhat surprisingly, the Re–
1
˚
DMAP bond distances (2.177(7) and 2.200(4) A) are quite
˚
similar to the Re–py bond distance (2.201(3) A) reported for
[21d]
7apy despite DMAP being a much more basic (electron-
donating) ligand. The mono-rhenium complexes are chiral and
NMR spectra) are formed initially and then the syn complex
selectively crystallizes from the mixture.[23]
(a)
(b)
e
f
h
g
d
a
c
b
DMAP
(c)
DMAP
7.5
DMAP
6.5
10.0 9.5
9.0
8.5
8.0
7.0
6.0
5.5
5.0
4.5
4.0
3.0
2.0
1.5
1.0
δ [ppm]
Fig. 3. Partial 1H NMR spectra (400 MHz, d6-DMSO, 298 K) of (a) ligand 6b, (b) 8bBr, and (c) 8bDMAP. See Scheme 1 for peak
labelling.
(a)
(b)
O22
Cl1
C22
O20ꢄ
C20ꢄ
Br1
N3
N1ꢄ
N3
Re1
C21
N2
N4
N4
C21ꢄ
Re1ꢄ
O21
O21ꢄ
C21
O20
O21
(c)
Re1
N4ꢄ
N2ꢄ
C20
N1
N1
N2
N3ꢄ
O20
C22ꢄ
Cl1ꢄ
C20
C22
O22
O22ꢄ
(d)
N2ꢄ
N6
N1ꢄ
O98ꢄ
O99
C99
N5ꢄ
C98ꢄ
Re1ꢄ
N3
C97ꢄ
O97ꢄ
N6ꢄ
N5
O97
N6
N4ꢄ
C97
Re1
N1
N3ꢄ
N4
O1 C22
N5
N4
C99ꢄ
O99ꢄ
Re1 N2
O98
N3
N1
O3
C24
C23
O2
C98
N2
Fig. 4. ORTEPs[24] of the molecular structures of the fac-rhenium tricarbonyl 2-pyridyl-1,2,3-triazole complexes: (a) 7aBr, (b) 8aCl, (c) 7aDMAP, and
(d) 8aDMAP. The thermal ellipsoids are shown at the 50 % probability level. Solvent molecules and counter anions are omitted for clarity. Selected bond
˚
lengths (A) and bond angles (8) for the rhenium complexes are listed in Table 1.

Antimicrobial Rhenium(I) 2-Pyridyl-1,2,3-triazole Complexes
E
Competition Experiments to Evaluate the Kinetic Stability
of the Rhenium(I) Complexes Versus Histidine
is kinetically stable in the presence of histidine over this time
period. Conversely, over a similar time period, additional
resonances appear in the 1H NMR spectra of the cationic com-
plex 8cDMAP. A new set of peaks begin to appear after
approximately 7 h, and after 24 h, two sets of additional reso-
nances are present (Fig. 5). One set of chemical shifts are con-
sistent with the presence of the free ligand 6c in the reaction
mixture. We attribute the second set of new resonances to
a mono-metallic complex where one of the fac-rhenium tri-
Before carrying out the antimicrobial testing, the kinetic sta-
bility of two of the di-rhenium(I) 2-pyridyl-1,2,3-triazole com-
plexes (8aCl and 8cDMAP) was examined using histidine as
a competitive ligand. One of the complexes (either 8aCl or
8cDMAP) was dissolved in d6-DMSO and DL-histidine (D- and
L-histidine) hydrochloride monohydrate (6 equiv.) and NaHCO3
(6 equiv.) were added. The resulting mixture was heated at 408C,
and the 1H NMR spectra of the mixtures were recorded at spe-
cific intervals of time over a period of 24 h. Upon addition
of DL-histidine hydrochloride monohydrate (6 equiv.) and
NaHCO3 (6 equiv.) to the rhenium(I) complexes, the triazole
proton (He) signal of the complexes shifted downfield. We
ascribe this shift to a hydrogen bonding interaction between
histidine and the triazole unit. For the neutral complex 8aCl,
the downfield shift of the triazole proton signal (He), is the
onlychangeobserved overa period of 24 h;nonew signals related
to the formation of free ligand or degradation products were
observed (Supplementary Material), suggesting that the complex
carbonyl units has been lost from the parent complex 8cDMAP
.
This postulate is supported by the mass spectral data of the
reaction mixture after 24 h. The mass spectrum displayed peaks
due to the intact 8cDMAP complex along with peaks at m/z
795.2577 and 425.2176, which correspond to [Re(CO)3(DMAP)
(6c)]þ and [6c þ Na]þ ions, respectively. It is noted that though
two new species have formed over the 24 h period of the reac-
tion, the major species (.85 %) in solution is the 8cDMAP
complex. These observations were consistent with the stability
studies carried out on analogous rhenium(I) complexes by
Schubert and coworkers.[21c] Presumably, the cationic charge on
the rhenium(I) complex 8cDMAP makes it more attractive to the
histidine nucleophile, leading to the faster decomposition of the
compound relative to the neutral 8aCl complex.
˚
Table 1. Selected bond lengths (A) and angles (8) of the mono- (7aBr
and 7aDMAP) and di- (8aCl and 8aDMAP) rhenium(I) ‘click’ complexes
Antibacterial Activity of Rhenium(I) Complexes and Ligands
Having confirmed that the rhenium(I) complexes displayed
good stability in the presence of biological nucleophiles, we
evaluated their antibacterial activity against the Gram-positive
bacterium Staphylococcus aureus (S. aureus) (ATCC 25923)
and the Gram-negative bacterium Escherichia coli (E. coli)
(ATCC 25922) using disk diffusion, disk dilution, and broth
microdilution methods[25] (Tables 2 and 3). Initially, we
examined the mono-metallic rhenium(I) complexes and their
corresponding ligands (Table 2). None of the ligands or
Compound
Npy–Re
Ntrz–Re
Ntrz–Re–Npy
X or L–ReA
7aBr
2.193(9)
2.197(5)
2.192(4)
2.204(3)
2.196(4)
2.175(7)
2.153(9)
2.127(6)
2.133(4)
2.138(2)
2.153(4)
2.141(7)
74.6(3)
74.4(2)
74.7(2)
74.43(9)
74.9(1)
74.6(3)
2.617(1)
2.471(2)
2.200(4)
2.201(3)
2.459(1)
2.177(7)
[21m]
7aCl
7aDMAP
[21d]
7apy
8aCl
8aDMAP
AX ¼ Clꢀ or Brꢀ and L ¼ py or DMAP.
∗
∗
Histidine
DMAP
e
a
8cDMAP
j
k
c
d
b
∗
∗
3 h
5 h
∗
∗
7 h
∗
∗
10 h
12 h
24 h
∗
∗
∗
∗
∗
∗
6c
e
a
d
c
b
10.2 10.0 9.8 9.6 9.4 9.2 9.0 8.8 8.6 8.4 8.2 8.0 7.8 7.6 7.4 7.2 7.0 6.8 6.6 6.4
δ [ppm]
Fig. 5. Partial 1H NMR spectra (500 MHz, d6-DMSO, 313 K) of mixtures containing the rhenium complex (8cDMAP
)
(1 equiv.), DL-histidine hydrochloride monohydrate (6 equiv.), and NaHCO3 (6 equiv.) recorded over a 24 h period.
For comparison, the partial 1H NMR spectra of histidine, DMAP, and 6c are also displayed. See Scheme 1 and the
Supplementary Material for peak labelling.

F
S. V. Kumar et al.
Table 2. Antibacterial activity of the neutral and cationic mono-
fac-rhenium tricarbonyl complexes against Gram-positive S. aureus
and Gram-negative E. coli evaluated by disk diffusion, disk dilution and
broth microdilution methods
activity of the di-metallic rhenium(I) complexes 8aCl–8dCl,
8aBr–8dBr, and 8aDMAP–8dDMAP were evaluated against
S. aureus and E. coli using disk diffusion, disk dilution and broth
microdilution methods (Table 3).
Similar to the smaller 2-pyridyl-1,2,3-triazole ligands
(5a and 5b), none of the di-(2-pyridyl-1,2,3-triazole) ligands
(6a–6d) showed activity against either the Gram-positive or
Gram-negative bacteria. Disappointingly, in most cases, the
neutral di-metallic rhenium(I) complexes were ineffective
against either S. aureus or E. coli. Of the neutral di-metallic
complexes, only 8bCl (MIC ¼ 128 mg mLꢀ1 versus S. aureus)
showed activity. More promisingly, all of the cationic rhenium(I)
complexes 8aDMAP–8dDMAP displayed activity against S. aureus
and one complex (8cDMAP, the octyl-substituted compound) was
Bacteria
S. aureus (ATCC 25923)
Zone of MIC
inhibition [mm] [mg mLꢀ1
E. coli (ATCC 25922)
Zone of MIC
inhibition [mm] [mg mLꢀ1
Compound
]
]
5a
Nil
Nil
10
21
Nil
12
11
16
26
–
–
Nil
Nil
Nil
Nil
Nil
Nil
Nil
Nil
23
–
7aCl
–
7aBr
512
128
–
–
7aDMAP
5b
–
–
–
7bCl
64
found to inhibit the growth of E. coli at an MIC of 32 mg mLꢀ1
.
7bBr
64
–
7bDMAP
Gentamicin
16
–
However, the MICs against S. aureus proved to be modest
(i.e. 16–128 mg mLꢀ1). This low activity suggests that it is
unlikely that these rhenium(I) complexes will find use as
antimicrobial agents, except possibly as topical agents (where
high concentrations are achievable) for the treatment of local-
ized, superficial infections such as occur in chronic wounds.[26]
The results are consistent with the idea that the overall charge on
the complex, spacing between the charges, and lipophilicity
influence activity.[10] The more lipophilic, cationic di-rhenium
(I) complexes displayed the highest antimicrobial activity.
Though these rhenium(I) complexes are structurally similar to
the related di-ruthenium(II) complexes (i.e. 2a), they are not as
active. Presumably, this lower activity is related to the lower
charge on the rhenium(I) complexes and it suggests that com-
plexes with a 2þ charge should be targeted to prepare
more effective antimicrobial agents. However, the difference
in the molecular shape of the [Re(pytri)(CO)3L]þ and [Ru(phen)
(N–N)]2þ units may also play a role in the biological activity.
,0.5
,0.5
Nil ¼ no zone of inhibition.
Table 3. Antibacterial activity of the neutral and cationic di-fac-
rhenium tricarbonyl complexes against Gram-positive S. aureus and
Gram-negative E. coli evaluated by disk diffusion, disk dilution and
broth microdilution methods
Bacteria
S. aureus (ATCC 25923)
Zone of MIC
inhibition [mm] [mg mLꢀ1
E. coli (ATCC 25922)
Zone of MIC
inhibition [mm] [mg mLꢀ1
Compound
]
]
6a
Nil
Nil
Nil
12
–
–
Nil
Nil
Nil
Nil
Nil
Nil
Nil
Nil
Nil
Nil
Nil
15
–
–
8aCl
8aBr
–
–
8aDMAP
6b
64
–
–
Nil
10
–
8bCl
128
–
–
Conclusion
8bBr
Nil
12
–
8bDMAP
6c
16
–
–
A family of mono- and di-fac-rhenium tricarbonyl 2-pyridyl-
1,2,3-triazole complexes with different aliphatic and aromatic
substituents was synthesized in good-to-excellent yields
(46–99 %). The complexes were characterized using a range of
spectroscopy techniques, high-resolution electrospray mass
spectrometry, and elemental analyses. In four examples, the
solid-state structures of the rhenium(I) complexes were con-
firmed by X-ray crystallography. The mono- and di-rhenium(I)
complexes and the corresponding 2-pyridyl-1,2,3-triazole
compounds were tested for antimicrobial activity in vitro against
both Gram-positive (S. aureus) and Gram-negative (E. coli)
microorganisms. Agar-based disk diffusion assays indicated
that most of the rhenium(I) complexes were active against
S. aureus and that the cationic rhenium(I) complexes were more
active than the related neutral systems. However, disappoint-
ingly, in all cases, the MICs for all complexes were modest
(i.e. 16–1024 mg mLꢀ1), indicating that these compounds are
unlikely to find use as antimicrobial agents, except possibly in
the more limited setting of topical application.
Nil
Nil
Nil
15
–
8cCl
–
–
8cBr
–
–
8cDMAP
6d
16
–
32
–
Nil
Nil
Nil
11
Nil
Nil
Nil
9
8dCl
–
–
8dBr
–
–
8dDMAP
Gentamicin
256
,0.5
1024
26
23
,0.5
Nil ¼ no zone of inhibition.
complexes displayed activity against E. coli. Neither of the
ligands (5a or 5b) displayed activity against S. aureus. However,
the neutral mononuclear rhenium(I) complexes, 7bCl, 7aBr and
7bBr, were effective against S. aureus at higher concentrations
(minimum inhibitory concentration (MIC) ¼ 64–512 mg mLꢀ1).
Furthermore, the cationic complexes 7aDMAP and 7bDMAP
were found to display better activity (MIC¼ 16–128 mg mLꢀ1
)
than the neutral complexes. Additionally, the presumably more
lipophilic octyl-substituted complexes were more active than
the corresponding benzyl-substituted compounds. Though the
activity of the cationic complexes was modest, the results were
promising given that Keene and coworkers had previously
demonstrated a significant increase in the antibacterial activity
upon moving from mono-metallic to di-metallic ruthenium(II)
polypyridyl complexes.[9b] Inspired by this, the antibacterial
Experimental
General Experimental
Unless otherwise stated, all reagents were purchased from
commercial sources and used without further purification.
A CEM S-class microwave reactor was used to carry out the
microwave-enhanced reactions. 1H and 13C NMR spectra were
recorded on either a 400 MHz Varian MR or 500 MHz Varian

Antimicrobial Rhenium(I) 2-Pyridyl-1,2,3-triazole Complexes
G
AR spectrometer at 298 K. Chemical shifts (d) are reported in
parts per million (ppm) and referenced to residual solvent peaks
(CDCl3: 1H d 7.26, 13C d 77.16 ppm; d6-DMSO: 1H d 2.50 ppm,
13C d 39.50 ppm). Coupling constants (J) are reported in Hertz
(Hz). Standard abbreviations indicating multiplicity were used
as follows: m ¼ multiplet, q ¼ quartet, p ¼ pentet, ddd ¼ doublet
of doublet of doublets, dt ¼ doublet of triplet, dd ¼ doublet of
doublet, t ¼ triplet, d ¼ doublet, and s ¼ singlet. IR spectra were
recorded on a Bruker ALPHA Fourier transform infrared
spectrometer with an attached ALPHA-P measurement module.
Microanalyses were performed at the Campbell Microanalytical
Laboratory, University of Otago. HR-ESMS patterns were
collected on a Bruker micrOTOF-Q spectrometer. UV-Visible
absorption spectra were obtained on a PerkinElmer Lambda-950
spectrophotometer in DMF (10ꢀ5 M). Melting points were
determined using a Leica VMHB melting bar. Bidentate
2-pyridyl-1,2,3-triazole ligands (5a and 5b),[16f] di-(2-pyridyl-
1,2,3-triazole) ligands (6a and 6b),[16g] and rhenium complexes
(7aCl and 7bCl)[20] were prepared by previously reported
procedures.
THF (8 mL), after which DMAP (1 equiv. or 2 equiv.) was
added. The mixture was then irradiated in a CEM microwave
reactor at 1008C (200 W, 200 psi) for 1 h. Removal of the solvent
under reduced pressure and subsequent purification by silica
gel column chromatography (10 % methanol in CH2Cl2),
followed by recrystallization afforded the complexes as pale
yellow solids.
Histidine Competition Experiment for the Rhenium
Complex 8aCl
The rhenium complex 8aCl (0.0080 g, 0.0079 mmol, 1 equiv.),
DL-histidine hydrochloride monohydrate (0.0100 g, 0.048mmol,
6 equiv.), and NaHCO3 (0.0040 g, 0.048mmol, 6 equiv.) were
dissolved in d6-DMSO, and the mixture was heated to 408C. The
1H NMR spectra of the solution were recorded at regular time
intervals for 24 h.
Histidine Competition Experiment for the Rhenium
Complex 8cDMAP
Safety Note: Though no problems were encountered during
the course of this work, azide compounds are potentially
explosive and appropriate precautions should be taken when
working with them.
The rhenium complex 8cDMAP (0.0020 g, 0.0013 mmol,
1 equiv.), DL-histidine hydrochloride monohydrate (0.0017 g,
0.0083 mmol, 6 equiv.), and NaHCO3 (0.0010 g, 0.0083 mmol,
6 equiv.), were dissolved in d6-DMSO, and the mixture was
heated to 408C. The 1H NMR spectra of the solution were
recorded at regular time intervals for 24 h.
General Procedure for the Synthesis of the Ligands
A dibromoalkane (1 equiv.) and sodium azide (3 equiv.) were
dissolved in 4 : 1 DMF/H2O (15 mL). The mixture was irradi-
ated in a CEM microwave reactor at 1258C (200 W, 200 psi) for
3 h. The reaction mixture was then cooled to room temperature,
and 2-ethynylpyridine (2 equiv.), sodium ascorbate (0.5 equiv.),
and CuSO4ꢁ5H2O (0.4 equiv.) were added to the reaction
mixture. The mixture was stirred at room temperature for
12 h. The suspension was partitioned between aqueous 0.1 M
NH4OH/ethylenediaminetetraacetic acid (EDTA) (100 mL) and
CH2Cl2 (100 mL), and the layers were separated. The organic
phase was washed with water (100 mL) and brine (100 mL),
dried over MgSO4, and the solvent was removed under reduced
pressure to provide the ligands as off-white solids.
X-Ray Crystallography
X-ray data for the rhenium complexes 7aBr and 8aCl were col-
lected at 89 K on a Bruker Kappa Apex II area detector dif-
fractometer using graphite monochromated Mo Ka radiation
˚
(l 0.71073 A). Intensities were corrected for Lorentz polariza-
tion effects.[27] Absorption corrections were applied by semi-
empirical methods (SADABS).[28] The structures were solved
using SIR-97[29] or by direct methods using SHELXS-97[30] and
refined against F2 using all data by full-matrix least-squares
procedures within SHELXL-97.[30] All non-hydrogen atoms
(except where noted in the crystallographic information file)
were refined with anisotropic thermal displacement parameters.
The hydrogen atoms were placed in the calculated positions
and refined using a riding model. In the crystal structure of 7aBr
,
General Procedure for the Synthesis of the Neutral
Rhenium(I) Complexes
the ISOR command was employed to restrain the atomic dis-
placement parameters of C6, C7, and N3 atoms. In the crystal
structure of 8aCl, the ISOR command was employed to restrain
the atomic displacement parameters of C20 atom.
Either pentacarbonylrhenium(I) chloride (1 or 2 equiv.) or
pentacarbonylrhenium(I) bromide (1 or 2 equiv.) and a
2-pyridyl-1,2,3-triazole or a di-(2-pyridyl-1,2,3-triazole) ligand
(1 equiv.) were dissolved in ethanol (15 mL). The resulting
mixture was refluxed at 788C for 24h in the absence of light. The
suspension was cooled to room temperature, and the solvent
volume was reduced by half using rotary evaporation. Additionof
diethyl ether led to the precipitation of the rhenium(I) complexes
as yellow solids, which were collected by filtration, washed with
diethyl ether and petroleum ether, and vacuum dried.
X-ray data of the rhenium complexes 7aDMAP and 8aDMAP
were collected at 100 K on an Agilent Technologies SuperNova
diffractometer with Atlas detector using either Cu Ka (l
˚
˚
1.54184 A) or Mo Ka radiation (l 0.71073 A), and the data
were treated using CrysAlisPro software.[31] The structures
were solved by either SIR-97[29] or SUPERFLIP[32] and refined
against F2 using anisotropic thermal displacement parameters
for all non-hydrogen atoms (except where noted in the crystal-
lographic information file) using SHELXL-97[30] running within
the WinGX program.[33] Hydrogen atoms were placed in calcu-
lated positions and refined using a riding model. The crystal
lattice of 8aDMAP contained diffuse electron density that could
not be appropriately modelled. The SQUEEZE routine within
PLATON[34] was employed to resolve this problem, resulting
in a void electron count of 241 that were assigned to one
diisopropyl ether, two acetonitrile, and two triflate molecules
(232 electrons in total, Supplementary Material).
General Procedure for the Synthesis of the
Cationic Rhenium(I) Complexes
One of the neutral mono- or di-rhenium bromide complexes and
silver triflate (1.25 equiv. or 2.5 equiv.) were dissolved in dry
CH2Cl2 (10 mL) and stirred overnight at room temperature in the
absence of light. The reaction mixture was filtered through
cotton wool, and the solvent was removed under reduced pres-
sure. The resultant golden yellow oil was re-dissolved in dry

H
S. V. Kumar et al.
Antibacterial Assays
Supplementary Material
Full synthetic procedures, 1H NMR, UV-visible, and HR-ESMS
spectra, molecular models, and crystallographic data are avail-
able on the Journal’s website.
The preliminary antibacterial activity of the neutral and cationic
rhenium complexes was evaluated against S. aureus (ATCC
25923) as a representative Gram-positive bacterial strain and
E. coli (ATCC 25922) as a representative Gram-negative bac-
terium. DMSO was used as a solvent to prepare stock solutions
of these complexes. Each bacterial strain was inoculated into a
separate cation-adjusted Mueller Hinton broth (MHB; BD,
Auckland, New Zealand) and incubated at 35 ꢂ 28C for a period
of 24 h. The bacterial suspensions were adjusted to a 0.5 Mac-
farland opacity standard (1–2 ꢃ 108 colony forming units CFU
mLꢀ1) and spread onto cation-adjusted Mueller Hinton agar
(BD, Auckland, New Zealand) plates before placing sterile
paper disks (4 per plate, 6 mm diameter; BD, Auckland, New
Zealand) equidistant on the plate. Stock solutions of the rhenium
(I) complexes and the 2-pyridyl-1,2,3-triazole ligands were
prepared by dissolving the compound (1 mg) in DMSO (1 mL).
The compounds (20 mL) were then introduced onto the disks.
The plates were incubated for a period of 24 h at 35 ꢂ 28C, after
which the zones of inhibition were measured. The disk assays
were performed using gentamicin (10 mg disks; BD, USA) as a
positive control and DMSO (20 mL) as a negative control, and
the experiments were done in duplicate.
Acknowledgements
The authors thank the Department of Chemistry and the Department of
Microbiology and Immunology, University of Otago for funding. SVK and
WKCL thank the University of Otago for PhD scholarships.
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