Homoleptic and heteroleptic bismuth(III) thiazole-thiolates and the influence of ring substitution on their antibacterial and antileishmanial activity

Article abstract of DOI:10.1002/ejic.201402958

Two new homo- and heteroleptic bismuth thiazole-thiolato complexes derived from 4-phenylthiazole-2-thiol MBT(H) have been synthesised and structurally characterised, [BiPh(MBT)₂]₂ and [Bi(MBT)₃]₂. Syntheses were achieved using BiPh₃ or Bi(OtBu)₃ in protolysis reactions with MBT(H), or by salt metathesis with BiCl₃ or BiPhCl₂ and the sodium thiolate, [NaMBT]. The complexes were obtained under both standard solvent-free and solvent-mediated conditions, and by microwave irradiation. The solid-state structures of [BiPh(MBT)₂]₂ and [Bi(MBT)₃]₂, were determined using single-crystal X-ray diffraction, showing them to be dimeric. The bactericidal properties of the complexes against Mycobacterium smegmatis, Staphylococcus aureus, methicillin-resistant Staphylococcus aureus (MRSA), Enterococcus faecalis, vancomycin-resistant Enterococcus (VRE) and Escherichia coli revealed [BiPh(MBT)₂]₂ to be the most effective against all the bacteria with MIC values of 0.6 μg/mL (0.25 μM) against S. aureus and 0.9 μg/mL (0.27 μM) against E. faecalis. [Bi(MBT)₃]₂ was less active overall. However, comparisons with the analogous complex [Bi(4-BrMTD)₃], revealed a significant hundred-fold enhanced activity against S. aureus, MRSA, VRE, and E. faecalis. Both complexes showed little or no toxicity towards mammalian COS-7 cells at 20 μg/mL. [BiPh(MBT)₂]₂ also was found to display good antileishmanial activity with an IC₅₀ value of 0.11 μg/mL (0.17 μM), at which concentration the complex was non-toxic to human fibroblast cells.

Full text of DOI:10.1002/ejic.201402958

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DOI:10.1002/ejic.201402958
Homoleptic and Heteroleptic Bismuth(III) Thiazole–
Thiolates and the Influence of Ring Substitution on Their
Antibacterial and Antileishmanial Activity
Ahmad Luqman,[a] Victoria L. Blair,[a] Rajini Brammananth,[b]
Paul K. Crellin,[b] Ross L. Coppel,[b] Lukasz Kedzierski,[c,d] and
Philip C. Andrews*[a]
Keywords: Bismuth / S ligands / Medicinal chemistry / Antibiotics / Antiparasitic agents
Two new homo- and heteroleptic bismuth thiazole-thiolato
complexes derived from 4-phenylthiazole-2-thiol MBT(H)
have been synthesised and structurally characterised,
[BiPh(MBT)2]2 and [Bi(MBT)3]2. Syntheses were achieved
using BiPh3 or Bi(OtBu)3 in protolysis reactions with MBT(H),
or by salt metathesis with BiCl3 or BiPhCl2 and the sodium
thiolate, [NaMBT]. The complexes were obtained under both
standard solvent-free and solvent-mediated conditions, and
by microwave irradiation. The solid-state structures of
[BiPh(MBT)2]2 and [Bi(MBT)3]2, were determined using sin-
gle-crystal X-ray diffraction, showing them to be dimeric.
The bactericidal properties of the complexes against Myco-
calis, vancomycin-resistant Enterococcus (VRE) and Escher-
ichia coli revealed [BiPh(MBT)2]2 to be the most effective
against all the bacteria with MIC values of 0.6 μg/mL
(0.25 μM) against S. aureus and 0.9 μg/mL (0.27 μM) against
E. faecalis. [Bi(MBT)3]2 was less active overall. However,
comparisons with the analogous complex [Bi(4-BrMTD)3], re-
vealed a significant hundred-fold enhanced activity against
S. aureus, MRSA, VRE, and E. faecalis. Both complexes
showed little or no toxicity towards mammalian COS-7 cells
at 20 μg/mL. [BiPh(MBT)2]2 also was found to display good
antileishmanial activity with an IC50 value of 0.11 μg/mL
(0.17 μM), at which concentration the complex was non-toxic
bacterium smegmatis, Staphylococcus aureus, methicillin-re- to human fibroblast cells.
sistant Staphylococcus aureus (MRSA), Enterococcus fae-
tural information on complexes derived from the simple
Introduction
parent triazole-2-thiol. However, for 4-methylthiazole-2-
Compounds constructed around a thiazole ring are rep-
resented by several important drugs currently on the mar-
ket; these include the antimicrobial drug, tulfathiazol; the
antiretroviral drug ritonavir; the antineoplastic drug tiazo-
furin; and the antifungal drug abafungin.[1] In recent years,
thiazole derivatives have also attracted considerable atten-
tion in drug development circles for the treatment of hyper-
tension,[2] allergies,[3] schizophrenia,[4] inflammation,[5] HIV
infection,[6] hypnotics,[7] pain,[8] and as a new inhibitors of
bacterial DNA gyrase.[9] Despite these important biological
and medicinal applications, their metal chemistry, and
hence the development of metallo-drugs based on these sys-
tems, is much less developed. There is no solid-state struc-
thiol there are complexes of W,[10] Au,[11] as well as the sole
Bi complex containing
a 2,6-[(dimethylamino)methyl]
pincer ligand;[12] the more unusual ligand 2-(2-mercapto-
4-methylthiazol-5-yl)acetic acid has been used to generate
complexes of Au,[13] Sn,[14] and Ru.[15]
Recently, we described the synthesis, characterization
and antibacterial activity of a series of homoleptic and het-
eroleptic BiIII thiolato complexes derived from various N-
heterocyclic thiones.[16] Two of the complexes incorporated
the thiolato ligand derived from 4-(4-bromophenyl)thi-
azole-2-thiol [4-BrMTD(H)]; these were [BiPh(4-BrMTD)2]
and [Bi(4-BrMTD)3]. The heteroleptic complex [BiPh(4-
BrMTD)2] displayed good activity towards several species
of bacteria, with minimum inhibitory concentrations (MIC)
of 1.21–6.06 μm against Staphylococcus aureus, methicillin-
resistant Staphylococcus aureus (MRSA) and vancomycin-
resistant Enterococcus (VRE). The homoleptic complex
[Bi(4-BrMTD)3], for which we described the crystal struc-
ture, was an order of magnitude less active than its hetero-
leptic counterpart, reflecting the observed general trend.
Bismuth thiolates, as a compound class, have significant
relevance in biology and medicine. These agents display
strong antimicrobial and fungicidal properties,[17–19] can be
[a] School of Chemistry, Monash University,
Clayton, Melbourne, VIC 3800, Australia
E-mail: phil.andrews@monash.edu
http://monash.edu/science/about/schools/chemistry/staff/
andrews/
[b] Department of Microbiology, Monash University,
Clayton, Melbourne, VIC 3800, Australia
[c] Walter and Eliza Hall Institute of Medical Research,
Parkville, Melbourne, VIC 3000, Australia
[d] Department of Medical Biology, University of Melbourne,
Parkville, Melbourne, VIC 3010, Australia
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejic.201402958.
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effective in controlling wound infection,[20] and are useful
for retarding biofilm growth on surfaces.[21–24] Several
classes of compounds, most notably xanthates and dithio-
carbamates, have shown significant in vitro antitumour ac-
tivities.[25–28]
Since the activity of thiazole-based Bi complexes appears
to be highly sensitive to subtle changes in the ligand, we
decided to study the structural chemistry and comparative
inhibitory activity of complexes derived from the related
but structurally more simple 4-phenylthiazol-2-thiol,
MBT(H). Although formally described as a thiol, the com-
pound actually exists predominantly in the thione form
(Figure 1). Surprisingly, only Hg and Cu complexes of
MBT have been reported to date.[29] The Cu complex
[Cu(MBT)] was synthesised as part of a broader synthetic
study, whereas the Hg compounds, [HgAr(MBT)], were pre-
pared and assessed for their antimicrobial activity.[30]
Scheme 1. Synthesis of [Bi(MBT)3] (1) and [BiPh(MBT)2] (2) from
4-phenylthiazole-2-thiol MBT(H). The various methods (i)–(vi) are
detailed in Table 1.
Table 1. Reaction conditions for the synthesis of complexes
[Bi(MBT)3]2 (1) and [BiPh(MBT)2]2 (2).
Complex
Reaction Reaction conditions
method
Color
Yield
[%]
(Scheme 1)
[Bi(MBT)3] (1)
(i)
BiPh3
BiPh3
BiPh3
solvent-free,
4 h
reflux, tolu-
ene, 6 h
MW, toluene, orange
115 °C, 8 min
orange
orange
72[a]
65[a]
76[a]
78[b]
71[a]
(ii)
(iii)
(iv)
(v)
Bi(OtBu)3 THF, –80 °C orange
to r.t, 12 h
BiCl3
MeOH, 0 °C orange
to r.t, 12 h
[BiPh(MBT)2] (2)
(vi)
PhBiCl2
MeOH, 12 h pale yellow 89[b]
Figure 1. Thiol-thione equilibrium in the target thiazole com-
pounds.
[a] Synthesis is reported in the Supporting Information;. [b] Syn-
thesis and full characterisation are reported in the Experimental
Section.
In this paper, we report the synthesis and full characteri-
sation (NMR, FT-IR, mass spectrometry, elemental analy-
sis) of two new bismuth complexes derived from 4-phen-
ylthiazol-2-thiol; [Bi(MBT)3]2 (1) and [BiPh(MBT)2]2 (2).
The solid-state structure of each complex has also been de-
termined by single-crystal X-ray diffraction and these are
described. The compounds were tested for their antibacte-
rial activity against a series of species: M. smegmatis, S.
aureus, MRSA, VRE, E. faecalis and E. coli. The antipara-
sitic activity against Leishmania major was also assessed.
These results and studies on toxicity against mammalian
cells are described.
Solution NMR Studies
Solution NMR studies of MBT(H) in [D6]DMSO reveal
a structural preference for the more stable thione form
given the presence of the NH proton signals at δ = 13.70
and 13.76 ppm respectively. Upon complexation with BiIII
,
the NH proton signals are absent in the spectra of both 1
and 2. This finding suggests that, upon deprotonation and
binding with bismuth, the thione is converted into the more
stable thiolate anion resulting in a more thermodynamically
stable Bi–S bond. The chemical shifts and assignments are
presented in full in the Experimental section and spectra
are shown in the Supporting Information.
Results and Discussion
In both complexes 1 and 2 the signals attributable to the
The synthesis of BiIII complexes [Bi(MBT)3]2 (1) and phenyl groups appended to each thiazole ring appear in the
[BiPh(MBT)2]2 (2), derived from 4-phenylthiazole-2-thiol range 7.83–7.16 ppm; in the parent thione these signals ap-
MBT(H), shown in Scheme 1, was achieved using a range pear in the range 7.72–7.41 ppm. The o-H of the Bi-Ph
of BiIII precursors [BiPh3, BiCl3 and Bi(OtBu)3] and reac- group in 2 appear at the highest frequency, with a chemical
tion strategies involving solvent-free and solvent mediated shift of 8.94 ppm. The resonances for the C-H protons on
reactions. Standard refluxing conditions as well as the use the thiazole rings in 1 and 2 shift to lower frequency values
of microwave irradiation were investigated. A comparison of 7.57 and 7.67 ppm, respectively, relative to the 7.28 ppm
of different reaction conditions and their corresponding noted in MBT(H). In the 1H NMR spectrum of
yields are conveyed in Table 1. The optimal reaction pro- [BiPh(MBT)2] (2) the thiolate to Bi-Ph ratio is 2:1, confirm-
cedures for the synthesis of 1 and 2, with full compound ing the general formulation as [BiPh(L)2] (Table S1). These
characterisation of each, are provided in the Experimental characteristic chemical shifts, multiplicities and integral val-
section. Alternative procedures providing the same outcome ues support the formation of the tris- and bis-thiolato BiIII
but with reduced yields, are provided in the Supporting In- complexes (Figures S1 and S2).[31]
formation. We have described the synthesis and characteri-
Both complexes 1 and 2 show the expected carbon chem-
sation of the comparator bismuth complexes [Bi(4-BrMTD) ical shifts in the 13C NMR spectra. The central carbon
3] (3) and [BiPh(4-BrMTD)2] (4) previously.[16]
atom surrounded by the three heteroatoms is not visible in
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the 13C spectra of either MBT(H) or the two complexes, Moreover, selected bond lengths and angles for 1 and 2 can
and so a direct comparison cannot be made. However, on be found in Table 3 and Table 4 respectively.
metallation and transition from the thione to thiolate ligand
Table 3. Selected bond lengths [Å] and angles [°] for [BiPh(MBT)2]2
(2).
forms there can be noted minor frequency shifts. Carbon
resonances in the phenyl group connected to the thiazole
Bi(1)–C(19)
Bi(1)–S(1)
Bi(1)–S(3)
Bi(1)–N(1)
Bi(1)–N(2)
S(1)–C(1)
S(2)–C(2)
N(1)–C(1)
2.260(3)
2.6324(7)
2.6451(8)
2.768(3)
2.669(2)
1.737(3)
1.717(3)
1.317(4)
C(19)–Bi(1)–S(1)
C(19)–Bi(1)–S(3)
C(19)–Bi(1)–N(2) 83.16(9)
C(19)–Bi(1)–N(1) 82.37(9)
S(1)–Bi(1)–S(3)
S(1)–Bi(1)–N(1)
S(3)–Bi(1)–N(2)
C(1)–S(1)–Bi(1)
93.74(7)
93.58(8)
ring in complexes 1 and 2 appear, respectively, at 125.9 and
126.0 (o), 128.5 and 128.7 (m), and 127.3 and 127.6
(p) ppm. Notably, these same resonances are observed at
125.8 (o), 129.1 (m) and 128.9 (p) ppm in the MBT(H) case.
The signals corresponding to the thiazole ring carbons
[SC(H)] appear at 113.9 ppm (in 1) and at 113.7 ppm (in 2)
and at 112.5 ppm in MBT(H). The signals attributable to
the phenyl group bound directly with Bi (Bi-Ph) are found
at a higher frequency; δ = 127.4 (p), 133.9 (m) and 139.7
(o) ppm (Table S2).
86.68(2)
59.70(5)
60.20(6)
86.92(10)
Table 4. Summary of crystallographic data for compounds (1) and
(2).
1
2
IR Spectroscopy
Chemical formula
Formula mass
C27H18BiN3S3
785.7
C24H17BiN2S4
670.62
The infrared spectrum of MBT(H) shows four character-
istic bands located at 1595–1390 cm–1 (i), 1461–1260 cm–1
(ii), 1187–940 cm–1 (iii) and 802–700 cm–1 (iv) due to the
presence of the thioamide (HNCS) group. The appearance
of broad stretching vibrations between 3050–3200 cm–1 (N–
H) supports the thione nature of these compounds in the
solid state. For both complexes 1 and 2, these bands are
no longer present, thus establishing that deprotonation and
binding through the thiol sulfur of both ligands to the Bi
metal centre (Table S4). Furthermore, lower frequency
bands appear in the range of 735–705 cm–1 indicative of a
weakening of the C=S bond and consequently, a moder-
ately high strength Bi–S bond.[32] In addition, the bands
appearing at 1597–1579 cm–1 are attributable to the azo-
methine groups (C=N) present at 1587 cm–1 in MBT(H).[33]
These characteristic shifts of azomethine groups (C=N) in
the spectra of these complexes is evidence of thiazole-
bourne N coordination. It can be concluded from these ob-
servations that MBT(H) behaves as a singly charged biden-
tate anionic ligand.
Crystal system
a /Å
b /Å
c /Å
triclinic
triclinic
10.4754(6)
10.7267(8)
14.1933(12)
108.754(7)
92.830(6)
113.760(6)
1352.41(18)
123(2)
9.4784(5)
9.6643(5)
13.9876(7)
86.969(4)
73.300(5)
68.662(5)
113.55(10)
123(2)
α/°
β /°
γ /°
Unit cell volume /Å3
Temperature /K
Space group
¯
P1
2
15682
8650
0.0320
0.0302
¯
P1
4
Formula units per unit cell, Z
Reflections measured
Independent reflections
Rint
13377
7286
0.0251
0.0259
0.0561
0.0308
0.0583
Final R1 values [IϾ2σ(I)]
Final wR(F2) values [IϾ2σ(I)] 0.0575
Final R1 values (all data) 0.0386
Final wR(F2) values (all data) 0.0609
Tris-substituted complex 1 is isostructural with the pre-
viously reported BiIII complex [Bi(4-BrMTD)3]2 3.[16] The
asymmetric unit, seen in Figure 2, contains three chelating
MBT ligands bonded covalently to the BiIII atom via the
deprotonated thiol group and datively through the N atom
of the thiazole ring. This is consistent with the FT-IR data
presented above. The three Bi–S bond lengths range from
2.5706(8)–2.6255(8) Å which lie in the typical covalent
bond range Σcov(Bi,S) = 2.54 Å[34–37] whereas the coordina-
tive (dative) Bi–N distances have an average bond length of
2.916 Å. The BiIII centre in the asymmetric unit is formally
six-coordinate with relatively small bite angles of the chelat-
ing N and S atoms i.e. [S–Bi–N: 57.37(5), 58.05(5) and
59.48(6)°]. These restricted bite angles result in an uncom-
mon hexagonal geometry,[38] and are again similar to those
found in isostructural 3.[16]
Dimerisation of two monomeric units of 1 takes place
through a long electrostatic interaction of the deprotonated
thiol group [Bi(1)–S(3Ј), 3.737(18) Å] to give a central
planar Bi2S2 ring (Figure 3). As a result of dimerization,
the coordination number of each BiIII centre increases to
seven giving an overall distorted pentagonal pyramidal co-
ordination geometry.
X-ray Crystallography
Crystallisation of both 1 and 2 from DMSO solutions
provided orange crystals suitable for X-ray diffraction stud-
ies. Table 2 gives a summary of the crystallographic data.
Table 2. Selected bond lengths [Å] and angles [°] for [Bi(MBT)3]2
(1).
Bi(1)–S(1)
Bi(1)–S(3)
Bi(1)–S(5)
Bi(1)–N(1)
Bi(1)–N(2)
Bi(1)–N(3)
Bi(1)–S(3Ј)
S(1)–Bi(1)–N(1) 59.48(6)
S(1)–Bi(1)–N(2) 81.33(5)
S(1)–Bi(1)–S(3) 86.54(5)
2.5706(8)
2.6255(8)
2.5714(8)
2.843(3)
2.972(3)
2.935(3)
3.737(18)
S(1)–Bi(1)–S(5)
N(1)–Bi(1)–N(2)
S(1)–Bi(1)–N(3)
N(1)–Bi(1)–N(3)
S(5)–Bi(1)–N(3)
S(3)–Bi(1)–N(2)
N(2)–Bi(1)–N(3)
N(2)–Bi(1)–S(5)
S(3)–Bi(1)–N(3)
S(3)–Bi(1)–S(5)
97.53(3)
87.05(13)
89.65(5)
84.32(7)
58.05(5)
57.37(5)
164.75(7)
135.11(5)
136.28(5)
78.25(3)
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Figure 4. Asymmetric unit of [BiPh(MBT)2] (2) with thermal ellip-
soids shown at 50% probability. Hydrogen atoms have been omit-
ted for clarity.
Figure 2. Asymmetric unit of [Bi(MBT)3]2 (1) with thermal ellip-
soids shown at 50% probability. Hydrogen atoms have been omit-
ted for clarity.
Figure 5. Dimer formation of [BiPh(MBT)2]2 (2) with thermal ellip-
soids shown at 50% probability. Hydrogen atoms have been omit-
ted for clarity. Symmetry operator Ј: –x, 1 – y, 1 – z.
Antibacterial Studies
Figure 3. Dimer formation for [Bi(MBT)3]2 (1) with thermal ellip-
soids shown at 50% probability. Hydrogen atoms have been omit-
ted for clarity. Symmetry operator Ј: 2 – x, 1 – y, 1 – z.
The in vitro antibacterial activity of both BiIII com-
pounds 1 and 2 was assessed against six different strains of
bacteria; M. smegmatis, S. aureus, MRSA, VRE, E. faecalis
In the asymmetric unit of complex 2 the BiIII centre and E. coli. For comparison, the activity of the heterocyclic
adopts a distorted pentagonal bipyramidal geometry com- thiols and BiPh3 was also assessed. DMSO was used as the
posed of two deprotonated thiadiazole ligands and one solvent during preparation of sample solutions of required
phenyl group (Figure 4). The thiadiazole ligands chelate to concentration. Isoniazid (isonicotinylhydrazide), a first-line
the BiIII via short Bi–S bonds [Bi(1)–S(1), 2.6324(7) and drug for the treatment of tuberculosis, was used as a con-
Bi(1)–S(3), 2.6451(8) Å], as expected from the FT-IR data, trol.
and are comparable to those in 1, [Bi(2-SC5H3N-SiMe3)3]
The in vitro activity of the BiIII thiolate complexes,
[Average 2.6451(8) Å][39] and other literature examples.[40] MBT(H) and isoniazid were initially assessed using drug-
The Bi–N bonds are relatively short [Bi(1)–N(1) 2.768(3) diffusion assays in which filter paper discs containing the
and Bi(1)–N(2), 2.669(2) Å], which is in contrast to the drug were placed onto the surface of agar plates spread
asymmetric coordination bonds seen in the similar thiadi- with bacterial cultures. Following incubation overnight, the
azole-containing complex [BiPh(5-MMTD)2] (5-MMTD = presence of a zone of inhibition of bacterial growth around
5-methyl-1,3,4-thiadiazole-2-thione).[16]
the disc indicated some level of antibacterial activity. Com-
Dimerisation of this unit takes place through a long elec- pounds that were positive in this initial screen were then
trostatic π-interaction [Bi(1)–Ph centroid, 3.591(17) Å] be- used in minimum inhibitory concentration (MIC) assays to
tween the Bi atom and the delocalised electron density of quantify their levels of antibacterial activity. The MICs are
an adjacent phenyl ring (Figure 5). This dimerization raises expressed as μg/mL (and calculated as μm), and represent
the coordination number of the BiIII centre in 2 to six.
the minimal drug concentration that completely inhibits
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Table 5. Antimicrobial activities of BiIII complexes 1 and 2 and MBT(H) against six strains of bacteria.
Compound
MIC [μg/mL] (μm)
M. smegmatis
S. aureus
MRSA
VRE
E. faecalis
E. coli
Isoniazid
1
Ͼ 100
Ͼ 100
Ͼ 100
Ͼ 100
Ͼ 100
(7.29)
Ͼ 100
Ͼ 100
100
MBT(H)
4Br-MTD(H)
[Bi(MBT)3] (1)
Ͼ 100
Ͼ 100
1.0
Ͼ 100
Ͼ 100
1.0
Ͼ 100
Ͼ 100
40
Ͼ 100
Ͼ 100
1.2
Ͼ 100
Ͼ 100
100
(149.10)
1.0
(1.27)
40
(39.14)
20
(24.25)
(1.49)
0.6
(0.76)
10
(9.78)
1.0
(1.21)
(1.49)
1.2
(1.52)
100
(90.78)
5.0
(6.06)
(59.64)
1.0
(1.27)
40
(39.14)
5.0
(6.06)
(1.79)
0.9
(1.14)
40
(39.14)
20
(24.25)
(149.10)
100
(127.26)
40
(39.14)
40
48.52
[BiPh(MBT)2] (2)
[Bi(4-BrMTD)3] (3)
[BiPh(4-BrMTD)2] (4)
bacterial growth in culture. The results are summarised in far superior to those obtained using [BiPh(4-BrMTD)2] (4);
Table 5. MICs against E. coli constitute the one exception to this
These experiments show that MBT(H) and BiPh3 are rel- apparent rule. Only one complex has performed better,
atively poor antimicrobial agents and having failed to dis- the unusual complex [BiPh(4-MMT)2{4-MMT(H)}2] (4-
play any detectable bactericidal activity at the maximum MMTH
=
4-methyl-4H-1,2,4-triazole-3-thiole); earlier
concentration tested (100 μg/mL). Complexes 1 and 2 dem- studies revealed this complex to have an MIC of 0.34 μm
onstrated significantly higher antimicrobial activities when tested against VRE.[16]
against the gram-positive bacteria than against E. coli, the
One significant difference between the complexes is the
single gram-negative species tested. This observation sup- ClogP values which show that 1 and 2 fall within the "drug
ports our recent studies on five-membered heterocyclic BiIII zone" with values of 3.98 and 4.75, respectively.[46] The
thiolates,[16] those of Kotani[41] on cyclic organobismuth- comparative values for 3 and 4 are 10.01 and 8.77, respec-
(III) compounds, and Domenico’s studies on BiIII thiol che- tively.
lators.[42] Gram-negative bacteria and Mycobacteria possess
a double membrane that forms a permeability barrier re-
stricting the penetration of some antimicrobial agents and
Cytotoxicity Studies towards Mammalian Cells (COS-7)
forbidding multi-drug resistance pumps to extrude toxins
across this barrier.[43] The inability to penetrate the outer
membrane of this double membrane system may explain
the low activity of BiIII thiolates against E. coli.[44] If cor-
rect, this indicates that interactions with a cytoplasmic tar-
get forms the basis of the antibacterial properties of these
compounds.
Although potent antibacterial activity is essential for po-
tential new therapeutic agents, compounds of interest must
also have low toxicity towards human or animal cells. Tox-
icity assays of these complexes using cultured COS-7 cell
lines revealed that the complexes were non-toxic to mam-
malian cells at 20 μg/mL, providing a good selectivity index.
The effect on toxicity of changing the ligand from 4-
BrMTD to MBT is quite dramatic, as shown in Table 5.
The tris-thiolato complex [Bi(MBT)3] (1), showed excellent
activity towards S. aureus, MRSA and E. faecalis with MIC
values of 1.49, 1.49 and 1.79 μm, respectively. These are by
far the lowest MIC values observed for any tris-thiolato
complex that we have studied. The values, as exemplified by
[Bi(4-BrMTD)3] (3), are generally between 40 and 100 μm.
Interestingly, complex 1 was less active than 3 against M.
smegmatis and E. coli. Thus, complex 1 appears to display
some of the toxicity traits normally associated with mono-
phenyl bis-thiolato complexes.
The bis-thiolato complex [BiPh(MBT)2] (2) displayed ex-
cellent activity towards all bacteria tested except E. coli,
having MIC values of 0.76 μm (S. aureus), 1.14 μm (E. fae-
calis), 1.27 μm (M. smegmatis and VRE), and 1.52 μm
(MRSA). For MRSA, this level of inhibition is comparable
to that of vancomycin.[45] Again, these data represent the
lowest MIC values against this range of bacteria for all
analogous [BiPh(SR)2] complexes we have tested, and are
Antileishmanial Studies
Complexes 1–4, along with their parent thiones, MBT(H)
and 4-BrMTD(H), were tested in vitro for antileishmanial
activities against Leishmania major promastigotes, and for
their possible cytotoxic activities against human fibroblast
cells. A summary of the results against L. major is presented
in Table 6.
Table 6. Comparison of IC50 of MBT(H), 4-BrMTD(H) and their
homoleptic and heteroleptic BiIII complexes 1–4.
Compound
L. major
IC50 [μg/mL] (μm)
Amphotericine B
MBT(H)
4-BrMTD(H)
2.02 (2.19)
20.52 (18.5)
27.25 (Ͼ 100)
4.04 (5.15)
[Bi(MBT)3] (1)
[BiPh(MBT)2] (2)
[Bi(4-BrMTD)3] (3)
[BiPh(4-BrMTD)2] (4)
0.11 (0.17)
11.77 (11.52)[16]
[16]
7.07 (8.54)
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Figure 6 shows the antiparasitic activity of the two free pounds 1 and 3 were the least active against the L. major
thiones MBT(H) and 4-BrMTD(H). MBT(H) proved to be promastigotes having IC50 values orders of magnitude
the more active of the two killing 80% of promastigotes at greater than 2.
a concentration of 50 μm. Interestingly this compound did
not show any toxicity against human fibroblast cells (Fig-
ure 7) up to a concentration of 50 μm. The heterocyclic 4-
BrMTD(H) killed only 20% of promastigotes at the highest
concentration of 100 μm. Again, this compound has negligi-
ble toxic effect on human fibroblasts even at 100 μm.
Figure 8. Effect of complexes 1–4 on L. major promastigotes.
Figure 6. Effect of MBT(H) and 4-BrMTD(H) on L. major proma-
stigotes.
Figure 9. Effect of complexes 1–4 on fibroblast cells.
Given the results of fibroblast toxicity assays, it is clear
that complexes 1, 3 and 4 have similar or even greater ac-
tivity towards these cells than against parasites at 6.25 μm
suggesting a level of generalised cell toxicity.
The differences between tris- and bis-thiolato complexes
likely derives in part from the presence of the Bi-Ph group
which increases the lipophilicity of the complexes. This ef-
fect was also observed in our recent study of a series of
bismuth thiobenzoates where mono-phenyl complexes
[BiPh{SC(=O)R}2] had activities of 0.39–4.69 μm towards
promastigotes, whereas the tris-substituted complexes were
effectively non-toxic (Ͼ 100 μm). The [BiPh{SC(=O)R}2]
complexes were also toxic to fibroblast cells having IC50
values only marginally better than those against the proma-
stigotes.
Figure 7. Effect of MBT(H) and 4-BrMTD(H) on human fibro-
blasts.
The activities of complexes 1–4 against the L. major pro-
mastigotes and human fibroblast cells are summarized in
Figure 8 and Figure 9. Mono-phenyl derivatives 2 and 4
proved to be more active than tris-thiolato complexes 1 and
3. Complex 2 showed the highest level of activity with a
very low IC50 value of 0.17 μm. At this concentration, a
Conclusions
In studying the synthesis of homoleptic and heteroleptic
complete lack of toxicity (100% viability) towards human BiIII thiolate complexes containing the thiazole moiety, two
fibroblast cells was maintained indicating this compound as novel compounds were synthesized and structurally charac-
an excellent candidate for further study. Tris-thiolato com- terized. The tris-thiolato complex 1 was successfully synthe-
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OXFORD Cryosystems 700 Cryostream and cooled to 123(1) K.
Data was collected with monochromatic (graphite) Mo-Kα radia-
tion (λ = 0.71073 Å) and processed using CrysAlisProv 1.171.34.36
software;[48] Lorentz, polarization and absorption corrections
(multi-scan) were applied. Compounds 3 and 4 were solved and
refined with SHELX-97.[49] All non-hydrogen atoms were refined
with anisotropic thermal parameters unless otherwise indicated and
hydrogen atoms were placed in calculated positions using a riding
model with C–H: 0.95–0.98 Å and Uiso(H) = xUiso(C), x = 1.2 or
1.5. CCDC numbers for compounds 1 and 2 are 1023758 and
sized by reaction of strong base, Bi(OtBu)3 and by a salt
metathesis reaction. The complex [Bi(MBT)3] (1) was also
synthesised by reacting BiPh3 with MBT(H) in a 1:3 ratio
by solvent-free, conventional refluxing and microwave irra-
diation conditions. The solid-state structures of 1 were ana-
lysed by single-crystal X-ray studies. Both ligands bind to
the bismuth centre in a bidentate fashion involving the exo-
cyclic sulfur and ring nitrogen.
A new bis-thiolato BiIII complex [BiPh(MBT)2] (2) was
synthesised by salt metathesis involving BiPhCl2 and the 1023759 respectively. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
sodium salt of MBT(H). The solid-state structure of com-
plex 2 was determined by X-ray crystallography and proved
to be a dimer with a coordination number of six possessing
distorted pentagonal pyramidal geometry. In the present
study these two new complexes 1 and 2 were evaluated
against six different strains of bacteria; M. smegmatis, S.
aureus, MRSA, VRE, E. faecalis and E. coli. The two com-
plexes (1, 2), along with [Bi(4-BrMTD)3]2 (3), and [BiPh(4-
BrMTD)2] (4), were also assessed against L. major promos-
togotes. Cytotoxicity studies against mammalian cells were
also carried out using COS-7 cell lines (monkey cells) and
human fibroblast cells. Complexes 1 and 2 proved to be
highly active against a diverse range of bacteria. The MIC
values obtained are, in some cases, superior to those of van-
comycin, a drug used for the treatment of drug resistant
bacteria. These compounds proved to be non-toxic to mam-
malian COS-7 cells even at 20 μg/mL. Considering selectiv-
ity indexes, mono-phenyl BiIII complex 2 emerges as the
most promising antileishmanial agent with a very low IC50
of 0.11 μg/mL. Notably, the antileishmanial IC50 of 2 is sev-
eral fold higher than that of the clinically employed ampho-
tericin B.
Antimicrobial Activity: Mycobacterium smegmatis was cultured in
Middlebrook 7H9/7H10 medium (Difco) for 3 d at 37 °C. Escher-
ichia coli was cultured overnight at 37 °C in LB (Luria–Bertani)
medium. Staphylococcus aureus, MRSA (methicillin-resistant S. au-
reus), Enterococcus faecalis and VRE (vancomycin-resistant E. fae-
calis) were cultured in BHI (brain heart infusion) medium (Oxoid)
overnight at 37 °C.
In initial activity screens, filter paper discs were soaked with 2 μL
of 5 mg/mL compound, then placed on the surface of agar plates
that had been pre-spread with a culture of the bacterial strain of
interest. Following incubation, the plates were examined for the
presence of zones of inhibition of bacterial growth around the discs.
Compounds that were negative in this assay were not examined
further, while minimum inhibitory concentration (MIC) assays
were performed for all positive compounds.
To determine MICs, liquid cultures of bacteria were prepared con-
taining serial dilutions of the compounds, from 80 μg/mL to
0.25 μg/mL. After incubation, the cultures were examined to deter-
mine the minimum concentration of compound that caused total
inhibition of growth; this value was recorded as the MIC. The anti-
mycobacterial drugs isoniazid and ethambutol were included as
controls.
Cell Toxicity Assays: Toxicities against eukaryotic cells were as-
sayed using the in vitro toxicology assay kit MTT-based (Sigma–
Aldrich; cat. no. TOX1–1KT), according to the manufacturer’s in-
structions. Compounds were added to cultured COS-7 (monkey
kidney-derived) cells at 10 and 20 μg/mL for 1 h prior to addition
of the tetrazolium dye MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-di-
phenyltetrazolium bromide] reagent. OD690 measurements were ex-
pressed as a percentage of DMSO-only negative controls. All assays
were performed in triplicate. Isoniazid and ethambutol-treated
COS-7 cells were included as controls.
Experimental Section
General: BiPh3 was synthesised through a standard Grignard
metathesis reaction from the treatment of BiCl3 with MgPhBr in
anhydrous Et2O at 0 °C, and subsequently recrystallised from
EtOH. Ph2BiCl was synthesised by mixing BiPh3 and BiCl3 in a
2:1 ratio in anhydrous Et2O, and Bi(OtBu)3 was synthesised accord-
ing to literature procedures.[47] EtOH, DMSO and toluene were
used as solvents for recrystallization. Et2O and THF were dried
prior to use by M-Braun-SPS-800 solvent purification system and
molecular sieves (4 Å) were used to store. All moisture-sensitive
reactions were conducted with oven dried glassware under an atmo-
sphere of dry N2 using a vacuum/N2 line and Schlenk techniques.
The heterocyclic compounds were purchased from Sigma–Aldrich
and used as supplied. Microwave irradiation was carried out with
a CEM Discoverer Microwave oven with maximum power 0–300W,
model number 9080, maximum current 6.38 A with 50/60 MHz fre-
quency. NMR spectra of complexes were recorded with a Bruker
DPX 400 spectrometer in [D6]DMSO with TMS as the internal
standard at room temperature. Elemental analyses (C, H, N) were
performed by the Campbell Microanalytical lab, Department of
Chemistry, University of Otago, Dunedin, New Zealand. Melting
points were determined using a Stuart Scientific SMP3 melting
point apparatus. Mass spectra were recorded with a Micromass
Platform Electrospray Mass Spectrometer.
Antileishmanial Activity
Cell Viability Assay: The Celltiter Blue Cell Viability Assay (Pro-
mega, Madison, WI, USA) was used for screening of antileishman-
ial activity and toxicity. Compounds were dissolved in DMSO at
10 mmol/L working stocks and diluted out in appropriate culture
media. The assay was set up in duplicates in 96-well plates accord-
ing to the manufacturer’s instructions. Assay cell batches contain-
ing 106 promastigotes/mL and 105/mL primary human fibroblasts
were used. Cell viability was assessed by measuring fluorescence
at 550 nm excitation and 590 nm emission as per manufacturer’s
instructions.[50] The Celltiter Blue dye was added to samples at the
time of setting up the assay and the negative control (no cells) value
was subtracted from all subsequent readings as a background
value. All readings were compared to no-drug controls and the per-
cent growth inhibition was calculated. DMSO controls were in-
cluded. All plates were assessed microscopically.[51] The graphs
Crystallographic Data: Crystallographic data for compounds 1 and
2 was obtained with an OXFORD Gemini Ultra equipped with an
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shown in this paper give the percentage of positive control vs. con-
centration.
ESI-MS– (solvent: DMSO/MeOH, 35 eV): m/z 706 {60,
[BiPhL2(Cl)]–}, 567 {30, [BiPhL(Cl)2]–}; calcd. (%) BiC24H17N2S4
(670.62): C 42.98, H 2.55, N 4.18; found C 43.22, H 2.54, N 3.95.
Cell Culture: L. major was maintained at 26 °C in M199 medium
(Invitrogen) supplemented with 10% heat inactivated fetal bovine
serum (HI-FBS) (Trace Biosciences). The human primary fibro-
blast line was cultured in Dulbecco’s Modified Eagle’s Medium
(DMEM) (Life Technologies) supplemented with 10% HI-FBS at
37 °C in 5% CO2.
Acknowledgments
The authors thank Monash University and the Australian Research
Council (DP110103812) for financial support. The authors also
wish to thank Associate Professor Benjamin Howden (Austin
Health) for supplying the MRSA and VRE strains for antimicro-
bial activity testing and Charles Ma for culturing the COS-7 cells.
Synthesis and Characterisation: All general reaction procedures
(GP) discussing bismuth sources and the type of reaction (solvent-
free, solvent-mediated, microwave) are given in the Supporting In-
formation.
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Compounds 1 and 2 used in the biological assays were prepared as
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described below.
Synthesis of [Bi(MBT)3] (1) Using [Bi(OtBu)3]: All manipulations
were carried out under a strictly dry N2 atmosphere using Schlenk
techniques. To a suspension of 4-phenylthiazole-2-thiol (0.20 g,
1.03 mmol, 3 equiv.) in dry THF (15 mL) at –78 °C was added a
solution of Bi(OtBu)3 (0.15 g, 0.34 mmol, 1 equiv.) solution in dry
THF (10 mL). The reaction mixture was stirred overnight being
warmed slowly to room temperature. The resultant orange precipi-
tate was filtered, washed with dry Et2O, and dried in vacuo, yield
0.21 g (78%). Mp: 192 °C. 1H NMR (400 MHz, [D6]DMSO,
30 °C): δ = 7.83 (d, J3 = 8.80 Hz, 6 H, Hb), 7.57 (s, 3 H, Hf), 7.16
(m, 9 H, Hcd) ppm. 13C NMR (100 MHz, [D6]DMSO, 30 °C): δ =
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128.5 (Cc), 127.3 (Cd), 125.9 (Cb), 113.7 (Cf) ppm. FT-IR: ν = 1596
˜
(m), 1472 (s), 1385 (m), 1269 (m), 1019 (s), 840 (s), 727 (s), 705
(m), 665 (s) cm–1. ESI-MS+ (DMSO/MeOH, 35 eV): m/z (%) = 787
{55%, [BiL3(H)]+}, 729 {20%, [BiL2(MeOH)2(H2O)4]+}, 594 (10%,
[BiL2]+); calcd. (%) for C27H18BiN3S6 (785.7): C, 41.27; H, 2.31; N,
5.35; S, 24.48; found C 41.07, H 1.92, N 5.25, S 24.30 (Figure 10).
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Synthesis of [BiPh(MBT)2] (2) by Salt Metathesis: All manipula-
tions were carried out under a dry N2 atmosphere. The sodium
salt of 4-phenylthiazole-2-thiol (0.2 g, 0.93 mmol) was placed in a
100 mL Schlenk-flask. Addition of dry MeOH (20 mL) resulted in
a clear solution that was allowed to stir for 15 min at room tem-
perature. The solution was cooled to 0 °C before the addition of
BiPhCl2 (0.17 g, 0.47 mmol, 1 equiv.) and stirring at room tempera-
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DMSO, 30 °C): δ = 8.94 (d, J3 = 7.60 Hz, 2 H, Ho), 7.82 (m, 6 H,
Hb,m), 7.67 (s, 2 H, Hf), 7.42 (t, J3 = 7.40 Hz, 1 H, Hp), 7.39 (m, 6
H, Hcd) ppm. 13C NMR (100 MHz, [D6]DMSO, 30 °C): δ = 139.7
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Eur. J. Inorg. Chem. 0000, 0–0
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Received: October 7, 2014
Published Online: ᭿
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Job/Unit: I42958
/KAP1
Date: 07-01-15 17:57:22
Pages: 10
www.eurjic.org
FULL PAPER
Bioactive Bi Complexes
A. Luqman, V. L. Blair, R. Brammananth,
P. K. Crellin, R. L. Coppel, L. Kedzierski,
P. C. Andrews* ................................ 1–10
Homoleptic and Heteroleptic Bismuth(III)
Thiazole–Thiolates and the Influence of
Ring Substitution on Their Antibacterial
and Antileishmanial Activity
Keywords: Bismuth / S ligands / Medicinal
chemistry
agents
/ Antibiotics / Antiparasitic
Thiazole-based bismuth(III) complexes,
[BiPh(MBT)2]2 and [Bi(MBT)3]2, derived
from 4-phenylthiazole-2-thiol, MBT(H),
have been synthesised and structurally
characterised; X-ray diffraction studies
played a central role in structure eluci-
dation efforts. [BiPh(MBT)2]2 is strongly
active against common and multi-resistant
bacteria, and against the Leishmania para-
site.
Eur. J. Inorg. Chem. 0000, 0–0
10
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim