A sweeter way to combat Helicobacter pylori? Bismuth(III) complexes and oxido-clusters derived from non-nutritive sweeteners and their activity against H. pylori

Article abstract of DOI:10.1016/j.jorganchem.2012.10.024

Eight new homo-and hetero-leptic bismuth(III) complexes and two new polynuclear bismuth(III) oxido clusters derived from acetosulfame (AceH) and cyclamic acid (CycH₂) have been synthesised and characterised. Complexes, [Ph2Bi(Ace)] 1, [Bi(Ace)3] 2, [PhBi(Ace)₂] 3, [Bi(CycH)₃] 6, [Ph₂Bi(CycH)] 7 and [PhBi(CycH) ₂] 8 were synthesised by treating BiPh₃ with the appropriate acid in 1:1, 1:2 and 1:3 stoichiometric ratios under solvent-free or solvent-mediated conditions. Complex 4, [Bi(OH)(Ace)₂], was obtained from the hydrolysis of 3. [Bi2(Cyc)₃] 9 was obtained from the reaction of cyclamic acid with (Bi(O^tBu)₃) in a 3:2 ratio under inert conditions. The polynuclear bismuth oxido clusters, [Bi ₅₀O₆₄(Ace)₂₂(H₂O)₁₀] 5 and [Bi₃₈O₄₅(CycH)₂₄(H₂O) ₁₄] 10 were obtained using Bi₂O₃ under sonication in water and their composition confirmed through elemental and thermogravimetric analyses. The DMSO soluble complexes, 1, 2, 4, 5, 6, 7 and 9, were all assessed for their in-vitro activity against three strains of H. pylori (251, 26695 and B128). All compounds gave an MIC value of 6.25 μg/mL, indicating that bactericidal activity is insensitive to increased substitution by acetosulfamate or cyclamate at the Bi(III) centre.

Full text of DOI:10.1016/j.jorganchem.2012.10.024

Journal of Organometallic Chemistry 724 (2013) 88e94
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Journal of Organometallic Chemistry
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A sweeter way to combat Helicobacter pylori? Bismuth(III) complexes and oxido-
clusters derived from non-nutritive sweeteners and their activity against H. pylori
,
b
c
a
Philip C. Andrews a , Richard L. Ferrero , Peter C. Junk , Roshani M. Peiris
*
a School of Chemistry, Monash University, P.O. Box 23, Melbourne, Vic. 3800, Australia
b Centre for Innate Immunity and Infectious Diseases, Monash Institute of Medical Research, Clayton, Melbourne, Vic., 3168, Australia
c School of Pharmacy and Molecular Sciences, James Cook University, Townsville, Qld. 4811, Australia
a r t i c l e i n f o
a b s t r a c t
Article history:
Eight new homo-and hetero-leptic bismuth(III) complexes and two new polynuclear bismuth(III) oxido
clusters derived from acetosulfame (AceH) and cyclamic acid (CycH2) have been synthesised and char-
acterised. Complexes, [Ph2Bi(Ace)] 1, [Bi(Ace)3] 2, [PhBi(Ace)2] 3, [Bi(CycH)3] 6, [Ph2Bi(CycH)] 7 and
[PhBi(CycH)2] 8 were synthesised by treating BiPh3 with the appropriate acid in 1:1, 1:2 and 1:3 stoi-
chiometric ratios under solvent-free or solvent-mediated conditions. Complex 4, [Bi(OH)(Ace)2], was
obtained from the hydrolysis of 3. [Bi2(Cyc)3] 9 was obtained from the reaction of cyclamic acid
Received 3 August 2012
Received in revised form
8 October 2012
Accepted 12 October 2012
Keywords:
Bismuth(III)
Non-nutritive sweeteners
Acetosulfame
Cyclamate
with (Bi(OtBu)3) in
a 3:2 ratio under inert conditions. The polynuclear bismuth oxido clusters,
[Bi50O64(Ace)22(H2O)10] 5 and [Bi38O45(CycH)24(H2O)14] 10 were obtained using Bi2O3 under sonication in
water and their composition confirmed through elemental and thermogravimetric analyses. The DMSO
soluble complexes, 1, 2, 4, 5, 6, 7 and 9, were all assessed for their in-vitro activity against three strains of
H. pylori (251, 26695 and B128). All compounds gave an MIC value of 6.25
bactericidal activity is insensitive to increased substitution by acetosulfamate or cyclamate at the Bi(III)
mg/mL, indicating that
Oxido-clusters
H. pylori
centre.
Ó 2012 Elsevier B.V. All rights reserved.
1. Introduction
treatment is rare and bismuth is considered a relatively safe heavy
metal, overdosing and in vivo biomethylation can increase the
Helicobacter pylori, a Gram-negative bacterium found in the
stomach, is responsible for gastritis, peptic and duodenal ulcers, and
gastric cancers [1e3]. Bismuth compounds have been used to treat
gastrointestinal disorders for centuries, even before the link
between H. pylori and above diseases was established [4]. Triple
therapy, a combination therapy of two antibiotics (commonly
amoxicillin and clarithromycin) and a proton pump inhibitor
(omeprazole), is the regimen most commonly recommended for
treatment of H. pylori but this has shown a failure rate in more than
20% of patients for many years [5]. The failure is mainly due to
increasing antibiotic resistance, especially against clarithromycin
[6]. Therapies in which a bismuth compound, usually the sub-
salicylate or subcitrate, is included as part of the treatment regimen
have greater success rates since H. pylori strains resistant to bismuth
compounds have not yet been reported [7]. They also have the
advantage of not requiring a neutral stomach pH to be effective [8].
A significant drawback for the bismuth-based therapies is the
amount of bismuth which is ingested. While intoxication during
possibility of toxic effects [9]. Greater activities at lower concen-
trations, combined with benign ligands, are principal targets in the
development of new bismuth-based drugs.
Despite their widespread availability and use, still little is known
about the biological action of bismuth and its compounds. This,
combined with their potential medicinal and antimicrobial appli-
cations, warrants continuing research into their synthesis, stability
and biological activity. Over the past few years our group has been
successful in developing and assessing the activity against H. pylori
of a range of homo-and heteroleptic bismuth(III) complexes con-
taining different ligands such as aryls, carboxylates, sulfonates,
saccharinates and thiosaccharinates [10e14]. The variance in
observed activities against the three different bacterial strains
indicates that the nature of the ligand(s) is important in moderating
the bactericidal activity of the compounds. For example, the
inclusion of a single sulfonate, saccharinate or thiosaccharinate
ligand onto a di-phenylbismuth(III) centre through protolysis
reactions with BiPh3, giving compounds of general formula
[Ph2BiL], can magnify the bactericidal properties significantly
relative to BiPh3.
As bismuth(III) complexes of saccharin and thiosaccharin
showed promising activity against H. pylori (Minimum Inhibitory
* Corresponding author.
E-mail address: phil.andrews@monash.edu (P.C. Andrews).
0022-328X/$ e see front matter Ó 2012 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.jorganchem.2012.10.024

P.C. Andrews et al. / Journal of Organometallic Chemistry 724 (2013) 88e94
89
Concentration; 6.25
m
g/mL), we turned our attention to other
for a period of 8e12 h. The solvent-free reactions involved heating
a mixture of the reactants, which had been ground together, to
a temperature of 80e90 ꢀC for a period of 30e60 min.
common non-toxic non-nutritive sweeteners; namely aceto-
sulfame (6-methyl-1,2,3-oxathiazin-4(3H)-one-2,2-dioxide) and
cyclamate (N-cyclohexylsulfamic acid/cyclamic acid).
The solvent-free reaction of AceH (pKa 2.0) [23] with BiPh3,
conducted in a 1:1 stoichiometric ratio at 80 ꢀC for 30 min produced
the expected di-phenyl product, [Ph2Bi(Ace)] 1, in 84% yield
(Scheme 1). Changing the stoichiometry to 3:1 produced the tri-
substituted product, [Bi(Ace)3] 2, in 86% yield, after heating at 90 ꢀC
for 1 h (Scheme 2). In contrast, the 2:1 solvent-free reaction did not
give [PhBi(Ace)2] 3 as a single isolable product, but instead
produced a mixture of all three products 1e3. This reaction
therefore was carried out under different conditions, varying the
time and temperature in an attempt to maximise the yield of 3. The
best conditions were found to be heating at 65 ꢀC for 60 min which
gave a ratio of products of 3:1:1 for 3, 2 and 1 respectively. Heating
at this temperature for 2 h gave the least favourable outcome
resulting in 3 and 2 in a 1:4 ratio. Since all three compounds proved
to be soluble only in DMSO and DMF, and crystallisation did not
occur, it was not possible to isolate 3 as a pure compound. Similar
behaviour has been previously observed in heteroleptic bismuth
saccharinates [14], sulfonates [10] and thiobenzoates [24], where
the 2:1 reaction did not yield the expected mono-phenyl product.
The 2:1 reaction was therefore attempted under solvent-
mediated conditions, changing the solvents and the reaction
conditions to attempt to isolate 3 in a pure form. Again, on almost
all occasions only a mixture of products 1e3 was isolated, with the
best ratio being 1:1:3 respectively.
Acetosulfame bears some structural similarity to saccharin
(Fig. 1) and has been used as a non-nutritive sweetener since 1988.
The potassium salt can be found in, for example, sweets, soft drinks,
cosmetics, and toothpastes [15]. Cyclamate, in the form of its
sodium or calcium salt, is used in more than 50 countries in both
food and pharmaceuticals [16].
Surprisingly, the metal-organic and organometallic chemistry of
acetosulfame and cyclamate is not well developed. Among the re-
ported complexes of acetosulfame many are transition metal
complexes involving Pt(II), Ag(I), Cu(II), Pd(II), Co(II) and Zn(II)
[15,17e21]. There is no single complex of the p-block metals yet
reported. The Ag(I) complex, [Ag(Ace)]n, has shown good activity
against Mycobacterium tuberculosis, Escherichia coli, Pseudomonas
aeruginosa and Enterococcus faecalis [19]. The Pt(II) complex,
K2[PtCl2(Ace)2], has shown some cytotoxicity towards human
cervix cancer cells, and has shown good activity against dengue
virus type 2 [19]. The complexes of cyclamate are limited only to
s-block metals; Na, K, Rb and Ca [16], and to Ag(I). Not surprisingly,
the Ag(I) cyclamate complex also shows some activity against
M. tuberculosis [22].
The acetosulfamate and cyclamate anions have heteroatoms
which are capable of forming ionic, covalent or dative bonds with
metals, and can thus act as polyfunctional complexing agents.
However, crystallographic studies have shown the most common
binding mode in acetosulfame is monodentate through the nitrogen
atom [15,17,20,21] and in cyclamate through the sulfonyl oxygen
atom [16]. The exceptions are the Cu(II), Pt(II) and Ag(I) complexes
which have the acetosulfamate ligand binding in a bidentate
manner. In the Cu complex it binds through the nitrogen and
carbonyl oxygen atoms, whereas in the Pt(II) and Ag(I) complexes it
is through the nitrogen and sulfonyl oxygen atoms [19].
In this paper we describe the synthesis and characterisation of
ten new homo-and heteroleptic bismuth(III) compounds bearing
acetosulfamate and cyclamate ligands; [Ph2Bi(Ace)] 1, [Bi(Ace)3] 2,
[PhBi(Ace)2] 3, [Bi(OH)(Ace)2] 4, [Bi(CycH)3] 6, [Ph2Bi(CycH)] 7,
[PhBi(Cyc-H)2] 8, [Bi2(Cyc)3] 9, and the polynuclear bismuth-oxido
Only in one instance was 3 ever able to be isolated in pure form,
when a homogeneous reaction was carried out in Et2O at room
temperature (RT) for a period of 4 h. With a degree of serendipity
this gave a quantitative yield of 3 (based on bismuth).
The single remaining Ph group in 3 appears to be highly sensi-
tive towards hydrolysis and resulted in formation of the unusual
bismuth hydroxo compound [Bi(OH)(Ace)2] 4, after 3 was left
exposed in air for 30 min (Scheme 1). The composition of 4 was
confirmed through elemental analysis. The 1H NMR spectrum of 3,
which was taken immediately after isolation, shows the expected
o-, m-, p-Ph protons resonating at 8.74, 8.04 and 7.42 ppm
respectively. A small singlet due to benzene is visible at 7.36 ppm,
indicative of the extreme lability of the Ph group. Confirmation of
this came when the 1H NMR spectrum of 3 was taken after 30 min
standing in air. This showed no resonances due to the phenyl group
but a prominent singlet due to benzene. Formation of similar
bismuth hydroxo species through the hydrolysis of analogous
R2BiCl species [R ¼ 2,6-diacetylpyridine bis-(2-thenoylhydrazone)
[25], phenyl-N,N-dimethylmethanamine [26] and 5,6,7,12-
tetrahydrodibenz-azabismocine [27]] have been reported previ-
ously in the literature, with associated crystallographic data
clusters; [Bi50O64(Ace)22(H2O)10] 5 and [Bi38O45(CycH)24(H2O)14
]
10. The bactericidal activity of compounds 1, 2, 4e7 and 9 against
Helicobacter pylori has been assessed and is reported.
2. Results and discussion
2.1. Acetosulfame
ꢀ
showing a strong BieO bond of length 2.08e2.18 A.
Acetosulfamate complexes of bismuth(III) were synthesised by
both solvent-mediated and solvent-free reactions with BiPh3. The
solvent-mediated reactions were conducted in ether at room
temperature for a period of 4 h or in ethanol at reflux temperature
From recent studies we have demonstrated that the reaction of
Bi2O3 with acids in water can lead to the formation of isolable
polynuclear bismuth oxido clusters [28]. Thus, three equivalents of
Fig. 1. Structures of saccharin, acetosulfame and cyclamic acid.

90
P.C. Andrews et al. / Journal of Organometallic Chemistry 724 (2013) 88e94
Scheme 3. Reactions of cyclamic acid with BiPh3. Reaction conditions: (i) n ¼ 1,
solvent-free conditions, 80 ꢀC, 20 min; (ii) n ¼ 3, solvent-free conditions, 80 ꢀC, 2.5 h.
(Scheme 5). This shows similarities with related bismuth oxido
clusters characterised through single crystal X-ray diffraction;
[Bi38O45(O3SeMes)24(H2O)14] (HO3SeMes ¼ mesitylsulfonic acid)
[28], [Bi38O45(OMc)24(DMSO)9] (HOMc ¼ methacrylic acid) [32],
[Bi38O45(NO3)20(DMSO)28](NO3)4 [33]. The cyclamate cluster is
insoluble in all solvents tested, including DMSO and DMF, and so
crystals could not be obtained. Analysis was therefore limited to
FT-IR, melting point elemental analysis and to TGA studies.
Scheme 1. Reactions of acetosulfame with BiPh3. Reaction conditions: (i)
n
¼
1,
solventefree, 80 ꢀC, 30 min; (ii) n ¼ 3, solvent-free, 90 ꢀC, 1 h; (iii) n ¼ 2, Et2O, RT, 4 h;
(iv) H2O, air, 30 min.
acetosulfame were sonicated together with Bi2O3 in water for five
days. Completion of the reaction can be monitored by the appear-
ance of a white precipitate and the disappearance of the yellow
colour of Bi2O3. From elemental analysis and thermogravimetric
(TGA) studies, the product was calculated to be [Bi50O64(Ace)22
(H2O)10] 5 (Scheme 2). Assuming that the solid was homogeneous
in composition. Although the compound shows some limited
solubility in DMSO, crystals of 5 could not be obtained, only an
amorphous solid was ever deposited. There are currently no
examples of a 50 nuclear homo-metallic bismuth oxido cluster fully
structurally authenticated. However a heterobimetallic cluster
containing bismuth and sodium, [Bi50Na2O64(OH)2(OSiMe3)22], has
been previously reported [29].
2.3. Infrared spectroscopy
The absorption bands corresponding to NeH stretching and
bending in acetosulfame (3358 and 1333 cmꢁ1) are absent in the IR
spectra of the corresponding bismuth compounds 1, 2, 4 and 5,
confirming deprotonation had occurred. A summary of the main
absorption bands for each complex and their assignments is given
in Table 1.
In the free acid, two absorption bands are observed in the
carbonyl stretching region at 1687 cmꢁ1 and 1644 cmꢁ1, arising
from Fermi-resonance [34]. The carbonyl stretching bands in all
four bismuth acetosulfamate compounds appears around 1650e
1652 cmꢁ1. This relatively small bathochromic shift suggests that
delocalisation and subsequent interaction with the Bi(III) centre is
not considerable. Analogous bismuth(III) saccharinate complexes
showed shifts in the carbonyl region of a similar scale, the X-ray
crystallography supporting the inference that the interaction with
the Bi(III) centre is not substantial [14].
All four bismuth acetosulfamate compounds also show a shift in
asymmetric and symmetric stretching vibrations of the SO2 groups
from nas(SO2) 1383 cmꢁ1 and ns(SO2) 1199 cmꢁ1 in the free acid, to
1342 and 1173 cmꢁ1 in 1, 1342 and 1175 cmꢁ1 in 2, 1321 and
1175 cmꢁ1 in 4, and 1319 and 1175 cmꢁ1 in 5. The observed bath-
ochromic shifts could be due to increased SeO bond lengths
resulting from interaction of this group with the bismuth(III)
centre. This is again similar to the bismuth(III) saccharinate
complexes, where polymerisation through the SO2 group was
proved by X-ray crystallography [14]. The larger shift observed in
the bismuth cluster 5 indicates a stronger BieO(¼S) interaction in
the bismuth cluster than in the other three complexes.
2.2. Cyclamic acid
In solvent cyclamic acid shows no tendency to react with BiPh3,
even when heated to reflux in ethanol for up to 24 h. The solvent-
free method though proved more productive. The 3:1 stoichio-
metric reaction of CycH with BiPh3 produced the tri-substituted
product, [Bi(Cyc-H)3] 6, in 80% yield, when heated at 80 ꢀC for 2.5 h
(Scheme 3). The 1:1 reaction produced [Ph2Bi(CycH)] 7, in 77%
yield, when conducted at 80 ꢀC for 20 min (Scheme 3). However,
the 2:1 reaction again proved troublesome, resulting in a mixture of
all three possible differently substituted products. This reaction was
repeated several times, altering the temperature and time, in order
maximise the yield of [PhBi(CycH)2] 8. 1H NMR spectra indicated
this peaked at 44% (7, 30%; 6, 26%) with the optimum conditions
being 80 ꢀC for 1.5 h. Unfortunately, separation of 8 from this
mixture again proved difficult due to solubility only in DMSO and
DMF.
Cyclamic acid contains two different acidic hydrogens; OH (pKa
1.9) [30], NH (pKa 3.45) [31]. However, it exists in the zwitterionic
form (see IR details below) and BiPh3 is not a strong enough base to
deprotonate the eNHþ2 group. To obtain the dianion therefore, the
stronger base Bi(tOBu)3 was employed. The 3:2 stoichiometric
reaction of CycH2 with Bi(OtBu)3 under inert conditions in dry THF
successfully resulted in the formation and isolation of [Bi2(Cyc)3] 9,
in 67% yield (Scheme 4).
In [Bi(OH)(Ace)2] 4 an additional broad absorbance corre-
sponding to OH stretching is observed at 3389 cmꢁ1
.
The IR spectrum of cyclamic acid shows the presence of a double
band at 3119 and 3020 cmꢁ1 due to NeH asymmetric and
symmetric stretching. These relatively low wavenumbers, typical of
a secondary amine salt, together with the absence of a broad band
above 3000 cmꢁ1 corresponding to OeH stretching, confirms that
cyclamic acid exists in its zwitterionic form. This has been
The reaction of three equivalents of cyclamic acid with Bi2O3 in
water produced another large polynuclear bismuth-oxido cluster,
[Bi38O45(CycH)24(H2O)14
]
10 after sonication for five days
Scheme 2. Reaction of acetosulfame with Bi2O3. Reaction conditions: (i) H2O, RT,
Scheme 4. Reaction of cyclamic acid with Bi(tOBu)3. Reaction conditions: (i) THF,
5 days.
RT, 18 h.

P.C. Andrews et al. / Journal of Organometallic Chemistry 724 (2013) 88e94
91
Table 2
Summary of IR bands (cmꢁ1) and assignments in Bi(III) cyclamates.
Cyclamic acid
6
7
9
10
n
(NH)
(NH)
nas(SO2)
(CN)
ns(SO2)
3119 m/3020 m
1535 m
1333 m
1264 m
1069 m
3248 m
e
3240 m
e
e
3305 m
e
Scheme 5. Reaction of cyclamic acid with Bi2O3. Reaction conditions: (i) H2O, RT,
5 days.
d
e
1305 m
1263 m
1028 m
1306 m
1265 m
1028 m
1307 m
1264 m
1037 m
1297 m
1265 m
1036 m
n
previously supported by X-ray crystallography [16]. The NeH
bending mode was observed at 1535 cmꢁ1. In the IR spectrum of
bismuth(III) complexes 6, 7 and 10, only absorbances due to NeH
stretching were observed, appearing at 3248 cmꢁ1 for 6,
3240 cmꢁ1 for 7, and 3305 cmꢁ1 for 10. Normal secondary amine
NeH stretches are expected in the region 3300e3500 cmꢁ1. Thus,
the IR absorbances for the three Bi(III) compounds indicate
deprotonation has occurred in all cases, but also suggests that in 6
and 7 chelation to the Bi(III) centre occurs through the anionic
sulfonyl O atom and N atom, while in 10 this is less likely. The latter
can be compared with the hexanuclear bismuth(III) oxido cluster
derived from sulfamic acid, [Bi6O4(OH)4(O3SNH2)6], where signifi-
cant hypsochromic shifts of 162 cmꢁ1 were observed in the NeH
stretching frequencies due to the absence of N atom coordination,
as supported by X-ray crystallography [28]. The spectrum of
[Bi2(Cyc)3] 9 shows no absorption in the NeH region, indicating
double deprotonation of the acid. A summary of the main absorp-
tion bands for each complex and their assignments is given in
Table 2.
the OH proton disappears and the cyclohexyl ring protons resonate
at lower frequencies. The protons associated with the phenyl
groups showed the same frequency shifts corresponding to degree
of substitution as observed in the acetosulfamate complexes.
The 13C NMR spectra of the bismuth acetosulfamate and cycla-
mate complexes did not show any significant shifts when compared
with their respective free acids.
2.5. Thermogravimetric analysis
Thermogravimetric analysis of 5 and 10 showed a net weight
loss of 24.4% (calc. 24.6%) for 5 and 35.1% (calc. 34.3%) for 10 over
the temperature range 50e800 ꢀC. This is consistent with complete
removal of water and combustion of the ligands to leave Bi2O3. The
traces (provided as Fig. S1 and S2 in Supplementary Information)
did not allow for unambiguous assignment of the number of water
molecules. However, the water and other ligands were calculated
together to give a final reasonable composition consistent with
elemental analysis. Powder X-ray diffraction studies of the TGA
These complexes also showed bathochromic shifts in SO3
symmetric and asymmetric stretching, indicating BieO(¼S) inter-
actions. Similar to cluster 5, cluster 10 also showed a large bath-
ochromic shift indicating stronger (S¼)OeBi interactions than for
the other bismuth(III) cyclamates.
residues showed the final formation of a-Bi2O3 in both cases.
2.6. Biological testing
2.4. NMR spectroscopy
2.6.1. Solubility and stability
The commercially available bismuth compounds, bismuth sub-
salicylate (BSS), colloidal bismuth subcitrate (CBS) and ranitidine
bismuth citrate (RBC) are not soluble in the acidic environment of
the stomach (pH 2) resulting in poor absorption of Bi ions into the
bloodstream of approximately 0.5% by mass. However, this still
provides bismuth levels above the minimum considered necessary
to kill Helicobacter pylori [35,36]. The low systemic toxicity of
current bismuth drugs derives in part from the low solubility and
poor absorption in the stomach at low pH. These seem desirable
features in minimising serum Bi levels, any concomitant toxic
effects, and the possibility of overdosing easily.
All the bismuth complexes of acetosulfame and cyclamate were
checked for their solubility in water and in 1 M HCl solution. There
was no evident dissolution or decomposition of the compounds
even after stirring for 18 h at room temperature. On recovery there
was no significant change in the mass of the compounds, and there
was no indication that any significant amount of acetosulfame or
cyclamic acid had been liberated into the aqueous HCl solution.
Composition of the recovered compounds was confirmed by NMR
spectroscopy. Thus, the activity appears to be independent of pH or
solubility.
Where possible 1H and 13C NMR spectra of the bismuth(III)
complexes were recorded in D6-DMSO. They showed no solubility
in other deuterated solvents. The chemical shifts for each
compound are compiled in Table 3. The 1H NMR spectrum of ace-
tosulfame shows three signals corresponding to NH, CHb and CH3d at
7.21, 5.91 and 2.14 ppm respectively (Fig. 2). The absence of NeH
proton signal in the spectra of complexes 1, 2, 3, 4 and in the
cluster 5, indicates the presence of only deprotonated ligands. The
observed lower frequency shifts observed for the CHb and CH3d
protons confirms anion formation and coordination to the bismuth
centre. The o-, m- and p-Ph signals for the heteroleptic bismuth
acetosulfamates showed increasing high frequency shifts as the
number of Ph groups bound to the Bi(III) centre changed from three
to two to one.
The 1H NMR spectrum of cyclamic acid taken in D6-DMSO
showed a broad signal at 9.79 ppm due to the acidic sulfonate OH
proton. However, the NeH proton was not visible in the spectrum.
The cyclohexyl ring protons appeared in the region 3.21e1.01 ppm.
On metallation to give complexes 6, 7, 8 and 9 the resonance due to
Table 1
Summary of IR bands (cmꢁ1) and assignments in Bi(III) acetosulfamates 1, 2, 4, and 5.
Table 3
Acetosulfame
1
2
4
5
1H chemical shifts of acetosulfame and Bi(III) acetosulfamates 1e5.
n
n
n
(OH)
(NH)
(C]O)
e
e
e
3389 br
e
e
AceH
BiPh3
1
2
3
4
5
3358 m
1687 s, 1644 s
1383 s
1333 m
1267 m
1199 m
e
e
e
1652 m
1342 m
e
1650 m
1342 m
e
1651 m
1321 m
e
1651 m
1319 m
e
o-Ph
m-Ph
p-Ph
CHb
e
7.76
7.38
7.31
e
8.26
7.72
7.35
5.45
1.92
e
8.74
8.04
7.42
5.41
1.96
e
e
nas(SO2)
d
(NH)
(CN)
n
1274 w
1173 m
1275 w
1175 m
1276 w
1175 m
1274 w
1175 m
5.91
2.14
5.37
1.94
5.36
1.94
5.50
2.01
ns(SO2)
CHd3
e

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P.C. Andrews et al. / Journal of Organometallic Chemistry 724 (2013) 88e94
nutritive sweeteners, acetosulfame and cyclamic acid, have been
synthesised and characterised. The mono-substituted complexes,
[Ph2Bi(Ace)] ] 1, Ph2Bi(CycH)] 7 and the fully substituted compounds
[Bi(Ace)3] 2 and Bi(CycH)3] 6 were generated through treatment of
acetosulfame or cyclamic acid with BiPh3 in a 1:1 or 3:1 stoichio-
metric ratio under solvent-free conditions. Compounds [PhBi(Ace)2]
3 and [PhBi(Cyc-H)2] 8 could not be isolated in pure form when
attempted using a solvent-free protocol due to concomitant forma-
tion of other substituted products together with 3 and 8. Even
though 3 was obtained pure by a solvent-mediated route, it proved
to be highly sensitive to moisture, and hydrolysed to give the
unusual hydroxo complex [Bi(OH)(Ace)2] 4. [Bi2(Cyc)3] 9 was ob-
tained from the reaction of cyclamic acid with [Bi(OtBu)3] in a 3:2
ratio under inert conditions. Polynuclear bismuth-oxo clusters,
[Bi50O64(Ace)22(H2O)10] 5 and [Bi38O45(CycH)24(H2O)14] 10 were
synthesised by the reaction of 3 equivalents of acid with Bi2O3. Pure
and soluble complexes, 1, 2, 4, 5, 6, 7 and 9 were assessed for their
activity against three strains of H. pylori, all giving an MIC value of
Fig. 2. Labelling system used for chemical shift assignments in NMR spectra.
2.7. Activity against H. pylori
The in-vitro bactericidal activity of compounds 1, 2, 4, 5, 6, 7, 9,
acetosulfame (aceH), cyclamic acid (cycH2) and BiPh3, was assessed
against three laboratory strains of H. pylori: B128, 251 and 26695.
DMSO was used as the control in each case as it has no activity
against these strains of H. pylori. and was used to solubilise the
compounds. The MIC of each compound was established using the
agar dilution method [37] (described in the Experimental section).
On repeated preparation of the bismuth compounds the analytical
data was checked to ensure uniformity of composition to ensure no
discrepancy in the in-vitro bacterial tests.
6.25 mg/mL. This indicates that while the activity is insensitive to the
degree of ligand substitution at the Bi(III) centre, comparison with
related compounds indicates it may be dependent on the structural
aspects of the ligands and their binding modes to bismuth.
Compared with the commercially available carboxylate derived
4. Experimental
bismuth compounds; BSS (MIC 12.5
CBS (MIC 12.5 g/mL) [38], all the novel Bi(III) acetosulfamate and
cyclamate compounds showed greater activity having a consistent
MIC value of 6.25 g/mL against all three H. pylori strains tested.
mg/mL), RBC (MIC 8 mg/mL) and
m
BiPh3 was synthesised through a standard Grignard metathesis
reaction from the treatment of BiCl3 with PhMgBr in dried
diethyl ether at 0 ꢀC, and subsequently recrystallised from ethanol.
Bi(OtBu)3, was synthesised according to a literature procedure [42].
Bi2O3, cyclamic acid and the potassium salt of acetosulfame was
purchased from SigmaeAldrich Co. Acetosulfame was made by
neutralising the potassium salt with 1 M HCl. NMR spectra were
recorded on a Bruker DRX 400 spectrometer. All spectra were
internally referenced using the deuterated solvent signal. Electro-
spray ionization spectra (ESI) were generated on a Micromass
Platform II QMS spectrometer using cone voltages varying from 35
to 50 V. spectra, as KBr disks or Nujol mulls, were recorded on
a PerkineElmer 1600 FT-IR spectrometer or on ART-IR spectrom-
eter. Elemental microanalyses were performed by the Campbell
Microanalytical Laboratory, Department of Chemistry, University of
Otago, Dunedin, New Zealand. Melting points were measured on
a Stuart Scientific melting point apparatus SMP3. Thermogravi-
metric measurements were performed with a Mettler-Toledo TGA/
DSC 1 Analyzer at a heating rate of 5 ꢀC/min to a maximum
temperature of 800 ꢀC.
m
This level of activity is similar to previously studied bismuth
carboxylates [39], sulfosalicylate [11], phenylbismuth sulfonates
[10] and saccharinates [14].
The acids and BiPh3 were not toxic to the bacteria at the highest
level tested (100 mg/mL). The replacement of a single Ph group in
BiPh3 by an acetosulfame or cyclamate ligand substantially
increased the bactericidal activity of all the complexes, reaching
a level that was not improved by further ligand substitution. The
similarity in activity of bismuth acetosulfamate and saccharinate
complexes (MIC 6.25
similarity of the saccharinate and acetosulfamate ligands. Inter-
estingly, the bismuth oxido cluster 5, also having an MIC 6.25 g/
mg/mL) [14], could result from the structural
m
mL, shows unexpectedly good activity. The commercially available
‘sub’ compounds, implicating oxido clusters [40], generally display
a lower level of activity than their mononuclear analogues. This
highlights that both the ligand and the metal are important in the
bactericidal effect on H. pylori.
The unusual result is for the tri-cylamate [Bi(CycH)3] 6. Our
studies on bismuth sulfonates have shown that an exponential
increase in activity is achieved on sequential replacement of phenyl
groups on BiPh3 by sulfonyl moieties. Thus we observed activities
4.1. Bacterial strains and culture conditions
H. pylori strains 251, B128 and 26695 were routinely cultured on
horse blood agar (HBA) or in brain heart infusion broth (BHI),
supplemented with either 7.5% (v/v) fresh horse blood or 10% (v/v)
FCS, respectively. Culture media were further supplemented with
155 mg/L polymyxin B, 6.25 mg/L vancomycin, 3.125 mg/L
trimethoprim, 1.25 mg/L amphotericin B [43].
of; > 50
0.078
g/mL for Bi(O3SR)3 (R ¼ p-tolyl,2,4,6-mesityl and S-(þ)-10-
camphoryl) [41]. However, an increase in cyclamate ligands at the
Bi(III) centre does not improve the activity beyond 6.25 g/mL. One
mg/mL for BiPh3, 6.25 mg/mL for Ph2Bi(O3SR), and 0.049e
m
m
structural difference between cyclamate and the previously studied
sulfonates, which may explain this, is the chelating nature of the
cyclamate ligands in the bismuth compounds, as suggested by the
IR spectra. This additional stability could decrease the availability of
bismuth ions and hence decrease the activity. This observation can
be extended to the suite of other compounds for which lower
activities have been obtained (vide infra).
4.2. Determination of the minimum inhibitory concentration (MIC)
The MIC of bismuth complexes 1, 2, 4, 5, 6, 7, and 9 were
determined by the agar dilution technique. All bismuth complexes
were dissolved in DMSO to give clear, colourless solutions of known
concentration. H. pylori cultures were incubated in BHI for 18 h
shaking at 140 rpm at 37 ꢀC under micro aerobic conditions.
Bacteria were pelleted, washed in phosphate-buffered saline then
resuspended in BHI [37]. Each suspension was adjusted to give an
approximate density of 106 bacteria/mL. Aliquots (10 mL) of these
3. Conclusions
Eight new homo-and hetero-leptic bismuth (III) compounds and
two new polynuclear bismuth oxido clusters derived from the non-

P.C. Andrews et al. / Journal of Organometallic Chemistry 724 (2013) 88e94
93
suspensions were then streaked onto HBA plates containing
doubling dilutions of the different concentrations of bismuth
compounds, ranging in concentration from 6.25 to 25 mg/mL. Each
compound was tested alongside BiPh3 and the free acids in
comparable concentrations. The MICs of the different compounds
were determined by examination of the plates after incubation for
3e5 days at 37 ꢀC.
reaction mixture was stirred at room temperature for about five days
until the yellow colour of Bi2O3 disappeared. The resultant white
precipitate was collected by filtration and dried. Yield 0.15 g, 64.4%.
M.P. (dec) > 265 ꢀC. FT-IR (cmꢁ1) 1651 m,1319 m,1274 m,1175 m, 939
w, 856 w. Elemental analysis; (C88H108Bi50N22O140S22) Calc (Found): C
6.94 (7.15), H 0.71 (0.87), N 2.02 (1.99). 1H NMR (400 MHz, D6-DMSO)
d
5.50 (s, 1H, CHb), 2.01 (s,3H, CH3d). 13C NMR (100.1 MHz, D6-DMSO)
170.9 (Ca),163.0 (Cc),101.8 (Cb),19.9 (Cd). Mass spectrum; 448.9 (25%,
d
4.3. Syntheses and characterisation
[Bi3O(L)4(H2O)3]3þ),1123.92 (65%, [Bi6O4(OH)4(L)4(H2O)3(MeOH)5]2þ),
1543.83 (100%, [Bi6O3L10(H2O)2(MeOH)4]2þ).
4.3.1. [Ph2Bi(ace)], 1
BiPh3 (0.22 g, 0.5 mmol) and acetosulfame (0.08 g, 0.5 mmol)
were ground together using a mortar and pestle. This mixture was
heated to 80 ꢀC in a Kugelrohr oven for 30 min. Elimination of
benzene was indicated by condensation on top of the tube. The
white product obtained was washed with toluene to remove any
unreacted BiPh3. Yield 0.22 g, 83.8%. M.P. (dec) > 160 ꢀC. FT-IR
(cmꢁ1) 1652 m, 1342 m, 1274 m, 1173 m, 939w, 868 w, 755 w.
Elemental analysis; (C16H14BiNO4S), Calc (Found): C 36.57 (35.82),
4.3.6. [Bi(CycH)3], 6
BiPh3 (0.22 g, 0.5 mmol) and cyclamic acid (0.27 g, 1.5 mmol)
were ground together using a mortar and pestle. This mixture was
heated at 80 ꢀC in a Kugelrohr oven for 2.5 h. Elimination of
benzene was indicated by condensation on top of the tube. The
white product obtained was washedꢁwith toluene. Yield 0.51 g,
68.6%. M.P. (dec) > 245 ꢀC. FT-IR (cm ) 3248 m, 1305 m, 1263 m,
1028 m, 923 m. Elemental analysis; (C18H36BiN3O9S3), Calc (Found):
C 29.07 (28.82), H 4.85 (5.64), N 5.65 (5.22) %. 1H NMR (400 MHz,
H 2.67 (2.20), N 2.67 (3.07) %. 1H NMR (400 MHz, D6-DMSO)
(d, 4H, o-Ph), 7.72 (t, 4H, m-Ph), 7.35 (t, 2H, p-Ph), 5.45 (s, 1H, CHb),
d
8.26
D6-DMSO) d
3.01 (br, 1H, CHa), 2.12 (br, 2H, CH2b), 1.74 (br, 2H, CHf2),
1.92 (s, 3H, CHd3). 13C NMR (100 MHz, D6-DMSO)
d
169.3 (Ca), 161.5
1.43e1.12 (m, 6H, CHc2,d,e). 13C NMR (100 MHz, D6-DMSO)
d 54.4
(Cc), 136.7 (C-Ph),131.6 (o-Ph),130.3 (m-Ph),128.3 (p-Ph),101.3 (Cb),
19.4 (Cd). Mass spectrum; ESþ 363 (100%, [Ph2Bi]þ), 441.2 (10%,
[Ph2Bi(DMSO)]þ), 548.2 (5%, [Ph2Bi(ace)Na]þ), 209 (100%, Biþ).
(CHa), 30.7 (CH2b,f), 24.9 (CH2c,e), 24.2 (CHd2). Mass spectrum;
ESþ 365.3 (15%, [Bi(LeH)2]þ), 386 (100%, [Bi(L)]þ), 744.3 (10%, [Bi(L-
H)3H]þ), 766.4 (30% [Bi(L-H)3Na]þ).
4.3.2. [Bi(ace)3], 2
4.3.7. [Ph2Bi(CycH)], 7
BiPh3 (0.22 g, 0.5 mmol) and acetosulfame (0.26 g, 1.5 mmol)
were ground together using a mortar and pestle. This mixture was
heated to 90 ꢀC in a Kugelrohr oven for 1 h. Elimination of benzene
was indicated by condensation on top of the tube. The white
product obtained was washed with toluene and ether to remove
any unreacted BiPh3 and acetosulfame. Yield 0.30 g, 86%. M.P.
(dec) > 98 ꢀC. FT-IR (cmꢁ1) 1650 m, 1342 m, 1274 m, 1173 m, 940w,
866 w. Elemental analysis; (C12H12BiN3O12S3), Calc (Found): C 20.72
(20.11), H 1.72 (2.00), N 6.04 (5.62) %. 1H NMR (400 MHz, D6-DMSO)
BiPh3 (0.220 g, 0.5 mmol) and cyclamic acid (0.089 g, 0.5 mmol)
were ground together using a motar and pestle. This mixture was
heated to 80 ꢀC in a Kugelrohr oven for 20 min. Elimination of
benzene was indicated by condensation on top of the tube. The
white product obtained was washed with toluene. Yield 0.21 g, 77%.
M.P. (dec) > 175 ꢀC. FT-IR (cmꢁ1) 3240 m, 1306 m, 1265 m, 1028 m,
726 s, 691 m. Elemental analysis; Calc (Found): C 39.93 (40.04), H
4.06 (4.23), N 2.58 (2.62) %. 1H NMR (400 MHz, D6-DMSO)
d 8.29 (d,
4H, o-Ph), 7.71 (t, 4H, m-Ph), 7.38 (t, 2H, p-Ph), 2.86 (t, 1H, CHa), 1.85
d
5.37 (s, 1H, CHb), 1.94 (s, 3H, CH3d). 13C NMR (100 MHz, D6-DMSO)
168.5 (Ca), 160.7 (Cc), 101.7 (Cb), 19.5 (Cd). Mass spectrum; ESꢁ:
(d, 2H, CH2b), 1.57 (d, 2H, CH2f ), 1.45e1.04 (m, 6H, CHc2,d,e). 13C NMR
d
(400 MHz, D6-DMSO) d 136.68 (C-Ph), 131.56 (o-Ph), 130.25 (m-Ph),
729.4 (80%, [BiL3Cl]ꢁ), 807.5 (100%, [BiL3Cl(DMSO)]ꢁ), 856.4 (100%,
[BiL4]ꢁ).
127.44 (p-Ph), 52.65 (CHa), 30.62 (CH2b,f), 25.26 (CH2c,e), 24.52 (CHd2).
Mass spectrum; ESþ 209 (65%, Biþ), 363.2 (85%, [Ph2Bi]þ), 386
(100%, [Bi(L)]þ), 564.2 (10%, [Ph2Bi(LeH)Na]þ, ESꢁ 719.0 (100%
[Ph2Bi(LeH)2]ꢁ).
4.3.3. [PhBi(Ace)2], 3
BiPh3 (0.22 g, 0.5 mmol) and acetosulfame (0.16 g, 1.0 mmol)
were stirred in diethyl ether at room temperature for a period of
4 h. Removal of the solvent resulted in a hydrolytically sensitive
4.3.8. [PhBi(CyceH)2], 8
BiPh3 (0.22 g, 0.5 mmol) and cyclamic acid (0.18 g, 1.0 mmol)
were ground together using a mortar and pestle. This mixture was
heated to 80 ꢀC in a Kugelrohr oven for 20 min. Elimination of
benzene was indicated by condensation on top of the tube. The
white product obtained was washed with toluene. This solid
proved to be a mixture of 6, 7 and 8 (44, 30 and 26% respectively).
NMR chemical shifts relating to 8 were extracted from the NMR
white solid. Yield 0.28 g, 91.8%. 1H NMR (400 MHz, D6-DMSO)
d 8.74
(d, 2H, o-Ph), 8.04 (t, 2H, m-Ph), 7.42 (t, 1H, p-Ph), 5.41 (s, 2H, Cb),
1.96(s, 6H, CHd3).
4.3.4. [Bi(OH)(Ace)2], 4
BiPh3 (0.22 g, 0.5 mmol) and acetosulfame (0.16 g, 1.0 mmol)
were stirred in diethyl ether at room temperature for a period of
4 h. Removal of the solvent resulted in a white solid 3 which on
exposure to moist air for a minimum of 30 min produced 4. Yield
0.22 g, 80.0%. M.P. (dec) > 210 ꢀC. FT-IR (cmꢁ1) 3389 br, 1651 m,
1321 m, 1276 m, 1175 m, 938 m, 866 w. Elemental analysis;
(C8H9BiN2O9S2), Calc (Found): C 17.45 (17.47), H 1.64 (1.80), N 5.09
spectrum of the white solid. 1H NMR (400 MHz, D6-DMSO)
d 8.86
(d, 2H, o-Ph), 7.95 (t, 2H, m-Ph), 7.36 (t, 1H, p-Ph), 2.97 (t, 2H, CHa),
1.88 (d, 4H, CH2b), 1.62 (d, 4H, CH2f ), 1.45e1.04 (m, 12H, CHc2,d,e).
4.3.9. [Bi2(Cyc)3], 9
A solution of cyclamic acid (0.13 g, 0.75 mmol) in THF (10 mL)
was cooled to ꢁ80 ꢀC and Bi(tOBu)3 (0.214 g, 0.5 mmol) in THF
(10 mL) was added drop wise under inert conditions. This reaction
mixture was stirred overnight. Evaporation of THF and washing
with dry Et2O to remove unreacted Bi(tOBu)3 left 9 as an off-white
solid. Yield 0.16 g, 67.4%. M.P. (dec) > 130 ꢀC. FT-IR (cmꢁ1) 1307 m,
(4.98) %. 1H NMR (400 MHz, D6-DMSO)
d
5.36 (s, 1H, CHb), 1.94 (s,
168.7 (Ca), 160.9 (Cc),
3H, CHd3). 13C NMR (100 MHz, D6-DMSO)
d
101.7 (Cb), 19.5 (Cd). Mass spectrum; ESþ: 209 (20%, Biþ), ESꢁ: 856.9
(5%, [BiL4]ꢁ).
4.3.5. [Bi50O64(Ace)22(H2O)10], 5
1264 m, 1037 m, 832 w, 707 m. Elemental analysis; (C18H36Bi2
-
To a suspension of Bi2O3 (0.23 g, 0.5 mmol) in water (20.0 ml) was
added an aqueous solution of acetosulfame (0.25 g, 1.5 mmol). This
N3O9S3), Calc (Found):C 22.68 (22.87), H 3.46 (3.86), N 4.41 (4.10) %.
1H NMR (400 MHz, D6-DMSO) 3.00 (br,1H, CHa), 2.12 (br, 2H, CHb2),
d

94
P.C. Andrews et al. / Journal of Organometallic Chemistry 724 (2013) 88e94
1.74 (br, 2H, CH2f ), 1.43e1.12 (m, 6H, CH2c,d,e). 13C NMR (400 MHz, D6-
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(2006) 4852.
DMSO)
d
54.4 (CHa), 30.7 (CH2b,f), 24.9 (CH2d,f), 24.2 (CH2e). Mass
spectrum; ESþ 386 (100%, [Bi(L)]þ).
[14] P.C. Andrews, R.L. Ferrero, C.M. Forsyth, P.C. Junk, J.G. MacLellan, R.M. Peiris,
Organometallics 30 (2011) 6283.
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To a suspension of Bi2O3 (0.23 g, 0.5 mmol) inwater (20.0 ml) was
added an aqueous solution of cyclamic acid (0.27 g, 1.5 mmol). This
reaction mixture was sonicated until the yellow colour of Bi2O3
disappeared and a white precipitate formed (about 5 days). The
resultant white precipitate was collected by filtration and dried.
Yield 0.29 g, 63%. M.P. (dec) > 265 ꢀC. FT-IR (cmꢁ1) 3305 m, 1297 m,
1265 m,1036 m, 936 w. Elemental analysis; (C144H40Bi38N24O131S24),
Calc (Found): C 13.10 (12.95), H 2.39 (2.29), N 2.54 (2.39) %.
[22] M. Cavicchioli, C.Q.F. Leite, D.N. Sato, A.C. Massabni, Arch. Pharm. Chem. Life
Sci. 340 (2007) 538.
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Notes/Techniques/LC/5990-6082EN.pdf.
Acknowledgements
[24] P.C. Andrews, R.L. Ferrero, Aust. J. Chem. 65 (2012) 883.
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(2008) 6590.
We thank the Australian Research Council, Bayer Schering
Pharma, and Monash University for financial support.
Appendix A. Supplementary data
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Supplementary data related to this article can be found online at
http://dx.doi.org/10.1016/j.jorganchem.2012.10.024.
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