Bismuth(III) saccharinate and thiosaccharinate complexes and the effect of ligand substitution on their activity against helicobacter pylori

Article abstract of DOI:10.1021/om2008869

Five bismuth(III) saccharinate and thiosaccharinate complexes, [Ph ₂Bi(sac)]_∞1, [Bi(sac)₃]_n2, [Ph₂Bi(tsac)]_∞4, [PhBi(tsac)₂] _n5, [Bi(tsac)₃]_n6 (sacH = saccharin, tsacH = thiosaccharin), have been synthesized and fully characterized. The tendency for ligand redistribution in [Ph₂Bi(sac)]_∞ has been investigated in solution by NMR spectroscopy. The structures of [Ph ₂Bi(sac)]_∞1 and [Ph₂Bi(tsac)] _∞4 have been confirmed by X-ray crystallography. In Ph ₂Bi(sac) the sac ligand is bound to a four-coordinate bismuth center via its imino nitrogen atom with an accompanying long-range Bi-O interaction. However, in the structure of [Ph₂Bi(tsac)]_∞ the ligand is σ-bound through the exocyclic sulfur atom, giving a thiolate complex, confirming the more thiophilic nature of bismuth(III). Both complexes consist of polymeric chain structures with formally four-coordinated bismuth atoms. The complexes were assessed for their activity against H. pylori. The activity is both ligand dependent and sensitive to the degree of ligand substitution. The saccharinate complexes, 1 and 2, show activity comparable with standard tris-carboxylato bismuth(III) compounds, 6.25 μg/mL, while the activity of the thiolato complexes, 4-6, increases dramatically on increasing the number of thiolate groups from one to three (range 50-6.25 μg/mL). Saccharin, thiosaccharin, and BiPh₃ were found to be inactive.

Full text of DOI:10.1021/om2008869

Article
pubs.acs.org/Organometallics
Bismuth(III) Saccharinate and Thiosaccharinate Complexes and the
Effect of Ligand Substitution on Their Activity against Helicobacter
pylori
,
†
‡
†
†
§
Philip C. Andrews,* Richard L. Ferrero, Craig M. Forsyth, Peter C. Junk, Jonathan G. Maclellan,
and Roshani M Peiris†
†
School of Chemistry, Monash University, P.O. Box 23, Melbourne, Victoria 3800, Australia
‡
Centre for Innate Immunity and Infectious Diseases, Monash Institute of Medical Research, Clayton, Melbourne, Victoria 3168,
Australia
§
Emerald Secondary College, 425 Belgrave-Gembrook Road, Emerald, Victoria 3782, Australia
ABSTRACT: Five bismuth(III) saccharinate and thiosaccharinate complexes, [Ph Bi(sac)] 1, [Bi(sac) ] 2, [Ph Bi(tsac)] 4,
2
∞
3 n
2
∞
[
PhBi(tsac) ] 5, [Bi(tsac) ] 6 (sacH = saccharin, tsacH = thiosaccharin), have been synthesized and fully characterized. The
2 n 3 n
tendency for ligand redistribution in [Ph Bi(sac)]∞ has been investigated in solution by NMR spectroscopy. The structures of
2
[
Ph Bi(sac)] 1 and [Ph Bi(tsac)] 4 have been confirmed by X-ray crystallography. In Ph Bi(sac) the sac ligand is bound to a
2 ∞ 2 ∞ 2
four-coordinate bismuth center via its imino nitrogen atom with an accompanying long-range Bi−O interaction. However, in the
structure of [Ph Bi(tsac)] the ligand is σ-bound through the exocyclic sulfur atom, giving a thiolate complex, confirming the
2
∞
more thiophilic nature of bismuth(III). Both complexes consist of polymeric chain structures with formally four-coordinated
bismuth atoms. The complexes were assessed for their activity against H. pylori. The activity is both ligand dependent and
sensitive to the degree of ligand substitution. The saccharinate complexes, 1 and 2, show activity comparable with standard tris-
carboxylato bismuth(III) compounds, 6.25 μg/mL, while the activity of the thiolato complexes, 4−6, increases dramatically on
increasing the number of thiolate groups from one to three (range 50−6.25 μg/mL). Saccharin, thiosaccharin, and BiPh were
3
found to be inactive.
INTRODUCTION
In addition, evidence is accumulating that metal−organic and
organometallic bismuth compounds generally show good in
vivo and in vitro antimicrobial and antitumor activity.
To be able to fully exploit the potential bismuth compounds
have in protective and therapeutic applications, we need to
understand more about the coordination chemistry of the
compounds, their structure, solubility, and stability, and their
activity and behavior in a biological environment. Currently,
our knowledge, when compared to related metals and their
complexes, is poorly developed.
■
That bismuth is considered to be relatively benign and of low
systemic toxicity in humans means that the metal and its
compounds are currently attracting considerable attention in
materials, environmental, and sustainable chemistry, and
though not as dramatic, there has also been some resurgence
1,11−16
1
−3
of interest in its biological and medicinal chemistry.
The
predominant use of bismuth compounds (bismuth subsalicy-
late, colloidal bismuth citrate) is in treating and eradicating
Helicobacter pylori, the bacterium responsible for gastritis, peptic
4
−8
Over the past few years we have been successful in
developing and describing reproducible and high-yielding
solvent-free and solvent-mediated methods to obtain a range
and duodenal ulcers, and gastric cancers.
The role of
bismuth in this arena is becoming more important as resistance
rates toward triple therapies, combining a proton pump
inhibitor (e.g., omeprazole) with a combination of regular
1
7
of homoleptic and heteroleptic bismuth(III) thiolates,
18−21
19,22
23
9
,10
carboxylates,
sulfonates,
and alkoxides. The pure
antibiotics, including clarithromycin, increases.
There has
been no evidence of resistance toward the bismuth compounds,
and they have the advantage of not requiring a neutral stomach
pH to be effective.
Received: September 21, 2011
Published: November 4, 2011
©
2011 American Chemical Society
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Article
tris-substituted bismuth carboxylates (including NSAID de-
rivatives) and sulfonate complexes generally display a greater
activity against Helicobacter pylori (minimum inhibitory
concentration (MIC) 6.25 μg/mL) than commercial com-
poundsBSS (12.5 μg/mL), RBC (8 μg/mL), CBS (12.5 μg/
mL)even in the case where only one sulfonate ligand is
RESULTS AND DISCUSSION
■
Saccharin. Saccharinate complexes of bismuth(III) were
synthesized by solvent-mediated and solvent-free reactions. The
solvent-mediated reactions were conducted in ethanol at reflux
temperature for a period of 8−12 h. The solvent-free reactions
involved heating a mixture of the reactants, which had been
ground together, to a temperature of 200 °C for 2 h.
22
present, e.g., [Ph Bi(O S-Tolyl)] .
2
3
∞
While sulfonic acids provide ligands that show little or no
toxic effects, it is still desirable to search for ligands that are
known to be regarded as safe for use in humans. Combining
this with a desire to explore a new class of bismuth
coordination compounds, we turned our attention to saccharin
and thiosaccharin. Saccharin (o-sulfobenzimide), Figure 1, is
The solvent-mediated reaction of saccharin (sacH) with
triphenylbismuth always produced the mono-substituted
complex, [Ph Bi(sac)] 1, irrespective of the ratio of the
2
∞
reactants used or the reaction temperature (Scheme 1). In
Scheme 1. Treatment of Saccharin (n = 1−3) with BiPh in
3
a
Ethanol under Reflux
a
t = 8−12 h.
contrast, complex 1 could also be produced through the
solvent-free reaction of sacH with BiPh in a 1:1 ratio, while the
3
tris-substituted saccharinate product, [Bi(sac)3]n 2, was
obtained when the reaction was conducted solvent-free using
a 3:1 ratio (Scheme 2).
Figure 1. Structures of saccharin and thiosaccharin.
24
one of the most widely used artificial sweetening agents.
Though known for over 100 years, it fell out of favor as studies
in rats seemed to suggest a link to some stomach cancers. This
was later shown to be species-specific, and saccharin regained
Scheme 2. Reaction of Saccharin with BiPh in a 3:1 Ratio
under Solvent-Free Conditions
3
a
2
5−27
the status of being nonharmful for humans.
More
generally it has been suggested as having potential in chelation
a
2
8
29
T = 200 °C, t = 2 h.
therapy, as an antidote for metal poisoning, and because of
its weak acidity may be useful as a salt former in enhancing the
30
Neither the solvent-mediated nor the solvent-free reactions
produced the expected bis-substituted saccharinate product,
solubility of certain drugs.
Many transition metal complexes of saccharin and
thiosaccharin have been reported, though complexes with p-
[
PhBi(sac) ] 3, from a 2:1 (sacH:BiPh ) reaction stoichiom-
2 n 3
31
etry. Therefore, the reaction was attempted using a simple
metathesis route involving the treatment of PhBiCl with two
equivalents of sodium saccharinate (sacNa). However, the
reaction in toluene did not produce 3 as expected; instead a
mixture of [Bi(sac) ] and BiPh was obtained in 2:1 ratio.
Since sacNa is soluble only in water and PhBiCl decomposes
in water, the metathesis reaction has to be conducted under
heterogeneous conditions. Using toluene as the solvent, in
which PhBiCl is insoluble, means any metathesis reaction is
slow, and hence the ultimate formation of [Bi(sac) ] and
BiPh3 can be rationalized as resulting either from the
rearrangement of PhBiCl into BiCl and BiPh and then
subsequent reaction with sacNa or from ligand rearrangement
of PhBi(sac) . Most likely both these processes occur
concurrently.
To examine further the lability of the sac ligands in the
heteroleptic complexes, a sample of 1 was dissolved in d6-
DMSO, and NMR spectra were recorded at different time
intervals: immediately and after several hours, days, or months.
The rearrangement is illustrated in Scheme 3. The spectra,
shown in Figure 2 (t = 0 and 24 h), show clearly the formation
block metals remain limited to Pb, Sn, and Tl. Interestingly,
the Zn, Cu, Ce, and Pb complexes of saccharin have all shown
2
32,33
an inhibitory effect, in vitro, over carbonic anhydrase.
The
biological chemistry of thiosaccharin and its derivatives is less
developed, though in one study it is claimed that they exhibit
3
n
3
34
2
powerful antifungal activity. While the coordination chemistry
of saccharin and thiosaccharin has been the subject of ongoing
study, the bioinorganic chemistry remains poorly developed
and is an area that deserves greater attention in terms of
antimicrobial and therapeutic potential.
2
3
n
The saccharinate and thiosaccarinate anions have heter-
oatoms that are able to form ionic, covalent, or dative bonds
with metals and can thus act as polyfunctional complexing
agents. The M−N interaction is most common in transition
metal complexes, while M−O or M−S bonds dominate for
alkali, alkaline-earth, and inner-transition metals. For p-block
metal complexes these ligands show monodentate (through S
or O atoms), bidentate (S/O and N), or bridging (through N
2
3
3
2
31
and O/S) bonding modes.
In this paper we describe the synthesis of five new
bismuth(III) compounds containing saccharinate and thio-
saccharinate ligands, [Ph Bi(sac)] 1, [Bi(sac) ] 2, [Ph Bi-
of 3 (o-Ph resonance at δ 8.75) and BiPh (p-Ph resonance at δ
3
2
∞
3 n
2
7.30) from 1. The amount of 3 formed increased on standing
and reached equilibrium after approximately 13 days. Using
integration of the various o-Ph and p-Ph resonances, the
equilibrium constant for the formation of 3 and BiPh from 1 is
calculated to be 0.25, reflecting the expected stoichiometric
ratios (Scheme 3).
(
tsac)]∞ 4, [PhBi(tsac)2]n 5, and [Bi(tsac)3]n 6, formed
through solvent-mediated and solvent-free methods. We also
describe their composition in the solid and solution states, a
tendency for ligand rearrangement in solution, and a ligand-
based sensitivity in their activity toward the bacterium H. pylori.
3
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Article
1
Scheme 3. Ligand Redistribution of 1 in d -DMSO to 3 and
BiPh3
Table 1. H NMR Shifts, in ppm, of Ph Protons in 1, 3, and
BiPh3
6
compound
BiPh3
o-H
m-H
p-H
7.75
8.29
8.75
7.42
7.74
8.05
7.30
7.40
7.40
[
[
Ph Bi(sac)]∞ 1
2
PhBi(sac) ] 3
2
n
Scheme 4. Treatment of Thiosaccharin (n = 1, 2) with BiPh3
in Ethanol under Reflux (t = 8−12 h), Giving Compounds 4
and 5
Attempts were made using a variety of solvents and solvent
mixtures (including ethanol, acetone, DMSO, and DMF) to
obtain crystals of 3 through cocrystallization with 1 and/or
BiPh . Unfortunately, this proved unsuccessful in all solvents
3
tried due to the preferential precipitation of 1 and, we believe, a
consequent shift in the equilibrium away from 3.
Thiosaccharin. The 1:1 and 2:1 reactions of thiosaccharin
Scheme 5. Reaction of Thiosaccharin with Bismuth tert-
Butoxide in a 3:1 Ratio in THF, N2
with BiPh under reflux in ethanol produced the expected
a
3
products, [Ph Bi(tsac)] 4 and [PhBi(tsac) ] 5, respectively,
2
∞
2 n
as depicted in Scheme 4.
In contrast, the 3:1 reaction did not give the expected
a
T = −80 °C to RT, t = 12 h.
product, [Bi(tsac) ] 6, but instead produced a mixture of 4 and
3
n
5
. As such, an alternative synthetic approach using the stronger
t
sac complexes, highlighting the greater kinetic stability of the
Bi−S bond.
base Bi( OBu) was employed (Scheme 5). A THF solution of
thiosaccharin was added to a THF solution of Bi( OBu) , under
3
t
3
Infrared Spectroscopy. The absorption bands corre-
dry nitrogen and already cooled to −80 °C. The reaction
mixture was allowed to warm slowly to room temperature,
giving the tris-substituted thiosaccharinate product 6 as a pale
orange solid in high yield.
sponding to N−H bond stretching and bending in saccharin
−1
(
2681 and 1591 cm ) and in thiosaccharin (3341 and 1318
−1
cm ) are absent in the IR spectra of the corresponding
bismuth complexes, indicating deprotonation of the acid from
N−H. A summary of the main absorption bands for each
complex and their assignments is given in Table 2.
1H and 13C NMR spectra were obtained on 4−6 in d6-
DMSO. The spectra showed all the expected chemical shifts
relating to the Ph and tsac ligands with no evidence of the facile
ligand rearrangement processes observed with the analogous
Both bismuth saccharinate complexes show a shift in the
carbonyl stretching vibration from 1717 cm− in the free acid to
1
1
Figure 2. H NMR spectra showing gradual rearrangement of Ph Bi(sac) 1 into PhBi(sac) 3 in d -DMSO: (a) 0 h, (b) 24 h. Chemical shift
2
2
6
assignments are given in Table 1.
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Organometallics
Table 2. Summary of IR Bands (cm ) and Assignments
Article
−1
saccharin
1
2
thiosaccharin
3341 s
4
5
6
ν(NH)
2681 s
1716 s
1335 m
1591 s
1296 m
1177 m
ν(CO)
1689 m
1270 m
1606 s
ν (SO )
1257 m
1376 m
1318 s
1247 m
1156 m
1039 m
817 w
1324 m
1324 m
1325 m
as
2
δ(NH)
ν(CN)
1337 m
1143 m
1337 m
1146 m
1420 m
1156 m
1005 m
805 w
1420 m
1156 m
1003 m
805 w
1419 m
1156 m
1001 m
805 w
ν (SO )
s
2
ν(CS)
ν(NS)
900 w
783 w
772 w
689 cm− in [Ph Bi(sac)] and 1606 cm in [Bi(sac) ] . The
1
−1
1
2 ∞ 3 n
relatively small bathochromic shift for [Ph Bi(sac)]∞ suggests
2
that delocalization and subsequent interaction with the Bi(III)
center is not substantial, subsequently supported by X-ray
crystallography (see below). A stronger chelate is certainly
suggested for the tris-substituted complex, [Bi(sac) ] , although
3
n
−1
the higher frequency shift (Δ 41 cm ) for the C−N bond is
identical for both complexes.
35
When compared with free thiosaccharin, the stretching
mode assigned to CS shifts to lower frequency in the three
−1
bismuth complexes by an average of 36 cm , the shift gradually
increasing as substitution by thiosaccharinate ligands increases.
Conversely, the C−N stretching mode shifts to higher
−1
wavenumbers by ca. 27 cm , indicating an increase in the
bond order. Taken together, these observations support the
thiolate nature of the ligand in its bonding with Bi(III).
The stretching vibrations of the SO groups are expected to
2
appear at lower wavenumbers in both bismuth saccharinate and
thiosaccharinate complexes due to increased S−O bond lengths
as a result of the interaction of this group with the bismuth(III)
center. This expectation can be seen clearly in the asymmetric
Figure 3. Molecular structure of [Ph Bi(sac)]∞ 1 with non-hydrogen
2
atoms represented by 50% thermal ellipsoids and hydrogen atoms as
spheres of arbitrary size. Only the crystallographically unique
component is shown.
SO stretching modes. Bismuth complexes of saccharin showed
2
−1
−1
−1
a shift from 1335 cm to 1270 cm (in 1) and 1257 cm (in
), whereas bismuth complexes of thiosaccharin showed a shift
of 1376 cm to 1324/1325 cm , indicating a stronger
3
than those typically observed in homoleptic bismuth(III)
−
1
−1
37
amides, e.g., 2.20(2) Å (av) in [Bi(NPh ) ], and compensates
2
3
(
S)O−Bi interaction in bismuth saccharinate complexes than
for the relatively weak CO···Bi interaction, which while long
in bismuth thiosaccharinate complexes.
is still comparable with similar neutral chelating bonds observed
1
8,19,38
Crystallography. Crystallization of [Ph Bi(sac)] 1 from
in bismuth(III) carboxylates.
2
∞
The Pb(II) complex [Pb(sac) ]·H O has Pb2+ in an eight-
coordinate environment, contrasting with the low coordination
number for Bi in 1, and shows definite N and O(C)
coordination to the metal, demonstrated by the more central
location of the Pb ion between the chelating atoms: in 1, the
C(13)−N(1)−Bi(1) angle of 114.6(3)° (cf. C−N−Pb 87.64°
in [Pb(sac) ]·H O) indicates that rather than a formal chelate
39
ethanol produces well-formed, colorless crystals. Unfortunately
obtaining good-quality diffraction data proved challenging.
Several data sets were collected on crystals from a number of
different batches using a standard CCD diffractometer, but all
showed evidence of twinning. The final data presented here
were collected on a single, but very small, crystal using the high-
intensity radiation available at the Australian Synchrotron.
The complex represents the first crystallographically
characterized bismuth(III) acid-amide derivative, and the
structure is shown in Figures 3 and 4 with selected bond
distances and angles in Table 3. The complex crystallizes in an
2
2
3
+
2
2
the proximity of the O(C) within a recognized Bi−O
bonding distance may be simply a result of ligand geometry.
The sulfonyl (S)O−Bi bond distance is 2.605(4) Å and is
−
located trans to that formed with the imino N atom, providing
orthorhombic crystal system with space group Pna2 . The
an almost linear N(1)−Bi(1)−O(1) bond angle of 170.2(2)°.
The short distance no doubt reflects the low coordination
environment of the bismuth(III) center. Only three other
1
saccharinate ligand is attached to the bismuth(III) center
−
primarily through its imino N atom. In gross structural terms
the complex forms a polymer through alternate bonding of the
structures allow for a comparison of this interaction; the most
−
t
central bismuth atom to the imino N and to a single O of the
similar is in the organometallic complex [(PhSO Bu)Bi(Tol)-
2
2
40
SO moiety of a second ligand, providing for an overall (κ -
Cl], which shows a (S)O−Bi distance of 2.592(5) Å and in
2
N,O) zigzag conformation. A similar bonding pattern is seen in
which Bi(III) is also four-coordinate, while longer bonds are
40
36
t
the heteroleptic Sn complex [Ph Sn(sac)] .
found in the analogous complex [(PhSO Bu) Bi(Tol)],
2 2
3
∞
The overall coordination number around the bismuth center
is formally four, but is raised to five when long-range
intramolecular Bi−O(C) interactions of 3.22 Å are included.
The Bi−N bond distance of 2.353(4) Å is only slightly longer
2.914(6) Å, and in (3-sulfanilamido-6-methoxypyridazine)-
41
bismuth(III) trichloride, 3.09(2) Å.
Crystallization of [Ph Bi(tsac)] 4 from ethanol gave orange
2
∞
cubic crystals, which proved suitable for single-crystal X-ray
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Figure 4. Polymeric structure of [Ph Bi(sac)] 1.
2
∞
−
Table 3. Selected Bond Distances (Å) and Angles (deg) for
Compounds 1 and 4
alternating bonds with the thiolate S and one of the sulfonyl O
atoms. The S(1)−Bi(1)−O(1) angle is almost linear at
171.35(5)°.
[
Ph Bi(sac)]∞
2
1
[Ph Bi(tsac)]∞
4
2
In contrast to 1, where bismuth bonds to the saccharinate
ligand through the imino N , the replacement of the carbonyl
O with S leads to 2 being classed as a bismuth thiolate, with
formal attachment to the ligand being through the Bi−S σ-
bond. This is not surprising given the thiophilic nature of
bismuth and earlier evidence from structural reports on a series
Bi(1)−C(1)
Bi(1)−C(7)
Bi(1)−N(1)/S(1)
Bi(1)−O(1)
C(1)−Bi(1)−C(7)
C(1)−Bi(1)−N(1)/S(1)
C(1)−Bi(1)−O(1)
C(7)−Bi(1)−N(1)/S(1)
C(7)−Bi(1)−O(1)
N(1)/S(1)−Bi(1)−O(1)
2.256(4)
2.245(9)
2.353(4)
2.605(4)
96.6(3)
90.8(2)
83.3(2)
89.2(2)
83.8(2)
170.2(2)
2.233(3)
2.243(3)
2.6399(7)
2.890(2)
94.1(1)
−
exo
90.09(7)
82.01(8)
90.34(7)
93.72(8)
171.35(5)
39,42
complexes with Pb(II).
The Bi(1)−S(1) bond distance of
.6399(7) Å is typical for bismuth thiolates,
43−46
2
while the
sulfonyl O(1)−Bi(1) distance of 2.890(2) Å is significantly
longer than in 1 and is comparable with that observed in
t
40
[
(PhSO Bu) Bi(Tol)], 2.914(6) Å. The imine double bond
2 2
in 2, N(1)−C(13), is 1.303(3) Å, while C(13)−S(2) is
diffraction studies. The complex crystallizes in the monoclinic
1
.719(3) Å and displays single-bond character. These can be
crystal system and in space group P2 /n. The asymmetric unit
42
1
compared with the analogous bonds in [Pb (tsac) (py) ],
2
4
4
is shown in Figure 5, and the polymeric chain in Figure 6, with
which show similar bond distances of 1.321(17) and 1.699(14)
Å, respectively, and can be contrasted with those in the crystal
thione form of thiosaccharin, which are 1.384(4) and 1.622(6)
47
Å, respectively.
More contentious is the long-range interaction of 3.143(2) Å
from Bi(1) to N(1). Comparison with compounds with similar
bonds indicates this to be, if real, one of the longest. Normally
CN···Bi bond lengths are found in the range 2.5−2.7 Å; for
i
example in [Bi(SC(Me)N Pr) ] the longest interaction is
2
3
48
.738(5) Å. However, the geometry would seem to suggest
a genuine if weak interaction: the C(13)−S(1)−Bi(1) angle is
96.50(9)°.
Biological Testing. The in vitro antibacterial activity of
compounds 1, 2, 4−6, saccharin (sacH), thiosaccharin (tsacH),
and BiPh was assessed against three standard laboratory strains
3
of H. pylori: B128, 251, and 26695. The MIC of each
compound was established using the agar dilution method
(
described in the Experimental Section). The homo- and
Figure 5. Molecular structure of [Ph Bi(tsac)] 4 with non-hydrogen
2
∞
heteroleptic composition of the compounds allows an
evaluation to be made on the effect of the degree and variance
of substitution at the Bi(III) center and also the structural
impact on changing from saccharin to thiosaccharin. The
results are summarized in Table 4.
atoms represented by 50% thermal ellipsoids and hydrogen atoms as
spheres of arbitrary size. Only the crystallographically unique
component is shown.
selected bond distances and angles listed in Table 2. The
complex comprises a zigzag polymeric chain with the Bi(III)
Our previous studies on heteroleptic organometallic bismuth
2
centers bridging thiosaccharinate ligands, (κ -S,O), forming
sulfonates of composition [Ph Bi(O SR)] showed that
2 3 ∞
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Figure 6. Polymeric structure of [Ph Bi(tsac)] 4 with hydrogen atoms omitted for clarity.
2
∞
Table 4. Minimum Inhibitory Concentrations (MIC) for
the presence of thermodynamically stable Bi−S bonds. Our
evidence from the MIC values obtained for 1 and 2, and for the
Complexes, 1, 2, 4−6, BiPh , sacH, and tsacH in Their
3
Activity against H. pylori
series of organobismuth sulfonates [Ph Bi(O SR)] studied
2 3 ∞
22
previously, indicates that more labile carboxylates and
sulfonates are less sensitive to the degree of substitution and
presence of more kinetically stable ligands.
MIC, mg/mL
compound
(26695)
(B128)
(251)
[
Ph Bi(sac)]∞
1
6.25
6.25
6.25
2
[
Bi(sac) ] 2
6.25
6.25
6.25
3
n
CONCLUSIONS
■
[Ph Bi(tsac)]∞
4
50.0
50.0
50.0
2
Five new homo- and heteroleptic bismuth(III) compounds
derived from saccharin and thiosaccharin have been synthesized
through solvent-free and solvent-mediated methods. The
compounds have been fully characterized, two by single-crystal
[PhBi(tsac) ] 5
12.5
12.5
12.5
2
n
[Bi(tsac) ] 6
6.25
6.25
6.25
3
n
sacH
tsacH
BiPh3
inactive
inactive
>64
inactive
inactive
>64
inactive
inactive
>64
X-ray diffraction. The mono-substituted complexes [Ph Bi-
2
(
sac)]∞ 1 and [Ph Bi(tsac)] 4 were generated through
2 ∞
treatment of saccharin or thiosaccharin with BiPh in a 1:1 ratio
in ethanol at reflux. The 2:1 reaction of thiosaccharin and BiPh3
at reflux in ethanol produced the bis-substituted compound
3
replacement of one Ph group with one sulfonate moiety
increased the activity toward H. pylori significantly with the
sulfonate compounds giving MICs of 6.25 μg/mL relative to
BiPh3 (>64 μg/mL) and the sulfonic acids, which were
essentially inactive.
[
PhBi(tsac) ] 5. The fully substituted complex [Bi(sac) ] 2
2
n
3
n
was obtained from the solvent-free combination of saccharin
and BiPh in a 3:1 ratio and heating to 200 °C. The fully
3
The activity of the two saccharinate complexes also seems
insensitive to the degree of substitution, with the MIC of both
substituted thiosaccharinate complex [Bi(tsac) ] 6 could not
3
n
be synthesized from BiPh cleanly by either solvent-free or
3
[
Ph Bi(sac)]∞ 1 and [Bi(sac) ] 2 found to be 6.25 μg/mL,
2 3 n
t
solvent-mediated methods, and so Bi(O Bu) was employed as
3
which is also comparable with the majority of bismuth
the base, producing the target compound cleanly and in high
yield from the required 3:1 reaction stoichiometry. It was not
possible to synthesize the “missing” complex [PhBi(sac) ] 3
1
9
carboxylates. In contrast, the thiosaccharinate complexes
showed activity that is highly sensitive to the degree of
2
n
substitution: [Ph Bi(tsac)] gave an MIC of 50 μg/mL,
2
∞
from reactions employing the required 2:1 stoichiometry of
reactants either by a solvent-free or solvent-mediated approach.
[
PhBi(tsac)2]n 12.5 μg/mL, and [Bi(tsac)3]n 6.25 μg/mL.
Saccharin and thiosaccharin were found to be inactive within
the concentrations 100−3.125 μg/mL.
These data support two previous studies indicating good
activity of bismuth thiolates against H. pylori and also the
dependency of the scale of the activity on the nature of the
ligands, degree of substitution, and their binding mode(s) to
NMR studies though showed that Ph Bi(sac) 1 slowly
2
undergoes ligand rearrangement in solution to give PhBi(sac)2
3
and BiPh ; however it was not possible to obtain a pure
3
sample of 3. The solid-state structures of [Ph Bi(sac)]∞ 1 and
2
[
Ph Bi(tsac)] 4 were determined by X-ray crystallography.
2 ∞
Both complexes are polymers, adopting zigzag conformations
with the ligands bridging Bi(III) centers through the anionic
imino N and sufonyl O atoms for 1 (with a possible long-range
interaction with the carbonyl O) and the exocyclic thiolato S
and sulfonyl O atoms for 2. The different coordination modes
reflect the high thiophilicity of bismuth.
the Bi(III) center. An MIC value of 3.13 μg/mL was observed
5
0
for a series of three bismuth(III) thiolate complexes derived
44
from 2-mercaptoethanol, while the effect of varying the actual
thiolato ligand was exemplified by a series of metallocyclic
homo- and heteroleptic bismuth thiolates, which gave MIC
49
values in the range 0.5−5.0 μg/mL. These studies taken with
evidence from compounds 4−6 indicate that increasing the
number of Bi−S bonds improves the bactericidal activity. The
more kinetically stable Bi−C bonds inhibit activity, but only in
Both saccharin and thiosaccharin show no inhibitory activity
against H. pylori; however their bismuth(III) compounds do.
The saccharin complexes, [Ph Bi(sac)] 1 and [Bi(sac) ] 2,
2
∞
3 n
show an MIC of 6.25 μg/mL, indicating that the activity is not
6
288
dx.doi.org/10.1021/om2008869|Organometallics 2011, 30, 6283−6291

Organometallics
Article
particularly sensitive to the degree of substitution. This is in
contrast to the thiosaccharin complexes, for which the
inhibitory activity is highly ligand- and substitution-dependent.
and pestle. This mixture was heated to 200 °C in a glass tube in a
Kugelrohr oven for 2 h. Elimination of benzene was indicated by
condensation at the top of the tube. The solid obtained was washed
with toluene and ethanol to remove any unreacted BiPh3 and
The MIC values of 50 μg/mL for [Ph Bi(tsac)] 4, 12.5 μg/
2
∞
saccharin. The remaining white solid was identified to be Bi(sac) .
3
mL for [PhBi(tsac) ] 5, and 6.25 μg/mL for [Bi(tsac) ] 6
−1
2
n
3 n
Yield: 0.3 g, 81%. Mp: 220 °C. FT-IR (cm ): 1606 m, 1257 m, 1117
w, 946 w, 757 w, 678 w. H NMR (400 MHz, d -DMSO): δ 7.69 (t,
indicate the high activity of homoleptic bismuth thiolates and
also illustrates the rapid increase in activity on increasing the
number of Bi−S bonds and reducing the number of kinetically
stable Bi−C bonds.
1
6
13
1
H), 7.62 (m, 3H). C NMR (100 MHz, d -DMSO): δ 169.5 (C
6
O), 144.4 (C-SO ), 137.5 (C-CO), 136.3 (CH ), 132.5 (CH ),
2
sac
sac
−
131.3 (CH ), 130.8(CH ), 119.8 (CH ). Mass spectrum, ES :
sac
sac
sac
−
−
7
90.8 (50%, [Bi(sac) Cl] ), 182 (75%, [L] ).
3
Synthesis of [PhBi(sac) ] , 3. Compound 3 formed as a ligand
2
n
EXPERIMENTAL SECTION
■
redistribution product of Ph Bi(sac). The complex could not be
2
Triphenylbismuth was synthesized through a standard Grignard
metathesis reaction from the treatment of BiCl3 with PhMgBr in
obtained in a pure form, and therefore complete analysis was not
1
possible. However H NMR resonances were observed as a part of the
1
dried diethyl ether at 0 °C and subsequently recrystallized from
mixture. H NMR (400 MHz, d -DMSO): δ 8.75 (dd, 2H, o-Ph), 8.05
6
t
ethanol. Bismuth tert-butoxide, Bi(O Bu) , was synthesized according
(t, 2H, m-Ph), 7.68 (m, Ar-H), 7.40 (t, 1H, p-Ph).
3
50
to a literature procedure. Saccharin was purchased from Sigma-
Synthesis of [Ph Bi(tsac)] , 4. A mixture of BiPh (0.22 g, 0.50
2
∞
3
Aldrich Co. Thiosaccharin was synthesized according to a literature
mmol) and thiosaccharin (0.10 g, 0.50 mmol) was refluxed in ethanol
for 30 min. All volatiles were removed under vacuum, and the
remaining solid product was washed with toluene. The yellow solid
51
procedure. NMR spectra were recorded on a Bruker DRX 400
spectrometer. All spectra were internally referenced using the
deuterated solvent signal. Electrospray ionization spectra (ESI) were
generated on a Micromass Platform II QMS spectrometer. Infrared
spectra, as KBr disks or Nujol mulls, were recorded on a Perkin-Elmer
was recrystallized from ethanol and identified as [Ph Bi(tsac)] . Yield:
2
∞
−
1
0.14 g, 50%. Mp (dec): >200 °C. FT-IR (cm ): 1324 w, 1243 w, 1167
m, 1117 w, 1003 m, 805 m, 768 w, 724 w, 693 w, 626 w. Anal.
(C H BiNO S ) Calcd (Found): C 40.64 (39.82), H 2.49 (2.25), N
1
600 FT-IR spectrometer. Elemental microanalyses were performed
1
9
14
2 2
1
by the Campbell Microanalytical Laboratory, Department of
Chemistry, University of Otago, Dunedin, New Zealand. Melting
points were measured on a Stuart Scientific SMP3 melting point
apparatus.
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%
2.49 (2.99). H NMR (400 MHz, d -DMSO): δ 8.33 (d, 4H, o-Ph),
6
7.93 (t, 1H, ArHtsac), 7.85 (t, 1H, ArHtsac), 7.76 (m, 2H, ArHtsac), 7.61
1
3
(t, 4H, m-Ph), 7.36 (t, 2H, p-Ph). C NMR (100 MHz, d -DMSO): δ
6
218.1 (CS), 137.8 (C-SO ), 134.9 (C-CS), 132.1 (CHtsac), 132.6
2
(CH ), 131.7 (CH ), 129.7 (C-Ph), 128.5 (o-Ph), 125.3 (m-Ph),
tsac
tsac
+
123.8 (p-Ph), 119.7 (CH ). Mass spectrum, ES : 363 (100%,
[Ph Bi] ), 483.9 (25%, [PhBi(tsac)] ), 584 (5% [Ph Bi(tsac)Na] ).
tsac
+
+
+
2
2
(
v/v) fresh horse blood or 10% (v/v) FCS, respectively. Culture media
Synthesis of [PhBi(tsac) ] , 5. A mixture of BiPh (0.22 g, 0.50
2 n 3
were further supplemented with 155 mg/L polymyxin B, 6.25 mg/L
vancomycin, 3.125 mg/L trimethoprim, and 1.25 mg/L amphotericin
B.
mmol) and thiosaccharin (0.20 g, 1.0 mmol) was refluxed in ethanol
for 1 h. All volatiles were removed under vacuum, and the residual
solid was washed with toluene. The yellow solid product was identified
52
Determination of the Minimum Inhibitory Concentration.
as PhBi(tsac) . Yield: 0.25 g, 73.0%. Mp (dec): >210 °C. FT-IR
2
−
1
The MICs of bismuth complexes 1, 2, 4, 5, and 6 were determined by
the agar dilution technique. All bismuth complexes were dissolved in
DMSO to give clear, colorless solutions of known concentration. H.
pylori cultures were incubated in BHI for 18 h, shaking at 140 rpm at
(cm ): 1324 w, 1244 w, 1167 m, 1119 w, 1005 m, 805 m, 768 w, 728
w, 695 w, 626 w. Anal. (C H BiN O S ) Calcd (Found): C 35.19
2
0
13
2
4 4
1
(35.53), H 1.91 (2.10), N 4.10 (4.04). H NMR (400 MHz, d6-
DMSO): δ 8.86 (d, 2H, o-Ph), 8.01 (t, 2H, m-Ph), 7.91 (t, 2H,
3
7 °C under micro aerobic conditions. Bacteria were pelleted, washed
ArHtsac), 7.80 (t, 2H, ArHtsac), 7.70 (q, 4H, ArHtsac), 7.45 (t, 1H, p-
5
3
13
in phosphate-buffered saline, then resuspended in BHI. Each
suspension was adjusted to give an approximate density of 10
Ph). C NMR (100 MHz, d -DMSO): δ 219.1 (CS), 137.8 (C-
6
6
SO ), 134.9 (C-CS), 133.1 (CH ), 132.5 (CH ), 131.6 (CH ),
2
tsac
tsac
tsac
bacteria/mL. Aliquots (10 mL) of these suspensions were then
streaked onto HBA plates containing doubling dilutions of the
different concentrations of bismuth compounds, ranging in concen-
tration from 6.25 to 25 mg/mL. Each compound was tested alongside
129.9 (C-Ph), 128.8 (o-Ph), 125.0 (m-Ph), 123.8 (p-Ph), 119.5
+
+
(CHtsac). Mass spectrum, ES : 484.0 (20%, [PhBi(tsac)] ), 561.9 (5%,
+
[PhBi(tsac)DMSO] ).
Synthesis of [Bi(tsac) ] , 6. All the manipulations were carried
3
n
BiPh and the free acids in comparable concentrations. The MICs of
the different compounds were determined by examination of the plates
out under nitrogen atmosphere with predried solvents. Thiosaccharin
(0.23 g, 1.50 mmol) was added to a solution of bismuth tert-butoxide
(0.21 g, 0.50 mmol) in THF (20 mL) at −80 °C and stirred overnight.
Removal of volatiles under vacuum left a light orange solid, which was
washed with ethanol to remove any unreacted acid and/or bismuth
3
after incubation for 3−5 days at 37 °C.
Synthesis of [Ph Bi(sac)] , 1. A mixture of BiPh (0.22 g, 0.50
2
∞
3
mmol) and saccharin (0.092 g, 0.50 mmol) was refluxed in ethanol
overnight to produce a cloudy solution. Filtration removed a small
butoxide. This solid product was identified as Bi(tsac) . Yield: 0.30 g,
3
−
1
amount of insoluble residue (later identified as Bi(sac) ), leaving a
75.0%. Mp (dec): >160 °C. FT-IR (cm ): 1325 w, 1241 w, 1167 m,
1001 w, 794 w, 694 w, 626 w. Anal. (C H BiN O S ) Calcd
(Found): C 31.38 (32.11), H 1.49 (1.76), N 5.23 (4.92). H NMR
3
clear, colorless solution. Volatiles were removed under vacuum, and
the remaining solid was washed with toluene to remove any unreacted
2
1
12
3
6 6
1
BiPh . The solid was recrystallized from ethanol and identified as
(400 MHz, d -DMSO): δ 7.91 (t, 1H, ArHtsac), 7.74 (t, 1H, ArHtsac),
3
6
−
1
13
[
1
Ph Bi(sac)] . Yield: 0.13 g, 47%. Mp (dec): >215 °C. FT-IR (cm ):
7.66 (t, 2H, ArHtsac). C NMR (100 MHz, d -DMSO): δ 191.3 (C
2
∞
6
689 w, 1270 w, 1110 w, 972 w, 726 w, 693 w, 601 w. Anal.
S), 137.7 (C-SO ), 136.5 (C-CS), 132.2 (CH ), 131.2 (CH ), 125.3
2
tsac
tsac
+
(
2
7
C H BiNO S) Calcd (Found): C 41.84 (42.71), H 2.59 (2.73), N
(CHtsac), 119.1 (CH ). Mass spectrum, ES : 604.7 (100%, [Bi-
(tsac) ] ), 825.5 (5%, [Bi(tsac) Na] ); ES- 198.0 (100%, tsac ),
2 3
1005.5 (5%, [Bi(tsac) ] ).
19
14
3
tsac
1
+
+
−
.57 (2.59). H NMR (400 MHz, d -DMSO): δ 8.29 (dd, 4H, o-Ph),
6
1
3
−
.74 (t, 4H, m-Ph), 7.68 (m, Ar-H-sac), 7.40 (t, 2H, p-Ph). C NMR
4
(
100 MHz, d -DMSO): δ 166.9 (CO), 144.1 (C-SO ), 137.2 (C-
Crystallography. Crystals of 1 were examined using the MX1
beamline at the Australian Synchrotron, Victoria Australia. A very
small crystal was mounted on a cryo-loop and then flash cooled to 100
K. Data were collected using a single wavelength (λ = 0.710698 Å).
The MX1 end station comprised a phi goniostat and ADSC Quantum
210r 210 × 210 mm large-area detector. Due to hardware constraints
(fixed detector angle, minimum detector distance), the maximum
6
2
CO), 136.5 (CH ), 132.2 (CH ), 131.9 (CH ), 130.2 (C-Ph),
1
spectrum, ES : 363.1 (53%, [Ph Bi] ), 441.2 (100%, [Ph Bi-
sac
sac
sac
28.2 (o-Ph), 127.2 (m-Ph), 122.9 (p-Ph), 119.5 (CH ). Mass
sac
+
+
2
2
+
+
(
DMSO)] ), 568.1 (20%, Ph BiLNa] ).
2
Synthesis of [Bi(sac) ] , 2. BiPh (0.22 g, 0.50 mmol) and
3
n
3
saccharin (0.28 g, 1.50 mmol) were ground together using a mortar
6
289
dx.doi.org/10.1021/om2008869|Organometallics 2011, 30, 6283−6291

Organometallics
Article
available data resolution on MX1 was limited to approximately 0.80 Å
(20) Andrews, P. C.; Deacon, G. B.; Junk, P. C.; Kumar, I.;
MacLellan, J. G. Organometallics 2009, 28, 3999.
54
at the detector edges. Data were collected using the Blu Ice GUI and
55
processed with the XDS software packages.
(21) Andrews, P. C.; Ferrero, R. L.; Junk, P. C.; Kumar, I.; Luu, Q.;
Nguyen, K.; Taylor, J. W. Dalton Trans. 2010, 39, 2861.
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39, 9633.
Crystals of 4 were examined using an Oxford Gemini Ultra CCD
diffractometer with Mo Kα radiation (λ = 0.71073 Å). A representative
yellow prismatic crystal of dimensions 0.25 × 0.10 × 0.10 mm was
mounted on a cryoloop and then flash cooled to 123 K. Data were
PRO
56
collected and processed using the Chrysalis
software package.
(23) Andrews, P. C.; Junk, P. C.; Nuzhnaya, I.; Spiccia, L. Dalton
Summary of Crystallographic Data. [Ph Bi(sac)], 1:
2
Trans. 2008, 2557.
C H BiNO S, M = 545.35 orthorhombic, space group Pna2 . a =
1
9
14
3
1
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3
1
4
2
1.762(2) Å, b = 16.999(3) Å, c = 8.823(2) Å, V = 1764.1(6) Å , Z =
, D = 2.053 g cm , μ= 10.130 mm , F = 1032, T = 100(2) K,
−
3
−1
c
000
θmax = 53.8°, 11 595 reflections collected, 3321 unique (Rint = 0.088).
R = 0.039, wR = 0.096 for 3287 data with I > 2σI; R = 0.039, wR =
1
2
1
2
0
.096 for all data. GoF = 1.141, Flack xabs = 0.038(8).
Ph Bi(tsac)], 4: C H BiNO S , M = 561.43, 0.25 × 0.10 × 0.10
[
2
19 14
2 2
mm, orthorhombic, space group P2 /n. a = 13.1449(2) Å, b =
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3
9
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−
3
−1
g cm , μ = 9.924 mm , F = 1064, T = 123 K, 2θmax = 62.98°, 6059
reflections collected, 5536 unique (Rint = 0.028). R = 0.022, wR =
000
1
2
0
.038 for 4272 data with I > 2σI; R = 0.035, wR = 0.042 for all data.
1 2
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8, 115.
AUTHOR INFORMATION
■
(33) Supuran, C. T. Rev. Roum. Chim. 1993, 38, 229.
Corresponding Author
(34) Yamada Y.; Saito J.; Sakawa S.; Sakawa N. (Nibon Tokushu
Noyaku Seizo) JP 81 150 004 (A01N43/80) 20 Nov, 1981.
35) Grupce, O; Jovanovski, G; Soptrajanov, B. J. Mol. Struct. 1993,
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37) Clegg, W.; Compton, N. A.; Errington, J. R.; Norman, N. C.;
*
E-mail: phil.andrews@monash.edu.
(
2
ACKNOWLEDGMENTS
■
(
We thank the Australian Research Council, Bayer Schering
Pharma, and Monash University for financial support. Part of
this research was undertaken on the MX1 beamline at the
Australian Synchrotron, Victoria, Australia.
(
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