Heterocyclic bismuth carboxylates based on a diphenyl sulfone scaffold: Synthesis and antifungal activity against Saccharomyces cerevisiae

Article abstract of DOI:10.1016/j.ejmech.2013.02.036

A series of heterocyclic organobismuth(III) carboxylates 4 and 5 [RCO ₂Bi(C₆H₄-2-SO₂C₆H ₄-1′-)] derived from diphenyl sulfone was synthesized to determine the influence of the carboxylate ligand structure on the lipophilicity and antifungal activity against the yeast Saccharomyces cerevisiae. In contrast to the clear structure-activity relationship between the size of the inhibition zone and the value of ClogP for specific substitution on diphenyl sulfone scaffold 1 [ClBi(5-RC₆H₃-2-SO₂C ₆H₄-1′-)], scaffolds 4 and 5 showed similar inhibition activities irrespective of the ClogP value. This suggests that these molecules function inside the yeast cell by separating into the cationic heterocyclic bismuth scaffold and the anionic carboxylate moiety, and that the bismuth scaffold plays an important role in the inhibition activity.

Full text of DOI:10.1016/j.ejmech.2013.02.036

European Journal of Medicinal Chemistry 63 (2013) 531e535
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European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Heterocyclic bismuth carboxylates based on a diphenyl sulfone
scaffold: Synthesis and antifungal activity against Saccharomyces
cerevisiae
,
b
,
a
b
c
Toshihiro Murafuji a , Kunito Kitagawa , Daisuke Yoshimatsu , Kei Kondo ,
*
Katsuya Ishiguro c, Ryo Tsunashima c, Isamu Miyakawa c, Yuji Mikata d
a Graduate School of Medicine, Yamaguchi University, Yamaguchi City 753-8512, Japan
b Department of Chemistry, Faculty of Science, Yamaguchi University, Yamaguchi 753-8512, Japan
c Graduate School of Science and Engineering, Yamaguchi University, Yamaguchi 753-8512, Japan
d Department of Chemistry, Faculty of Science, Nara Women’s University, Nara 630-8506, Japan
a r t i c l e i n f o
a b s t r a c t
A series of heterocyclic organobismuth(III) carboxylates 4 and 5 [RCO2Bi(C6H4-2-SO2C6H4-10-)] derived
from diphenyl sulfone was synthesized to determine the influence of the carboxylate ligand structure on
the lipophilicity and antifungal activity against the yeast Saccharomyces cerevisiae. In contrast to the clear
structureeactivity relationship between the size of the inhibition zone and the value of ClogP for specific
substitution on diphenyl sulfone scaffold 1 [ClBi(5-RC6H3-2-SO2C6H4-10-)], scaffolds 4 and 5 showed
similar inhibition activities irrespective of the ClogP value. This suggests that these molecules function
inside the yeast cell by separating into the cationic heterocyclic bismuth scaffold and the anionic
carboxylate moiety, and that the bismuth scaffold plays an important role in the inhibition activity.
Ó 2013 Elsevier Masson SAS. All rights reserved.
Article history:
Received 30 August 2012
Received in revised form
22 February 2013
Accepted 25 February 2013
Available online 14 March 2013
Keywords:
Bismuth
Saccharomyces cerevisiae
Antifungal activity
Diphenyl sulfone
Lipophilicity
1. Introduction
of this relationship, we enhanced the hydrophilicity of the diphenyl
sulfone scaffold by introducing hydroxyl substituents (2a). How-
The biological activity of bismuth compounds has attracted
considerable interest [1e5]. Although inorganic bismuth com-
plexes have a long history in medicinal chemistry, the biological
activity of organobismuth compounds is not well understood [5]
because their chemistry has only been established over the last
two decades [6]. We have previously reported the synthesis and
antifungal properties of organobismuth compounds against the
yeast Saccharomyces cerevisiae [7a]. The Lewis acidy at the bismuth
center was essential for the antifungal activity and compound 1a,
which was derived from diphenyl sulfone, showed the highest ac-
tivity (Chart 1). The inhibition activity of 1 depended on substituent
R and there was a clear structureeactivity relationship between the
size of the inhibition zone and the value of ClogP [7b]; the anti-
fungal activity decreased as the lipophilicity increased. On the basis
ever, the activity of 2a was lower than that of 1a. A preliminary
experiment revealed that carboxylate 3a, which was derived from
1a, exhibited an activity comparable to that of 1a, despite its high
ClogP value. Therefore, the potency of antifungal organobismuth
compounds could be interested by changing the structural and
biological properties of the carboxylate ligand of 3a rather than the
ClogP value. Furthermore, the biological activity of 3a may also
elucidate the mechanism of the action when compared with that
of 1a.
Herein, we report the synthesis and antifungal activity of
various bismuth carboxylates 4ael and 5aed against the yeast S.
cerevisiae. The present work provides an important insight into the
mechanism of action of these compounds.
2. Synthesis
The structures of 4ael and 5aed and their synthetic routes are
shown in Scheme 1. The biological activity of compound can be
enhanced by the efficient delivery to specific cells or organelles. For
* Corresponding author. Graduate School of Medicine, Yamaguchi University,
Yamaguchi City 753-8512, Japan. Fax: þ81 83 933 5738.
E-mail address: murafuji@yamaguchi-u.ac.jp (T. Murafuji).
0223-5234/$ e see front matter Ó 2013 Elsevier Masson SAS. All rights reserved.
http://dx.doi.org/10.1016/j.ejmech.2013.02.036

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T. Murafuji et al. / European Journal of Medicinal Chemistry 63 (2013) 531e535
Chart 1. Structures of reported bismuth compounds.
example, a carbohydrate moiety has been introduced to antitumor
platinum(II) complexes for cell recognition [8]. Therefore, we aimed
to introduce an organic fragment that would be recognized by or-
ganelles inside the yeast cell. This approach may shed light on the
mechanism of the action of the organobismuth compounds against
yeast. Thus, a variety of aromatic carboxylic acids were used as
carboxylate ligands for 4ael and 5aed. In particular, 4-
aminobenzoic acid [9], nicotinic acid [10] and indole-3-acetic acid
[11] play key roles in eukaryotic cells; therefore, the corresponding
carboxylate ligands in 4g, 5a and 5c, respectively, could interact
Scheme 1. Synthesis of compounds 4ael and 5aed by Method 1 and 2.

T. Murafuji et al. / European Journal of Medicinal Chemistry 63 (2013) 531e535
533
with specific biomolecules. In addition, azulene derivatives are
biologically active and are used in medicine [12]. Azulene is char-
acterized by its high electron affinity, low ionization potential, low
aromatic resonance energy, and its dipole moment vector with the
negative end toward the five-membered ring. These structural
characteristics are reflected in the intermolecular interactions of its
derivatives in crystal [13]. Hence, the introduction of an azulene
unit in 4hel should allow the bismuth carboxylate to undergo
intermolecular interactions with various biomolecules.
highest. However, all the bismuth carboxylates showed moderate
to high activities irrespective of the structure of the carboxylate
ligands and its ClogP value. In particular, highly lipophilic com-
pounds, 4d, 4j and 4k (ClogP > 5.00), had activities comparable
with that of 5a which has much more hydrophilic (ClogP ¼ 1.99). In
contrast, 1b, 1c and 2b were inactive, and these compounds had
ClogP values of 3.06, 3.00 and 6.13, respectively [7b]. Therefore, we
conclude that heterocyclic bismuth chlorides 1 and 2 and carbox-
ylates 3a, 4ael and 5aed are probably separated into two organic
fragments inside the yeast cell. The cationic heterocyclic bismuth
scaffold may be responsible for the inhibitory activity, whereas the
chloride or carboxylate anion affects the drug absorption and
bioavailability. This is in good agreement with the finding that the
inhibition activity of 1 depends on substituent R in the heterocyclic
bismuth scaffold.
Initially, 4 and 5 were synthesized by Method 1 (Scheme 1). The
reaction of 1a with benzoic acid, naphthoic acids, anthranic acid
and cinnamic acid in the presence of potassium tert-butoxide
proceeded smoothly to afford 4aee, respectively, in acceptable
yields (Table 1). In contrast, the reaction of 1a with 4-acetoxy and 4-
aminobenzoic acids under basic conditions produced low yields of
4f and g, suggesting that the deprotonation of the acetoxy and
amino substituents competed with the desired reaction. The
azulenecarboxylic acids were synthesized according to literature
methods [14]. The reaction of 1a with azulene carboxylic acids gave
4hel. However, the synthesis of 5a using Method 1 was unsuc-
cessful, and the majority of the starting material was recovered. The
coordination of the pyridinyl group to the bismuth center may have
prevented the nucleophilic attack of the carboxylate anion gener-
ated in situ. The synthesis of 5b using Method 1 also failed, because
of the reactive acetoxy ortho substituent. In contrast, 4f, which
bears this substituent at the para position, was formed in low yield.
Method 2 was used to overcome the low yields achieved under
basic conditions. Bismuth carboxylates 5aed were obtained in
acceptable yields by the acidolysis of the bismuthecarbon bond of
3b by the corresponding carboxylic acid. The structure of the new
compounds was confirmed by elemental analysis, IR, and 1H and
13C NMR. Compounds 4ael and 5aed were stable in water and
DMSO.
In conclusion, the present study provides insight into the
mechanism of action of heterocyclic bismuth carboxylates 3a, 4 and
5 and chlorides 1 and 2 against S. cerevisiae. Further studies are now
underway to confirm these findings.
4. Experimental
Compounds 3b and 1a were synthesized in accordance with our
reported procedure [7b]. Azulene-1-carboxylic acid [14a], -2-
carboxylic acid [14b] and -6-carboxylic acid [14d] were prepared
in accordance with the reported procedure. 1,3-Dibromoazulene-2-
carboxylic acid and 1,3-dichloroazulene-2-carboxylic acid were
prepared from 1,3-dibromo-2-lithioazulene and 1,3-dichloro-2-
lithioazulene, respectively, by the reaction with CO2 [14c].
4.1. Synthesis of 4 (Method 1)
A typical example is exemplified by the synthesis of 4a: To a
solution of 1a (230 mg, 0.5 mmol) in THF (10 ml) was added at room
temperature carboxylic acid (0.5 mmol) and potassium tert-but-
oxide (62 mg, 0.55 mmol). After the resulting mixture was stirred
for 30 min, the mixture was diluted by the addition of brine (5 ml)
and the organic layer was extracted with ethyl acetate (20 ml ꢀ 3).
The extracts were concentrated to leave an oily residue, which was
crystallized from MeOH to give the product.
3. Results and discussion
The inhibition activity and biological activity of 4 and 5 were
compared with those of 1, 2 and 3a reported in our previous anti-
fungal study (Scheme 1 and Table 1). The activities of 4gel, 5a and
5c were slightly lower, whereas those of 3a, 4a and 4f were the
4.1.1. 10-(Benzoyloxy)phenothiabismine 5,5-dioxide (4a)
Table 1
Yield: 58%; mp 174e176 ꢁC; 1H NMR (400 MHz, CDCl3):
d 7.43e
Synthesis and antifungal assay of bismuth carboxylates 4 and 5.
7.48 (4H, m), 7.55 (1H, t, J ¼ 7.2 Hz), 7.77 (2H, t, J ¼ 7.4 Hz), 8.11 (2H,
Compound
Method
Yield (%)
Inhibition
zone (mm)
ClogP
d, J ¼ 7.8 Hz), 8.38 (2H, d, J ¼ 7.6 Hz), 8.80 (2H, d, J ¼ 7.2 Hz); 13C
NMR (100 MHz, CDCl3):
d 128.2, 128.5, 128.7, 130.3, 132.2, 132.6,
4a
4b
4c
4d
4e
4f
4g
4h
4i
1
1
1
1
1
1
1
1
1
1
1
1
2
2
2
2
1
58
42
79
70
48
16
11
80
62
58
70
71
81
47
28
77
83
17
13
12
14
14
17
15
11
14
12
13
12
14
12
13
12
17
18
0
3.49
4.66
4.66
5.84
4.45
2.84
2.26
4.66
4.66
6.39
6.09
4.66
1.99
2.84
3.53
2.97
2.68
1.18
3.06
3.00
0.81
6.13
3.99
135.2, 136.0, 141.0, 173.9, 184.7; IR (KBr):
1290, 1140, 760, 740, 710, 680, 590 and 560 cmꢂ1. Anal. Calc. for
19H13BiO4S: C, 41.77; H, 2.40. Found: C, 41.58; H, 2.75%.
n
¼ 1610, 1570, 1340, 1300,
C
4.1.2. 10-(1-Naphthoyloxy)phenothiabismine 5,5-dioxide (4b)
Yield: 42%; mp 142e145 ꢁC; 1H NMR (400 MHz, CDCl3):
d
7.46
(2H, t, J ¼ 7.4 Hz), 7.51 (1H, t, J ¼ 7.5 Hz), 7.53 (1H, t, J ¼ 7.4 Hz), 7.61
(1H, t, J ¼ 8.1 Hz), 7.69 (2H, t, J ¼ 7.4 Hz), 7.91 (1H, d, J ¼ 8.1 Hz), 8.01
(1H, d, J ¼ 8.2 Hz), 8.30 (1H, d, J ¼ 7.2 Hz), 8.40 (2H, d, J ¼ 7.4 Hz),
8.89 (2H, d, J ¼ 7.4 Hz), 9.18 (1H, d, J ¼ 8.4 Hz); 13C NMR (100 MHz,
4j
4k
4l
5a
5b
5c
5d
3a
1a
1b
1c
2a
2b
3b
CDCl3):
d 124.6, 126.0, 126.5, 127.4, 128.5, 128.6, 128.7, 129.1, 131.2,
131.7, 133.1, 134.0, 135.1, 136.2, 141.1, 175.3, 184.9; IR (KBr):
n
¼ 1540,
1350, 1300, 1290, 1250, 1140, 790, 760, 740, 590 and 560 cmꢂ1. Anal.
Calc. for C23H15BiO4S: C, 46.32; H, 2.54. Found: C, 46.26; H, 2.73%.
0
8
0
0
4.1.3. 10-(2-Naphthoyloxy)phenothiabismine 5,5-dioxide (4c)
Yield: 79%; mp 213e215 ꢁC; 1H NMR (400 MHz, CDCl3):
d 7.46
(2H, t, J ¼ 7.6 Hz), 7.47 (1H, t, J ¼ 7.6 Hz), 7.53 (1H, t, J ¼ 7.6 Hz), 7.72
(2H, t, J ¼ 7.4 Hz), 7.89 (1H, d, J ¼ 8.4 Hz), 7.90 (1H, d, J ¼ 8.8 Hz), 7.96

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T. Murafuji et al. / European Journal of Medicinal Chemistry 63 (2013) 531e535
(1H, d, J ¼ 8.4 Hz), 8.14 (1H, d, J ¼ 8.4 Hz), 8.39 (2H, d, J ¼ 7.6 Hz),
8.67 (1H, s), 8.86 (2H, d, J ¼ 7.4 Hz); 13C NMR (100 MHz, CDCl3):
140.4, 141.0, 173.2, 184.6; IR (KBr):
1260, 1140, 1090, 800, 780, 740, 590 and 560 cmꢂ1. Anal. Calc. for
C23H15BiO4S: C, 46.32; H, 3.08. Found: C, 46.47; H, 2.72%.
n
¼ 1580, 1490, 1440, 1340, 1310,
d
126.2, 126.5, 127.7, 127.9, 128.0, 128.5, 128.7, 129.3, 129.4, 131.5,
132.6, 135.2, 135.4, 136.0, 141.0, 174.0, 184.9; IR (KBr):
n
¼ 1600,
1590, 1570, 1360, 1330, 1290, 1240, 1200, 1140, 1110, 1090, 790, 760,
740, 710, 590 and 560 cmꢂ1. Anal. Calc. for C23H15BiO4S: C, 46.32; H,
2.54. Found: C, 46.03; H, 2.73%.
4.1.10. 10-(1,3-Dibromoazulene-2-carboxy)phenothiabismine 5,5-
dioxide (4j)
Yield: 58%; mp 252 ꢁC (decomp.); 1H NMR (400 MHz, CDCl3):
d
7.32 (2H, t, J ¼ 10.0 Hz), 7.46 (2H, t, J ¼ 7.6 Hz), 7.70e7.74 (3H, m),
4.1.4. 10-(9-Anthranoyloxy)phenothiabismine 5,5-dioxide (4d)
8.38 (2H, d, J ¼ 7.6 Hz), 8.46 (2H, d, J ¼ 10.0 Hz), 9.04 (2H, d,
Yield: 70%; mp 172e174 ꢁC; 1H NMR (400 MHz, CDCl3):
d
7.44e
J ¼ 7.6 Hz); 13C NMR (100 MHz, CDCl3):
d 102.8, 125.1, 128.5, 128.7,
7.51 (6H, m), 7.68 (2H, t, J ¼ 7.6 Hz), 8.00e8.04 (2H, m), 8.26e8.30
135.3, 136.3, 136.5, 138.2, 139.3, 140.9, 141.5, 171.2, 185.1; IR (KBr):
(2H, m), 8.45 (2H, d, J ¼ 7.6 Hz), 8.51 (1H, s), 8.99 (2H, d, J ¼ 7.2 Hz);
n
¼ 1580,1460,1370, 1330,1290, 1270, 1140,1010, 840, 760, 730, 590
13C NMR (100 MHz, CDCl3):
d
125.3, 125.8, 126.5, 128.4, 128.6, 128.7,
and 570 cmꢂ1. Anal. Calc. for C23H13BiBr2O4S: C, 36.63; H, 1.74.
Found: C, 36.43; H, 1.38%.
128.8, 128.9, 130.0, 131.2, 135.2, 136.6, 141.0, 177.0, 185.0; IR (KBr):
n
¼ 1580, 1370, 1310, 1270, 1250, 1140, 760, 740, 590 and 570 cmꢂ1
.
Anal. Calc. for C27H17BiO4S: C, 50.16; H, 2.65. Found: C, 49.92; H,
2.83%.
4.1.11. 10-(1,3-Dichloroazulene-2-carboxy)phenothiabismine 5,5-
dioxide (4k)
Yield: 70%; mp 252 ꢁC (decomp.); 1H NMR (400 MHz, CDCl3):
4.1.5. 10-(Cinnamoyloxy)phenothiabismine 5,5-dioxide (4e)
d
7.23 (2H, t, J ¼ 10.0 Hz), 7.46 (2H, t, J ¼ 7.6 Hz), 7.67e7.74 (3H, m),
Yield: 48%; mp 198e200 ꢁC; 1H NMR (400 MHz, CDCl3):
d
6.57
8.38 (2H, d, J ¼ 7.6 Hz), 8.47 (2H, d, J ¼ 10.0 Hz), 9.00 (2H, d,
(1H, d, J ¼ 16.0 Hz), 7.38e7.40 (3H, m), 7.46 (2H, t, J ¼ 7.6 Hz), 7.53e
J ¼ 7.6 Hz); 13C NMR (100 MHz, CDCl3):
d 114.9, 124.4, 128.5, 128.7,
7.55 (2H, m), 7.68e7.71 (3H, m), 8.37 (2H, d, J ¼ 7.6 Hz), 8.77 (2H, d,
133.3,135.3, 136.5,138.0,140.9,142.1,170.3,185.0, one carbon signal
J ¼ 7.2 Hz); 13C NMR (100 MHz, CDCl3):
d
120.3, 128.0, 128.5, 128.7,
was too weak to be assigned; IR (KBr):
n
¼ 1580, 1470, 1300, 1140,
128.9, 130.1, 134.8, 135.2, 136.0, 141.0, 144.8, 174.4, 184.5; IR (KBr):
1110, 740, 590 and 570 cmꢂ1. Anal. Calc. for C23H13BiCl2O4S: C,
41.52; H, 1.97. Found: C, 41.29; H, 1.57%.
n
¼ 1760, 1610, 1350, 1290, 1200, 1130, 1010, 920, 770, 740, 710, 590
and 560 cmꢂ1. Anal. Calc. for C21H15BiO4S: C, 44.07; H, 2.64. Found:
C, 43.76; H, 2.92%.
4.1.12. 10-(Azulene-6-carboxy)phenothiabismine 5,5-dioxide (4l)
Yield: 71%; mp 226e228 ꢁC; 1H NMR (400 MHz, CDCl3):
d 7.45
4.1.6. 10-(4-Acetoxybenzoyloxy)phenothiabismine 5,5-dioxide (4f)
(2H, d, J ¼ 4.0 Hz), 7.48 (2H, t, J ¼ 7.6 Hz), 7.74 (2H, t, J ¼ 7.6 Hz), 8.04
(1H, t, J ¼ 4.0 Hz), 8.17 (2H, d, J ¼ 10.8 Hz), 8.40 (2H, d, J ¼ 7.6 Hz),
8.44 (2H, d, J ¼ 10.8 Hz), 8.85 (2H, d, J ¼ 7.6 Hz); 13C NMR (100 MHz,
Yield: 16%; mp 217e219 ꢁC; 1H NMR (400 MHz, CDCl3):
d 2.32
(3H, s), 7.17 (2H, d, J ¼ 8.8 Hz), 7.46 (2H, t, J ¼ 7.6 Hz), 7.70 (2H, t,
J ¼ 7.6 Hz), 8.13 (2H, d, J ¼ 8.8 Hz), 8.38 (2H, d, J ¼ 7.6 Hz), 8.77 (2H,
CDCl3):
d 118.6, 123.0, 128.6, 128.8, 134.9, 135.3, 135.9, 138.2, 139.8,
d, J ¼ 7.2 Hz); 13C NMR (100 MHz, CDCl3):
d
21.1, 121.4, 128.5, 128.7,
141.0, 141.3, 175.3, 185.3; IR (KBr):
n
¼ 1600, 1570, 1340, 1310, 1290,
129.9, 131.8, 135.2, 136.0, 141.0, 154.1, 169.0, 173.1, 184.8; IR (KBr):
1140, 770, 740, 590 and 560 cmꢂ1. Anal. Calc. for C23H15BiO4S: C,
46.32; H, 2.54. Found: C, 45.97; H, 2.69%.
n
¼ 1640, 1560, 1350, 1310, 1290, 1230, 1140, 1090, 1000, 870, 770,
740, 590 and 570 cmꢂ1. Anal. Calc. for C21H15BiO6S: C, 41.73; H, 2.50.
Found: C, 42.13; H, 2.79%.
4.2. Synthesis of 5 (Method 2)
4.1.7. 10-(4-Aminobenzoyloxy)phenothiabismine 5,5-dioxide (4g)
A typical example is exemplified by the synthesis of 5a: A
mixture of 3b (258 mg, 0.5 mmol) and nicotinic acid (62 mg,
0.5 mmol) in toluene (7 ml) was refluxed for 6 h. The resulting
mixture was cooled to room temperature and concentrated to leave
an oily residue, which was crystallized from MeOH to give the
product.
Yield: 11%; mp 238 ꢁC (decomp.); 1H NMR (400 MHz, CDCl3):
d
4.04 (2H, s), 6.66 (2H, d, J ¼ 8.4 Hz), 7.44 (2H, t, J ¼ 7.4 Hz), 7.67
(2H, t, J ¼ 7.4 Hz), 7.92 (2H, d, J ¼ 8.4 Hz), 8.36 (2H, d, J ¼ 7.6 Hz),
8.79 (2H, d, J ¼ 7.6 Hz); 13C NMR (100 MHz, CDCl3):
d 113.8, 127.0,
128.1, 128.4, 128.5, 132.3, 135.0, 136.1, 141.1, 150.6, 174.0; IR (KBr):
n
¼ 3450, 3390, 1600, 1560, 1510, 1440, 1340, 1290, 1170, 1140, 1090,
1010, 850, 780, 760, 740, 640, 590 and 570 cmꢂ1. Anal. Calc. for
19H14BiNO4S$MeOH: C, 40.48; H, 3.06; N, 2.36. Found: C, 40.68; H,
4.2.1. 10-(Nicotinoyloxy)phenothiabismine 5,5-dioxide (5a)
C
Yield: 81%; mp 248 ꢁC; 1H NMR (400 MHz, CDCl3):
d 7.39 (1H, dd,
3.13; N, 2.55%.
J ¼ 4.8, 7.6 Hz), 7.48 (2H, t, J ¼ 7.6 Hz), 7.72 (2H, d, J ¼ 7.4 Hz), 8.36 (1H,
m), 8.39 (2H, d, J ¼ 7.8 Hz), 8.76 (1H, dd, J ¼ 1.6, 7.2 Hz), 8.80 (2H, d,
4.1.8. 10-(Azulene-1-carboxy)phenothiabismine 5,5-dioxide (4h)
J ¼ 7.2 Hz), 9.29 (1H, d, J ¼ 1.6 Hz); 13C NMR (100 MHz, CDCl3):
d 123.2,
Yield: 80%; mp 248e250 ꢁC; 1H NMR (400 MHz, CDCl3):
d
7.32
128.0, 128.7, 128.8, 135.3, 135.9, 137.6, 140.9, 151.7, 153.0, 172.3, 184.8;
(1H, d, J ¼ 4.4 Hz), 7.42e7.47 (3H, m), 7.55 (1H, t, J ¼ 9.8 Hz), 7.68
(2H, t, J ¼ 7.4 Hz), 7.81 (1H, t, J ¼ 9.8 Hz), 8.38 (2H, d, J ¼ 7.6 Hz), 8.45
(1H, d, J ¼ 4.4 Hz), 8.48 (1H, d, J ¼ 9.2 Hz), 8.91 (2H, d, J ¼ 7.2 Hz),
IR (KBr):
n
¼ 1610,1560,1420,1350, 1290,1200,1140,1110,1030, 850,
740, 710, 590 and 560 cmꢂ1. Anal. Calc. for C18H12BiNO4S: C, 39.50; H,
2.21; N, 2.56. Found: C, 39.64; H, 2.33; N, 2.59%.
9.79 (1H, d, J ¼ 9.6 Hz); 13C NMR (100 MHz, CDCl3):
d 100.0, 117.5,
126.6, 127.3, 128.4, 128.5, 135.0, 136.3, 138.0, 138.1, 138.8, 140.7,
4.2.2. 10-(2-Acetoxybenzoyloxy)phenothiabismine 5,5-dioxide (5b)
141.3, 141.4, 144.9, 173.0, 183.3; IR (KBr):
n
¼ 1540, 1460, 1440, 1400,
Yield: 47%; mp 200e202 ꢁC; 1H NMR (400 MHz, CDCl3):
d 2.03
1360,1300,1290,1260,1140, 780, 740, 590 and 560 cmꢂ1. Anal. Calc.
for C23H15BiO4S: C, 46.32; H, 2.54. Found: C, 45.94; H, 2.60%.
(3H, s), 7.09 (1H, t, J ¼ 8.0 Hz), 7.30 (1H, t, J ¼ 8.0 Hz), 7.46 (2H, t,
J ¼ 7.6 Hz), 7.53 (1H, t, J ¼ 7.8 Hz), 7.71 (2H, t, J ¼ 7.4 Hz), 8.06 (1H, d,
J ¼ 8.0 Hz), 8.38 (2H, d, J ¼ 7.6 Hz), 8.75 (2H, d, J ¼ 7.2 Hz); 13C NMR
4.1.9. 10-(Azulene-2-carboxy)phenothiabismine 5,5-dioxide (4i)
(100 MHz, CDCl3): d 21.0, 123.5, 125.6, 125.9, 128.5, 128.6, 132.5,
Yield: 62%; mp 222 ꢁC; 1H NMR (400 MHz, CDCl3):
d
7.19 (2H, t,
133.4, 135.2, 136.0, 140.9, 150.7, 169.7, 172.0, 184.8; IR (KBr):
J ¼ 9.8 Hz), 7.46 (2H, t, J ¼ 7.6 Hz), 7.64e7.72 (3H, m), 7.83 (2H, s),
n
¼ 1760, 1610, 1570, 1480, 1440, 1370, 1340, 1290, 1190, 1140, 1090,
8.37e8.43 (4H, m), 8.88 (2H, d, J ¼ 7.8 Hz); 13C NMR (100 MHz,
1010, 760, 740, 710, 590 and 570 cmꢂ1. Anal. Calc. for C21H15BiO6S:
C, 41.73; H, 2.50. Found: C, 41.47; H, 2.70%.
CDCl3):
d 119.6, 123.7, 128.5, 128.6, 135.1, 136.2, 140.0, 140.1, 140.3,

T. Murafuji et al. / European Journal of Medicinal Chemistry 63 (2013) 531e535
535
4.2.3. 10-(Indol-3-carboxy)phenothiabismine 5,5-dioxide (5c)
Yield: 28%; mp 206e208 ꢁC; 1H NMR (400 MHz, CDCl3):
affiliated to Faculty of Science, Kyushu University. This work was
performed under the Cooperative Research Program of “Network
Joint Research Center for Materials and Devices”.
d
3.88
(2H, s), 7.13 (1H, t, J ¼ 7.4 Hz), 7.20e7.24 (2H, m), 7.38 (1H, d,
J ¼ 8.0 Hz), 7.42 (2H, t, J ¼ 7.6 Hz), 7.59 (2H, t, J ¼ 7.4 Hz), 7.70 (1H, d,
J ¼ 8.0 Hz), 8.07 (1H, s), 8.34 (2H, d, J ¼ 7.6 Hz), 8.60 (2H, d,
Appendix A. Supplementary data
J ¼ 7.2 Hz); 13C NMR (100 MHz, CDCl3):
d 33.0, 110.0, 111.2, 119.4,
119.5, 122.2, 123.0, 127.4, 128.4, 128.6, 135.0, 136.0, 136.2, 140.9,
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.ejmech.2013.02.036.
179.9, 184.5; IR (KBr):
n
¼ 3320, 1620, 1430, 1360, 1300, 1250, 1230,
1140, 1090, 1010, 740, 590 and 570 cmꢂ1. Anal. Calc. for C22H16Bi-
NO4S: C, 44.08; H, 2.69; N, 2.34. Found: C, 43.92; H, 2.79; N, 2.40%.
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4.2.4. 10-(N-Phthalylglycyloxy)phenothiabismine 5,5-dioxide (5d)
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Acknowledgments
Support from the Japan Society for the Promotion of Science
(Grant-in-Aid for Scientific Research, No. 19550043) is gratefully
acknowledged. We are grateful to the Center of Instrumental
Analysis, Yamaguchi University and the Elemental Analytical Center
(c) K. Kurotobi, H. Tabata, M. Miyauchi, A.F.M. Mustafizur Rahman, K. Migita,
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1346e1350.