Synthesis of novel di- and tricationic carbapenems with potent anti-MRSA activity

Article abstract of DOI:10.1016/j.bmcl.2008.11.039

A new series of 1β-methyl carbapenems possessing a 6,7-disubstituted imidazo[5,1-b]thiazol-2-yl group directly attached to the C-2 position of the carbapenem nucleus was prepared, and their activities against methicillin-resistant Staphylococcus aureus (M

Full text of DOI:10.1016/j.bmcl.2008.11.039

Bioorganic & Medicinal Chemistry Letters 19 (2009) 447–450
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis of novel di- and tricationic carbapenems with potent
anti-MRSA activity
b
b
b
b
Takahisa Maruyama a, , Yasuo Yamamoto , Yuko Kano , Mizuyo Kurazono , Eiki Shitara ,
*
Katsuyoshi Iwamatsu b, Kunio Atsumi b,
*
a Process Development Section Kitakami-Plant, Meiji Seika Kaisha, Ltd., 3-3 Kita-Kougyoudanchi, Kitakami-shi, Iwate 024-0012, Japan
b Pharmaceutical Research Center, Meiji Seika Kaisha, Ltd., 760 Morooka-cho, Kohoku-ku, Yokohama 222-8567, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A new series of 1b-methyl carbapenems possessing a 6,7-disubstituted imidazo[5,1-b]thiazol-2-yl group
directly attached to the C-2 position of the carbapenem nucleus was prepared, and their activities against
methicillin-resistant Staphylococcus aureus (MRSA) were evaluated. First, a benzyl moiety was introduced
at the C-6 position of imidazo[5,1-b]thiazole attached to the carbapenem. These benzylated molecules
showed potent anti-MRSA activity, but poor water solubility. In order to overcome this drawback, we
designed and synthesized di- and tricationic carbapenems and finally discovered a novel carbapenem
(15i), which exhibited excellent anti-MRSA activity and good water solubility.
Received 1 October 2008
Revised 11 November 2008
Accepted 13 November 2008
Available online 18 November 2008
Keywords:
Carbapenem
MRSA
Ó 2008 Elsevier Ltd. All rights reserved.
Imidazo[5,1-b]thiazol
Cationic charge
Beta-lactam
Infections caused by methicillin-resistant Staphylococcus aureus
(MRSA)1 are one of the most serious clinical problems worldwide
because only a few therapeutic agents such as Arbekacin, vanco-
mycin (VCM), and teicoplanin are effective against MRSA. More-
over, glycopeptide-resistant strains have been emerging due to
the increasing use of glycopeptide.2 Recently, linezolid and dapto-
mycin have also been available for MRSA infections. However, new
resistant strains against many drugs including them have already
been reported.3 Therefore, new and potent anti-MRSA agents are
urgently required.
During the past decade, a number of research groups have at-
tempted to synthesize novel b-lactams with anti-MRSA activity.
These efforts yielded cephalosporins4 and carbapenems5 with po-
tent activity against MRSA. Recently, we have discovered a novel
anti-MRSA b-lactam, CP50686, which had an imidazo[5,1-b]thiazo-
lium side chain at the C-2 position of the carbapenem skeleton.
Most anti-MRSA b-lactams have a hydrophobic side chain, such
as an aryl7, a benzothiazolylthio8, or a fluorenyl9 group, at the C-2
position of carbapenem or the C-3 position of cephalosporin. It sug-
gested that introduction of a hydrophobic side chain increases the
binding affinity of the b-lactam to PBP2’ protein of MRSA.10
Based on the above findings, we introduced a benzyl moiety as a
hydrophobic side chain at the 6-position of imidazo[5,1-b]thiazole
in place of the carbamoylmethyl moiety of CP5068 in an attempt
to increase anti-MRSA activity (Fig. 1). Moreover, we designed and
synthesized novel di- and tricationic carbapenems containing the
benzyl moiety to increase water solubility.5a Herein we report the
synthesis and SAR study of benzyl-substituted imidazo[5,1-b]thia-
zolium di- and tricationic carbapenems having excellent anti-MRSA
activity and good water solubility.
Carbapenem derivatives having a benzyl moiety were prepared
as shown in Scheme 1. 7-Iodoimidazo[5,1-b]thiazole 2, which was
derived from 1 by iodination with N-iodosuccinimide in 70% yield,
was converted to 3 using Grignard reagent followed by sulfenyla-
tion. The stannane 4 was synthesized in order to introduce
imidazothiazole into the carbapenem nucleus through Stille cou-
pling. Then the key intermediate 6 was smoothly obtained in NMP
at 50 °C via the Stille coupling reaction of 4 and 5. This key interme-
diate 6 could be reacted with several benzyl bromides 7a–h and led
to the corresponding quaternary ammonium salts 8a–h. Deprotec-
tion of 8a–h was performed by hydrogenation with Pd/C and H2.
After purification of the crude products by reversed-phase column
chromatography, the desired carbapenem derivatives 9a–h were
obtained, each as a lypophilized amorphous powder.
Introduction of a quaternary ammonium substituent into the
benzyl moiety is illustrated in Scheme 2. We selected
moxylenes as a building block to synthesize several dicationic
carbapenems. Thus, the reaction of 6 with o-, m-, and p-
a0-dibro-
a,
a0-dibro-
a,
moxylene provided 10a–c, respectively. In these reactions,
dicationic carbapenem dimers were obtained as by-products.
However, these dimers were easily removed by resin purification.
* Corresponding authors. Tel.: +81 197 66 3114; fax: +81 197 66 3137 (T.M.).
E-mail address: takahisa_maruyama@meiji.co.jp (T. Maruyama).
0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.11.039

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T. Maruyama et al. / Bioorg. Med. Chem. Lett. 19 (2009) 447–450
Figure 1. Strategy for synthesizing anti-MRSA carbapenems.
The intermediates 10a–c were converted to 11a–f by the reaction
with pyridine or 4-methylmorpholine. Removal of the 4-nitroben-
zyl group of 11a–f afforded the desired dicationic carbapenems
12a–f, which showed good water solubility.
We next planned to synthesize various water-soluble dicationic
carbapenems starting from 10b (Scheme. 3). We chose m-substi-
tuted derivatives because of their strongest anti-MRSA activities
compared to those of o- and p- substituted compounds (Table. 2).
Reaction of 10b with 13a–e, followed by deprotection of the
4-nitrobenzyl groups afforded the corresponding dicationic carba-
penems 15a–e.
To study the influence of an additional cationic charge on anti-
MRSA activity, we synthesized tricationic carbapenems. Reaction
of 10b with cationic analogs of DABCO (1,4-diaza-[2,2,2]-bicyc-
looctane), 13f–i, resulted in tricationic ammonium salts 14f–i.
These ammonium salts were converted to the desired tricationic
carbapenems 15f–i by removal of the protecting groups.
Table 1 shows the antibacterial activities of the novel benzyl-
substituted carbapenems 9a–h together with those of CP5068,
imipenem (IPM), and VCM. Compound 9a showed potent anti-
MRSA activity, like other carbapenems with a hydrophobic side
chain.7–9 It was more potent than CP5068 and IPM by 1-, 2- and
8-fold, respectively, and equipotent with VCM. Substituted benzyl
compounds 9b–f also exhibited potent anti-MRSA activity, but
showed insufficient water solubility11 because of their hydropho-
bic side chain. Compound 9g with a diethylcarbamoyl group
showed neither good anti-MRSA activity nor water solubility.
Although 9h had sufficient water solubility owing to the introduc-
tion of the carboxylic acid, it showed poor anti-MRSA activity. We
considered that higher water solubility (>20 mg/mL) without
decrease of activity (MIC value of MRSA M126 HR 61.56) was
indispensable for the target profile of our compounds.
To increase water solubility, we designed and synthesized di- and
tricationic derivatives (Scheme 2). Their anti-MRSA activities are
Scheme 1. Synthesis of carbapenem derivatives (1). Reagents and conditions: (a) NIS, CH2C12, rt, 70%; (b) EtMgBr, CH3SO2SCH3, THF, 0 °C, 84%; (c) i—n-BuLi; ii—n-Bu3SnCl;
iii—LHMDS, THF, ꢀ40 °C, 86%; (d) i—DIPEA, Tf2O, CH3CN, ꢀ35 °C; ii—4, Pd2(dba)3, P(2-furyl)3, ZnCl2, NMP, 50 °C, 71%; (e) CHC13–CH3CN, rt; (f) Pd/C, H2, THF–H2O, rt, 4–57%
(for 9b, TBAF and AcOH were added before deprotection of the 4-nitrobenzyl group).

T. Maruyama et al. / Bioorg. Med. Chem. Lett. 19 (2009) 447–450
449
Scheme 2. Synthesis of carbapenem derivatives (2). Reagents and conditions: (a) CHCI3–CH3CN, rt; (b) pyridine or 4-methylmorpholine, CHC13–CH3CN, rt; (c) Pd/C, H2, THF–
H2O, rt.
Scheme 3. Synthesis of carbapenem derivatives (3). Reagents and conditions: (a) 13a–i, CHCI3–CH3CN, rt; (b) Pd/C, H2, THF–H2O, rt, 20–63% (from 10b).
shownin Table 2. All compoundsshowedgood water solubility. Con-
sidering the anti-MRSA activity of 12a–f, we decided to focus on the
synthesis of m-substituted derivatives. Among the dicationic deriv-
atives, aliphatic ammonium salts ( 12d–f, 15a) showed reduced
activity, but aromatic ammonium salts (15b–e) were as potent as
9a. All tricationic derivatives (15f–i) showed excellent anti-MRSA
activity. Compound 15i, possessing a primary amine, exhibited the
most potent anti-MRSA activity, superior to VCM.
In order to clarify the anti-MRSA activity of 15i, we evaluated
the anti bacterial activity of 15i and VCM against 54 MRSA strains
isolated in the clinic (Table 3). MIC50 and MIC90 of 15i were 0.39
and 0.78 lg/mL, respectively, being superior to those of VCM.

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T. Maruyama et al. / Bioorg. Med. Chem. Lett. 19 (2009) 447–450
Table 1
In order to improve the anti-MRSA activity of CP5068, we intro-
duced a benzyl moiety as a hydrophobic side chain at the 6-posi-
tion of imidazo[5,1-b]thiazole in place of the carbamoylmethyl
moiety of CP5068. The anti-MRSA activity was increased, but the
water solubility was decreased. To improve water solubility, we
designed and synthesized di- and tricationic derivatives, and ob-
tained novel carbapenems with excellent anti-MRSA activity and
sufficient water solubility. Among them, 15i12 showed very strong
anti-MRSA activity, superior to VCM, with sufficient water solubil-
ity for use as an injectable antimicrobial.
Antibacterial activities of 9a–h and reference compounds (MICa;
lg/mL)
Test organism
S. aureus 209P JC-1
S. aureus M-126a
S. aureus M-126HRb
9a
9b
9c
9d
9e
9f
9g
9h
<0.006
<0.006
<0.006
<0.006
<0.006
<0.006
0.013
0.025
<0.006
0.013
0.39
0.39
0.78
0.78
0.78
0.78
1.56
3.13
1.56
25
1.56
1.56
1.56
3.13
1.56
3.13
6.25
12.5
3.13
100
CP5068
IPM
VCM
Acknowledgment
0.78
1.56
1.56
a
MRSA.
We are grateful to Dr. T. Ida for the biological study.
References and notes
b
Carbapenem-resistant MRSA.
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Table 2
Antibacterial activities of 12a–f and 15a–i (MIC;
l
g/mL)
Test organism
S. aureus 209P JC-1
S. aureus M-126a
S. aureus M-126HRb
3. (a) Woodford, N. Clin. Microbiol. Infect. 2005, 11, 2; (b) Mangili, A.; Bica, I.;
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11. Evaluation of water solubility as first screening was performed by dissolving
our new compounds in water at the concentration of ca. 5 mg/mL.
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Atsumi, K.; Iwamatsu, K.; Ida, T. PCT Int. Appl. 2001, 528, WO0155154.
12a
12b
12c
12d
12e
12f
15a
15b
15c
15d
15e
15f
<0.006
<0.006
<0.006
<0.006
<0.006
<0.006
<0.006
<0.006
<0.006
<0.006
<0.006
<0.006
<0.006
<0.006
<0.006
1.56
0.78
0.78
1.56
0.78
1.56
0.78
0.39
0.78
0.78
0.78
0.78
0.78
0.78
0.39
3.13
1.56
1.56
3.13
3.13
3.13
3.13
1.56
3.13
1.56
1.56
1.56
1.56
1.56
0.78
15g
15h
15i
a
MRSA.
b
Carbapenem-resistant MRSA.
Table 3
Anti-MRSA (n = 54) activities of 15i and VCM
Compounds
MIC
90%
50%
Range
15i
VCM
0.39
1.56
0.78
1.56
<0.05–1.56
0.78–3.13
The water solubility of 15i was over 20 mg/mL, which is acceptable
for parenteral injection.