Synthesis and antibacterial activity of new 7-piperazinylquinolones containing a functionalized 2-(furan-3-yl)ethyl moiety

Article abstract of DOI:10.1002/ardp.200600169

A number of 7-piperazinylquinolones carrying a functionalized 2-(furan-3-yl)ethyl moiety attached to the piperazine ring have been synthesized and evaluated as antibacterial agents against a panel of Gram-positive and Gram-negative bacteria. Most of the synthesized compounds exhibited significant antibacterial activity, and this activity can be modulated through the nature of the functionality on ethyl spacer attached to piperazine ring and the type of side chain present at the N-1 position of quinolone ring.

Full text of DOI:10.1002/ardp.200600169

Arch. Pharm. Chem. Life Sci. 2007, 340, 47–52
A. Foroumadi et al.
47
Full Paper
Synthesis and Antibacterial Activity of New 7-Piperazinyl-
quinolones Containing a Functionalized 2-(Furan-3-yl)ethyl
Moiety
Alireza Foroumadi1, Negar Mohammadhosseini2, Saeed Emami3, Bahram Letafat4,
Mohammad Ali Faramarzi1, Nasrin Samadi1, and Abbas Shafiee1
1 Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Tehran University of Medical
Sciences, Tehran, Iran
2 Islamshahr Young Researchers Club, Faculty of Sciences, Islamic Azad University, Islamshahr, Iran
3 Department of Medicinal Chemistry, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari,
Iran
4 Department of Chemistry, Faculty of Sciences, Islamic Azad University, Islamshahr, Iran
A number of 7-piperazinylquinolones carrying a functionalized 2-(furan-3-yl)ethyl moiety atta-
ched to the piperazine ring have been synthesized and evaluated as antibacterial agents against
a panel of Gram-positive and Gram-negative bacteria. Most of the synthesized compounds exhibi-
ted significant antibacterial activity, and this activity can be modulated through the nature of
the functionality on ethyl spacer attached to piperazine ring and the type of side chain present
at the N-1 position of quinolone ring.
Keywords: Antibacterial activity / Furan / Quinolones / Synthesis /
Received: October 18, 2006; accepted: November 21, 2006
DOI 10.1002/ardp.200600169
Introduction
Quinolone antibacterial agents are among the most
important drugs in the anti-infective chemotherapy
field. Since the discovery of norfloxacin 1 and ciprofloxa-
cin 2 (Fig. 1), quinolones have changed the landscape of
antibacterial chemotherapy. Although the current qui-
nolones are generally characterized by a broad antibac-
terial spectrum, their activities against clinically impor-
tant Gram-positive pathogens including Staphylococcus
aureus are relatively moderate [1–5]. In addition, exten-
sive use of quinolones has brought increasing quinolone
resistance to many pathogens and the majority of methi-
Figure 1. Structures of compounds 1–5.
cillin-resistant Staphylococcus aureus (MRSA) have
obtained resistance to ciprofloxacin 2, a representative
fluoroquinolone, as well as other antibacterials [6–8].
Recent trends of the application of quinolones for the
treatment of respiratory tract infections by improving
their antibacterial activities against Gram-positive bac-
teria are likely associated with a relative decrease in activ-
ity against Gram-negative bacteria. Therefore, the devel-
opment of quinolones with potential utility for the treat-
Correspondence: Dr. Alireza Foroumadi, Pharmaceutical Sciences Re-
search Center, Tehran University of Medical Sciences, Tehran, Iran.
E-mail: aforoumadi@yahoo.com
Fax: +98 21 664-61178
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48
A. Foroumadi et al.
Arch. Pharm. Chem. Life Sci. 2007, 340, 47–52
Table 1. Structures and in vitro antibacterial activities of compounds 5a–l against selected strains (MICs in lg /mL).
Compd
X
Y
R
Gram-positive organisms
Gram-negative organisms
K. pneu- P. aerugi-
S. aureus MRSAa) I MRSA II S. epider- B. subtilis E. coli
midis
moniae
nosa
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
CH
CH
N
CH
CH
N
CH
CH
N
CH
CH
N
O
O
O
Et
c-Pr
Et
Et
c-Pr
Et
Et
c-Pr
Et
Et
c-Pr
Et
1.56
0.39
0.78
0.39
0.098
0.39
0.78
0.19
0.78
6.25
1.56
1.56
0.39
0.78
0.78
0.19
0.39
0.78
0.39
0.78
6.25
1.56
12.5
0.78
0.39
1.56
0.39
0.78
0.78
0.19
0.39
0.78
0.39
0.78
6.25
1.56
1.56
0.39
0.78
0.78
0.098
0.39
0.78
0.19
0.78
6.25
1.56
0.19
0.049
0.39
1.56
0.19
1.56
1.56
0.049
1.56
1.56
0.39
3.13
0.025
0.012
0.19
0.049
0.39
1.56
0.19
1.56
1.56
0.19
1.56
1.56
0.39
3.13
0.049
0.012
0.098
0.025
0.19
0.098
0.025
0.39
0.39
0.098
0.78
0.19
0.19
1.56
0.025
0.012
25
3.13
12.5
100
12.5
50
100
12.5
A100
100
NOH
NOH
NOH
NOCH3
NOCH3
NOCH3
NOBn
NOBn
NOBn
100
A100
25
0.39
0.19
12.5
0.78
0.39
12.5
0.39
0.19
Norfloxacin, 1
Ciprofloxacin, 2
3.13
0.39
a)
MRSA = methicillin-resistant S. aureus
ment of infections caused by both Gram-positive and position of the piperazine ring and allows manipulation
Gram-negative bacteria would represent significant pro- of selectivity and potency.
gress [9, 10].
Previously, we described the synthesis and antibacter-
Historically, the first quinolones contained a bicyclic ial activity of certain piperazinyl quinolones 4 (Fig. 1),
aromatic core in which a pyridone-3-carboxylic acid is with 2-(furan-2-yl)-2-oxoethyl or 2-(furan-2-yl)-2-oxyimi-
essential for antibacterial activity. These quinolones noethyl moieties attached to the piperazine ring at the C-
exhibited moderate Gram-negative activity and were 7 position [19]. In continuation of our search for more
used in the clinic to treat urinary tract infections. The potent antibacterial agents, herein we report prepara-
addition of piperazine ring at C-7 resulted in an increase tion and evaluation of N-[2-(furan-3-yl)-2-oxoethyl] and N-
in Gram-negative activity and oral absorption. Norfloxa- [2-(furan-3-yl)-2-oxyiminoethyl] piperazinyl quinolones 5
cin 1 was the first of the quinolones to have the C-6 fluor- as regioisomers of 4 (Fig. 1).
ine that increased quinolone activity and cell penetra-
tion. Further modification at the N-1, C-7, and C-8 posi-
tions yielded improvement activity against Gram-posi-
tives and anaerobes [1, 9, 10]. According to the inhibition
Results and discussion
mechanisms of the quinolones, proposed by Shen et al., Chemistry
the site near the C-7 substituent is regarded as drug- The target compounds 5a–l (Table 1) were prepared by
enzyme interaction domain and controls the spectrum the synthetic route reported in Scheme 1. 3-Acetylfuran 7
and selectivity of quinolone molecule [11–13].
was obtained from tributyl(3-furyl)stannane 6 according
Over the past few years, we were particularly inter- to the method reported in the literature [20]. Ketone 7
ested in the synthesis and evaluation of N-substituted 7- was brominated with CuBr2 in refluxing chloroform-
piperazinyl quinolones for their antibacterial activities ethyl acetate to give a-bromoketone 8 [21]. Compound 8
[14–18]. Although the nature of the C-7 substituent was was converted to oxime derivatives 9a–c by stirring with
known to influence quinolone activity in bacteria, we excess of appropriate hydroxylamine hydrochloride
identified that addition of a certain bulky group as a par- derivatives in methanol at room temperature [19]. Reac-
ticular chemical modification is permitted at the C-7 tion of quinolones 1, 2, or 3 with a-bromoketone 8 or
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Arch. Pharm. Chem. Life Sci. 2007, 340, 47–52
New N-substituted Piperazinylquinolone Antibacterials
49
Reagents and conditions: (a) CH3COCl, PdCl2 (Ph3P)2 (3 mol%), THF, rt; (b) CuBr2,
CHCl3-EtOAc, reflux; (c) hydroxylamine hydrochloride or O-methyl hydroxylamine
hydrochloride or O-benzyl hydroxylamine hydrochloride, MeOH, rt; (d) DMF, NaHCO3,
rt.
Scheme 1. Synthesis of compounds 5a–l.
a-bromooxime derivatives 9a–c in DMF, in the presence
of NaHCO3 at room temperature, afforded the corre-
sponding target compounds 5a–l [19]. Physicochemical
and spectroscopic data of these compounds are shown in
Table 2. Among oxime derivatives 5d–l, the unsubsti-
tuted oximes 5d–f were isolated as pure (E)-isomer while
O-substituted oximes 5g–l were obtained as a mixture of
(E)- and (Z)-isomers, mainly in the (E)-configuration. The
configuration of the oxime derivatives 5d–l was eluci-
dated by 1H-NMR spectroscopy (Table 2) [22–24]. In parti-
cular, this configurational assignment was simple due to
the de-shielding effect of oxime oxygen on the methylene
proton in the (Z)-configuration and on furan ring protons
in the (E)-configuration [22–24]. As representative 1H-
NMR data, the chemical shifts of the methylene protons
and furan ring in (E)- and (Z)-isomer of compound 5g and
(E)-isomer of compound 5d (norfloxacin derivatives) are
shown in Fig. 2. The protons of furan ring shifted down-
field in (E)-isomers of compounds 5d and 5g, while the
protons of methylene shifted downfield in compound (Z)-
5g.
Figure 2. Representative 1H-NMR data for configurational
assignment of oxime derivatives. The selected chemical shifts
(d ppm) of the methylene protons and furan ring in (E)-isomer of
compound 5d and (E)- and (Z)-isomers of compound 5g are
shown.
Antibacterial activity
5a–i and 5k, showed good activity (MIC = 0.098–1.56 lg/
mL) against the tested strain of staphylococci including
methicillin-resistant Staphylococcus aureus (MRSA). The
most active compound was 5e, an oxime derivative
which showed potency (MIC = 0.098–0.19 lg/mL) com-
parable, if not superior, to those of ciprofloxacin 2 (MIC =
0.19–0.39 lg/mL). However, the potency of this com-
pound was superior to norfloxacin against staphylococci.
In addition, the activities of compounds 5b, 5d, 5f, and
5h against staphylococci strains were comparable to nor-
floxacin 1. The MIC values of test derivatives indicate that
most of the compounds have noticeable activity against
another Gram-positive microorganism, B. subtilis (MIC =
Compounds 5a–l were evaluated for their antibacterial
activity against Staphylococcus aureus ATCC 6538p, methi-
cillin-resistant Staphylococcus aureus (MRSA I and MRSA II,
clinical isolate), Staphylococcus epidermidis ATCC 12228,
Bacillus subtilis ATCC 6633, Escherichia coli ATCC 8739,
Klebsiella pneumoniae ATCC 10031, and Pseudomonas aeru-
ginosa ATCC 9027 bacteria using a conventional agar-
dilution method [25]. The MIC (minimum inhibitory con-
centration) values were determined and compared to
norfloxacin 1 and ciprofloxacin 2 as reference drugs
(Table 1).
Overall, with the exception of 5j and 5l, which expli-
cated a moderate activity (MIC A 1.56 lg/mL), compounds
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50
A. Foroumadi et al.
Arch. Pharm. Chem. Life Sci. 2007, 340, 47–52
Table 2. Chemical, physical and spectral data of compounds 5a–l.
Compound
Mp
(8C)
Yield
(%)
1H NMR (500 MHz, DMSO-d6); d ppm
IR
(KBr, cm– 1
)
5a
217–218
54
1.40 (t, 3H, CH3, J =6.9 Hz), 2.68 –2.77 (m, 4H, piperazine), 3.33 –3.40 (m, 4H, piperazine), 1681 (C=O),
3.69 (s, 2H, COCH2), 4.59 (q, 2H, CH2-CH3, J= 6.9 Hz), 6.82–6.84 (m, 1H, furyl), 7.19 (d, 1H, 1619
H-8, J= 7.12 Hz), 7.81 (s, 1H, furyl), 7.91 (d, 1H , H-5, J=13.27 Hz), 8.73 (s, 1H, furyl), 8.95 (s,
1H, H-2), 15.34 (s, 1H, COOH).
5b
208–210
59
1.17–1.22 (m, 2H, cyclopropyl), 1.30–1.36 (m, 2H, cyclopropyl), 3.35–3.40 (m, 4H,
piperazine), 3.69 (s, 2H, COCH2), 3.72 –3.77 (m, 4H, piperazine), 3.80 –3.86 (m, 1H,
cyclopropyl), 6.83–6.84 (m, 1H, furyl), 7.59 (d, 1H, H-8, J = 7.40 Hz), 7.81 –7.82 (m, 1H,
furyl), 7.92 (d, 2H, H-5, J= 13.3 Hz), 8.67 (s, 1H, furyl), 8.74 (s, 1H, H-2), 15.34 (s, 1H, COOH).
1685 (C=O),
1618
5c
204–205
268–270
46
52
1.40 (t, 3H, CH3, J = 7.01Hz), 2.69–2.73 (m, 4H, piperazine), 3.30–3.40 (m, 4H, piperazine), 1721 (C=O),
3.70 (s, 2H, COCH2), 4.55–4.65 (m, 2H, CH2-CH3), 6.82 –6.85 (m, 1H, furyl), 7.71 (s, 1H,
1695, 1629
furyl),7.92 (d, 1H, H-5, J = 13.26 Hz), 8.75 (s, 1H, furyl),8.95 (s, 1H, H-2), 15.33 (s, 1H, COOH).
1.40 (t, 3H, CH3, J = 7.0 Hz), 2.60–2.66 (m, 4H, piperazine), 3.26–3.35 (m, 4H, piperazine), 3405 (NOH),
3.40 (s, 2H, CH2), 4.58 (q, 2H, CH2-CH3, J = 7.0 Hz), 6.96 –6.98 (m, 1H, furyl), 7.19 (d, 1H, H-8, 1721 (C=O),
5d (E-isomer)
J = 7.1 Hz), 7.70 (s, 1H, furyl), 7.92 (d, 1H, H-5, J = 13.2 Hz), 8.47 (s, 1H, furyl), 8.95 (s, 1H,
H-2), 11.48 (s, 1H, NOH), 15.36 (s, 1H, COOH).
1634
5e (E-isomer)
5f (E-isomer)
5g (E/Z=79/21)
258–259
249–251
203–204
47
59
44
1.16–1.21 (m, 2H, cyclopropyl), 1.29–1.36 (m, 2H, cyclopropyl), 2.62–2.68 (m, 4H,
piperazine), 3.28 –3.36 (m, 4H, piperazine), 3.38 (s, 2H, CH2), 3.77–3.83 (m, 1H, cyclo-
propyl), 6.97 (s, 1H, furyl), 7.20 (d, 1H, H-8, J = 7.40 Hz), 7.70 (s ,1H, furyl), 7.90 (d, 2H, H-5, 1634
J = 13.2 Hz), 8.47 (s, 1H, furyl), 8.66 (s, 1H, H-2), 11.49 (s, 1H, NOH), 15.20 (s, 1H, COOH).
3411(NOH),
1716 (C=O),
1.38 (t, 3H, CH3, J = 7.0Hz), 2.57 –2.63 (m, 4H, piperazine), 3.34 (s, 2H, CH2), 3.77–3.83 (m, 3408 (NOH),
4H, piperazine), 4.49 (q, 2H, CH2-CH3, J= 6.91Hz), 6.97 (s, 1H, furyl), 7.71 (s, 1H, furyl),
8.09 (d, 1H, H-5, J=13.26 Hz), 8.47 (s, 1H, furyl), 8.98 (s, 1H, H-2), 11.48 (s, 1H, NOH),
15.32 (s, 1H, COOH).
1.41 (t, 3H, CH3, J =7.0 Hz), 2.62 –2.68 (m, 4H, piperazine), 3.26-3.32 (m, 4H, piperazine),
3.58 (s, 2H, CH2, E-isomer), 3.83 (s, 2H, CH2, Z-isomer), 3.88 (s, 3H, OCH3, Z-isomer), 3.94
(s, 3H, OCH3, E-isomer), 4.50 (q, 2H, CH2-CH3, J = 7.0 Hz), 6.72–6.74 (m, 1H, furyl, Z-isomer),
6.95–6.97 (m, 1H, furyl, E-isomer), 7.19 (d, 1H, H-8, J=7.22 Hz), 7.67 (s, 1H, furyl, Z-isomer),
7.72 (s, 1H, furyl, E-isomer), 7.92 (d, 1H, H-5, J= 13.26 Hz), 8.25 (s, 1H, furyl, Z-isomer), 8.42
(s, 1H, furyl, E-isomer), 8.94 (s, 1H, H-2), 15.33 (s, 1H, COOH).
1720 (C=O),
1633
1726 (C=O),
1629
5h (E/Z=57/43)
135–136
44
1.16–1.21 (m, 2H, cyclopropyl), 1.28–1.36 (m, 2H, cyclopropyl), 2.62–2.70 (m, 4H,
piperazine), 3.28 –3.34 (m, 4H, piperazine), 3.38 (s, 2H, CH2, E-isomer), 3.58 (s, CH2,
Z-isomer),3.78 –3.84 (m, 1H, cyclopropyl), 3.88 (s, 2H, OCH3, Z-isomer), 3.94 (s, 2H, OCH3,
E-isomer), 6.72 (s, 1H, furyl, Z-isomer), 6.95 (s, 1H, furyl, E-isomer), 7.57 (d, 1H, H-8, J= 7.4
Hz), 7.68 (s, 1H, furyl,Z-isomer), 7.73 (s, 1H, furyl, E-isomer), 7.90 (d, 2H, H-5, J= 12.6 Hz),
8.26 (s, 1H, furyl, Z-isomer), 8.43 (s, 1H, furyl, E-isomer) 8.66 (s, 1H, H-2), 15.21 (s, 1H,
COOH).
1734 (C=O),
1617
5i (E/Z=73/27)
5j (E/Z=62/38)
5k (E/Z=64/36)
169–170
169–171
154–156
45
49
48
1.38 (t, 3H, CH3, J = 7.0 Hz), 2.57–2.63 (m, 4H, piperazine), 3.34 (s, 2H, CH2-E isomer),
3.54 (s, 2H, CH2-Z isomer), 3.77–3.84 (m, 4H, piperazine), 3.86 (s, 2H, OCH3, Z-isomer),
3.92(s, 2H, OCH3, E-isomer), 4.49 (q, 2H, CH2-CH3, J=7.0 Hz), 6.71 (s, 1H, furyl, Z-isomer),
6.95 (s, 1H, furyl, E-isomer), 7.68 (s, 1H, furyl, Z-isomer), 7.74 (s, 1H, furyl, E-isomer),
8.09 (d, 1H, H-5, J= 13.24 Hz), 8.27 (s, 1H, furyl, Z-isomer), 8.43 (s, 1H, furyl, E-isomer),
15.32 (s, 1H, COOH).
1721 (C=O),
1634
1.40 (t, 3H, CH3, J =7.13 Hz), 3.23–3.32 (m, 4H, piperazine), 3.38 (s, 2H, CH2, E-isomer),
1731 (C=O),
3.58–3.65 (m, 4H, piperazine), 3.62 (s, 2H, CH2, Z-isomer), 4.58 (q, 2H, CH2-CH3, J= 6.93 Hz), 1629
5.17 (s, 2H, OCH2, Z-isomer), 5.23 (s, 2H, OCH2, E-isomer), 6.71 (s, 2H, furyl, Z-isomer), 6.96
(s, 2H, furyl, E-isomer), 7.17 (d, 1H, H-8, J = 7.18 Hz), 7.29–7.43 (m, 5H, phenyl), 7.67 (s, 2H,
furyl, Z-isomer), 7.73 (s, 2H, furyl, E-isomer), 7.93 (d, 2H, H-5, J=13.20 Hz), 8.25 (s, 1H, furyl,
Z-isomer), 8.44 (s, 1H, furyl, E-isomer), 8.95 (s, 1H, H-2), 15.34 (s, 1H, COOH).
1.13–1.20 (m, 2H, cyclopropyl), 1.29–1.35 (m, 2H, cyclopropyl), 2.59–2.68 (m, 4H,
piperazine), 3.25 –3.32 (m, 4H, piperazine), 3.38 (s, 2H, CH2, E-isomer), 3.62 (s, CH2,
Z-isomer), 3.77 –3.85 (m, 1H, cyclopropyl), 5.17 (q, 2H, OCH2, Z-isomer), 5.23 (q, 2H, OCH2,
E-isomer), 6.70 (s, 1H, furyl, Z-isomer), 6.96 (s, 1H, furyl, E-isomer), 7.30–7.43 (m, 5H,
phenyl), 7.55 (d, 2H, H-8, J = 7.28 Hz), 7.67 (s, 1H, furyl, Z-isomer), 7.73 (s, 1H, furyl,
E-isomer), 7.90 (d, 2H, H-5 , J=13.2 Hz), 8.25 (s, 1H, furyl, Z-isomer), 8.44 (s, 1H, furyl,
E-isomer) 8.66 (s, 1H, H-2), 15.20 (s, 1H, COOH).
1730 (C=O),
1623
5l (E/Z=51/49)
167–169
41
1.34–1.43 (m, 3H, CH3), 2.53–2.61 (m, 4H, piperazine), 3.74 –3.83 (m, 4H, piperazine),
3.32 (s, 2H, CH2, E-isomer), 3.78 (s, 2H, CH2, Z-isomer), 4.49 (q, 2H, CH2-CH3, J=6.89 Hz),
5.15(s, 2H, OCH2, Z-isomer), 5.22 (s, 2H, OCH2, E-isomer), 6.70 (s, 1H, furyl, Z-isomer),
6.96 (s, 1H, furyl, E-isomer), 7.28-7.41 (m, 5H, phenyl), 7.68 (s, 1H, furyl, Z-isomer), 7.74
(s, 1H, furyl, E-isomer), 8.09 (d, 1H, H-5, J=13.44 Hz), 8.26 (s, 1H, furyl, Z-isomer), 8.45
(s, 1H, furyl, E-isomer), 8.98 (s, 1H, H-2), 15.32 (s, 1H, COOH).
1720 (C=O),
1629
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Arch. Pharm. Chem. Life Sci. 2007, 340, 47–52
New N-substituted Piperazinylquinolone Antibacterials
51
Table 3. In vitro antibacterial activities of N-[2-(furan-2-yl)ethyl]
piperazinyl quinolone derivatives 4a–h against selected strains
(MICs in lg /mL)a).
2-oxoethyl or 2-(furan-2-yl)-2-oxyiminoethyl moieties
attached to the piperazine ring (Table 3). Compounds 4,
despite having comparable antibacterial activity with
respect to reference drugs, against staphylococci, showed
less activity against Gram-negative bacteria [19]. In the
present study, we primarily investigated the effect of
positional isomerism of furan ring by preparing and anti-
bacterial evaluation of furan-3-yl- regioisomer of 4. Simi-
larly, N-[2-(furan-3-yl)ethyl] piperazinyl moiety are well
tolerated at C-7 position, in the terms of antibacterial
activity, and the nature of the functionality on the ethyl
spacer attached to the piperazine ring can modulate the
antibacterial activity. For more comparison, some signifi-
cant antibacterial data of our previously described com-
pounds 4 are presented in Table 3 for two Gram-positive
(S. aureus and S. epidermidis) and two Gram-negative (E.
coli and K. pneumoniae) microorganisms [19]. Comparison
between MIC values of furan-2-yl derivatives 4 and corre-
sponding furan-3-yl derivatives 5 against S. aureus and S.
epidermidis reveal that this positional modification can-
not improve the potency against Gram-positives.
Comparison between MIC values of furan-2-yl deriv-
atives 4 and corresponding furan-3-yl derivatives 5 against
selected Gram-negative bacteria (E. coli and K. pneumoniae)
indicate that all oxime derivatives of furan-2-yl series 4c–
h are less active than their furan-3-yl counterparts. Thus,
this pharmacomodulation (change of furan-2-yl regioi-
somer to furan-3-yl) in oxime series exerts a positive effect
in the term of activity against Gram-negatives, with main-
taining activityagainst staphylococci.
Com-
pound
Y
R
S. aureus S. epide- E. coli
rmidis
K. pneu-
moniae
4a
4b
4c
4d
4e
4f
O
O
Et
c-Pr
Et
1
0.5
0.06
0.03
4
1
8
0.5
4
0.5
0.25
0.03
8
2
8
2
8
2
0.5
0.5
0.13
1
0.25
1
0.25
0.25
0.13
0.5
0.25
1
NOH
NOH
NOCH3 Et
NOCH3 c-Pr
NOBn
NOBn
c-Pr
4g
4h
Et
c-Pr
0.13
0.25
a)
Data from our previous work [19].
0.049–1.56 lg/mL). Compounds 5b and 5h demonstrated
MIC = 0.049 lg/mL, comparable to those of norfloxacin 1
against this microorganism.
The activities of compounds 5a–l were significant
against Gram-negative bacteria, with the exception of
activity against P. aeruginosa. Indeed, all compounds with
the exception of 5b, exhibited poor or no activity against
this microorganism. The better activities against Gram-
negatives were observed for compound 5b.
When the antibacterial activity of the ketones 5a–c
was compared with their corresponding oximes 5d–f; a
relative increase in anti-staphylococci activity was found
but a decrease in activity against Gram-negative strains.
Although the O-methylation of oxime 5e (ciprofloxacin
derivative) resulted in improvement of activity against
Gram-negative bacteria with maintaining activity
against Gram-positives, this type of substitution could
not change the activity of oximes 5d (norfloxacine deriv-
ative) and 5f (enoxacin derivative) and differences were
not significant. Thus, the impact of functionality of ethyl
spacers attached to the piperazine ring on antibacterial
activity is highly dependent on the side chain present at
the N-1 position of the quinolone core. It also should be
noticed that, when the oxime or O-methyl oxime groups
are replaced by bulky O-benzyl groups, the antimicrobial
activity diminishes. SAR studies show that, in all series,
compounds bearing a cyclopropyl substituent at posi-
tions 1 are more potent than that carrying an ethyl sub-
stituent. Thus, the cyclopropyl group confers higher
potency than the ethyl group similar to the parent quino-
lones.
As can be deduced from these data, most of the synthe-
sized compounds exhibited significant antibacterial
activity and this activity can be modulated through the
nature of the functionality on the ethyl spacer attached
to the piperazine ring and the type of side chain present
at the N-1 position.
The results demonstrated that the introduction of
furan-3-yl group instead of furan-2-yl group at 2-position
of 2-oxyiminoethyl moiety attached to the piperazine
ring in 7-piperazinyl quinolones improved the antibac-
terial activity against Gram-negative bacteria while
maintaining good activity against Gram-positives.
This work was supported by grants from the Research Coun-
cil of Tehran University of Medical Sciences and Islamic Azad
University.
Experimental
Chemicals and all solvents used in this study were purchased
from Merck AG and Aldrich Chemical (Merck, Darmstadt and
Aldrich, Steinhein, both Germany). The 3-Acetylfuran 7 and 3-
Previously, we described the synthesis and antibacter-
ial activity of piperazinyl quinolones 4 with 2-(furan-2-yl)-
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52
A. Foroumadi et al.
Arch. Pharm. Chem. Life Sci. 2007, 340, 47–52
(bromoacetyl)furan 8 were prepared according to the literature
[20, 21]. Melting points were determined on a Kofler hot stage
apparatus (C. Reichert, Vienna, Austria) and are uncorrected.
The IR spectra were obtained on a Shimadzu 470 spectro-
photometer (potassium bromide disks; Shimadzu, Tokyo, Japan).
1H NMR spectra were measured using a Bruker 500 spectrometer
(Bruker, Rheinstetten, Germany), and chemical shifts are
expressed as d (ppm) with tetramethylsilane as internal stan-
dard. Elemental analyses were carried out on a HERAEUS CHN-O-
rapid elemental analyzer (Heraeus GmbH, Germany) for C, H,
and N and the results are within l0.4% of the theoretical values.
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A solution of 3-(bromoacetyl)furan 8 (1.0 mmol) and hydroxyl-
amine hydrochloride derivatives (2.0 mmol) in methanol
(10 mL) was stirred at room temperature for 3–7 days. Water
(40 mL) was added and it was extracted with CHCl3. The organic
layer was washed (H2O), dried (Na2SO4), and evaporated in vacuo
to give 9a–c.
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5a–l
A mixture of 3-(bromoacetyl)furan 8 or a-bromooxime deriv-
atives 9a–c (0.55 mmol), quinolone 1–3 (0.5 mmol), and
NaHCO3 (0.5 mmol) in DMF (5 mL), was stirred at room tempera-
ture for 12–72 h. After consumption of quinolone 1–3, water
(20 mL) was added and the precipitate was filtered, washed with
water, and crystallized from methanol-chloroform to give com-
pound 5a–l.
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A. Zeynali, Pharmazie 2003, 58, 432–433.
Compounds 5a–l were evaluated for their antibacterial activity
using conventional agar-dilution method [25]. Twofold serial
dilutions of the compounds and reference drugs were prepared
in Mꢀller–Hinton agar. Drugs (10.0 mg) were dissolved in DMSO
(1 mL) and the solution was diluted with water (9 mL). Further
progressive double dilution with melted Mꢀller–Hinton agar
was performed to obtain the required concentrations of 100, 50,
25, 12.5, 6.25, 3.13, 1.56, 0.78, 0.39, 0.19, 0.098, 0.049, 0.025,
0.012, and 0.06 lg/mL. Petri dishes were incubated with 1–
56104 colony forming units (cfu) and incubated at 378C for
18 h. The minimum inhibitory concentration (MIC) was the low-
est concentration of the test compound, which resulted in no
visible growth on the plate. To ensure that the solvent had no
effect on bacterial growth, a control test was performed with
test medium supplemented with DMSO at the same dilutions as
used in the experiment.
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[21] K. A. Lutomski, U.S. Patent 4,908,357, 1990.
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i 2007 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com