Synthesis and in-vitro antimycobacterial activity of fluoroquinolone derivatives containing a coumarin moiety

Article abstract of DOI:10.1002/ardp.201000256

A series of gatifloxacin, ciprofloxacin, and 8-OCH₃ ciprofloxacin coumarin derivatives with remarkable improvement in lipophilicity as compared to the parent fluoroquinolones was designed, synthesized, and characterized by ¹H-NMR, MS, and HRMS. These derivatives were evaluated for their in-vitro activity against Mycobacterium smegmatis CMCC 93202 and MTB H37Rv ATCC 27294. All of the synthesized compounds were less active than the parent compounds against M. smegmatis CMCC 93202, but the activity of compound 6 was found to be 2-8-fold more potent than ciprofloxacin, 8-OCH ₃ ciprofloxacin, moxifloxacin, and rifampin, and comparable to gatifloxacin against MTB H37Rv ATCC 27294. These results indicated that the lipophilicity of the tested compounds is not the sole parameter affecting antimycobacterial activity. A series of gatifloxacin, ciprofloxacin, and 8-OCH₃ ciprofloxacin coumarin derivatives was designed, synthesized, characterized and evaluated for their in-vitro activity. The activity of one compound (6) was found to be 2-8-fold more potent than the respective parent GTFX, CPFX, and 8-OCH₃ CPFX, indicating that the lipophilicity of the tested compounds is not the sole parameter affecting antimycobacterial activity. Copyright

Full text of DOI:10.1002/ardp.201000256

802
Arch. Pharm. Chem. Life Sci. 2011, 344, 802–809
Full Paper
Synthesis and In-Vitro Antimycobacterial Activity of
Fluoroquinolone Derivatives Containing a Coumarin Moiety
Qiang Guo*, Ming-Liang Liu*, Lian-Shun Feng, Kai Lv, Yan Guan, Hui-Yuan Guo, and Chun-Ling Xiao*
Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical
College, Beijing, P. R. China
A series of gatifloxacin, ciprofloxacin, and 8-OCH3 ciprofloxacin coumarin derivatives with remark-
able improvement in lipophilicity as compared to the parent fluoroquinolones was designed,
synthesized, and characterized by 1H-NMR, MS, and HRMS. These derivatives were evaluated for
their in-vitro activity against Mycobacterium smegmatis CMCC 93202 and MTB H37Rv ATCC 27294. All of
the synthesized compounds were less active than the parent compounds against M. smegmatis CMCC
93202, but the activity of compound 6 was found to be 2–8-fold more potent than ciprofloxacin,
8-OCH3 ciprofloxacin, moxifloxacin, and rifampin, and comparable to gatifloxacin against MTB H37Rv
ATCC 27294. These results indicated that the lipophilicity of the tested compounds is not the sole
parameter affecting antimycobacterial activity.
Keywords: 8-OCH3 ciprofloxacin / Antimycobacterial activity / Ciprofloxacin / Coumarin / Gatifloxacin
Received: September 6, 2010; Revised: November 22, 2010; Accepted: November 30, 2010
DOI 10.1002/ardp.201000256
Introduction
HIV-positive patients [1, 3]. Accordingly, there is an urgent
need to develop novel and highly effective anti-TB drugs.
Fluoroquinolone (FQ) antibacterial agents act by inhibiting
bacterial type II DNA topoisomerases, DNA gyrase, and top-
oisomerase IV which are both required for cell growth and
division [4]. DNA gyrase seems to be the sole topoisomerase
drug target of FQs in MTB [5]. Resistance to FQs remains
relatively low in clinical isolates of MTB currently, and there
are no reports of cross-resistance or antagonism with other
classes of antimycobacterial agents [6, 7]. Some early FQs,
including ciprofloxacin (CPFX, Fig. 1), ofloxacin, and sparflox-
acin were recommended as second-line agents for the treat-
ment of TB mainly in cases involving resistance or
intolerance to first-line anti-TB therapy by WHO in
1996 [8]. It was noted that newer FQs as moxifloxacin
(MXFX, Fig. 1) and gatifloxacin (GTFX, Fig. 1), having a particu-
larly strong in-vitro and in-vivo activity against MTB, could be
promising agents for the treatment of TB [9].
Tuberculosis (TB) is a common deadly contagious disease
caused by various mycobacteria, mainly by Mycobacterium tuber-
culosis (MTB) in human [1]. The global epidemic of TB is assum-
ing alarming proportions. The World Health Organization
(WHO) has estimated that approximately 2 billion people have
been infected with MTB, and about 2 million people are killed
by this bacterial pathogen annually [2]. The increasing emer-
gence of drug-resistant TB (DR-TB), especially multidrug-
resistant TB (MDR-TB) is causing particular concern; Besides
the emergence of DR-TB and MDR-TB, another contributing
factor underlying the resurgence of TB is HIV co- infection with
TB, in which TB is the leading cause of death among
Correspondence: Dr. Ming-Liang Liu, Institute of Medicinal Biotechnol-
ogy, Chinese Academy of Medical Sciences and Peking Union Medical
College, Beijing 100050, P. R. China.
Structure–activity relationship studies of FQs have been
extensively investigated and the substituent at the C-7 pos-
ition has great influence on their potency, spectrum, and
E-mail: xiaocl@163.com
Fax: þ86-10-63036965
Dr. Chun-Ling Xiao, Institute of Medicinal Biotechnology, Chinese Academy
of Medical Sciences and Peking Union Medical College, Beijing 100050,
P. R. China.
E-mail: xiaocl@163.com
Fax: þ86-10-63020226
* These two authors contributed equally to this article.
ß 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Arch. Pharm. Chem. Life Sci. 2011, 344, 802–809
New fluoroquinolone derivatives
803
O
N
remarkable improvement in the lipophilicity was not
assayed. It was reported that 8-OCH3 FQs with N1-cyclopropyl
substitution are much more active against resistant MTB
than C-8 hydrogen analogs [20]. Accordingly, in this report,
three classes of GTFX, a 8-OCH3 FQ with strong anti-TB
activity, CPFX, one of anti-TB agents, and its 8-OCH3 analog
(8-OCH3 CPFX, Fig. 1) derivatives containing an (un)substi-
tuted coumarin moiety were designed and synthesized to
explore the effect of lipophilic character at 7-position of these
FQs on activity against mycobacteria.
O
F
COOH
F
COOH
H
HN
R
N
X
N
N
O
CH3
HN
H
Gatifloxacin: R = CH3, X = C-OCH3
Ciprofloxacin: R = H, X = CH
Moxifloxacin
8-Methoxycprofloxacin: R = H, X = C-OCH3
Figure 1. Chemical structures of some fluoroquinolones.
safety [10–12]. The lipophilicity of FQs was suggested to play
an important role in the penetration of them into bacterial Results and discussion
cells, and simply increasing the lipophilic character at C-7
position could also increase the anti-TB activity [7, 13]. For
example, some of FQs (CPFX, GTFX, and balofloxacin) deriva-
tives containing a lipophilic isatin moiety were found to be
far more active than the respective parent drugs [1, 7, 13].
Coumarin is an endogenous compound identified in many
organisms [14], and its derivatives have variety of biological
activities like antibacterial [15], anti-inflammatory [16], anti-
tumor [17], and anti-TB activity [18]. Emami et al. synthesized
a series of norfloxacin-, enoxacin-, and CPFX-coumarin con-
jugates and found that one of them showed comparable or
better antibacterial activity than the parent FQ [19]. It was a
pity that antimycobacterial activity of these derivatives with
Chemistry
Detailed synthetic pathways to GTFX, CPFX and 8-OCH3 CPFX
coumarin derivatives 5–22 are depicted in Scheme 1. Aldol
condensation and cyclization of 2-hydroxybenzaldehydes
1a–c with ethyl acetoacetate in the presence of diethylamine
gave 3-acetyl coumarins 2a–c (40.6–72.8%). The compounds
2a–c were converted to 3-(bromoacetyl)coumarins 3a–c
(54.6–80.6%) by refluxing with Br2 in CHCl3 or tetra-n-butyl-
ammonium tribromide (TBABr3) in CH2Cl2. The oxime func-
tional groups were introduced into the a-bromoketones 3a–c
by coupling with methoxyamine hydrochloride or ethoxy-
amine hydrochloride in the presence of NaOAc to afford
O
O
NX
Br
CHO
OH
(iii)
(ii)
(i)
Br
R1
O
R1
R1
O
O
O
R1
O
O
4a-d
2a-c
3a-c
1a-c
4a: R1 = H, X = OCH3
1-3a: R1 = H
4b: R1 = H, X = OC2H5
4c: R1 = OCH3, X = OCH3
4d: R1 = OCH3, X = OC2H5
1-3b: R1 = OCH3
1-3c: R1 = OH
(iv)
(iv)
O
COOH
F
N
X
N
R2
N
R
O
R1
O
5-22
5: R1 = H, R2 = O, X = C-OCH3, R = H
14: R1 = H, R2 = NOC2H5, X = C-OCH3, R = CH3
15: R1 = OCH3, R2 = NOCH3, X = C-OCH3, R = CH3
16: R1 = OCH3, R2 = NOC2H5, X = C-OCH3, R = CH3
17: R1 = OCH3, R2 = O, X = CH, R = H
6: R1 = OCH3, R2 = O, X = C-OCH3, R = H
7: R1 = OH, R2 = O, X = C-OCH3, R = H
8: R1 = H, R2 = NOCH3, X = C-OCH3, R = H
9: R1 = H, R2 = NOC2H5, X = C-OCH3, R = H
10: R1 = OCH3, R2 = NOCH3, X = C-OCH3, R = H
18: R1 = OH, R2 = O, X = CH, R = H
19: R1 = H, R2 = NOCH3, X = CH, R = H
11: R1 = OCH3, R2 = NOC H , X = C-OCH , R = H
20: R1 = H, R2 = NOC2H5, X = CH, R = H
21: R1 = OCH3, R2 = NOCH3, X = CH, R = H
22: R1 = OCH3, R2 = NOC2H5, X = CH, R = H
5
12: R1 = OCH3, R2 = O, X 2= C-OCH3, R = 3CH3
13: R1 = H, R2 = NOCH3, X = C-OCH3, R = CH3
(i) CH3COCH2COOCH2CH3, Et2NH, EtOH; (ii) Br2, CHCl3 (for 2a) or TBABr3, CH2Cl2 (for 2b,c);
(iii) CH3ONH2.HCl or C2H5ONH2.HCl, NaOAc, MeOH; (iv) GTFX, CPFX or 8-OCH3 CPFX, NaHCO3, DMF
Scheme 1. Synthetic route of fluoroquinolone derivatives 5–22.
ß 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

804
Q. Guo et al.
Arch. Pharm. Chem. Life Sci. 2011, 344, 802–809
Table 1. Structures, lipophilicity, and antimycobacterial activity of compounds 5–22
O
COOH
F
N
X
N
R2
N
R
O
R1
O
5-22
Compd.
R1
R2
R
X
logP a
MIC (mg/mL)
M.s. b
MTB c
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
H
OCH3
OH
H
H
OCH3
OCH3
OCH3
H
O
O
O
H
H
H
H
H
H
H
CH3
CH3
CH3
CH3
CH3
H
C–OCH3
C–OCH3
C–OCH3
C–OCH3
C–OCH3
C–OCH3
C–OCH3
C–OCH3
C–OCH3
C–OCH3
C–OCH3
C–OCH3
CH
2.24
6.25
6.25
6.25
6.25
6.25
6.25
6.25
>12.5
>12.5
>12.5
6.25
6.25
12.5
3.12
12.5
>12.5
12.5
12.5
0.10
0.39
0.1
1.0
0.25
1.0
2.11
1.85
2.89
3.23
2.76
3.10
2.43
3.21
3.55
3.08
3.42
2.24
1.98
3.02
3.36
2.89
3.23
1.51
1.32
1.20
1.68
NOCH3
NOC2H5
NOCH3
NOC2H5
O
NOCH3
NOC2H5
NOCH3
NOC2H5
O
1.0
>128
>128
>128
1.0
1.0
>128
1.0
1.0
>128
H
OCH3
OCH3
OCH3
OH
H
H
O
H
H
H
H
CH
CH
CH
CH
0.5
1.0
2.0
4.0
4.0
0.25
1.0
0.5
0.5
2.0
0.125
NOCH3
NOC2H5
NOCH3
NOC2H5
OCH3
OCH3
H
CH
GTFX
CPFX
8-OCH3CPFX
MXFX
RIF
0.1
3.12
0.78
INH
c
aThe logP is calculated by ChemOffice 2009 software; bM.s.: M. smegmatis CMCC 93202; MTB: MTB H37Rv ATCC 27294.
a-bromooxime derivatives 4a–d (68.2-93.8%) [14, 19, 21, 22].
Nucleophilic substitution reactions of FQs (GTFX, CPFX, and
8-OCH3 CPFX) with a-bromoketones 3a–c or a-bromooximes
4a–d in DMF, in the presence of NaHCO3, provide FQs deriva-
tives 5–22 (35.4-68.6%).
using t-test). This may be rendering them more capable of
penetrating various biomembranes, consequently improving
their penetrability toward mycobacterial cell membrane. In
other words, the improvement of the lipophilic character of
the target compounds 5–22 probably enhances their antimy-
cobacterial activity.
Lipophilicity
Lipophilicity of the synthesized GTFX, CPFX, and 8-OCH3
CPFX coumarin derivatives 5–22, the parent compounds
GTFX, CPFX, and 8-OCH3 CPFX are expressed in the terms
of their logP values which were calculated with ChemOffice
2009 software. As shown in Table 1, a remarkable improve-
ment was seen in the lipophilicity of the derivatives 5–22
(1.85–3.55) as evidenced by logP values which were higher
than compared with the respective parent GTFX, CPFX, and
8-OCH3 CPFX (1.20–1.51) (statistically significant at p <0.0001
Pharmacology
The target compounds 5–22 were initially evaluated for their
in-vitro antimycobacterial activity against M. smegmatis CMCC
93202 using serial double dilution technique in duplicate,
and then against MTB H37Rv ATCC 27294 using rapid direct
susceptibility test technique [1]. The minimum inhibitory
concentration (MIC) is defined as the concentration of the
compound required to give complete inhibition of mycobac-
terial growth, and MICs of the synthesized compounds along
ß 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

Arch. Pharm. Chem. Life Sci. 2011, 344, 802–809
New fluoroquinolone derivatives
805
with GTFX, CPFX, 8-OCH3 CPFX, MXFX, and rifampin (RIF) for ionization (ESI) mass spectra and high resolution mass spec-
comparison are presented in Table 1. These data suggested tra (HRMS) were obtained on a MDSSCIEX Q-Tap mass spec-
that all of the target compounds had considerable activity trometer and AccuTOF CS JMS-T100CS (JEOL) mass
against M. smegmatis CMCC 93202 (MIC: 3.12–>12.5 mg/mL), spectrometer, respectively. Unless otherwise noted, the
although less active than the respective parent GTFX, CPFX, reagents were obtained from commercial supplier and used
and 8-OCH3 CPFX (MIC: 0.1–0.39 mg/mL, respectively).
without further purification. TLC was performed on silica gel
Compounds 5–8, 12, 13, 15, 16, 18, and 19 (MIC: 0.25– plates (Merck, ART5554 60F254).
1.0 mg/mL) showed good potency in inhibiting the growth
of MTB H37Rv ATCC 27294. Among them, the activity of General procedure for the synthesis of 2a–c
compound 18 (MIC: 0.5 mg/mL) was 2-fold more potent than A solution of 2-hydroxybenzaldehydes 1a–c (0.38 mol), ethyl
its parent CPFX (1.0 mg/mL) and comparable to MXFX. The acetoacetate (50 mL, 0.39 mol), and diethylamine (1 mL,
most active compound 6 (MIC: 0.25 mg/mL) was found to be 0.02 mol) in ethanol (100 mL) was stirred at room tempera-
2–8-fold more potent than 8-OCH3 CPFX, CPFX, MXFX, and RIF ture for 10 h. The yellow solid obtained was filtered, washed
and comparable to GTFX against this strain.
with ether and recrystallized from alcohol to afford the title
compounds 2a–c.
Conclusion
3-Acetylcoumarin 2a
Yield: 72.8%. mp: 115–1188C ([23], mp: 1188C). 1H-NMR
(400 MHz, DMSO-d6) dppm: 2.57 (3H, s, COCH3), 7.39–7.46
(2H, m, Ph-H), 7.71–7.75 (1H, m, Ph-H), 7.93–7.95 (1H, m,
Ph-H), 8.64 (1H, s, Ph-H). ESI-MS: m/z 189 (MþH)þ.
In summary, a series of GTFX, CPFX, and 8-OCH3 CPFX cou-
marin derivatives was designed, synthesized, and character-
ized by 1H-NMR, MS, and HRMS. These derivatives were
initially evaluated for their in-vitro antimycobacterial activity
against M. smegmatis CMCC 93202, and then against MTB
H37Rv ATCC 27294. The data showed that all of the target
compounds with improved lipophilicity were less active than
the respective parent GTFX, CPFX, and 8-OCH3 CPFX against
M. smegmatis CMCC 93202. Some of them showed good
activity against MTB H37Rv ATCC 27294 and the activity of
8-OCH3 CPFX derivative 6 (MIC: 0.25 mg/mL) was found to be
2–8-fold more potent than 8-OCH3 CPFX, CPFX, MXFX, and RIF
and comparable to GTFX against this strain.
3-Acetyl-7-methoxycoumarin 2b
Yield: 65.5%. mp: 171–1738C ([23], mp: 1708C). 1H-NMR
(400 MHz, DMSO-d6) dppm: 2.54 (3H, s, COCH3), 3.88 (3H,
s, OCH3), 6.99–7.05 (2H, m, Ph-H), 7.85–7.87 (1H, m, Ph-H),
8.62 (1H, s, Ph-H). ESI-MS: m/z 219 (MþH)þ.
3-Acetyl-7-hydroxycoumarin 2c
Yield: 40.6%. mp: 244–2458C ([24], mp: 2408C). 1H-NMR
(400 MHz, DMSO-d6) dppm: 2.54 (3H, s, COCH3), 6.74–6.85
(2H, m, Ph-H), 7.76–7.79 (1H, m, Ph-H), 8.58 (1H, s, Ph-H).
ESI-MS: m/z 204 (MþH)þ.
The relative contribution of GTFX, CPFX, and 8-OCH3 CPFX
moieties to activity against MTB H37Rv ATCC 27294 is as
follows: (1) for 7-OCH3 coumarin, 8-OCH3 CPFX (MIC:
0.25 mg/mL) > GTFX (MIC: 0.5 mg/mL) > CPFX (MIC: 1.0 mg/mL),
when R ¼ O; GTFX (MIC: 1.0 mg/mL) > CPFX (MIC: 4.0 mg/mL) >
8-OCH3 CPFX (MIC: >128 mg/mL), when R ¼ NOCH3 or NOC2H5;
(2) for 7-OH coumarin, CPFX (MIC: 0.5 mg/mL) > 8-OCH3 CPFX
(MIC: 1.0 mg/mL), when R ¼ O; (3) for 7-H coumarin, GTFX (MIC:
1.0 mg/mL) ꢀ CPFX (MIC: 1.0 mg/mL) ꢀ 8-OCH3 CPFX (MIC:
1.0 mg/mL), when R ¼ NOCH3; CPFX (MIC: 2.0 mg/mL) >>
GTFX (MIC: >128 mg/mL) ꢀ 8-OCH3 CPFX (MIC: >128 mg/mL),
when R ¼ NOC2H5. Our results indicated that the lipophilicity
of the tested compounds was not the sole parameter affecting
antimycobacterial activity.
Synthesis of 3a–c
3-Bromoacetylcoumarin 3a
To a solution of 2a (10.0 g, 53.0 mmol) in CHCl3 (100 mL) was
added dropwise a solution of Br2 (3.1 mL, 57.7 mmol) in
CHCl3 (20 mL) over a period of 0.5 h. The reaction mixture
was stirred for 15 min at 608C and concentrated under
reduced pressure. The residue was treated with acetic acid
(100 mL), filtered, and dried to provide the title compound 3a
(11.4 g, 80.6%) as a white solid. Mp: 163–1648C ([14], mp: 163–
1658C). 1H-NMR (400 MHz, DMSO-d6) dppm
: 4.88 (2H,
s, BrCH2CO), 7.42–7.50 (2H, m, Ph-H), 7.75–7.80 (1H, m,
Ph-H), 7.97–7.99 (1H, m, Ph-H), 8.82 (1H, s, Ph-H). ESI-MS:
m/z 267 (MþH)þ, 269 (Mþ2þH)þ.
Experimental section
Chemistry
General procedure for the synthesis of 3b,c
Melting points were determined in open capillaries and are A solution of 2b,c (9.0 mmol) and TBABr3 (8.80 g, 18.0 mmol)
uncorrected. 1H-NMR spectra were determined on a Varian in CH2Cl2 (100 mL) was stirred at room temperature for 12 h.
Mercury-400 spectrometer in DMSO-d6 or CDCl3 using tetra- The off-white solid obtained was collected to give the title
methylsilane (TMS) as an internal standard. Electrospray compounds 3b,c.
ß 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

806
Q. Guo et al.
Arch. Pharm. Chem. Life Sci. 2011, 344, 802–809
3-Bromoacetyl-7-methoxycoumarin 3b
Yield: 63.5%. mp: 206–2078C ([25], mp: 210–2118C). H-NMR
(400 MHz, CDCl3) dppm 3.93 (3H, s, OCH3), 4.75 (2H,
(20 mL) was added and the precipitate was filtered. The white
solid obtained was recrystallized from alcohol to give the title
compounds 5–22.
1
:
s, BrCH2CO), 6.85–6.94 (2H, m, Ph-H), 7.57–7.59 (1H, m, Ph-H),
8.61 (1H, s, Ph-H). ESI-MS: m/z 297 (MþH)þ, 299 (Mþ2þH)þ.
1-Cyclopropyl-6-fluoro-8-methoxy-7-{4-[2-(coumarin-3-yl)-
2-oxo]ethylpiperazin-1-yl}-1,4-dihydro-4-oxoquinoline-3-
carboxylic acid 5
3-Bromoacetyl-7-hydroxycoumarin 3c
Yield: 54.6%. mp: 214–2168C. 1H-NMR (400 MHz, DMSO-d6)
dppm: 4.82 (2H, s, BrCH2CO), 6.74–6.88 (2H, m, Ph-H), 7.76–
7.89 (1H, m, Ph-H), 8.58–8.85 (1H, m, Ph-H). ESI-MS: m/z 283
(MþH)þ, 285 (Mþ2þH)þ.
Yield: 40.6%. mp: 219–2218C. 1H-NMR (400 MHz, CDCl3) dppm
:
1.01–1.26 (4H, m, 2 cyclopropyl CH2), 3.36–3.66 (4H, m, piper-
azine), 3.84 (3H, s, OCH3), 3.95–4.02 (4H, m, piperazine), 4.42
(2H, s, NCH2CO), 4.70 (1H, s, cyclopropyl CH), 7.42–7.45 (2H,
m, Ph-H), 7.75–7.79 (2H, m, Ph-H), 7.91–7.94 (1H, m, Ph-H),
8.82–8.84 (2H, m, Ph-H). ESI-MS: m/z 548 (MþH)þ. HRMS-ESI:
m/z calcd. for C29H27FN3O7 (MþH)þ: 548.18330; Found:
548.18225.
General procedure for the synthesis of 4a–d
A mixture of 3a–c (1.8 mmol), methoxyamine hydrochloride
or ethoxyamine hydrochloride (3.7 mmol), and anhydrous
sodium acetate (0.20 g, 2.7 mmol) in methanol (30 mL) was
stirred at 408C for 10–12 h and concentrated under reduced
pressure. The residue was treated with water (20 mL) and
then filtered. The solid obtained was recrystallized from
alcohol to afford the title compounds 4a–d.
1-Cyclopropyl-6-fluoro-8-methoxy-7-{4-[2-
(7-methoxycoumarin-3-yl)-2-oxo]ethylpiperazin-1-yl}-1,
4-dihydro-4-oxoquinoline-3-carboxylic acid 6
Yield: 42.6%. mp: 216–2188C. 1H-NMR (400 MHz, DMSO-d6)
dppm: 1.01–1.11 (4H, m, 2 cyclopropyl CH2), 2.65–2.72
(4H, m, piperazine), 3.30 (3H, s, OCH3), 3.34–3.35 (4H, m,
piperazine), 3.75 (2H, s, NCH2CO), 3.90 (3H, s, OCH3), 4.15
(1H, s, cyclopropyl CH), 7.02–7.08 (2H, m, Ph-H), 7.72–7.89 (2H,
m, Ph-H), 8.66–8.68 (2H, m, Ph-H). ESI-MS: m/z 578 (MþH)þ.
HRMS-ESI: m/z calcd. for C30H29FN3O8 (MþH)þ: 578.19387;
Found: 578.19461.
3-[2-Bromo-1-(methoxyimino)ethyl]coumarin 4a
Yield: 93.8%. mp: 147–1498C. 1H-NMR (400 MHz, DMSO-d6)
dppm: 4.01 (3H, s, OCH3), 4.47 (2H, s, BrCH2CN), 7.37–7.46
(2H, m, Ph-H), 7.65–7.87 (2H, m, Ph-H), 8.28 (1H, s, Ph-H).
ESI-MS: m/z 296 (MþH)þ, 298 (Mþ2þ H)þ.
3-[2-Bromo-1-(ethoxyimino)ethyl]coumarin 4b
Yield: 90.5%. mp: 126–1278C. 1H-NMR (400 MHz, DMSO-d6) dppm
1.28 (3H, t, J ¼ 7.2 Hz, CH2CH3), 4.27 (2H, q, J ¼ 7.2 Hz,
CH2CH3), 4.49 (2H, s, BrCH2CN), 7.38–7.47 (2H, m, Ph-H),
7.66–7.70 (1H, m, Ph-H), 7.86–7.88 (1H, m, Ph-H), 8.30 (1H, s,
Ph-H). ESI-MS: m/z 310 (MþH)þ, 312 (Mþ2þH)þ.
:
1-Cyclopropyl-6-fluoro-8-methoxy-7-{4-[2-(7-
hydroxycoumarin-3-yl)-2-oxo]ethylpiperazin-1-yl}-1,4-
dihydro-4-oxoquinoline-3-carboxylic acid 7
Yield: 36.5%. mp: 210–2128C. 1H-NMR (400 MHz, DMSO-d6)
dppm: 0.99–1.13 (4H, m, 2 cyclopropyl CH2), 2.48–2.49 (4H,
m, piperazine), 3.34 (4H, s, piperazine), 3.75 (3H, s, OCH3),
3.87 (2H, s, NCH2CO), 4.13–4.17 (1H, m, cyclopropyl CH), 6.61–
6.75 (2H, m, Ph-H), 7.69–7.74 (2H, m, Ph-H), 8.54 (1H, s, Ph-H),
8.68 (1H, s, C2-H). ESI-MS: m/z 564 (MþH)þ. HRMS-ESI:
m/z calcd. for C29H27FN3O8 (MþH)þ: 564.17822; Found:
564.17646.
3-[2-Bromo-1-(methoxyimino)ethyl]-7-methoxycoumarin
4c
Yield: 74.6%. mp: 120–1218C. 1H-NMR (400 MHz, DMSO-d6) dppm
:
3.87 (3H, s, OCH3), 4.00 (3H, s, OCH3), 4.48 (2H, s, BrCH2CN),
6.99–7.06 (2H, m, Ph-H), 7.77–7.79 (1H, m, Ph-H), 8.23 (1H,
s, Ph-H). MS (ESI, m/z): 326 (MþH)þ, 328 (Mþ2þH)þ.
1-Cyclopropyl-6-fluoro-8-methoxy-7-{4-[2-(coumarin-3-yl)-
2-(methoxyimino)]ethylpiperazin-1-yl}-1,4-dihydro-4-
oxoquinoline-3-carboxylic acid 8
3-[2-Bromo-1-(ethoxyimino)ethyl]-7-methoxycoumarin 4d
Yield: 68.2%. mp: 106–1088C. 1H-NMR (400 MHz, DMSO-d6)
dppm: 1.28 (3H, t, J ¼ 7.2 Hz, CH2CH3), 3.87 (3H, s, OCH3),
4.26 (2H, q, J ¼ 7.2 Hz, CH2CH3), 4.48 (2H, s, BrCH2CN),
6.99–7.07 (2H, m, Ph-H), 7.77–7.80 (1H, m, Ph-H), 8.22 (1H,
s, Ph-H). ESI-MS: m/z 340 (MþH)þ, 342 (Mþ2þH)þ.
Yield: 66.2%. mp: 207–2098C. 1H-NMR (400 MHz, DMSO-d6)
dppm: 0.98–1.10 (4H, m, 2 cyclopropyl CH2), 2.49–2.61
(4H, m, piperazine), 3.10–3.27 (4H, m, piperazine), 3.61
(3H, s, OCH3), 3.70 (3H, s, OCH3), 3.74–3.92 (2H, m,
NCH2CN), 4.08–4.13 (1H, m, cyclopropyl CH), 7.38–7.46
(2H, m, Ph-H), 7.62–7.81 (3H, m, Ph-H), 8.15–8.19 (1H, m,
Ph-H), 8.65–8.67 (1H, m, C2-H). ESI-MS: m/z 577 (MþH)þ.
HRMS-ESI: m/z calcd. for C30H30FN4O7 (MþH)þ: 577.20985;
Found: 577.21041.
General procedure for the synthesis of 5–22
A mixture of GTFX, CPFX or 8-OCH3 CPFX (2.5 mmol), 4a–d
(2.7 mmol), and sodium bicarbonate (0.42 g, 5.0 mmol) in
DMF (30 mL) was stirred at 0–108C for 10–15 h. Water
ß 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

Arch. Pharm. Chem. Life Sci. 2011, 344, 802–809
New fluoroquinolone derivatives
807
1-Cyclopropyl-6-fluoro-8-methoxy-7-{4-[2-(coumarin-3-yl)-
2-(ethoxyimino)]ethylpiperazin-1-yl}-1,4-dihydro-4-
oxoquinoline-3-carboxylic acid 9
2.38 (1H, m, piperazine), 2.55–3.23 (6H, m, piperazine), 3.60
(3H, s, OCH3), 3.92 (3H, s, OCH3), 3.94–3.98 (2H, m, NCH2CN),
4.07–4.11 (1H, m, cyclopropyl CH), 7.36–7.42 (2H, m, Ph-H),
7.62–7.69 (2H, m, Ph-H), 7.80–7.82 (1H, m, Ph-H), 8.18 (1H,
s, Ph-H), 8.65 (1H, s, C2-H). ESI-MS: m/z 591 (MþH)þ. HRMS-ESI:
m/z calcd. for C31H32FN4O7 (MþH)þ: 591.22550; Found:
591.22784.
Yield: 64.5%. mp: 226–2288C. 1H-NMR (400 MHz, DMSO-d6)
dppm: 0.97–1.07 (4H, m, 2 cyclopropyl CH2), 1.26 (3H,
t, J ¼ 6.8 Hz, CH2CH3), 2.49–2.51 (4H, m, piperazine), 3.14
(4H, s, piperazine), 3.64 (3H, s, OCH3), 3.71 (2H,
s, NCH2CN), 4.09–4.11 (1H, m, cyclopropyl CH), 4.18 (2H,
q, J ¼ 6.8 Hz, CH2CH3), 7.36–7.46 (2H, m, Ph-H), 7.62–7.81
(3H, m, Ph-H), 8.19 (1H, s, Ph-H), 8.65 (1H, s, C2-H). ESI-MS:
m/z 591 (MþH)þ. HRMS-ESI: m/z calcd. for C31H32FN4O7
(MþH)þ: 591.22550; Found: 591.22327.
1-Cyclopropyl-6-fluoro-8-methoxy-7-{4-[2-(coumarin-3-yl)-
2-(ethoxyimino)]ethyl-3-methylpiperazin-1-yl}-1,4-dihydro-
4-oxoquinoline-3-carboxylic acid 14
Yield: 68.6%. mp: 229–2318C. 1H-NMR (400 MHz, DMSO-d6) dppm
:
0.97–1.07 (7H, m, 2 cyclopropyl CH2 and CH3), 1.26 (3H, t,
J ¼ 6.8 Hz, CH2CH3), 2.34–2.38 (1H, m, piperazine), 2.57–3.23
(6H, m, piperazine), 3.58 (1H, s, cyclopropyl CH), 3.60 (3H,
s, OCH3), 3.95–4.09 (2H, m, NCH2CN), 4.18 (2H, q, J ¼ 6.8 Hz,
CH2CH3), 7.36–7.47 (2H, m, Ph-H), 7.62–7.70 (2H, m, Ph-H),
7.81–7.83 (1H, m, Ph-H), 8.17 (1H, s, Ph-H), 8.65 (1H, s, C2-H).
ESI-MS: m/z 605 (MþH)þ. HRMS-ESI: m/z calcd. for C32H34FN4O7
(MþH)þ: 605.24115; Found: 605.24459.
1-Cyclopropyl-6-fluoro-8-methoxy-7-{4-[2-
(7-methoxycoumarin-3-yl)-2-(methoxyimino)]ethylpiperazin-
1-yl}-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 10
Yield: 58.6%. mp: 235–2378C. 1H-NMR (400 MHz, DMSO-d6) dppm
:
0.93–1.06 (4H, m, 2 cyclopropyl CH2), 2.49 (4H, s, piperazine),
3.13 (4H, s, piperazine), 3.66 (3H, s, OCH3), 3.69 (1H,
s, cyclopropyl CH), 3.86 (3H, s, OCH3), 3.90 (2H, s, NCH2CN),
6.96–7.06 (2H, m, Ph-H), 7.64–7.72 (2H, m, Ph-H), 8.11 (1H, s,
Ph-H), 8.60 (1H, s, C2-H). ESI-MS: m/z 607 (MþH)þ. HRMS-ESI: m/z
calcd. for C31H32FN4O8 (MþH)þ: 607.22042; Found: 607.22036.
1-Cyclopropyl-6-fluoro-8-methoxy-7-{4-[2-
(7-methoxycoumarin-3-yl)-2-(methoxyimino)]ethyl-3-
methylpiperazin-1-yl}-1,4-dihydro-4-oxoquinoline-3-
carboxylic acid 15
1-Cyclopropyl-6-fluoro-8-methoxy-7-{4-[2-(ethoxyimino)-
2-(7-methoxycoumarin-3-yl)]ethylpiperazin-1-yl}-1,4-
dihydro-4-oxoquinoline-3-carboxylic acid 11
Yield: 57.0%. mp: 235–2378C. 1H-NMR (400 MHz, DMSO-d6)
dppm: 0.89–1.07 (7H, m, 2 cyclopropyl CH2 and CH3), 2.32–
2.37 (1H, m, piperazine), 2.49–3.20 (6H, m, piperazine), 3.28
(1H, s, cyclopropyl CH), 3.62 (3H, s, OCH3), 3.86 (2H,
s, NCH2CN), 3.90 (3H, s, OCH3), 6.96–7.06 (2H, m, Ph-H),
7.62–7.73 (2H, m, Ph-H), 8.09 (1H, s, Ph-H), 8.57 (1H, s,
C2-H). ESI-MS: m/z 621 (MþH)þ. HRMS-ESI: m/z calcd.
for C32H34FN4O8 (MþH)þ: 621.23607; Found: 621.23851.
Yield: 65.3%. mp: 211–2128C. 1H-NMR (400 MHz, DMSO-d6) dppm
:
0.97–1.08 (4H, m, 2 cyclopropyl CH2), 1.25 (3H, t, J ¼ 7.2 Hz,
CH2CH3), 2.49 (4H, s, piperazine), 3.15 (4H, s, piperazine), 3.66
(3H, s, OCH3), 3.70 (2H, s, NCH2CN), 3.86 (3H, s, OCH3), 4.13–4.19
(3H, m, CH2CH3 and cyclopropyl CH), 6.69–7.05 (2H, m, Ph-H),
7.67–7.72 (2H, m, Ph-H), 8.11 (1H, s, Ph-H), 8.65 (1H, s, C2-H). ESI-
MS: m/z 621 (MþH)þ. HRMS-ESI: m/z calcd. for C32H34FN4O8
(MþH)þ: 621.23607; Found: 621.23835.
1-Cyclopropyl-6-fluoro-8-methoxy-7-{4-[2-(ethoxyimino)-
2-(7-methoxycoumarin-3-yl)]ethyl-3-methylpiperazin-1-yl}-
1,4-dihydro-4-oxoquinoline-3-carboxylic acid 16
1-Cyclopropyl-6-fluoro-8-methoxy-7-{4-[2-
(7-methoxycoumarin-3-yl)-2-oxo]ethyl-3-methylpiperazin-
1-yl}-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 12
Yield: 62.6%. mp: 231–2338C. 1H-NMR (400 MHz, DMSO-d6)
dppm: 1.01–1.09 (7H, m, 2 cyclopropyl CH2 and CH3),
2.31–2.43 (1H, m, piperazine), 2.65–3.25 (6H, m, piperazine),
3.30 (3H, s, OCH3), 3.74 (2H, s, NCH2CO), 3.89 (3H, s, OCH3),
4.09–4.13 (1H, m, cyclopropyl CH), 7.03–7.09 (2H, m, Ph-H),
7.72–7.94 (2H, m, Ph-H), 8.61 (1H, s, Ph-H), 8.68 (1H, s, C2-H).
ESI-MS: m/z 592 (MþH)þ. HRMS-ESI: m/z calcd. for C31H31FN3O8
(MþH)þ: 592.20952; Found: 592.20786.
Yield: 64.3%. mp: 231–2338C. 1H-NMR (400 MHz, DMSO-d6) dppm
:
0.84–1.03 (7H, m, 2 cyclopropyl CH2 and CH3), 1.26 (3H, t,
J ¼ 7.2 Hz, CH2CH3), 2.32–2.37 (1H, m, piperazine), 2.53–3.28
(6H, m, piperazine), 3.56–3.60 (1H, m, cyclopropyl CH), 3.62
(3H, s, OCH3), 3.86 (3H, s, OCH3), 3.88-3.93 (2H, m, NCH2CN),
4.16 (2H, q, J ¼ 7.2 Hz, CH2CH3), 6.96–7.06 (2H, m, Ph-H), 7.58–
7.74 (2H, m, Ph-H), 8.09 (1H, s, Ph-H), 8.50 (1H, s, C2-H). ESI-MS:
m/z 635 (MþH)þ. HRMS-ESI: m/z calcd. for C33H36FN4O8 (MþH)þ:
635.25172; Found: 635.25391.
1-Cyclopropyl-6-fluoro-8-methoxy-7-{4-[2-(coumarin-3-yl)-
2-(methoxyimino)]ethyl-3-methylpiperazin-1-yl}-1,4-
dihydro-4-oxoquinoline-3- carboxylic acid 13
Yield: 54.5%. mp: 247–2508C. 1H-NMR (400 MHz, DMSO-d6)
dppm: 0.96–1.07 (7H, m, 2 cyclopropyl CH2 and CH3), 2.33–
1-Cyclopropyl-6-fluoro-7-{4-[2-(7-methoxycoumarin-3-yl)-
2-oxo]ethylpiperazin-1-yl}-1,4-dihydro-4-oxoquinoline-3-
carboxylic acid 17
Yield: 35.4%. mp: 222–2248C. 1H-NMR (400 MHz, DMSO-d6)
dppm: 1.16–1.29 (4H, m, 2 cyclopropyl CH2), 2.49–2.88
ß 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

808
Q. Guo et al.
Arch. Pharm. Chem. Life Sci. 2011, 344, 802–809
(4H, m, piperazine), 3.22–3.28 (5H, m, piperazine and
cyclopropyl CH), 3.89 (3H, s, OCH3), 3.81 (2H, s, NCH2CO),
7.01–7.08 (2H, m, Ph-H), 7.55–7.57 (1H, m, Ph-H), 7.88–7.90
(2H, m, Ph-H), 8.66 (1H, s, C2-H). ESI-MS: m/z 548 (MþH)þ.
HRMS-ESI: m/z calcd. for C29H27FN3O7 (MþH)þ: 548.18330;
Found: 548.18487.
577 (MþH)þ. HRMS-ESI: m/z calcd. for C30H30FN4O7 (MþH)þ:
577.20985; Found: 577.21007.
1-Cyclopropyl-6-fluoro-7-{4-[2-(ethoxyimino)-2-
(7-methoxycoumarin-3-yl)]ethylpiperazin-1-yl}-1,
4-dihydro-4-oxoquinoline-3-carboxylic acid 22
Yield: 54.3%. mp: 193–1958C. 1H-NMR (400 MHz, DMSO-d6)
dppm: 1.09–1.27 (7H, m, 2 cyclopropyl CH2 and CH2CH3),
2.56 (4H, s, piperazine), 3.13 (4H, s, piperazine), 3.71 (3H, s,
OCH3), 3.84–3.87 (3H, m, CH2CH3 and cyclopropyl CH), 4.14–
4.19 (2H, m, NCH2CN), 6.95–7.03 (2H, m, Ph-H), 7.43-7.45
(1H, m, Ph-H), 7.70–7.85 (2H, m, Ph-H), 8.12 (1H, s, Ph-H),
8.59 (1H, s, C2-H). ESI-MS: m/z 591 (MþH)þ. HRMS-ESI:
m/z calcd. for C31H32FN4O7 (MþH)þ: 591.22550; Found:
591.22910.
1-Cyclopropyl-6-fluoro-7-{4-[2-(7-hydroxycoumarin-3-yl)-
2-oxo]ethylpiperazin-1-yl}-1,4-dihydro-4-oxoquinoline-3-
carboxylic acid 18
Yield: 45.7%. mp: >3008C. 1H-NMR (400 MHz, DMSO-
d6 þ D2O) dppm: 1.09–1.28 (4H, m, 2 cyclopropyl CH2), 2.71
(4H, s, piperazine), 3.29 (4H, s, piperazine), 3.71 (1H, s, cyclo-
propyl CH), 3.78 (2H, s, NCH2CO), 6.14–6.17 (1H, m, Ph-H),
7.23–7.26 (1H, m, Ph-H), 7.48–7.50 (1H, m, Ph-H), 7.81–7.85
(1H, m, Ph-H), 8.18 (1H, s, Ph-H), 8.59 (1H, s, C2-H). ESI-MS:
m/z 534 (MþH)þ. HRMS-ESI: m/z calcd. for C28H25FN3O7
(MþH)þ: 534.16765; Found: 534.16671.
MIC determination
The target compounds 5–22 were initially evaluated for their
in-vitro activity against M. smegmatis CMCC 93202. The com-
pounds were dissolved in DMSO and two-fold diluted at
concentrations from 12.5 to 0.05 mg/ml. The tested strains
were prepared in 54 medium in a volume of 150 mL in 96-well
microplates. The plates were incubated at 378C for 72 h.
The entire compounds 5–22 were further evaluated for
their in-vitro activity against MTB H37Rv ATCC 27294 using
rapid direct susceptibility test technique. The tested com-
pounds were dissolved in DMSO and two-fold diluted at
concentrations from 128 to 0.125 mg/ml. The strain was
obtained from Jiangsu Province Hospital, Nanjing, China.
1-Cyclopropyl-6-fluoro-7-{4-[2-(coumarin-3-yl)-2-
(methoxyimino)]ethylpiperazin-1-yl}-1,4-dihydro-4-
oxoquinoline-3-carboxylic acid 19
Yield: 43.5%. mp: 142–1448C ([19], mp: 138–1408C). 1H-NMR
(400 MHz, DMSO-d6) dppm: 1.10–1.24 (4H, m, 2 cyclopropyl
CH2), 2.53–2.57 (4H, m, piperazine), 3.13–3.16 (4H, m, pipera-
zine), 3.72 (2H, s, NCH2CN), 3.73–3.74 (1H, m, cyclopropyl CH),
3.92 (3H, s, OCH3), 7.35–7.86 (6H, m, Ph-H), 8.20 (1H, s, Ph-H),
8.60 (1H, s, C2-H). ESI-MS: m/z 547 (MþH)þ. HRMS-ESI: m/z calcd.
for C29H28FN4O6 (MþH)þ: 547.19929; Found: 547.20188.
This work was supported by the key project of Major infectious disease (No.
2008ZX10003-006), National S&T Major Special Project on Major New Drug
Innovation (No. 2009ZX09301-003) and Central Public-Interest Scientific
Institution Basal Research Fund IMBF200912.
1-Cyclopropyl-6-fluoro-7-{4-[2-(ethoxyimino)-2-(coumarin-
3-yl)]ethylpiperazin-1-yl}-1,4-dihydro-4-oxoquinoline-3-
carboxylic acid 20
Yield: 38.2%. mp: 218–2208C. 1H-NMR (400 MHz, DMSO-d6)
dppm: 1.11–1.28 (7H, m, 2 cyclopropyl CH2 and CH2CH3),
2.56–2.58 (4H, m, piperazine), 3.13–3.14 (4H, m, piperazin),
3.73–3.75 (3H, m, NCH2CN and cyclopropyl CH), 4.16–4.21
(2H, m, CH2CH3), 7.35–7.47 (3H, m, Ph-H), 7.60–7.86 (3H, m,
Ph-H), 8.20 (1H, s, Ph-H), 8.61 (1H, s, C2-H). ESI-MS: m/z 561
(MþH)þ. HRMS-ESI: m/z calcd. for C30H30FN4O6 (MþH)þ:
561.21494; Found: 561. 21820.
The authors have declared no conflict of interest.
References
[1] L. S. Feng, M. L. Liu, B. Wang, Y. Chai, X. Q. Hao, S. Meng, H. Y.
Guo, Eur. J. Med. Chem. 2010, 45, 3407–3412.
[2] WHO. Global Tuberculosis Control a Short Update to the 2009
Report, World Health Organization, Geneva 2009.
1-Cyclopropyl-6-fluoro-7-{4-[2-(7-methoxycoumarin-3-yl)-
2-(methoxyimino)]ethylpiperazin-1-yl}-1,4-dihydro-4-
oxoquinoline-3-carboxylic acid 21
Yield: 56.6%. mp: 249–2508C. 1H-NMR (400 MHz, DMSO-d6)
dppm: 1.11–1.24 (4H, m, 2 cyclopropyl CH2), 2.49 (4H, s, piper-
azine), 3.14 (4H, s, piperazine), 3.70 (2H, s, NCH2CN), 3.75
(1H, s, cyclopropyl CH), 3.85 (3H, s, OCH3), 3.91 (3H, s, OCH3),
6.95–7.03 (2H, m, Ph-H), 7.45–7.47 (1H, m, Ph-H), 7.70–7.87
(2H, m, Ph-H), 8.12 (1H, s, Ph-H), 8.62 (1H, s, C2-H). ESI-MS: m/z
[3] A. Nayyar, V. Monga, A. Malde, E. Coutinho, R. Jain, Bioorg.
Med. Chem. 2007, 15, 626–640.
[4] P. S. Charifson, A. L. Grillot, T. H. Grossman, J. D. Parsons, M.
Badia, S. Bellon, D. D. Deininger, J. E. Drumm, C. H. Gross, A.
LeTiran, Y. S. Liao, N. Mani, D. P. Nicolau, E. Perola, S.
Ronkin, D. Shannon, L. L. Swenson, Q. Tang, P. R. Tessier,
S. K. Tian, M. Trudeau, T. S. Wang, Y. Y. Wei, H. Zhang, D.
Stamos, J. Med. Chem. 2008, 51, 5243–5263.
[5] A. Aubry, X. S. Pan, L. M. Fisher, V. Jarlier, C. Emmanuelle,
Antimicrob. Agents. Chemother. 2004, 48, 1281–1288.
ß 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

Arch. Pharm. Chem. Life Sci. 2011, 344, 802–809
New fluoroquinolone derivatives
809
[6] G. Anquetiin, J. Greiner, N. Mahmoud, M. H. Santillana, R.
Gozalbes, K. Farhati, F. Derouin, E. Cambau, P. Vierling, Eur.
J. Med. Chem. 2006, 41, 1478–1493.
[16] R. G. Kalkhambkar, G. M. Kulkarni, C. M. Kamanavalli, N.
Premkumar, S. M. B. Asdaq, C. M. Sun, Eur. J. Med. Chem. 2008,
43, 2178–2188.
[7] D. Sriram, P. Yogeeswari, J. S. Basha, D. R. Radha, V. J.
Nagaraja, Bioorg. Med. Chem. 2005, 13, 5774–5778.
[17] C. Ito, M. Itoigawa, S. Onoda, A. Hosokawa, N. Ruangrungsi,
T. Okuda, H. Tokuda, H. Nishino, H. Furukawa, Phytochem.
2005, 66, 567–572.
[8] WHO. Guidelines for the Management of Drug-Resistant
(rev.1)
Tuberculosis, WHO/TB/96-210
Organization, Geneva 1997.
World
Health
[18] A. Manvar, A. Malde, J. Verma, V. Virsodia, A. Mishra, K.
Upadhyay, H. Acharya, E. Coutinbo, A. Shah, Eur. J. Med.
Chem. 2008, 43, 2395–2403.
[9] A. S. Ginsburg, J. H. Grosset, W. R. Bishai, Lancet. Infect. Dis.
2003, 37, 432–442.
[19] S. Emami, A. Foroumad, M. A. Faramarzi, N. Samadi, Arch.
Pharm. Chem. Life Sci. 2008, 341, 42–48.
[10] H. Koga, A. Itoh, S. Murayama, S. Suzue, T. Irikura, J. Med.
Chem. 1980, 23, 1358–1363.
[20] S. H. Zhao, R. Pine, J. Domagala, K. Drlica, Antimicrob. Agents
Chemother. 1999, 43, 661–666.
[11] Z. Dang, Y. S. Yang, R. Y. Ji, S. H. Zhang, Bioorg. Med. Chem. Lett.
2007, 17, 4523–4526.
[21] R. G. Kalkhambkar, G. M. Kulkarni, H. Shivkumar, R. N. Rao,
Eur. J. Med. Chem. 2007, 42, 1272–1276.
[12] L. L. Shen, L. A. Mitscher, P. N. Sharma, T. J. Odonnell, D. W.
T. Chu, C. S. Cooper, T. Rosen, A. G. Pernet, Biochemistry 1989,
28, 3886–3894.
[22] A. Foroumadi, M. Oboudiat, S. Emami, Bioorg. Med. Chem.
2006, 14, 3421–3427.
[13] D. Sriram, A. Aubry, P. Yogeeswaria, L. M. Fisher, Bioorg. Med.
Chem. Lett. 2006, 16, 2982–2985.
[23] X. H. Liu, J. C. Fan, Y. Liu, Z. C. Shang, J. Zhejiang Univ. Sci. B.
2008, 9, 990–995.
[14] C. F. Koelsch, J. Am. Chem. Soc. 1950, 72, 2993–2995.
[24] D. N. Shan, N. M. Shan, J. Org. Chem. 1954, 19, 1681–
1685.
[15] M. Basanagouda, K. Shivashankar, M. V. Kulkarni, V. P.
Rasal, R. H. Patel, S. S. Mutha, A. A. Mohite, Eur. J. Med.
Chem. 2010, 45, 1551–1557.
[25] A. Takadate, T. Masuda, C. Tajima, C. Murata, M. Irikura, S.
Goya, Anal. Sci. 1992, 8, 663–668.
ß 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com