Design, Synthesis, and In Vitro Antibacterial Activities of Propylene-tethered Gatifloxacin-isatin Hybrids

Article abstract of DOI:10.1002/jhet.3226

A series of novel mono-/bis-isatin-gatifloxacin hybrids 3a–f and 4a–f tethered through propylene were designed, synthesized, and evaluated for their in vitro antibacterial activities against representative Gram-positive and Gram-negative pathogens. The results indicated that all mono-isatin-gatifloxacin hybrids exhibited considerable antibacterial activities with minimum inhibitory concentration ranging from 0.06 to 4?μg/mL against the majority of the tested strains. In particular, the mono-isatin-gatifloxacin hybrid 3b was found as potent as the parent gatifloxacin against Gram-positive organisms and could act as a starting point for further optimization.

Full text of DOI:10.1002/jhet.3226

Month 2018
Design, Synthesis, and In Vitro Antibacterial Activities of Propylene-
tethered Gatifloxacin-isatin Hybrids
Hua Guo*
School of Chemistry and Life Science, Anshan Normal University, Anshan 114007, People’s Republic of China
*
E-mail: m13704127672@163.com
Received January 25, 2018
DOI 10.1002/jhet.3226
Published online 00 Month 2018 in Wiley Online Library (wileyonlinelibrary.com).
A series of novel mono-/bis-isatin-gatifloxacin hybrids 3a–f and 4a–f tethered through propylene were
designed, synthesized, and evaluated for their in vitro antibacterial activities against representative
Gram-positive and Gram-negative pathogens. The results indicated that all mono-isatin-gatifloxacin hybrids
exhibited considerable antibacterial activities with minimum inhibitory concentration ranging from 0.06 to
4
μg/mL against the majority of the tested strains. In particular, the mono-isatin-gatifloxacin hybrid 3b
was found as potent as the parent gatifloxacin against Gram-positive organisms and could act as a starting
point for further optimization.
J. Heterocyclic Chem., 00, 00 (2018).
INTRODUCTION
IV is the target for most Gram-positive bacteria [5]. The
fourth generation fluoroquinolone antibiotics can act at
both DNA gyrase and topoisomerase IV, so this dual
action makes the strains resistant to them relatively
slow [6]. Besides their typical antibacterial activities,
fluoroquinolones also endow with diverse atypical
biological profiles such as antimalarial [7], antitumor [8],
anti-human immunodeficiency virus [9], and anti-
tuberculosis [10–13] properties, which play a pivotal role
in new drug discovery.
However, the resistance of pathogens to fluoroquinolone
agents develops rapidly and spreads widely due to
the long-term, broad, inappropriate use, and even abuse
of this kind of antibiotics, making this kind of antibiotics
more and more ineffective. Thus, enhancing the potency
of fluoroquinolones has become increasingly urgent.
Isatin (1H-indole-2,3-dione) derivatives also demonstrated
a broad range of biological properties such as antibacterial
activity [14–19]. Therefore, incorporation of isatin into
fluoroquinolones may lead to more active candidates.
As an ongoing research program and to continue our
effort to develop new antibacterial agents, a series of
novel propylene-tethered mono-/bis-isatin-gatifloxacin
hybrids were designed, synthesized, and assessed for
their in vitro antibacterial activities against clinically
Bacterial infections caused by Gram-positive and
Gram-negative organisms are responsible for the majority
of hospital-acquired infections and result in extensive
mortality and burden on global healthcare systems [1,2].
The emergency and widespread of bacteria new
virulent forms such as drug-resistant pathogens like
methicillin-resistant Staphylococcus aureus, methicillin-
resistant Staphylococcus epidermidis, vancomycin-resistant
S. aureus, and extended spectrum β-lactamase-producing
Escherichia coli has already increased up to alarming
level in the recent decades and is associated with
considerable mortality [3,4]. Thus, new antibiotics are
needed urgently.
Fluoroquinolones, which bearing a carboxyl group at C-3
position, a keto group at C-4 position, a fluorine atom at C-6
position, and a basic nitrogen heterocycle moiety at the C-7
position, are a family of synthetic broad spectrum
antibiotics widely used in clinical practice for infections
including upper and lower respiratory infections,
gastrointestinal infections, gynecologic infections,
sexually transmitted diseases, prostatitis, and some skin,
bone, and soft tissue infections, and their value and role in
the treatment of bacterial infections continue to expand
[1]. Fluoroquinolones mainly act by binding two type II
important pathogens in this study. A preliminary
bacterial topoisomerase enzymes, DNA gyrase, and
topoisomerase IV, and DNA gyrase is the predominately
target for Gram-negative bacteria, whereas topoisomerase
structure–activity relationship (SAR) study is also
explored to facilitate the further design. The design
strategy is illustrated in Figure 1.
©
2018 Wiley Periodicals, Inc.

H. Guo
Vol 000
Figure 1. Illustration of design strategy. [Color figure can be viewed at wileyonlinelibrary.com]
RESULTS AND DISCUSSION
performed with 1,3-dibromopropane to afford N-(3-
bromopropyl) isatins 2a–c (yield: 56–78%), which were
then incorporated into gatifloxacin to provide the desired
mono-isatin-gatifloxacin 3a–c (yield: 26–33%) and
bis-isatin-gatifloxacin hybrids 4a–c (yield: 22–35%).
The synthetic routes for propylene-tethered mono-/bis-
isatin-gatifloxacin hybrids 3a–f and 4a–f are depicted in
Scheme 1. Alkylation of C-5 substituted isatins 1a–c was
Scheme 1. Synthetic route for mono-/bis-isatin-gatifloxacin hybrids 3a–f and 4a–f.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Design, Synthesis, and In Vitro Antibacterial Activities of Propylene-tethered
Gatifloxacin-isatin Hybrids
Table 1
In vitro antibacterial activity of hybrids 3a–f and 4a–f against Gram-positive strains.
MIC (μg/mL)
Compound
MSSE
MRSE
MSSA
MRSA
E.fa.1
E.fa.2
E.fm.1
E.fm.2
3
3
3
3
3
3
4
4
4
4
4
4
a
b
c
d
e
f
a
b
c
d
e
f
0.50
0.25
0.25
0.5
0.25
0.5
64
16
32
64
32
0.25
0.125
0.125
0.25
0.125
0.25
>64
32
>64
>64
>64
>64
0.25
0.125
0.25
0.125
0.25
0.5
0.25
0.25
>64
64
>64
>64
>64
>64
0.5
1
0.5
1
1
1
2
>64
64
>64
>64
>64
>64
0.5
1
2
1
1
1
2
32
32
32
32
32
64
32
64
>64
64
64
>64
>64
>64
>64
>64
>64
>64
32
64
2
64
64
64
>64
>64
>64
>64
>64
>64
64
>64
>64
>64
>64
>64
>64
0.5
0.5
>64
>64
>64
>64
>64
>64
>64
16
>64
>64
>64
>64
0.125
0.125
Ciprofloxacin
Gatifloxacin
32
0.25
E.fa.1, Enterococcus faecalis ATCC 29212; E.fa.2, Enterococcus faecalis ATCC 51299; E.fm.1, Enterococcus faecium ATCC 700221; E.fm.2,
Enterococcus faecium 13-7; MIC, minimum inhibitory concentration; MRSA, methicillin-resistant Staphylococcus aureus ATCC 33591; MRSE, meth-
icillin-resistant Staphylococcus epidermidis 13-3; MSSA, methicillin-sensitive Staphylococcus aureus ATCC 29213; MSSE, methicillin-sensitive
Staphylococcus epidermidis ATCC 12228.
Subsequently, condensation of hybrids 3a–c or 4a–c
with ethylhydroxylamine hydrochloride yielded other
conjugates 3d–f (yield: 43–56%) and 4d–f (yield:
The SAR revealed that all mono-isatin-gatifloxacin
hybrids were more potent than the corresponding bis-
isatin-gatifloxacin analogs against both Gram-positive and
Gram-negative organisms, which was in accordance with
the previous study that carboxylic acid at C-3 position is
essential for gyrase binding and bacterial membrane
transport [1]; substituents at C-3 and C-5 positions of
isatin moiety influenced the antibacterial activity
significantly: introduction of ethoxyimino at C-3 position
disfavored the activity; hybrids with electron-withdrawing
-F and -Br at C-5 position of isatin moiety exhibited
higher potency than unsubstituted analogs.
33–57%).
All propylene-tethered mono-/bis-isatin-gatifloxacin
a–f and 4a–f were assessed for their in vitro
3
antibacterial activity against representative Gram-positive
and Gram-negative pathogens using standard
techniques [4]. The minimum inhibitory concentration
MIC) is obtained from three independent experiments,
(
defined as the concentration of the compound required to
give complete inhibition of bacterial growth, and the MIC
values of the hybrids 3a–f and 4a–f against Gram-
positive and Gram-negative strains, along with those of
gatifloxacin and ciprofloxacin for comparison, were listed
in Tables 1 and 2, respectively.
CONCLUSIONS
As it can be seen from Table 1, all mono-isatin-
gatifloxacin 3a–f displayed promising activities against
the majority of the tested Gram-positive strains with MIC
ranging from 0.125 to 2 μg/mL. Among them, the most
active hybrid 3b was highly potent against clinically
important pathogens methicillin-sensitive S. epidermidis,
methicillin-sensitive S. aureus, methicillin-resistant
S. aureus, and Enterococcus faecalis with MIC of 0.25,
In summary, a series of novel propylene-tethered mono-/
bis-isatin-gatifloxacin hybrids 3a–f and 4a–f were
designed, synthesized, and assessed for their in vitro
antibacterial activities against representative Gram-
positive and Gram-negative pathogens. The results
revealed that all mono-isatin-gatifloxacin hybrids
endowed with considerable antibacterial activities, and
hybrid 3b was comparable with the parent gatifloxacin
against Gram-positive organisms, could act as a starting
point for further investigation. Moreover, the enriched
SAR paves the way for further optimization.
0.125, 0.125, and 0.5 μg/mL, respectively, and was no
inferior to gatifloxacin (MIC: 0.125–0.5 μg/mL).
From Table 1, it can be concluded that all mono-
isatin-gatifloxacin 3a–f showed considerable activities
against most of the tested Gram-negative organisms with
MIC in a range of 0.06 to 4 μg/mL but less active
than the parent gatifloxacin (MIC: ≤0.03–1 μg/mL).
Interestingly, the hybrid 3b also exhibited the most active
potency against the tested Gram-negative strains.
EXPERIMENTAL
The mixture of isatin (10 mmol), 1,3-dibromopropane
(30 mmol), and potassium carbonate (50 mmol) in
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DOI 10.1002/jhet

H. Guo
Vol 000
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DOI 10.1002/jhet

Month 2018
Design, Synthesis, and In Vitro Antibacterial Activities of Propylene-tethered
Gatifloxacin-isatin Hybrids
dimethylformamide (100 mL) was stirred at room
temperature for 3 days and then filtered. The filtrate was
concentrated under reduced pressure, and the reside was
purified by silica gel chromatography eluted with PE:
EA = 2 : 1 to give N-(2-bromopropyl) isatin 2a–c (yield:
3.98–4.01 (1H, m, cyclopropyl-CH), 4.18 (2H, t –CH –),
2
7.25 (1H, d, Ar–H), 7.59–7.64 (2H, m, Ar–H), 7.88 (1H,
s, Ar–H), 8.38 (1H, s, C2-H). ESI-MS m/z: 641
+
+
[
M + H] , 643 [M + 2 + H] . Elemental Anal. Calcd (%)
for C H FBrN O : C, 56.17; H, 4.71; N, 8.73. Found:
30
30
4 6
56–78%) as red solids.
C, 55.94; H, 4.49; N, 8.55.
The mixture of intermediates 2a–c (1.2 mmol),
1
-Cyclopropyl-7-(4-(3-(3-(ethoxyimino)-2-oxoindolin-1-yl)
gatifloxacin (1 mmol), and potassium carbonate (3 mmol)
in dimethylformamide (10 mL) was stirred at room
temperature overnight. After filtration, the filtrate was
concentrated under reduced pressure, and the residue was
purified by reverse phase chromatography with formic
acid as additive to afford mono-/bis-isatin-gatifloxacin
hybrids 3a–c (yield: 26–33%) and 4a–c (yield: 22–35%).
The mixture of hybrids 3a–c or 4a–c (1 mmol), sodium
bicarbonate (3 mmol), and ethoxyamine hydrochloride
propyl)-3-methylpiperazin-1-yl)-6-fluoro-8-methoxy-4-oxo-
1,4-dihydroquinoline-3-carboxylic acid (3d). Yellow solid,
1
yield: 49%. H NMR (400 MHz, DMSO-d ) δ 0.94–1.08
6
(7H, m, 2 × cyclopropyl-CH and CH ), 1.34 (3H, t,
2
3
NOCH CH ), 2.00–2.05 (2H, m, –CH –), 2.91–3.32 (7H,
2
3
2
m, piperazine-7H), 3.79 (3H, s, OCH ), 3.88 (2H, t, –
3
CH –), 3.99–4.01 (1H, m, cyclopropyl-CH), 4.19 (2H, t,
2
–CH –), 4.42 (2H, q, NOCH CH ), 7.06 (1H, t, Ar–H),
2
2
3
7.28 (1H, d, Ar–H), 7.42–7.45 (1H, m, Ar–H), 7.63 (1H,
d, Ar–H), 7.84 (1H, d, Ar–H), 8.42 (1H, s, C2-H).
(1.2 mmol) in water (10 mL) and MeOH (50 mL) was
+
stirred at 50°C for 12 h. After removal of the solvent, the
residue was purified by reverse phase chromatography
with formic acid as additive to afford mono-/bis-isatin-
gatifloxacin hybrids 3d–f (yield: 43–56%) and 4d–f
ESI-MS m/z: 606 [M + H] . Elemental Anal. Calcd (%)
for C H FN O : C, 63.46; H, 5.99; N, 11.56. Found: C,
32
36
5 6
63.17; H, 5.74; N, 11.39.
1
-Cyclopropyl-7-(4-(3-(3-(ethoxyimino)-5-fluoro-2-
(
yield: 33–57%).
oxoindolin-1-yl)propyl)-3-methylpiperazin-1-yl)-6-fluoro-8-
methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (3e).
1
-Cyclopropyl-7-(4-(3-(2,3-dioxoindolin-1-yl)propyl)-3-
1
methylpiperazin-1-yl)-6-fluoro-8-methoxy-4-oxo-1,4-
Yellow solid, yield: 56%.
H NMR (400 MHz,
dihydroquinoline-3-carboxylic acid (3a).
yield: 26%. H NMR (400 MHz, DMSO-d ) δ 0.95–1.09
Yellow solid,
DMSO-d ) δ 0.94–1.09 (7H, m, 2 × cyclopropyl-CH2
6
1
6
and CH ), 1.34 (3H, t, NOCH CH ), 1.99–2.04 (2H, m, –
3
2
3
(
7H, m, 2 × cyclopropyl-CH and CH ), 1.99–2.06 (2H,
CH –), 2.93–3.33 (7H, m, piperazine-7H), 3.79 (3H, s,
2
3
2
m, –CH –), 2.96–3.31 (7H, m, piperazine-7H), 3.77 (3H,
OCH ), 3.89 (2H, t, –CH –), 3.99–4.00 (1H, m,
2
3
2
s, OCH ), 3.86 (2H, t, –CH –), 4.00–4.02 (1H, m,
cyclopropyl-CH), 4.18 (2H, t, –CH –), 4.41 (2H, q,
3
2
2
cyclopropyl-CH), 4.24 (2H, t, –CH –), 7.07 (1H, t,
NOCH CH ), 7.30–7.32 (2H, m, Ar–H), 7.57–7.64 (2H,
2
2
3
Ar–H), 7.32 (1H, d, Ar–H), 7.46 (1H, d, Ar–H),
m, Ar–H), 8.41 (1H, s, C2-H). ESI-MS m/z: 624
+
7
.60–7.63 (2H, m, Ar–H), 8.46 (1H, s, C2-H). ESI-MS
[M + H] . Elemental Anal. Calcd (%) for C H F N O :
32 35 2 5 6
+
m/z: 563 [M + H] . Elemental Anal. Calcd (%) for
C, 61.63; H, 5.66; N, 11.23. Found: C, 61.39; H, 5.51;
N, 11.03.
C H FN O : C, 64.05; H, 5.55; N, 9.96. Found: C,
3
0
31
4 6
63.81; H, 5.37; N, 9.73.
7
-(4-(3-(5-Bromo-3-(ethoxyimino)-2-oxoindolin-1-yl)
1
-Cyclopropyl-6-fluoro-7-(4-(3-(5-fluoro-2,3-dioxoindolin-
-yl)propyl)-3-methylpiperazin-1-yl)-8-methoxy-4-oxo-1,4-
dihydroquinoline-3-carboxylic acid (3b).
propyl)-3-methylpiperazin-1-yl)-1-cyclopropyl-6-fluoro-8-
1
methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (3f).
1
Yellow solid,
Yellow solid, yield: 43%.
H NMR (400 MHz,
1
yield: 33%. H NMR (400 MHz, DMSO-d ) δ 0.94–1.08
DMSO-d ) δ 0.93–1.08 (7H, m, 2 × cyclopropyl-CH2
6
6
(
4H, m, 2 × cyclopropyl-CH ), 1.14 (3H, d, CH ),
and CH ), 1.33 (3H, t, NOCH CH ), 1.98–2.03 (2H, m, –
2
3
3
2
3
1
.97–2.03 (2H, m, –CH –), 3.00–3.34 (7H, m,
CH –), 2.88–3.31 (7H, m, piperazine-7H), 3.80 (3H, s,
2
2
piperazine-7H), 3.80 (3H, s, OCH ), 3.88 (2H, t, –CH –),
OCH ), 3.89 (2H, t, –CH –), 3.98–4.00 (1H, m,
3
2
3
2
3
7
8
.90–3.99 (1H, m, cyclopropyl-CH), 4.23 (2H, t –CH –),
cyclopropyl-CH), 4.19 (2H, t, –CH –), 4.43 (2H, q,
2
2
.21–7.31 (2H, m, Ar–H), 7.76–7.63 (2H, m, Ar–H),
NOCH CH ), 7.25 (1H, d, Ar–H), 7.58–7.64 (2H, m,
2
3
+
.40 (1H, s, C2-H). ESI-MS m/z: 581 [M + H] .
Ar–H), 7.88 (1H, s, Ar–H), 8.38 (1H, s, C2-H). ESI-MS
+
+
Elemental Anal. Calcd (%) for C H F N O : C, 62.06;
m/z: 684 [M + H] , 686 [M + 2 + H] . Elemental Anal.
3
0 30 2 4 6
H, 5.21; N, 9.65. Found: C, 61.89; H, 5.03; N, 9.41.
Calcd (%) for C H FBrN O : C, 56.15; H, 5.15; N,
32
35
5 6
1
-7-(4-(3-(5-Bromo-2,3-dioxoindolin-1-yl)propyl)-3-
methylpiperazin-1-yl)-1-cyclopropyl-6-fluoro-8-methoxy-4-
oxo-1,4-dihydroquinoline-3-carboxylic acid (3c).
10.23. Found: C, 55.91; H, 5.01; N, 10.03.
3
-(2,3-Dioxoindolin-1-yl)propyl 1-cyclopropyl-7-(4-(3-(2,3-
dioxoindolin-1-yl)propyl)-3-methylpiperazin-1-yl)-6-fluoro-8-
methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate (4a).
Yellow
solid, yield: 29%. H NMR (400 MHz, DMSO-d ) δ
.84–0.96 (4H, m, 2 × cyclopropyl-CH ), 1.06 (3H, d,
1
1
6
1
0
Yellow solid, yield: 22%.
H NMR (400 MHz,
2
CH ), 1.98–2.04 (2H, m, –CH –), 2.90–3.31 (7H, m,
DMSO-d ) δ 0.96–1.08 (7H, m, 2 × cyclopropyl-CH2
3
2
6
piperazine-7H), 3.80 (3H, s, OCH ), 3.89 (2H, t, –CH –),
and CH ), 1.82–1.86 (2H, m, –CH –), 2.02–2.12 (4H, m,
3
2
3
2
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

H. Guo
CH –), 3.13–3.64 (7H, m, piperazine-7H), 3.76–3.88
Vol 000
–
(
C, 64.66; H, 6.03; N, 11.73. Found: C, 64.39; H, 5.78;
N, 11.47.
2
7H, m, OCH3 and 2 × –CH –), 4.00–4.02 (1H, m,
2
cyclopropyl-CH), 4.24 (2H, t, –CH –), 7.07 (1H, t,
Ar–H), 7.17 (1H, t, Ar–H), 7.28–7.33 (2H, m, Ar–H),
3-(3-(Ethoxyimino)-5-fluoro-2-oxoindolin-1-yl)
1-cyclopropyl-7-(4-(3-(3-(ethoxyimino)-5-fluoro-2-oxoindolin-
-yl)propyl)-3-methylpiperazin-1-yl)-6-fluoro-8-methoxy-4-
oxo-1,4-dihydroquinoline-3-carboxylate (4e).
propyl
2
1
7
.46 (1H, d, Ar–H), 7.60–7.3 (4H, m, Ar–H), 8.48 (1H,
Yellow
+
s, C2-H). ESI-MS m/z: 750 [M + H] . Elemental Anal.
1
solid, yield: 57%. H NMR (400 MHz, DMSO-d ) δ
6
Calcd (%) for C H FN O : C, 55.68; H, 5.38; N, 9.34.
41
40
5 8
0
1
–
.93–1.06 (7H, m, 2 × cyclopropyl-CH2 and CH3),
Found: C, 55.39; H, 5.11; N, 9.17.
.32–1.38 (6H, m, 2 × NOCH CH ), 1.81–1.84 (2H, m,
2
3
3
-(5-Fluoro-2,3-dioxoindolin-1-yl)propyl 1-cyclopropyl-6-
CH –), 1.99–2.04 (2H, m, –CH –), 2.38–2.40 (2H, m, –
2
2
fluoro-7-(4-(3-(5-fluoro-2,3-dioxoindolin-1-yl)propyl)-3-
methylpiperazin-1-yl)-8-methoxy-4-oxo-1,4-
CH –), 2.85–3.27 (7H, m, piperazine-7H), 3.74–3.89
2
(
7H, m, OCH3 and 2 × –CH –), 3.92–3.94 (1H, m,
2
dihydroquinoline-3-carboxylate (4b). Yellow solid, yield:
1
cyclopropyl-CH), 4.18 (2H, t, –CH –), 4.40–4.50 (4H, m,
2
2
3%. H NMR (400 MHz, DMSO-d ) δ 0.93–1.06
6
2
× NOCH CH ), 7.21–7.38 (4H, m, Ar–H), 7.57–7.71
2 3
(
(
(
7H, m, 2 × cyclopropyl-CH2 and CH ), 1.83–1.85
3
(
[
3H, m, Ar–H), 8.40 (1H, s, C2-H). ESI-MS m/z: 872
2H, m, –CH –), 1.97–2.03 (2H, m, –CH –), 2.28–2.34
2
2
+
M + H] . Elemental Anal. Calcd (%) for C H F N O :
45 48 3 7 8
2H, m, –CH –), 2.83–3.24 (7H, m, piperazine-7H),
2
C, 61.99; H, 5.55; N, 11.25. Found: C, 61.71; H, 5.29;
N, 11.01.
3
.75–3.87 (5H, m, OCH and –CH –), 3.90 (2H, t, –
3 2
CH –), 3.98–3.99 (1H, m, cyclopropyl-CH), 4.20 (2H, t,
2
3
-(5-Bromo-3-(ethoxyimino)-2-oxoindolin-1-yl)propyl 7-(4-
–
CH –), 7.25–7.32 (4H, m, Ar–H), 7.57–7.72 (3H, m,
2
+
(3-(5-bromo-3-(ethoxyimino)-2-oxoindolin-1-yl)propyl)-3-
methylpiperazin-1-yl)-1-cyclopropyl-6-fluoro-8-methoxy-4-
Ar–H), 8.40 (1H, s, C2-H). ESI-MS m/z: 786 [M + H] .
Elemental Anal. Calcd (%) for C H F N O : C, 62.67;
4
1 38 3 5 8
oxo-1,4-dihydroquinoline-3-carboxylate (4f). Yellow solid,
H, 4.87; N, 8.91. Found: C, 62.41; H, 4.63; N, 8.72.
1
yield: 41%. H NMR (400 MHz, DMSO-d ) δ 0.92–1.04
6
3
-(5-Bromo-2,3-dioxoindolin-1-yl)propyl 7-(4-(3-(5-bromo-
,3-dioxoindolin-1-yl)propyl)-3-methylpiperazin-1-yl)-1-
cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-
(
7H, m, 2 × cyclopropyl-CH and CH ), 1.31–1.40 (6H,
2 3
2
m, 2 × NOCH CH ), 1.81–1.84 (2H, m, –CH –),
2
3
2
1
1.99–2.03 (2H, m, –CH –), 2.27–2.32 (2H, m, –CH –),
2 2
3
(
2
-carboxylate (4c). Yellow solid, yield: 35%. H NMR
400 MHz, DMSO-d6) 0.92–1.04 (7H, m,
× cyclopropyl-CH2 and CH ), 1.82–1.85 (2H, m, –
2
.80–3.22 (7H, m, piperazine-7H), 3.74–3.90 (7H, m,
δ
OCH and 2 × –CH –), 3.92–3.94 (1H, m, cyclopropyl-
3
2
3
CH), 4.18 (2H, t, –CH –), 4.40–4.51 (4H, m,
2
CH –), 1.99–2.03 (2H, m, –CH –), 2.27–2.32 (2H, m, –
2
2
2
× NOCH CH ), 7.21 (1H, d, Ar–H), 7.26 (1H, d,
2 3
CH –), 2.80–3.26 (7H, m, piperazine-7H), 3.74–3.87
2
Ar–H), 7.59 (2H, dd, Ar–H), 7.68 (1H, d, Ar–H), 7.87
1H, s, Ar–H), 8.00 (1H, s, Ar–H), 8.36 (1H, s, C2-H).
(
5H, m, OCH3 and –CH –), 3.90 (2H, t, –CH –),
2 2
(
3
7
7
.90–3.92 (1H, m, cyclopropyl-CH), 4.19 (2H, t, –CH –),
2
+
ESI-MS m/z: 994 [M + H] . Elemental Anal. Calcd (%)
.20–7.37 (2H, m, Ar–H), 7.58–7.69 (3H, m, Ar–H),
.87 (1H, s, Ar–H), 8.00 (1H, s, Ar–H), 8.36 (1H, s,
for C H FBr N O : C, 54.39; H, 4.87; N, 9.87. Found:
45
48
2 7 8
+
+
C, 54.11; H, 4.59; N, 9.59.
C2-H). ESI-MS m/z: 906 [M + H] , 908 [M + 2 + H] ,
+
910 [M + 4 + H] . Elemental Anal. Calcd (%) for
C H FBr N O : C, 54.26; H, 4.22; N, 7.72. Found: C,
4
1
38
2 5 8
Acknowledgment. We gratefully acknowledge the financial
support from the Natural Science Fund of Liaoning Province
54.01; H, 3.97; N, 7.46.
3
-(3-(Ethoxyimino)-2-oxoindolin-1-yl)propyl
-cyclopropyl-7-(4-(3-(3-(ethoxyimino)-2-oxoindolin-1-yl)
propyl)-3-methylpiperazin-1-yl)-6-fluoro-8-methoxy-4-oxo-
,4-dihydroquinoline-3-carboxylate (4d).
(
2015020680).
1
1
Yellow solid,
NMR (400 MHz, DMSO-d6)
.92–1.04 (7H, m, 2 × cyclopropyl-CH2 and CH3),
.31–1.40 (6H, m, 2 × NOCH CH ), 1.81–1.84 (2H, m,
1
REFERENCES AND NOTES
yield: 33%.
H
δ
0
1
–
–
[
1] Hu, Y. Q.; Zhang, S.; Xu, Z.; Lv, Z. S.; Liu, M. L.; Feng, L. S.
Eur J Med Chem 2017, 141, 335.
2] Zhang, G. F.; Zhang, S.; Pan, B. F.; Liu, M. L.; Feng, L. S. Eur
J Med Chem 2018, 143, 710.
3] Tay, S. B.; Yew, W. S. Int J Mol Sci 2013, 14, 16570.
2
3
[
CH –), 2.00–2.03 (2H, m, –CH –), 2.31–2.33 (2H, m,
2
2
CH –), 2.79–3.25 (7H, m, piperazine-7H), 3.74–3.91
2
[
(
7H, m, OCH3 and 2 × –CH –), 3.96–3.98 (1H, m,
[4] Xu, Z.; Zhang, S.; Feng, L. S.; Li, X. N.; Huang, G. C.; Chai,
Y.; Lv, Z. S.; Guo, H. Y.; Liu, M. L. Molecules 2017, 22, 1171.
2
cyclopropyl-CH), 4.18 (2H, t, –CH –), 4.38–4.47 (4H,
m, 2 × NOCH CH ), 7.06–7.10 (2H, m, Ar–H), 7.20
(
Ar–H), 7.46 (1H, d, Ar–H), 7.84 (1H, d, Ar–H), 7.92
(
[
2
[5] Kerns, R. J.; Rybak, M. J.; Kaatz, G. W.; Vaka, F.; Cha, R.;
2
3
Grucz, R. G.; Diwadkar, V. U.; Ward, T. D. Bioorg Med Chem Lett
2003, 13, 1745.
1H, d, Ar–H), 7.26 (1H, d, Ar–H), 7.43–7.49 (2H, m,
[
6] Mather, R.; Karenchak, L. M.; Romanowski, E. G.; Kowalski,
R. P. Am J Ophthalmol 2002, 133, 463.
7] Hu, Y. Q.; Gao, C.; Zhang, S.; Xu, L.; Xu, Z.; Feng, L. S.; Wu,
X.; Zhao, F. Eur J Med Chem 2017, 139, 22.
1H, d, Ar–H), 8.40 (1H, s, C2-H). ESI-MS m/z: 836
[
+
M + H] . Elemental Anal. Calcd (%) for C H FN O :
4
5
50
7 8
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Design, Synthesis, and In Vitro Antibacterial Activities of Propylene-tethered
Gatifloxacin-isatin Hybrids
[8] Jia, X. D.; Wang, S.; Wang, M. H.; Liu, M. L.; Xia, G. M.;
[14] Xu, Z.; Song, X. F.; Qiang, M.; Lv, Z. S.; Heterocyclic, J.
Liu, X. J.; Chai, Y.; He, H. W. Chin Chem Lett 2017, 28, 235.
Chem 2017, 54, 3735.
[
9] Xu, Z.; Lv, Z. S.; Gao, C.; Ren, Q. C.; Feng, L. S. World Notes
on Antibiotics 2017, 38, S63.
10] Xu, Z.; Zhang, S.; Gao, C.; Zhao, F.; Lv, Z. S.; Feng, L. S.
Chin Chem Lett 2017, 28, 159.
11] Zhang, S.; Xu, Z.; Gao, C.; Ren, Q. C.; Le, C.; Lv, Z. S.; Feng,
L. S. Eur J Med Chem 2017, 138, 501.
12] Hu, Y. Q.; Zhang, S.; Zhao, F.; Gao, C.; Feng, L. S.; Lv, Z. S.;
Xu, Z.; Wu, X. Eur J Med Chem 2017, 133, 255.
13] Hu, Y. Q.; Xu, Z.; Zhang, S.; Wu, X.; Ding, J. W.; Lv, Z. S.;
Feng, L. S. Eur J Med Chem 2017, 136, 122.
[15] Hu, Y. Q.; Meng, L. D.; Qiang, M.; Song, X. F.; Heterocyclic,
J. Chem 2017, 54, 3725.
[16] Hu, Y. Q.; Fan, J.; Song, X. F.; Heterocyclic, J. Chem 2018,
55, 246.
[17] Hu, Y. Q.; Xu, Z.; Qiang, M.; Lv, Z. S.; Heterocyclic, J. Chem
2018, 55, 187.
[18] Xu, Z.; Zhang, S.; Song, X. F.; Qiang, M.; Lv, Z. S. Bioorg
Med Chem Lett 2017, 37, 3643.
[
[
[
[
[19] Xu, Z.; Song, X. F.; Hu, Y. Q.; Qiang, M.; Lv, Z. S. Eur J Med
Chem 2017, 138, 66.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet