The simple synthesis and antimicrobial activity of novel fluoroquinolone derivatives from natural amino acid salts

Article abstract of DOI:10.1007/s00044-010-9509-9

A simple synthetic route was developed to prepare novel fluoroquinolone derivatives from amino acid salts. A facile route preparing the quinolone intermediates in one pot was explored which can facilitate the industrial operation. A series of new compounds were prepared conveniently and characterized by IR, 1H NMR, MS, and elemental analysis. The preliminary bioassays results revealed that they have certain antimicrobial activity against Bacillus subtilis, Staphylococcus aureus, and Aspergillus fumigatus. Springer Science+Business Media, LLC 2010.

Full text of DOI:10.1007/s00044-010-9509-9

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2012) 21:53–59
DOI 10.1007/s00044-010-9509-9
ORIGINAL RESEARCH
The simple synthesis and antimicrobial activity of novel
fluoroquinolone derivatives from natural amino acid salts
•
Hui Zheng Juan Liu Pengfei Zhang
•
Received: 5 March 2010 / Accepted: 8 November 2010 / Published online: 21 November 2010
Ó Springer Science+Business Media, LLC 2010
Abstract A simple synthetic route was developed to
prepare novel fluoroquinolone derivatives from amino acid
salts. A facile route preparing the quinolone intermediates
in one pot was explored which can facilitate the industrial
operation. A series of new compounds were prepared
C3-carboxylic acid, C4-carbonyl, C6-F, and C7-piperazine
are essential or beneficial for antibacterial activity (Najma
et al., 2009; Jayashree et al., 2009; Patel and Patel 2009).
As part of our ongoing interests to find new fluoroquino-
lone derivatives, we have focused our attention on intro-
ducing natural amino acid piece to the fluoroquinolone ring
at N1-position. Herein a series of novel fluoroquinolone
derivatives from natural amino acid salts were designed
and prepared. A simple synthetic route was developed and
gives good yields. The preliminary bioassays results
revealed that they have certain bactericidal activity against
Bacillus subtilis, Staphylococcus aureus, and Aspergillus
fumigatus. Our primary objective was to find the new
bioactive compounds and then optimize it further in our
subsequent research. The synthetic routes are shown in
Fig. 1.
1
conveniently and characterized by IR, H NMR, MS, and
elemental analysis. The preliminary bioassays results
revealed that they have certain antimicrobial activity
against Bacillus subtilis, Staphylococcus aureus, and
Aspergillus fumigatus.
Keywords Fluoroquinolone Á Amino acid salts Á
Antimicrobial
Introduction
Quinoline and fluoroquinolone derivatives are receiving
much attention for their broad-spectrum bioactivities, such
as antiasthmatic, antibacterial, antimalarial, and tyrosine-
kinase PDGF-RTK inhibitor agent, etc. (Silva et al., 2003;
Chide and Orisakwe 2007; Chen et al., 2001; Miyauchi
et al., 2009). Due to such a wide range of applicability in
medicine, bioorganic chemistry, as well as synthetic
organic chemistry, there has been increasing interests in the
development of new quinolone and fluoroquinolone
derivatives to enrich this domain (Sakineh et al., 2009;
Murugesan et al., 2008; Chai et al., 2009). Structure–
activity relationship studies discovered that N1, C2-H,
Experimental
Materials and methods
All the reagents were purchased commercially and used
without further purification. The melting point was deter-
mined using a XT-4 melting-point apparatus and uncor-
rected. IR spectra were recorded on a Bruker Equinox-55
spectrophotometer using KBr discs in the 4000–400 cm-1
1
region. The H NMR was obtained on a Bruker AC-400
(400 MHz) instrument in DMSO-d6 using TMS as internal
standard. Chemical shifts (d) are expressed in ppm and
coupling constants J are given in Hz. Mass spectra were
obtained on an Agilent 5973N mass spectrometer operat-
ing at 70 eV by electron ionization technique (EI MS).
Elemental analyses were performed on an EA-1110
instrument.
H. Zheng Á J. Liu Á P. Zhang (&)
College of Material, Chemistry & Chemical Engineering,
Hangzhou Normal University, Hangzhou 310036, China
e-mail: chxyzpf@hotmail.com
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Med Chem Res (2012) 21:53–59
Fig. 1 The synthesis of novel fluoroquinolone derivatives. (a) SOCl2; (b) (E)-ethyl-3-(dimethylamino)acrylate; (c) amino acid ethyl ester
hydrochloride; (d) K2CO3; (e) hydrolysis; (f) substitute reaction; (g) merge step (a), (b), and (c) to one pot, and no individual separation
General procedure
Antimicrobial activity
2,3,4,5-Tetrafluorobenzoic acid 1 1.94 g (0.01 mol) was
dissolved in thionyl chloride 14.5 ml in a 50-ml round-
bottomed flask, stirring, and reflux for 3 h, removing the
superfluous SOCl2 on a rotary evaporator. (E)-ethyl-3-
(dimethylamino)acrylate 1.43 g (0.01 mol) was added
dropwise to the toluene solution of above leavings with
stirring at 50°C, monitoring with TLC (PE/EA = 1/1
(v/v)) to the end of reactants, adding amino acid ethyl
ester hydrochloride (0.01 mol) directly and stirring for
about 5 h at room temperature, checking the reaction via
TLC, then potassium carbonate 1.66 g (0.012 mol) was
added and stirring for 8 h at 100°C. When the reaction
was complete (determined by TLC), the mixture was
acidified with diluted hydrochloride acid (5%) to
pH = 2–3. the reaction mixture was poured into separa-
tory funnel and separated. The organic layer was con-
centrated under reduced pressure and the residual was
chromatographed on silica gel (PE/EA = 2/1 (v/v)) to
give compound 5, which was added to the 20% sulfuric
acid solution, refluxing for about 6 h, cooled to room
temperature and filter. The filter cake 6 was dissolved in
9 ml sulfoxide and added to 1-methylpiperazine 0.04 mol,
raising the temperature slowly to 100–110°C and main-
taining this temperature for about 5 h. After concentra-
tion, the mixture was poured into 20 ml water and
separated. The crude product was recrystallized from
ethanol solvent, giving compound 7.
All of the synthesized compounds were tested for their
antibacterial and antifungal activity in vitro by broth
dilution method with some bacteria Bacillus subtilis,
Staphylococcus aureus, Aspergillus fumigatus, and Can-
dida albicans according to the literature (Kong et al.,
2009; Andre and Patrick 1984). The antimicrobial discs
(diameter, 0.55 cm) were prepared at concentrations of 1,
0.2, and 0.1 mg/ml and applied to each of the culture
plates previously seeded with the test bacteria. These
culture plates were then incubated at 37°C for 24 h. The
preliminary antimicrobial activity was determined by the
diameter of inhibition zone. For each compound,
three replicate trials were conducted against each
organism.
Results and discussion
Chemistry
The common synthetic routes of fluoroquinolone deriva-
tives are carried out from compounds 1 to 5 step by step
with separation and purification, then to the final products.
To simplify the synthetic routes, we explored a facile and
simple route from compounds 1 to 5 in one pot without
separation, which is very beneficial for the industrial
operation to save manufacturing costs.
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Med Chem Res (2012) 21:53–59
55
The structures of synthesized compounds of 7a–7f were
1
confirmed by IR, H NMR, MS, and elemental analysis.
functionality in these compounds to block bacterial repli-
cation which intrigued us to study its QSAR further and
synthesize higher activity compound, the in-depth research
work is undergoing.
The Infrared spectra of all synthesized compounds showed
easily distinguishable carbonyl stretching of the carboxylic
acid group at 1728–1752 cm-1, and 1628–1557 cm-1 is
assigned to ring carbonyl stretching. Furthermore, the
absence of free NH stretching between 3300 and
3200 cm-1 confirmed that the reaction had taken place at
NH of the piperazine ring as well as amino acids deriva-
tives. In 1H NMR spectrum, common signals of carboxylic
group appear between 12.99 and 14.74 ppm and the two
kind of carboxylic group signals demonstrate that the piece
of amino acids combined to the title compounds. The
characteristic data are almost similar with the literature
(Murugesan et al., 2008; Zhu et al., 2009).
Chemical data and analyses
Synthesis of ethyl 1-(2-ethoxy-2-oxoethyl)-6,7,8-trifluoro-
4-oxo-1,4-dihydroquinoline-3-carboxylate (5a)
Yield: 75%. Mp: 198–200°C. IR (KBr) v: 3426, 3070,
2986, 1760, 1678, 1488, 1381, 1329, 1269, 1108,
1078 cm-1
.
1H NMR (CDCl3, 400 MHz): 1.31 (t,
J = 7.2 Hz, 3H, CH3), 1.38 (t, J = 7.2 Hz, 3H, CH3), 4.30
(q, J = 6.8 Hz, J = 14.8 Hz, 2H, CH2), 4.36 (q,
J = 6.4 Hz, J = 14.6 Hz, 2H, CH2), 5.03 (d, J = 6.0 Hz,
2H, CH2), 8.12 (t, J = 9.2 Hz, 1H, ArH), 8.33 (s, 1H, CH).
13C NMR (CDCl3, 100 MHz): 13.21, 14.17, 59.83, 61.23,
Biological activities
2
All the title compounds were tested for their antibacterial
and antifungal activity. From the screening results, all of
the title compounds have activity against Bacillus subtilis
and no activity against Candida albicans. Some com-
pounds have certain activity against Staphylococcus aureus
and Aspergillus fumigatus. The detail results are listed in
Table 1. Compared to the activity of control compound,
the biological value is not so good, while some new
compounds exhibit certain activities against Aspergillus
fumigatus which the control agent has not owned. The
results show that those new compounds can expand
the application of fluoroquinolone compounds on the
Aspergillus fumigatus.
62.26, 109.82, 110.15 (d, JC–F = 13.8 Hz), 125.97 (d,
3JC–F = 7.1 Hz), 128.13 (d, 2JC–F = 14.2 Hz), 142.44 (dd,
2
1JC–F = 105.7 Hz, JC–F = 14.1 Hz), 145.37, 146.92 (dd,
2
1
1JC–F = 106.1 Hz, JC–F = 14.2 Hz), 150.12 (dd, JC–F
=
2
103.3 Hz, JC–F = 14.2 Hz), 166.34, 168.11, 179.15. MS
(70 eV): m/z (%) = 357 (M?).
Synthesis of ethyl 1-(1-ethoxy-3-methyl-1-oxobutan-2-yl)-
6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate
(5b)
Yield: 77%. Mp: 72–74°C. IR (KBr) v: 3459, 3068, 2982,
2937, 1739, 1696, 1523, 1486, 1415, 1370, 1241, 1188,
.
1056 cm-1 1H NMR (CDCl3, 400 MHz): 0.92 (d,
It was found that all the new synthesized compounds
have certain antibacterial and antifungal bioactivity,
although the biological results are not as good as our
wishes. It maybe attribute to the lack of crucial
J = 6.8 Hz, 3H, CH3), 1.16 (d, J = 6.8 Hz, 3H, CH3), 1.28
(t, J = 7.2 Hz, 3H, CH3), 1.39 (t, J = 7.2 Hz, 3H, CH3),
2.55-2.59 (m, 1H, CH), 4.21–4.30 (m, 2H, CH2), 4.35–4.41
Table 1 The preliminary antimicrobial activity of title compounds
Conc. (mg/ml)
7a
7b
7c
7d
7e
7f
Controlc
Bacillus subtilis
Staphylococcus aureus
Aspergillus fumigatus
a
1
1.1a
0.9
1.0
0.7
–
1.15
0.95
–
1.2
1.15
0.6
0.6
–
1.05
0.9
0.6
0.6
–
1.2
0.95
–
4.60
3.80
3.60
3.30
2.90
2.60
–
0.2
0.1
1
0.65
0.7
–
0.6
–
0.8
–
b
0.2
0.1
1
–
–
–
–
–
–
–
–
1.0
0.6
–
–
–
–
0.6
–
0.75
–
0.2
0.1
–
–
–
–
–
–
–
–
–
–
Diameter of inhibition zone (cm)
b
c
No inhibition
Levofloxacin Hydrochloride
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Med Chem Res (2012) 21:53–59
(m, 2H, CH2), 5.14 (s, 1H), 8.13–8.19 (m, 1H, ArH), 8.73 (s,
1H, CH). 13C NMR (CDCl3, 100 MHz): 13.34, 14.25, 21.88,
22.12, 29.54, 60.13, 61.12, 61.63, 109.11, 111.42 (d,
1059 cm-1
.
1H NMR (CDCl3, 400 MHz): 1.22 (t,
J = 7.2 Hz, 3H, CH3), 1.28 (t, J = 7.2 Hz, 3H, CH3),
4.17–4.22 (m, 2H, CH2), 4.29–4.39 (m, 2H, CH2), 6.65 (s,
1H, CH), 7.37–7.39 (m, 2H, ArH), 7.52–7.54 (m, 3H,
ArH), 8.11–8.16 (m, 1H, ArH), 8.12 (s, 1H, CH). 13C NMR
(CDCl3, 100 MHz): 14.11, 15.12, 61.24, 62.13, 68.93,
3
2JC–F = 14.3 Hz), 125.92 (d, JC–F = 7.2 Hz), 127.34 (d,
1
2
2JC–F = 14.1 Hz), 141.45 (dd, JC–F = 104.6 Hz, JC–F
=
1
2
14.8 Hz), 144.11, 146.39 (dd, JC–F = 105.3 Hz, JC–F
=
13.8 Hz), 150.09 (dd, 1JC–F = 103.6 Hz, 2JC–F = 13.6 Hz),
168.42, 169.79, 177.25. MS (70 eV): m/z (%) = 399 (M?).
110.82, 112.44 (d, JC–F = 14.1 Hz), 126.67 (d, JC–F =
2
7.3 Hz), 128.34, 128.55 (d, JC–F = 14.6 Hz), 129.65,
1
130.22, 131.59, 142.76 (dd, JC–F = 104.2 Hz, JC–F
2
3
2
=
1
2
Synthesis of ethyl 1-(1-ethoxy-4-methyl-1-oxopentan-2-yl)-
6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate
(5c)
14.3 Hz), 146.79, 147.70 (dd, JC–F = 106.4 Hz, JC–F
=
14.4 Hz), 150.28 (dd, 1JC–F = 106.1 Hz, 2JC–F = 14.3 Hz),
166.23, 167.49, 178.11. MS (70 eV): m/z (%) =
435 (M?).
Yield: 73%. Mp: 98-100°C. IR (KBr) v: 3452, 3061, 2988,
2943, 1742, 1686, 1533, 1476, 1410, 1373, 1239, 1183,
Synthesis of ethyl 1-(1-ethoxy-1-oxo-3-phenylpropan-2-yl)-
6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate
(5f)
1088 cm-1
.
1H NMR (CDCl3, 400 MHz): 0.95 (d,
J = 6.0 Hz, 6H, CH3), 1.24 (t, J = 7.2 Hz, 3H, CH3), 1.39
(t, J = 7.2 Hz, 3H, CH3), 1.58–1.59 (m, 1H, CH),
2.05–2.19 (m, 2H, CH2), 4.25 (q, J = 7.2 Hz, J = 14.2 Hz,
2H, CH2), 4.38 (q, J = 7.2 Hz, J = 14.2 Hz, 2H, CH2),
Yield: 72%. Mp: 133–135°C. IR (KBr) v: 3425, 2968,
1724, 1668, 1621, 1532, 1443, 1321, 1221, 1125,
.
1064 cm-1 1H NMR (CDCl3, 400 MHz): 1.21 (t, J =
5.54 (s, 1H), 8.14–8.19 (m, 1H, ArH), 8.50 (s, 1H, CH). 13
C
NMR (CDCl3, 100 MHz): 13.75, 14.23, 22.12, 22.89,
28.34, 35.87, 60.14, 61.42, 63.33, 108.92, 112.22 (d,
7.2 Hz, 3H, CH3), 1.31 (t, J = 7.2 Hz, 3H, CH3),
3.18–3.21 (m, 2H, CH2), 3.57–3.59 (m, 1H, CH), 4.19–4.24
(m, 4H, CH2), 7.55–7.61 (m, 5H, ArH), 8.13–8.17 (m, 1H,
ArH), 8.21 (s, 1H, CH). 13C NMR (CDCl3, 100 MHz):
14.16, 14.92, 37.97, 60.34, 61.77, 71.62, 111.12, 113.41 (d,
3
2JC–F = 14.2 Hz), 125.97 (d, JC–F = 7.2 Hz), 127.39 (d,
1
2
2JC–F = 14.1 Hz), 142.15 (dd, JC–F = 104.3 Hz, JC–F
=
1
14.2 Hz), 145.51, 146.37 (dd, JC–F = 105.1 Hz, JC–F
13.9 Hz), 149.89 (dd, 1JC–F = 104.1 Hz, 2JC–F = 13.9 Hz),
166.32, 167.69, 178.17. MS (70 eV): m/z (%) = 413 (M?).
2
=
3
2JC–F = 14.2 Hz), 127.68 (d, JC–F = 7.1 Hz), 128.95 (d,
2JC–F = 13.6 Hz), 127.14, 128.62, 129.32, 131.29, 142.71
1
(dd, JC–F = 103.4 Hz, JC–F = 14.1 Hz), 147.75, 148.12
2
1
(dd, JC–F = 105.8 Hz, JC–F = 14.1 Hz), 150.45 (dd,
2
Synthesis of ethyl 1-(1-ethoxy-3-methyl-1-oxopentan-2-yl)-
6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate
(5d)
2
1JC–F = 105.9 Hz, JC–F = 14.1 Hz), 166.43, 168.29,
177.39. MS (70 eV): m/z (%) = 447 (M?).
Yield: 72%. Mp: 58–60°C. IR (KBr) v: 3456, 3069, 2990,
2965, 1744, 1609, 1511, 1427, 1405, 1356, 1206, 1108,
Synthesis of 1-(carboxymethyl)-6,7,8-trifluoro-4-oxo-1,4-
dihydroquinoline-3-carboxylic acid (6a)
1072 cm-1
.
1H NMR (CDCl3, 400 MHz): 0.71 (t,
J = 7.6 Hz, 3H, CH3), 0.84 (t, J = 7.6 Hz, 1H, CH), 0.97 (d,
J = 6.4 Hz, 3H, CH3), 1.11 (t, J = 7.2 Hz, 3H, CH3), 1.20
(t, J = 7.2 Hz, 3H, CH3), 4.07–4.21 (m, 4H, CH2),
5.11–5.13(m, 1H, CH), 7.90–7.95 (m, 1H, ArH), 8.60 (s, 1H,
CH). 13C NMR (CDCl3, 100 MHz): 12.69, 13.29, 14.35,
15.54, 23.42, 32.67, 61.24, 62.48, 63.33, 109.62, 112.34 (d,
Yield: 68%. Mp: 249–251°C. 248-250IR (KBr) v: 3422,
3058, 2982, 1725, 1619, 1523, 1492, 1448, 1351, 1226,
1078 cm-1 1H NMR (DMSO-d6, 400 MHz): 5.42 (d,
.
J = 6.8 Hz, 2H, CH2), 8.19 (m, 1H, ArH), 9.07 (s, 1H),
13.67 (s, br, 1H, COOH), 14.24 (s, br, 1H, COOH). 13C NMR
2
(DMSO-d6, 100 MHz): 59.83, 108.41, 112.35 (d, JC–F
=
=
3
3
2
14.1 Hz), 126.42 (d, JC–F = 7.3 Hz), 128.64 (d, JC–F
2JC–F = 14.2 Hz), 126.77 (d, JC–F = 7.1 Hz), 128.21 (d,
1
2
2JC–F = 14.4 Hz), 142.35 (dd, JC–F = 104.6 Hz, JC–F
=
14.6 Hz), 141.39 (dd, 1JC–F = 106.4 Hz, 2JC–F = 15.2 Hz),
1
14.2 Hz), 146.01, 147.29 (dd, JC–F = 106.1 Hz, JC–F
2
1
143.62, 147.38 (dd, JC–F = 104.3 Hz, JC–F = 13.6 Hz),
2
=
14.2 Hz), 149.78 (dd, 1JC–F = 105.2 Hz, 2JC–F = 14.2 Hz),
165.13, 166.89, 177.37. MS (70 eV): m/z (%) = 413 (M?).
149.92 (dd, JC–F = 102.1 Hz, JC–F = 14.2 Hz), 169.41,
171.32, 179.15. MS (70 eV): m/z (%) = 301 (M?).
1
2
Synthesis of ethyl 1-(2-ethoxy-2-oxo-1-phenylethyl)-6,7,8-
trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate (5e)
Synthesis of 1-(1-carboxy-2-methylpropyl)-6,7,8-trifluoro-
4-oxo-1,4-dihydroquinoline-3-carboxylic acid (6b)
Yield: 69%. Mp: 121–123°C. IR (KBr) v: 3434, 2958,
1748, 1690, 1631, 1510, 1483, 1341, 1317, 1242, 1188,
Yield: 70%. Mp: 221–223°C. IR (KBr) v: 3425, 2986,
1735, 1617, 1465, 1349, 1232, 1122, 1065 cm-1. 1H NMR
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Med Chem Res (2012) 21:53–59
57
1
129.68, 130.02, 131.56, 142.74 (dd, JC–F = 106.8 Hz,
(DMSO-d6, 400 MHz): 0.54–1.43 (m, 6H, CH3), 2.57–2.65
(m, 1H, CH), 5.29–5.49 (m, 1H, CH), 8.18–8.23 (m, 1H),
9.17 (s, 1H, CH), 14.02 (s, br, 2H, COOH). 13C NMR
(DMSO-d6, 100 MHz): 21.88, 22.12, 29.54, 61.63, 109.11,
1
2JC–F = 14.4 Hz), 146.57, 147.39 (dd, JC–F = 106.5 Hz,
1
2
2JC–F = 13.8 Hz), 150.21 (dd, JC–F = 104.8 Hz, JC–F
=
14.2 Hz), 165.69, 168.98, 178.68. MS (70 eV): m/z
(%) = 377 (M?).
2
3
111.42 (d, JC–F = 14.3 Hz), 125.92 (d, JC–F = 7.2 Hz),
127.34 (d, 2JC–F = 14.1 Hz), 141.45 (dd, 1JC–F = 104.6 Hz,
1
2JC–F = 14.8 Hz), 144.11, 146.39 (dd, JC–F = 105.3 Hz,
Synthesis of 1-(1-carboxy-2-phenylethyl)-6,7,8-trifluoro-4-
oxo-1,4-dihydroquinoline 3-carboxylic acid (6f)
1
2
2JC–F = 13.8 Hz), 150.09 (dd, JC–F = 103.6 Hz, JC–F
=
13.6 Hz), 167.31, 172.12, 178.91. MS (70 eV): m/z
(%) = 343 (M?).
Yield: 72%. Mp: 218–220°C. IR (KBr) v: 3442, 1735,
1645, 1442, 1336, 1213, 1125, 1047 cm-1 1H NMR
.
Synthesis of 1-(1-carboxy-3-methylbutyl)-6,7,8-trifluoro-4-
oxo-1,4-dihydroquinoline-3-carboxylic acid (6c)
(DMSO-d6, 400 MHz): 3.71–3.76 (m, 2H, CH2), 6.06–6.08
(m, 1H, CH), 7.00–7.16 (m, 5H, ArH), 8.18–8.20 (s, 1H,
ArH), 8.54 (s, 1H, CH), 13.90 (s, br, 2H, COOH). 13C
NMR (DMSO-d6, 100 MHz): 36.98, 74.88, 109.38, 111.54
Yield: 72%. Mp: 230–232°C. IR (KBr) v: 3427, 2988,
1727, 1607, 1484, 1349, 1239, 1112, 1045 cm-1. 1H NMR
(DMSO-d6, 400 MHz): 0.81–0.96 (m, 6H, CH3), 1.49–1.50
(m, 1H, CH), 2.17–2.22 (m, 2H, CH2), 5.72–5.76 (m, 1H,
CH), 8.18–8.23 (m, 1H), 9.21 (s, 1H, CH), 13.99 (s, br, 2H,
COOH). 13C NMR (DMSO-d6, 100 MHz): 22.13, 22.45,
2
3
(d, JC–F = 13.6 Hz), 125.54 (d, JC–F = 7.1 Hz), 126.36,
2
127.98, 128.69 (d, JC–F = 14.2 Hz), 129.35, 135.78,
1
2
142.88 (dd, JC–F = 107.1 Hz, JC–F = 14.2 Hz), 146.68
1
(dd, JC–F = 106.2 Hz, JC–F = 14.3 Hz), 148.27, 149.91
2
1
2
(dd, JC–F = 104.5 Hz, JC–F = 13.8 Hz), 166.19, 169.34,
179.11. MS (70 eV): m/z (%) = 391 (M?).
2
26.34, 31.16, 63.89, 108.34, 112.12 (d, JC–F = 14.1 Hz),
3
2
126.02 (d, JC–F = 6.8 Hz), 128.51 (d, JC–F = 14.3 Hz),
1
2
142.14 (dd, JC–F = 105.8 Hz, JC–F = 14.4 Hz), 146.45,
1
147.21 (dd, JC–F = 106.2 Hz, JC–F = 13.9 Hz), 149.69
2
Synthesis of 1-(carboxymethyl)-6,8-difluoro-7-(4-
methylpiperazin-1-yl)-4-oxo-1,4-dihydroquinoline-3-
carboxylic acid (7a)
1
2
(dd, JC–F = 104.8 Hz, JC–F = 14.2 Hz), 167.65, 169.69,
177.85. MS (70 eV): m/z (%) = 357 (M?).
Total yield: 56%. Mp: 277–279°C. IR (KBr) v: 3542, 3128,
2988, 2872, 1728, 1628, 1513, 1488, 1462, 1321, 1236,
Synthesis of 1-(1-carboxy-2-methylbutyl)-6,7,8-trifluoro-4-
oxo-1,4-dihydroquinoline-3-carboxylic acid (6d)
1
1088 cm-1. H NMR (DMSO-d6, 400 MHz): 2.71 (s, 3H,
CH3), 2.82-2.85 (m, 4H, CH2), 3.14-3.17 (m, 4H, CH2), 5.78
(d, J = 6.8 Hz, 2H, CH2), 8.19 (m, 1H, ArH), 9.03 (s, 1H),
13.97 (s, br, 1H, COOH), 14.74 (s, br, 1H, COOH). MS
(70 eV): m/z (%) = 381 (M?). 13C NMR (DMSO-d6,
100 MHz): 45.89, 56.89, 56.93, 57.99, 58.03, 59.97, 109.61,
Yield: 69%. Mp: 197–199°C. IR (KBr) v: 3432, 2989,
1731, 1612, 1482, 1329, 1242, 1121, 1062 cm-1. 1H NMR
(DMSO-d6, 400 MHz): 0.59–0.62 (m, 6H, CH3), 1.19–1.21
(m, 1H, CH), 2.07–2.12(m, 2H, CH2), 5.13–5.16 (m, 1H,
CH), 8.21–8.26 (m, 1H), 9.08 (s, 1H, CH), 13.56 (s, br, 2H,
COOH). 13C NMR (DMSO-d6, 100 MHz): 11.87, 15.89,
2
3
110.38 (d, JC–F = 13.7 Hz), 123.64 (d, JC–F = 7.2 Hz),
126.56 (d, 2JC–F = 14.2 Hz), 139.22 (dd, 1JC–F = 103.6 Hz,
2
25.64, 35.89, 68.97, 107.14, 112.19 (d, JC–F = 14.8 Hz),
1
2JC–F = 12.9 Hz), 146.62, 147.22 (d, JC–F = 105.1 Hz),
3
2
125.92 (d, JC–F = 7.1 Hz), 128.62 (d, JC–F = 14.1 Hz),
151.52 (d, 1JC–F = 104.6 Hz), 166.67, 170.62, 178.35. Anal.
Calcd. for C17H17F2N3O5: C, 53.54; H, 4.49; N, 11.02.
Found: C, 53.37; H, 4.54; N, 10.98.
1
142.65 (dd, JC–F = 106.2 Hz, JC–F = 14.1 Hz), 146.99,
2
1
147.67 (dd, JC–F = 106.1 Hz, JC–F = 14.2 Hz), 149.82
2
1
2
(dd, JC–F = 104.2 Hz, JC–F = 13.8 Hz), 166.88, 169.89,
178.22. MS (70 eV): m/z (%) = 357 (M?).
Synthesis of 1-(1-carboxy-2-methylpropyl)-6,8-difluoro-7-
(4-methylpiperazin-1-yl)-4-oxo-1,4-dihydroquinoline-3-
carboxylic acid (7b)
Synthesis of 1-(carboxy(phenyl)methyl)-6,7,8-trifluoro-4-
oxo-1,4-dihydroquinoline-3-carboxylic acid (6e)
Yield: 74%. Mp: 221–223°C. IR (KBr) v: 3433, 1729,
1631, 1484, 1349, 1243, 1115, 1052 cm-1 1H NMR
.
Total yield: 55%. Mp: 274–276°C. IR (KBr) v: 3468, 3028,
2982, 2932, 1742, 1672, 1533, 1488, 1414, 1361, 1246,
(DMSO-d6, 400 MHz): 7.11 (s, 1H, CH), 7.43–7.45 (m,
5H, ArH), 8.20–8.22 (m, 1H, ArH), 8.39 (s, 1H, CH), 14.04
(s, br, 2H, COOH). 13C NMR (DMSO-d6, 100 MHz):
1098 cm-1 1H NMR (DMSO-d6, 400 MHz): 0.95 (d,
.
J = 6.8 Hz, 6H, CH3), 2.51–2.53 (m, 1H, CH), 2.64 (s, 3H,
CH3), 2.67–2.69 (m, 4H, CH2), 3.26–3.28 (m, 1H, CH),
3.66–3.68 (m, 4H, CH2), 8.16–8.19 (m, 1H, ArH), 9.22 (s,
2
69.79, 108.98, 112.69 (d, JC–F = 14.2 Hz), 126.45 (d,
2
3JC–F = 7.2 Hz), 127.62, 128.57 (d, JC–F = 14.6 Hz),
123

58
Med Chem Res (2012) 21:53–59
1H), 12.99 (s, br, 1H, COOH), 13.64 (s, br, 1H, COOH). 13
C
Synthesis of 1-(carboxy(phenyl)methyl)-6,8-difluoro-7-(4-
methylpiperazin-1-yl)-4-oxo-1,4-dihydroquinoline-3-
carboxylic acid (7e)
NMR (DMSO-d6, 100 MHz): 21.62, 22.23, 46.11, 56.35,
=
2
56.41, 57.78, 57.91, 61.07, 109.43, 111.28 (d, JC–F
3
14.2 Hz), 122.85 (d, JC–F = 6.8 Hz), 126.77 (d, JC–F
2
=
14.1 Hz), 140.10 (dd, 1JC–F = 104.1 Hz, 2JC–F = 13.4 Hz),
Total yield: 54%. Mp: 205–207°C. IR (KBr) v: 3343, 3091,
3072, 1736, 1631, 1484, 1349, 1243, 1114, 1052 cm-1. 1H
NMR (DMSO-d6, 400 MHz): 2.42–2.46 (m, 4H, CH2),
2.67 (s, 3H, CH3), 3.31–3.33 (m, 4H, CH2), 3.75–3.77 (m,
1H, CH), 7.44–7.46 (m, 5H, ArH), 8.20–8.24 (m, 1H,
ArH), 9.16 (s, 1H), 13.96 (s, br, 1H, COOH), 14.11 (s, br,
1H, COOH). 13C NMR (DMSO-d6, 100 MHz): 45.78,
55.98, 56.11, 57.45, 57.65, 70.12, 109.31, 112.12 (d,
1
145.32, 148.11 (d, JC–F = 104.8 Hz), 150.33 (d,
1JC–F = 105.1 Hz), 165.47, 171.92, 179.23. MS (70 eV): m/
z (%) = 410 (M?). Anal. Calcd. for C20H23F2N3O5: C,
56.73; H, 5.48; N, 9.92. Found: C, 56.82; H, 5.32; N, 10.02.
Synthesis of 1-(1-carboxy-3-methylbutyl)-6,8-difluoro-7-(4-
methylpiperazin-1-yl)-4-oxo-1,4-dihydroquinoline-3-
carboxylic acid (7c)
3
2JC–F = 13.8 Hz), 124.59 (d, JC–F = 6.9 Hz), 126.72 (d,
2JC–F = 14.1 Hz), 127.66, 128.76, 128.98, 129.34, 130.21,
1
134.54, 142.22 (dd, JC–F = 104.6 Hz, JC–F = 13.8 Hz),
2
Total yield: 51%. Mp: 238–240°C. IR (KBr) v: 3439, 3033,
2968, 2936, 1752, 1645, 1557, 1448, 1434, 1323, 1236,
.
1078 cm-1 1H NMR (DMSO-d6, 400 MHz): 0.93 (d,
1
146.27, 147.66 (d, JC–F = 104.8 Hz), 149.25 (d,
1JC–F = 104.2 Hz), 165.49, 169.22, 178.82. MS (70 eV):
m/z (%) = 457 (M?). Anal. Calcd. for C23H21F2N3O5: C,
60.39; H, 4.63; N, 9.19. Found: C, 59.99; H, 4.70; N, 9.23.
J = 6.8 Hz, 6H, CH3), 1.49–1.51 (m, 1H, CH), 1.62–1.64
(m, 2H, CH2), 2.03–2.05 (m, 2H, CH2), 2.74 (s, 3H, CH3),
3.51–3.54 (m, 1H, CH), 3.78–3.79 (m, 4H, CH2), 8.12–8.14
(m, 1H, ArH), 9.02 (s, 1H), 13.22 (s, br, 1H, COOH), 13.94
(s, br, 1H, COOH). 13C NMR (DMSO-d6, 100 MHz):
22.12, 22.34, 25.98, 30.99, 46.45, 56.23, 56.33, 57.45,
Synthesis of 1-(1-carboxy-2-phenylethyl)-6,8-difluoro-7-(4-
methylpiperazin-1-yl)-4-oxo-1,4-dihydroquinoline-3-
carboxylic acid (7f)
2
57.52, 62.27, 108.86, 112.18 (d, JC–F = 13.8 Hz), 125.55
3
2
(d, JC–F = 6.9 Hz), 127.13 (d, JC–F = 14.2 Hz), 141.31
Total yield: 56%. Mp: 225-227°C. IR (KBr) v: 3342, 3106,
3087, 1735, 1642, 1493, 1380, 1257, 1112, 1065 cm-1. 1H
NMR (DMSO-d6, 400 MHz): 2.33–2.35 (m, 4H, CH2), 2.71
(s, 3H, CH3), 3.42–3.44 (m, 4H, CH2), 3.53–3.54 (m, 1H,
CH), 3.71–3.75 (m, 2H), 7.11–7.16 (m, 5H, ArH),
8.11–8.20 (m, 1H, ArH), 8.55 (s, 1H), 13.21 (s, br, 1H,
COOH), 13.98 (s, br, 1H, COOH). 13C NMR (DMSO-d6,
100 MHz): 39.67, 46.18, 55.11, 55.89, 57.15, 57.79, 75.17,
1
(dd, JC–F = 104.8 Hz, JC–F = 14.5 Hz), 146.78, 147.39
2
1
1
(d, JC–F = 104.8 Hz), 149.89 (d, JC–F = 104.6 Hz),
166.89, 170.42, 178.14. MS (70 eV): m/z (%) = 408 (M?).
Anal. Calcd. for C21H25F2N3O5: C, 57.66; H, 5.76; N, 9.61.
Found: C, 57.81; H, 5.72; N, 9.72.
Synthesis of 1-(1-carboxy-2-methylbutyl)-6,8-difluoro-7-(4-
methylpiperazin-1-yl)-4-oxo-1,4-dihydroquinoline-3-
carboxylic acid (7d)
2
3
109.76, 112.92 (d, JC–F = 14.5 Hz), 125.12 (d, JC–F
=
2
7.1 Hz), 126.12 (d, JC–F = 14.6 Hz), 127.69, 128.21,
1
128.69, 129.54, 129.77, 130.15, 142.46 (dd, JC–F
=
=
104.2 Hz, 2JC–F = 14.1 Hz), 146.95 (d, 1JC–F
Total yield: 55%. Mp: 239–241°C. IR (KBr) v: 3433, 3023,
2988, 2843, 1734, 1642, 1555, 1447, 1432, 1321, 1232,
.
1078 cm-1 1H NMR (DMSO-d6, 400 MHz): 0.91 (t,
1
104.6 Hz), 148.17, 150.18 (d, JC–F = 103.9 Hz), 165.57,
168.82, 179.96. MS (70 eV): m/z (%) = 471 (M?). Anal.
Calcd. for C24H23F2N3O5: C, 61.14; H, 4.92; N, 8.91.
Found: C, 61.31; H, 5.01; N, 9.01.
J = 6.8 Hz, 3H, CH3), 1.09 (d, J = 6.8 Hz, 3H, CH3),
1.31–1.34 (m, 2H, CH2), 1.62–1.64 (m, 1H, CH), 2.23 (s,
3H, CH3), 2.51–2.54 (m, 4H, CH2), 3.28–3.29 (m, 4H,
CH2), 3.67–3.69 (m, 1H, CH), 8.12–8.14 (m, 1H, ArH),
9.13 (s, 1H), 13.14 (s, br, 1H, COOH), 13.59 (s, br, 1H,
COOH). 13C NMR (DMSO-d6, 100 MHz): 11.56, 15.43,
23.63, 29.38, 46.67, 56.31, 56.65, 57.67, 57.86, 66.49,
108.89, 111.98 (d, 2JC–F = 14.1 Hz), 124.89 (d,
3JC–F = 7.1 Hz), 126.63 (d, 2JC–F = 14.6 Hz), 141.39 (dd,
Acknowledgments The authors are grateful to Zhejiang Provincial
Natural Science Foundation of China (No. Y4090052) and National
Science and Technology Ministry of China (No. 2007BAI34B05) for
providing financial support.
References
2
1JC–F = 105.2 Hz, JC–F = 13.9 Hz), 145.89, 147.54 (d,
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1JC–F = 105.1 Hz), 150.06 (d, JC–F = 104.9 Hz), 165.99,
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Calcd. for C21H25F2N3O5: C, 57.66; H, 5.76; N, 9.61.
Found: C, 57.75; H, 5.78; N, 9.73.
123

Med Chem Res (2012) 21:53–59
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