Synthesis and antimicrobial study of fluoroquinolonebased 4-thiazolidinones

Article abstract of DOI:10.1007/s00044-009-9228-2

The title compounds 2-substituted phenyl-3-{1-cyclopropyl-6-fluoro- 7-[4-(4-methoxyphenylpiperazin-1-yl]-4-oxo-1,4-dihydroquinoline} carboxamido-1, 3-thiazolidin-4-ones 6a-j have been synthesized from lead molecule 7-chloro-1- cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid 1; this reacted with thionyl chloride to give acid chloride 2 and with hydrazine hydrate to afford hydrazide 3. The hydrazide 3 on condensation with substituted aromatic aldehydes a-j gave Schiff base; these on reaction with N-(4-methoxyphenyl) piperazine and thioglycolic acid furnished title compounds 6a-j. All of the synthesized compounds have been established by elemental analysis. IR and NMR spectral data and have been screened for antifungal and antibacterial activities. Birkhaeuser Boston 2009.

Full text of DOI:10.1007/s00044-009-9228-2

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2010) 19:757–770
DOI 10.1007/s00044-009-9228-2
ORIGINAL RESEARCH
Synthesis and antimicrobial study of fluoroquinolone-
based 4-thiazolidinones
Navin B. Patel Æ Sarvil D. Patel
Received: 12 April 2009 / Accepted: 2 July 2009 / Published online: 29 July 2009
¨
ꢀ Birkhauser Boston 2009
Abstract The title compounds 2-substituted phenyl-3-{1-cyclopropyl-6-fluoro-
7-[4-(4-methoxyphenylpiperazin-1-yl]-4-oxo-1,4-dihydroquinoline} carboxamido-1,
3-thiazolidin-4-ones 6a–j have been synthesized from lead molecule 7-chloro-1-
cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid 1; this reacted
with thionyl chloride to give acid chloride 2 and with hydrazine hydrate to afford
hydrazide 3. The hydrazide 3 on condensation with substituted aromatic aldehydes
a–j gave Schiff base; these on reaction with N-(4-methoxyphenyl) piperazine and
thioglycolic acid furnished title compounds 6a–j. All of the synthesized compounds
have been established by elemental analysis. IR and NMR spectral data and have
been screened for antifungal and antibacterial activities.
Keywords Thiazolidinone Á Fluoroquinolone Á N-(4-methoxyphenyl) piperazine Á
Antibacterial Á Antifungal activity
Introduction
After the discovery of nalidixic acid by Lesher in 1962, a new class of antibacterial
compounds was developed with the 1-substituted-4-oxo-1,4-dihydroquinoline-3-
carboxylic acid moiety, known as quinolones. Quinolone and its derivatives play an
important role as an anti-infective agent and are widely prescribed for various
infections, e.g., upper and lower respiratory infection, gastrointestinal infection,
gynecological infections, sexually transmitted diseases, prostatitis and skin, bone
and soft tissue infections (Mitscher, 2005). They act by the interaction with DNA
gyrase/topoisomerase IV system and block the enzyme activity. The function of
these enzymes is to settle the long bacterial DNA or circular DNA into the cell
N. B. Patel (&) Á S. D. Patel
Department of Chemistry, Veer Narmad South Gujarat University, Surat 395007, Gujarat, India
e-mail: drnavin@satyam.net.in

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Med Chem Res (2010) 19:757–770
through supercoiling; inactivation kills the bacterial cell by disrupting the DNA
supercoiling so that DNA can no longer be contained within the cell (Emani et al.,
2005; Bhanot et al., 2001). The structure activity relationship study of fluoroquin-
olones suggested that the carboxylic acid or hydrolyzable amide and ester group at
C-3 position is essential for activity, and basic group at C-7 can influence the
potency and pharmacokinetics of fluoroquinolones. They are extensively investi-
gated as antidiabetic (Edmont et al., 2000), anticancer (Shaharyar et al., 2007),
antiviral (Lucero et al., 2006), and anti-HIV (Tabarrini et al., 2008) agents.
O
O
O
O
F
F
OH
Benzene
Cl
5 - 6 h
- SO2
- HCl
SOCl2
+
N
N
Cl
Cl
2
1
O
N
O
O
O
F
N2H2.H2O
F
Cl
NH NH2
CHCl3
0 - 5oC
- HCl
N
Cl
Cl
2
3
O
O
R
F
NH NH2
+
O
N
Substituted aromatic aldehydes
Cl
3
Refluxed in
Benzene
6 - 8 h
-H2O
O
O
F
N
NH
R
N
Cl
4a-j
Scheme 1 Synthetic route of compounds 5a–j and 6a–j

Med Chem Res (2010) 19:757–770
759
O
O
F
N
NH
R
OCH3
N
HN
+
N
Cl
1-(4-Methoxyphenyl)piperazine
4a-j
8 - 10 h
Refluxed in
- HCl Pyridine
O
O
F
N
NH
R
N
N
N
5a-j
H3CO
12 - 14 h
Refluxed in
1,4-dioxane
SHCH2COOH
-H2O
O
O
O
S
F
NH
N
R
N
N
N
6a-j
H3CO
Scheme 1 continued
Thiazolidinone was prepared by cyclization of Schiff base with thioglycolic acid.
Reaction is proceeding by nucleophilic attack of anion of mercaptoacetic acid upon
the carbon atom of Schiff base, followed by the capture of proton by nitrogen, and
subsequent cyclization with removal of water molecule (Brown, 1961). 4-Thiazo-
lidinones contain b-lactum ring with sulfur atom in the ring; its derivatives interact
with MurB enzyme and inhibit the biosynthesis of the peptidoglycan polymer
essential for cell wall of bacteria (Andres et al., 2000). MurB enzyme is a unique
target for antibacterial activity of thiazolidinone. They also have some significant

760
Med Chem Res (2010) 19:757–770
activity, viz. anti-inflammatory (Vazzanaa et al., 2004), antitubercular (Dandia et al.,
2004), anticancer (Ali and Hassan, 2007), antitumor (Faidallah et al., 2007), anti-
HIV (Ravichandran et al., 2008), antibacterial (Tsyalkovsky et al., 2005), antifungal
(Ulusoy et al., 2002), anesthetic (Surrey, 1949), antiviral (Terzioglu et al., 2006),
anticonvulsant (Gursoy and Terzioglu, 2005), diuretics (Raikwar et al., 2008),
nematicidal (Srinivas et al., 2008), and antihistaminic activity (Diurno et al., 1992).
We observed from the literature survey that the fluoroquinolones with hydrolyzable
group, viz. amide and ester (Patel and Bhagat, 2006; Patel and Modi, 2006; Patel
et al., 2007; Sharma and Jain, 2008), were synthesized and some of the compounds
were found potent. Hence, we decided to synthesize thiazolidinones and Schiff bases
incorporated fluoroquinolones through the hydrolyzable amide linkage to observe the
variation in antimicrobial activity (Scheme 1).
Results and discussion
Chemistry
The structures of synthesized compounds 5a–j were confirmed by elemental
analysis and IR-spectra (cm-1) absorption bands at 3446 (NH), 2910, 2845 (C-H),
1752 ([C=O for quinolone), 1632 (amide-I), 1620 (-N=CH-), 1545 (amide-II),
1346 (C-N), 1263 (C-F), 1220 (amide-III), 1041 (C-N, piperazine), 1025, 1212
(C-O-C). Some additional peaks appear due to substitution in aromatic ring
showing absorption band at 3235 (O-H), 1356, 1550 (-NO2 sym, asym), 756 (C-
1
Cl). In H-NMR spectra common signals that appear are: dH (ppm): singlet signals
at d 8.72, 8.53, and 8.20 corresponds to H2, H8, and H5 of quinolone ring, a multiplet
at d 3.68 corresponds to [N-CH-, a multiplet at d 1.11 to 1.70 corresponding to
cyclopropyl, a singlet at d 8.68 corresponds to [CO.NH, a singlet at d 7.76 for
-N=CH-, a multiplet at d 2.37–3.15 for piperazine, multiplet at d 6.82–8.58
corresponds to aromatic proton. A singlet at d 3.55 for –OCH3, and due to the
substitution on aromatic ring, a singlet appeared at d 7.80 corresponding to -OH.
The structure of compounds 6a–j were supported by elemental analysis and IR
spectra as observed in 5a–j with disappearance of 1620 cm-1 for -N=CH- band
with 1715 cm-1 for [C=O of thiazolidinone. The 1H-NMR singlet signals of
cyclilized thiazolidinone was observed at d 3.37–4.06, corresponding to -CH2– in
the ring, and d 5.67–6.20, corresponding to C2-H. The other signals observed were
same as 5a–j.
Antimicrobial activity
All of the synthesized compounds were tested for their antibacterial and antifungal
activity (MIC) in vitro by broth dilution method with two Gram-positive bacteria
S. aureus, S. pyogenes, and two Gram-negative bacteria E. coli, P. aeruginosa,
and fungi C. albicans, A. niger, and A. clavatus organisms, taking gentamicin,

Med Chem Res (2010) 19:757–770
761
ampicillin, chloramphenicol, ciprofloxacin, norfloxacin, nystatin, and griseofulvin
as standard drugs.
From the screening results, lead molecule 1 displayed broad-spectrum antimi-
crobial activity against the both Gram-negative and Gram-positive bacteria
compared with ampicillin. For all bacteria, it showed good-to-moderate activity
compared with other standard drugs.
Hydrazide 2 showed good-to-moderate activity against all bacteria compared
with all standard drugs. Compound 4i (R=2-Cl) showed excellent activity against
all bacteria, whereas compound 4g (R=2-NO2) showed excellent activity against
both of the Gram-positive bacteria. Compound 4c (R=4-OH, 3-OCH3) was found
significantly active against Gram-negative bacteria E. coli and Gram-positive
bacteria S. aureus compared with ampicillin. Remaining compounds showed good-
to-moderate activity against other bacteria compared with the remaining standard
drugs.
Compounds 5g (R=2-NO2) showed excellent activity against both Gram-
negative bacteria, whereas compounds 5b and 5i (R=4-OCH3 and 2-Cl) displayed
excellent activity against Gram-negative bacteria E. coli, 5i and 6g (R=2-Cl and
2-NO2) against Gram-negative bacteria P. aeruginosa; 6j (R=4-Cl) against Gram-
positive bacteria S. aureus, 5b, 5i, and 6i (R=4-OCH3, 2-Cl, and 2-Cl) against
Gram-positive bacteria S. pyogenes compared with the standard drug ampicillin,
whereas other compounds showed poor activity compared with the standard drugs
gentamicin, chloramphenicol, ciprofloxacin, and norfloxacin.
Lead molecule 1 and hydrazide 2 showed excellent activity against C. albicans
compared with the standard drug griseofulvin. Both of them demonstrated good-to-
moderate activity against the remaining fungal species compared with both standard
drugs. Excellent activity was observed for compounds 5a, 5b, 5d, 5i, 6b, 6c, and 6e
(R=-H, 4-OCH3, 4-F, 2-Cl, 4-OCH3, 3-OCH3, 4-OH, and -OH) against
fungi C. albicans compared with the standard drug griseofulvin, whereas other
compounds showed moderate-to-poor activity against the rest of the fungal species
compared with the standard drugs nystatin and griseofulvin.
Conclusions
•
The lead molecule showed excellent activity but activity was significantly
decreased when it was converted to hydrazide; activity also decreased when
hydrazide converted to Schiff base and cyclization to thiazolidinones (with some
exception).
•
•
All of the synthesized compounds were found to be active against C. albicans
but for other fungal species they were found to be poor.
Activity of fluoroquinolones was not improved on formation of 4-thiazolidinone
via Schiff base through the hydrolyzable amide linkage at C-3 position.
Carboxylic acid group at C-3 is essential for in vitro antibacterial activity.
The present work provides more information about SAR of fluoroquinolones.
•
•

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Med Chem Res (2010) 19:757–770
Experimental
Melting points were determined in open capillaries and were left uncorrected. The
IR spectra were recorded on Shimadzu FTIR spectrophotometer, using KBr pallets.
1H-NMR spectra were scanned on Bruker advance II FT-NMR spectrometer at
400 MHz, using TMS as the internal standard and (CDCl3:DMSO d6) (2:1) as
solvent (chemical shift in d ppm). The elemental analysis (C, H, N) of compounds
was performed on Carlo Erba 1108. The compounds gave satisfactory C, H, and N
analysis.
General procedure for synthesis of compound (5a–j and 6a–j)
1-Cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-chloro-3-quinoline carbonyl chloride
(2)
The mixture of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-chloro-3-quinoline car-
boxylic acid 1 (0.01 mol), DMF 1 ml, and thionyl chloride (0.01 mol) was refluxed
using benzene as a solvent on water bath at 80ꢁC for 5–6 h in anhydrous condition
with the help of calcium chloride guard tube, until the HCl gas evolution was ceased
and then solvent and thionyl chloride were removed by distillation. The solid
material of the title compound obtained was cooled and used in next step.
1-Cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-chloro quinoline-3-carbohydrazide (3)
To a mixture of hydrazine hydrate (0.03 mol) in dry chloroform and triethyl amine
(1 ml), acid chloride 2 (0.01 mol) in dry chloroform added drop wise in 45 min and
temperature was maintained at 0–5ꢁC. The reaction mixture was further stirred at
room temperature for 2 h and the solvent was removed by distillation and solid
product obtained was neutralized with NaHCO3 (10%) and washed with distilled
water. The product was filtered, dried, and recrystallized from DMF. The mp was
324–327ꢁC. The reaction was monitored by TLC on silica gel using a chloroform to
methanol ratio (9:1).
IR: (KBr) m (cm-1): 3446 (NH), 3072, 2980 (C-H), 1750 ([C=O of quinolone),
1627 (amide-I), 1533 (amide-II), 1361 (C-N), 1263 (C-F), 1220 (amide-III), 746
(C-Cl); 1H NMR (DMSO-d6(1) : CDCl3(2)) : 8.3 (s, 1H, H2), 8.1 (s, 1H, H8), 7.7 (s,
1H, H5), 3.64 (m, 1H, [N-CH-), 1.10–1.65 (m, 4H, Cyclopropyl), 8.80 (s, 1H,
[CO.NH), 4.33 (s, 2H, -NH2)
1-Cyclopropryl-6-fluoro-1,4-dihydro-4-oxo-7-chloro-3-[-N-(benzol hydrazinyl)-
carbonyl]quinoline (4a)
The mixture of 3 (0.01 mol) and benzaldehyde a (0.012 mol) in dry benzene was
taken and was refluxed for 6–8 hr and maintained dry condition by using dean stark
apparatus. Solvent was removed by distillation; solid product obtained was washed
with distilled water, dried, and recrystallized in benzene to acetone ratio (9:1). The

Med Chem Res (2010) 19:757–770
763
reaction was monitored by TLC on silica gel using chloroform to methanol ratio
(9:1) The mp was 240–245ꢁC.
IR: (KBr) m (cm-1): 3450 (NH), 3010, 2980 (C–H), 1627 (amide-I), 1547 (amide-
II), 1226 (amide-III), 1355 (C-N), 1627 (-N=CH-), 1261 (C-F), 1748 ([C=O),
750 (C-Cl);1H NMR (DMSO-d6(1) : CDCl3(2)) : 8.3 (s, 1H, H2), 8.1 (s, 1H, H8),
7.8 (s, 1H, H5), 3.75 (m, 1H, [N-CH-), 1.11–1.58 (m, 4H, Cyclopropyl), 8.9 (s,
1H, [CO.NH), 7.3 (s, 1H, -N=CH-).
1-Cyclopropyl- 6-fluoro-1,4-dihydro-4-oxo-7-[4-(4methoxyphenyl)piperazin-1-yl]-
3-[N-(benzol hydrazinyl)-carbonyl]quinoline (5a)
The mixture of compound 4a (0.01 mol) and N-(4-methoxyphenyl)piperazine
(0.05 mol) in pyridine was refluxed for 8–10 h, poured into crushed ice, and
neutralized with diluted HCl. The product was stirred for half an hour, filtered,
dried, and recrystallized from DMF. The reaction was monitored by TLC on silica
gel plate using benzene to acetone ratio (9:1).
2-Phenyl-3-{1-cyclopropyl-6-fluoro-7-[4-(4-methoxyphenylpiperazin-1-yl]-4-oxo-
1,4-dihydroquinoline}carboxamido-1,3-thiazolidin-4-ones (6a)
The mixture of compound 5a (0.01 mol) and thioglycolic acid (0.015 mol) was
taken in dry 1,4 dioxane, added a pinch of anhydrous zinc chloride, and the mixture
was refluxed for 12–14 hr and cooled to room temperature. It was then poured into
crushed ice. The solid product was filtered, neutralized with distilled water, dried,
and recrystallized from DMF. The reaction was monitored on TLC on silica gel
using toluene to ethylacetate ratio (9:1).
Other thiazolidinone derivatives have been prepared by the same method. Their
physical constants and antimicrobial activity are given in Tables 1 and 2,
respectively.
(5a) IR: (KBr) m (cm-1): 3446 (NH), 2910, 2845 (C-H), 1750 ([C=O), 1632
(amide-I), 1620 (-N=CH-), 1545 (amide-II), 1346 (C-N), 1263 (C-F), 1220
1
(amide-III), 1041 (C-N, piperazine), 1025, 1212 (C-O-C); H NMR (DMSO-
d6(1) : CDCl3(2)) : 8.72 (s, 1H, H2), 8.53 (s, 1H, H8), 8.20 (s, 1H, H5), 3.68 (m, 1H,
[N-CH-), 1.11–1.68 (m, 4H, cyclopropyl), 8.68 (s, 1H, [CO.NH), 7.76 (s, 1H,
-N=CH-), 2.37–3.15 (m, 8H, piperazine), 6.82–8.58 (m, 9H, Ar-H), 3.55 (s, 1H,
-OCH3); Anal. Calcd. for C31H30N5O3F: C, 69.00; H, 05.60; N, 12.98. Found: C,
69.05; H, 05.61; N, 12.95.
(5b) IR: (KBr) m (cm-1): 3426 (NH), 2910, 2835 (C-H), 1751 ([C=O), 1631
(amide-I), 1626 (-N=CH-), 1560 (amide-II), 1356 (C-N), 1261 (C-F), 1220
1
(amide-III), 1042 (C-N, piperazine), 1028,1202, (C-O-C); H-NMR (DMSO-
d6(1) : CDCl3(2)) : 8.65 (s, 1H, H2), 8.45 (s, 1H, H8), 8.12 (s, 1H, H5), 3.45 (m, 1H,
[N-CH-), 1.08–1.65 (m, 4H, cyclopropyl), 8.60 (s, 1H, [CO.NH), 7.57 (s, 1H,
-N=CH-), 2.22–3.05 (m, 8H, piperazine), 6.73–8.45 (m, 8H, Ar-H), 3.61 and
3.98 (s, 3H, -OCH3); Anal. Calcd. for C32H32N5O4F: C, 67.47; H, 05.66; N, 12.29.
Found: C, 67.48; H, 05.64; N, 12.21.

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Med Chem Res (2010) 19:757–770
Table 1 Physical constant of the synthesized compounds
O
O
O
O
N
O
S
F
F
NH
N
NH
N
R
R
N
N
N
N
N
H
CO
3
H
CO
3
6a-j
5a-j
Compound
R
Yield (%)
MP (ꢁC)
Molecular formula
31H30O3N5F
Molecular weight
5a
5b
5c
5d
5e
5f
-H
4-OCH3
62
61
59
64
59
55
59
64
58
64
55
62
71
52
59
61
68
63
67
55
312–316
297–301
307–309
287–293
261–267
315–319
265–270
271–272
295–297
251–255
298–301
307–310
289–291
265–268
251–257
315–319
311–315
285–287
319–321
198–201
C
539.23
569.24
585.23
557.22
555.61
555.61
584.61
584.61
574.05
574.05
613.71
643.73
659.73
631.70
629.71
629.71
658.70
658.70
648.15
648.15
C32H32 O4N5F
C32H32O5N5F
4-OH, 3-OCH3
4-F
C31H29O3N5F2
C31H30O4N5F
C31H30O4N5F
2-OH
4-OH
5g
5h
5i
2-NO2
3-NO2
2-Cl
C31H29O5N6F
C31H29O5N6F
C31H29O3N5FCl
C31H29O3N5FCl
C33H32O4N5FS
5j
4-Cl
6a
6b
6c
6d
6e
6f
-H
4-OCH3
4-OH, 3-OCH3
4-F
C34H34O5N5FS
C34H34O6N5FS
C33H31O4N5F2S
C33H32O5N5FS
C33H32O5N5FS
2-OH
4-OH
6g
6h
6i
2-NO2
3-NO2
2-Cl
C33H31O6N6FS
C33H31O6N6FS
C33H31O4N5FClS
6j
4-Cl
C33H31O4N5FClS
(5c) IR: (KBr) m (cm-1): 3420 (NH), 3235 (O-H), 2935, 2840 (C-H), 1741
([C=O), 1638 (amide-I), 1625 (-N=CH-), 1545 (amide-II), 1325 (C-N), 1255
(C-F), 1215 (amide-III), 1031 (C-N, piperazine), 1022, 1210 (C-O-C); 1H NMR
(DMSO-d6(1) : CDCl3(2)) : 8.56 (s, 1H, H2), 8.35 (s, 1H, H8), 8.05 (s, 1H, H5), 3.73
(m, 1H, [N-CH-), 1.19–1.61 (m, 4H, cyclopropyl), 8.47 (s, 1H, [CO.NH), 7.35
(s, 1H, -N=CH-), 1.97–2.93 (m, 8H, piperazine), 6.53–8.22 (m, 7H, Ar-H), 4.12
and 3.84 (s, 3H, -OCH3), 7.80 (s, 1H, -OH); Anal. Calcd. for C32H32N5O5F: C,
65.63; H, 05.51; N, 11.96. Found: C, 65.29; H, 05.52; N, 11.94.
(5d) IR: (KBr) m (cm-1): 3420 (NH), 2932, 2856 (C-H), 1742 ([C=O), 1618
(amide-I), 1588 (-N=CH-), 1548 (amide-II), 1345 (C-N), 1232, 1264 (C-F),
1210 (amide-III), 1041 (C-N, piperazine), 1018,1222 (C-O-C); 1H NMR

Med Chem Res (2010) 19:757–770
765
Table 2 Antibacterial and antifungal activity of synthesized compounds
Compd.
Minimum inhibition concentration (l/ml)
Gram-negative Gram-positive
Fugal species
E. coli P. aeruginosa S. aureus S. pyogenus C. albicans A. niger A. clavatus
1
100
500
500
200
100
500
500
500
500
200
50
100
500
1000
500
200
500
500
500
200
200
100
1000
500
200
200
500
500
200
100
500
100
1000
200
500
1000
500
1000
500
100
200
500
500
1
100
500
500
500
200
500
500
500
100
1000
200
1000
1000
500
500
500
500
500
150
1000
500
1000
500
1000
1000
1000
500
500
200
500
500
100
100
500
500
200
500
500
100
1000
500
500
500
1000
1000
1000
500
500
1000
500
500
1000
1000
1000
500
1000
1000
500
500
1000
500
1000
1000
1000
1000
1000
–
1000
500
1000
500
3
4a
1000
1000
500
1000
1000
4b
[1000 [1000
4c
500
1000
500
1000
1000
500
4d
500
4e
1000
500
4f
500
500
4g
200
1000 [1000
1000 [1000
4h
1000
100
4i
500
500
500
500
500
500
4j
1000
500
100
150
250
500
500
50
1000
500
5a
5b
100
[1000 [1000
5c
500
1000
500
1000
500
5d
500
5e
500
500 [1000
5f
1000
150
1000
1000
1000
1000
1000
1000
5g
5h
1000
100
1000
1000
500
1000
1000
500
500
500
500
1000
500
500
5i
100
[1000 [1000
5j
500
1000
500
1000
500
6a
1000
1000
1000
1000
500
6b
500 [1000
6c
[1000
1000
1000
1000
6d
1000
1000
6e
6f
500
1000 [1000
1000 1000
1000 [1000
6g
500
6h
1000
100
6i
[1000
1000
6j
1000
500 [1000
Gentamicin
Ampicillin
Chloramphenicol
Ciprofloxacin
Norfloxacin
Nystatin
Griseofulvin
0.05
0.25
0.5
–
–
–
–
100
50
25
10
–
100
50
250
50
50
10
–
100
50
50
10
–
–
–
–
–
25
–
–
–
10
–
–
–
–
100
500
100
100
100
100
–
–
–
–

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(DMSO-d6(1) : CDCl3(2)) : 8.77 (s, 1H, H2), 8.25 (s, 1H, H8), 7.99 (s, 1H, H5), 3.82
(m, 1H, [N-CH-), 1.15–1.63 (m, 4H, cyclopropyl), 8.52 (s, 1H, [CO.NH), 7.35
(s, 1H, -N=CH-), 1.93–3.03 (m, 8H, piperazine), 6.53–8.32 (m, 8H, Ar-H), 3.56
(s, 3H, -OCH3); Anal. Calcd. for C31H29N5O3F2: C, 66.78; H, 05.24; N, 12.56.
Found: C, 66.81; H, 05.27; N, 12.55.
(5e) IR: (KBr) m (cm-1): 3484 (NH), 3235 (O-H), 2915,2860 (C-H), 1747
([C=O), 1615 (amide-I), 1580 (-N=CH-), 1545 (amide-II), 1357 (C-N), 1267
(C-F), 1211 (amide-III), 1057 (C-N, piperazine), 1012, 1205, (C-O-C); 1H
NMR (DMSO-d6(1) : CDCl3(2)) : 8.30 (s, 1H, H2), 8.00 (s, 1H, H8), 8.10 (s, 1H,
H5), 3.75 (m, 1H, [N-CH-), 1.21–1.66 (m, 4H, cyclopropyl), 8.80 (s, 1H,
[CO.NH), 7.50 (s, 1H, -N=CH-), 2.15–2.75 (m, 8H, piperazine), 6.82–8.36 (m,
8H, Ar-H), 4.05 (s, 3H, -OCH3), 7.20 (s, 1H, -OH); Anal. Calcd. for
C31H30N5O4F: C, 67.01; H, 05.44; N, 12.60. Found: C, 67.03; H, 05.46; N, 12.62.
(5f) IR: (KBr) m (cm-1): 3410 (NH), 3245 (O-H), 2908, 2835 (C-H), 1758
([C=O), 1625 (amide-I), 1600(-N=CH-), 1532 (amide-II), 1360 (C-N), 1265
(C-F), 1217 (amide-III), 1039 (C-N piperazine), 1011, 1221 (C-O-C); 1H NMR
(DMSO-d6(1) : CDCl3(2)) : 8.85 (s, 1H, H2), 8.66 (s, 1H, H8), 8.15 (s, 1H, H5), 3.87
(m, 1H, [N-CH-), 1.13–1.67 (m, 4H, cyclopropyl), 8.32 (s, 1H, [CO.NH), 7.66
(s, 1H, -N=CH-), 2.15–3.18 (m, 8H, piperazine), 6.21–8.35 (m, 8H, Ar-H), 3.98
(s, 3H, -OCH3), 7.87 (s, 1H, -OH); Anal. Calcd. for C31H30N5O4F: C, 67.01; H,
05.44; N, 12.60. Found: C, 67.05; H, 05.40; N, 12.55.
(5g) IR: (KBr) m (cm-1): 3448 (NH), 2932, 2845 (C-H), 1757 ([C=O), 1630
(amide-I), 1615 (-N=CH-), 1535 (amide-II), 1345 (C-N), 1356, 1550 (-NO2
sym, asym), 1265 (C-F), 1210 (amide-III), 1035 (C-N, piperazine), 1009, 1225
(C-O-C); 1H NMR (DMSO-d6(1) : CDCl3(2)) : 8.66 (s, 1H, H2), 8.15 (s, 1H, H8),
8.12 (s, 1H, H5), 3.49 (m, 1H,[N-CH-), 1.11–1.59 (m, 4H, cyclopropyl), 8.20 (s,
1H, [CO.NH), 7.55 (s, 1H, -N=CH-), 2.12–3.04 (m, 8H, piperazine), 6.21–8.35
(m, 8H, Ar-H), 3.67 (s, 3H, -OCH3); Anal. Calcd. for C31H29N6O5F: C, 63.69; H,
05.00; N, 14.38. Found: C, 63.68; H, 05.02; N, 14.31.
(5h) IR: (KBr) m (cm-1): 3402 (NH), 2935, 2845 (C-H), 1750 ([C=O), 1621
(amide-I), 1610 (-N=CH-), 1566 (amide-II), 1355 (C-N), 1365, 1533 (-NO2
sym, asym), 1263 (C-F), 1222 (amide-III), 1046 (C-N, piperazine), 1011, 1229
(C-O-C); 1H NMR (DMSO-d6(1) : CDCl3(2)) : 8.41 (s, 1H, H2), 8.24 (s, 1H, H8),
7.98 (s, 1H, H5), 3.87 (m, 1H,[N-CH-), 1.18–1.62 (m, 4H, cyclopropyl), 8.11 (s,
1H, [CO.NH), 7.68 (s, 1H, -N=CH-), 2.77–2.93 (m, 8H, piperazine), 6.21–8.35
(m, 8H, Ar-H), 3.56 (s, 3H, -OCH3); Anal. Calcd. for C31H29N6O5F: C, 63.69; H,
05.00; N, 14.38. Found: C, 63.67; H, 05.05; N, 14.42.
(5i) IR: (KBr) m (cm-1): 3452 (NH), 2935, 2825 (C-H), 1757 ([C=O), 1645
(amide-I), 1592 (-N=CH-), 1525 (amide-II), 1307 (C-N), 1255 (C-F), 1215
(amide-III), 1047 (C-N, piperazine), 1018, 1222 (C-O-C), 771 (C-Cl); 1H NMR
(DMSO-d6(1) : CDCl3(2)) : 8.35 (s, 1H, H2), 8.12 (s, 1H, H8), 7.75 (s, 1H, H5), 3.77
(m, 1H, [N-CH-), 1.15–1.65 (m, 4H, cyclopropyl), 7.89 (s, 1H, [CO.NH), 7.44
(s, 1H, -N=CH-), 2.01–3.37 (m, 8H, piperazine), 6.21–8.35 (m, 8H, Ar-H), 3.98
(s, 3H, -OCH3); Anal. Calcd. for C31H29N5O3FCl: C, 64.86; H, 05.09; N, 12.20.
Found: C, 64.88; H, 05.12; N, 12.24.

Med Chem Res (2010) 19:757–770
767
(5j) IR: (KBr) m (cm-1): 3420 (NH), 2952, 2825 (C-H), 1753 ([C=O), 1627
(amide-I), 1617 (-N=CH-), 1568 (amide-II), 1365 (C-N), 1263 (C-F), 1224
(amide-III), 1091 (C-N, piperazine), 1031, 1201 (C-O-C), 744 (C-Cl); 1H NMR
(DMSO-d6(1) : CDCl3(2)) : 8.55 (s, 1H, H2), 8.24 (s, 1H, H8), 7.86 (s, 1H, H5), 3.54
(m, 1H, [N-CH-), 1.05–1.68 (m, 4H, cyclopropyl), 7.66 (s, 1H, [CO.NH), 7.32
(s, 1H, -N=CH-), 2.11–3.21 (m, 8H, piperazine), 6.21–8.35 (m, 8H, Ar-H), 4.11
(s, 3H, -OCH3); Anal. Calcd. for C31H29N5O3FCl: C, 64.86; H, 05.09; N, 12.20.
Found: C, 64.88; H, 05.11; N, 12.26.
(6a) IR: (KBr) m (cm-1): 3451 (NH), 3064, 2980 (C-H), 1752 ([C=O of
quinolone), 1725 ([C=O of 4-thiazolidinone), 1632 (amide-I), 1534 (amide-II),
1350 (C-N), 1264 (C-F), 1230 (amide-III), 1046 (C-N, piperazine), 1012, 1215
(C-O-C); 1H NMR (DMSO-d6(1) : CDCl3(2)) : 8.33 (s, 1H, H2), 8.20 (s,1H, H8),
8.10 (s, 1H, H5), 3.65 (m, 1H,[N-CH-), 1.25–1.58 (m, 4H, Cyclopropyl), 8.80 (s,
1H,[CO.NH), 5.75 (s, 1H, -N-CH-), 3.90 (s, 2H, -CH2-S), 2.40–2.70 (m, 8H,
piperazine), 6.40–8.40 (m, 9H, Ar-H), 4.20 (s, 1H, -OCH3); Anal. Calcd. for
C33H32N5O4FS: C, 64.59; H, 05.26; N, 11.41. Found: C, 64.55; H, 05.24; N, 11.37.
(6b) IR: (KBr) m (cm-1): 3454 (NH), 3071, 2990 (C-H), 1745 ([C=O of
quinolone), 1721 ([C=O of 4-thiazolidinone), 1615 (amide-I), 1533 (amide-II),
1352 (C-N), 1264 (C-F), 1225 (amide-III), 1031 (C-N, piperazine), 1018, 1218
(C-O-C); 1H NMR (DMSO-d6(1) : CDCl3(2)) : 8.87 (s, 1H, H2), 8.54 (s, 1H, H8),
8.05 (s, 1H, H5), 3.82 (m, 1H,[N-CH-), 1.15–1.69 (m, 4H, cyclopropyl), 8.65 (s,
1H,[CO.NH), 5.96 (s, 1H, -N-CH-), 3.63 (s, 2H, -CH2-S), 2.82–3.15 (m, 8H,
piperazine), 6.46–8.55 (m, 8H, Ar-H), 3.45 and 3.98 (s, 3H, -OCH3); Anal. Calcd.
for C34H34N5O5FS: C, 63.44; H, 05.32; N, 10.88. Found: C, 63.32; H, 05.25; N,
10.85.
(6c) IR: (KBr) m (cm-1): 3465 (NH), 3245 (O-H), 2910, 2810 (C-H), 1748
([C=O of quinolone), 1725 ([C=O of 4-thiazolidinone), 1635 (amide-I), 1535
(amide-II), 1325 (C-N), 1245 (C-F), 1220 (amide-III), 1045 (C-N, piperazine),
1025, 1212 (C-O-C); 1H NMR (DMSO-d6(1) : CDCl3(2)) : 8.77 (s, 1H, H2), 8.42
(s, 1H, H8), 7.87 (s, 1H, H5), 3.53 (m, 1H, [N-CH-), 1.19–1.57 (m, 4H,
cyclopropyl), 8.52 (s, 1H,[CO.NH), 6.11 (s, 1H, -N-CH-), 3.36 (s, 2H, -CH2-
S), 1.87–3.05 (m, 8H, piperazine), 6.44–8.44 (m, 7H, Ar-H), 3.92 (s, 3H, -OCH3),
7.46 (s, 1H, -OH); Anal. Calcd. for C34H34N5O6FS: C, 61.90; H, 05.19; N, 10.62.
Found: C, 61.89; H, 05.17; N, 10.65.
(6d) IR: (KBr) m (cm-1): 3415 (NH), 2915, 2864 (C-H), 1757 ([C=O of
quinolone), 1730 ([C=O of 4-thiazolidinone), 1635 (amide-I), 1552 (amide-II),
1367 (C-N), 1260, 1235 (C-F), 1212 (amide-III), 1061 (C-N, piperazine),
1
1025,1218 (C-O-C); H NMR (DMSO-d6(1) : CDCl3(2)) : 8.77 (s, 1H, H2), 8.25
(s, 1H, H8), 7.99 (s, 1H, H5), 3.82 (m, 1H, [N-CH-), 1.15–1.63 (m, 4H,
cyclopropyl), 8.52 (s, 1H,[CO.NH), 5.87 (s, 1H, -N-CH-), 3.45 (s, 2H, -CH2-
S), 1.93–3.03 (m, 8H, piperazine), 6.53–8.32 (m, 8H, Ar-H), 3.56 (s, 3H, -OCH3);
Anal. Calcd. for C33H31N5O4F2S: C, 62.75; H, 04.95; N, 11.09. Found: C, 62.73; H,
04.93; N, 11.12.
(6e) IR: (KBr) m (cm-1): 3420 (NH), 3245 (O-H), 2925, 2825 (C-H), 1758
([C=O of quinolone), 1715 ([C=O of 4-thiazolidinone), 1615 (amide-I), 1525
(amide-II), 1345 (C-N), 1245 (C-F), 1207 (amide-III), 1031 (C-N piperazine),

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Med Chem Res (2010) 19:757–770
1025, 1210 (C-O-C); 1H NMR (DMSO-d6(1) : CDCl3(2)) : 8.66 (s, 1H, H2), 8.11
(s, 1H, H8), 7.75 (s, 1H, H5), 3.74 (m, 1H, [N-CH-), 1.15–1.59 (m, 4H,
cyclopropyl), 8.52 (s, 1H,[CO.NH), 6.20 (s, 1H, -N-CH-), 3.87 (s, 2H, -CH2-
S), 1.92–3.05 (m, 8H, piperazine), 6.35–8.15 (m, 8H, Ar-H), 3.42 (s, 3H, -OCH3),
7.5 (s, 1H, -OH); Anal. Calcd. for C33H32N5O5FS: C, 62.94; H, 05.12; N, 11.12.
Found: C, 62.93; H, 05.11; N, 11.10.
(6f) IR: (KBr) m (cm-1): 3425 (NH), 3248 (O-H), 2920, 2819 (C-H), 1751
([C=O of quinolone), 1721 ([C=O of 4-thiazolidinone), 1622 (amide-I), 1519
(amide-II), 1352 (C-N), 1252 (C-F), 1210 (amide-III), 1031 (C-N piperazine),
1
1025,1212 (C-O-C); H NMR (DMSO-d6(1) : CDCl3(2)) : 8.75 (s, 1H, H2), 8.57
(s, 1H, H8), 7.98 (s, 1H, H5), 3.42 (m, 1H, [N-CH-), 1.05–1.69 (m, 4H,
cyclopropyl), 8.45 (s, 1H,[CO.NH), 6.02 (s, 1H, -N-CH-), 3.65 (s, 2H, -CH2-
S), 2.11–3.05 (m, 8H, pipreazine), 6.37–8.20 (m, 8H, Ar-H), 3.87 (s, 3H, -OCH3),
7.9 (s, 1H, -OH); Anal. Calcd. for C33H32N5O5FS: C, 62.94; H, 05.12; N, 11.12.
Found: C, 62.92; H, 05.10; N, 11.09.
(6g) IR: (KBr) m (cm-1): 3430 (NH), 2955, 2860 (C-H), 1747 ([C=O of
quinolone), 1719 ([C=O of 4-thiazolidinone), 1628 (amide-I), 1545 (amide-II),
1335 (C-N), 1540, 1355 (-NO2 sym, asym), 1270 (C-F), 1215 (amide-III), 1032
1
(C-N, piperazine), 1015, 1220 (C-O-C); H NMR (DMSO-d6(1) : CDCl3(2)) :
8.77 (s, 1H, H2), 8.10 (s, 1H, H8), 7.87 (s, 1H, H5), 3.52 (m, 1H,[N-CH-), 1.11–
1.67 (m, 4H, cyclopropyl), 8.15 (s, 1H,[CO.NH), 6.15 (s, 1H, -N-CH-), 3.67 (s,
2H, -CH2-S), 1.87–2.96 (m, 8H, piperzine), 6.42–8.22 (m, 8H, Ar-H), 3.87 (s,
3H, -OCH3); Anal. Calcd. for C33H31N6O6FS: C, 60.17; H, 04.74; N, 12.76.
Found: C, 60.14; H, 04.73; N, 12.75.
(6h) IR: (KBr) m (cm-1): 3430 (NH), 2925, 2835 (C-H), 1756 ([C=O of
quinolone), 1719 ([C=O of 4-thiazolidinone), 1632 (amide-I), 1535 (amide-II),
1331 (C-N), 1245 (C-F), 1215 (amide-III), 1045 (C-N, piperazine), 1545, 1355
1
(-NO2 sym, asym), 1010, 1200 (C-O-C); H NMR (DMSO-d6(1) : CDCl3(2)) :
8.55 (s, 1H, H2), 8.14 (s, 1H, H8), 8.08 (s, 1H, H5), 3.57 (m, 1H,[N-CH-), 1.13–
1.59 (m, 4H, cyclopropyl), 8.22 (s, 1H,[CO.NH), 6.01 (s, 1H, -N-CH-), 3.69 (s,
2H, -CH2-S), 2.11–3.12 (m, 8H, piperazine), 6.25–8.05 (m, 8H, Ar-H), 3.87 (s,
3H, -OCH3); Anal. Calcd. for C33H31N6O6FS: C, 60.17; H, 04.74; N, 12.76.
Found: C, 60.12; H, 04.72; N, 12.74.
(6i) IR: (KBr) m (cm-1): 3425 (NH), 2912, 2820 (C-H), 1745 ([C=O of
quinolone), 1732 ([C=O of 4-thiazolidinone), 1632 (amide-I), 1540 (amide-II),
1310 (C-N), 1245 (C-F), 1210 (amide-III), 1065 (C-N, piperazine), 1035, 1220
(C-O-C), 756 (C-Cl); 1H NMR (DMSO-d6(1) : CDCl3(2)) : 8.67 (s, 1H, H2), 8.20
(s, 1H, H8), 7.95 (s, 1H, H5), 3.47 (m, 1H, [N-CH-), 1.14–1.54 (m, 4H,
cyclopropyl), 7.92 (s, 1H,[CO.NH), 5.93 (s, 1H, -N-CH-), 3.87 (s, 2H, -CH2-
S), 2.11–3.15 (m, 8H, piperazine), 6.15––8.25 (m, 8H, Ar-H), 4.02 (s, 3H,
-OCH3); Anal. Calcd. for C33H31N5O4FClS: C, 61.15; H, 04.82; N, 10.81. Found:
C, 61.12; H, 04.84; N, 10.77.
(6j) IR: (KBr) m (cm-1): 3452 (NH), 2925, 2815 (C-H), 1742 ([C=O of
quinolone), 1732 ([C=O of 4-thiazolidinone), 1618 (amide-I), 1515 amide-II), 1367
(C-N), 1265 (C-F), 1210 (amide-III), 1052 (C-N, piperazine), 1012,1217 (C-
O-C), 756 (C-Cl); 1H NMR (DMSO-d6(1) : CDCl3(2)) : 8.77 (s, 1H, H2), 8.29 (s,

Med Chem Res (2010) 19:757–770
769
1H, H5), 8.06 (s, 1H, H8), 3.82 (m, 1H,[N-CH-), 1.11–1.66 (m, 4H, cyclopropyl),
7.87 (s, 1H,[CO.NH), 5.99 (s, 1H, -N-CH-), 3.77 (s, 2H, -CH2-S), 1.87–2.98
(m, 8H, piperazine), 6.29-8.20 (m, 8H, Ar-H), 4.12 (s, 3H, -OCH3); Anal. Calcd.
for C33H31N5O4FClS: C, 61.15; H, 04.82; N, 10.81. Found: C, 61.18; H, 04.84; N,
10.77.
Acknowledgements The authors thank Professor and Head, Department of Chemistry, VNSGU, Surat,
for providing laboratory facilities and D. Rajani, Microcare Laboratory, Surat, for antimicrobial activity.
The authors also thank S.A.I.F., Chandigarh for IR and 1H-NMR spectral analysis.
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