Design and synthesis of new N-substituted amino methyl-[1,2,3] triazolyl moieties of fluoroquinolones as antibacterial agents

Article abstract of DOI:10.1007/s00044-012-0394-2

A series of twenty new N-substituted amino methyl-[1,2,3] triazolyl derivatives at C-7 position of fluoroquinolones were designed and synthesized through multistep synthesis. The synthesized compounds were characterized by ¹H NMR, ¹³C NMR, ESI-MS, and IR. The antibacterial activities of these new fluoroquinolones were evaluated using a standard broth micro dilution technique. Out of the twenty derivatives, aryl substituted amino derivatives (6m to 6q) exhibited very good potency in inhibiting the growth of Methicillin-sensitive Staphylococcus aureus (MSSA), Methicillin-resistant Staphylococcus aureus (MRSA), and Vancomycin-Resistant Enterococcus faecalis (VRE faecalis) (MIC: 0.25-4.00 μg/mL) as compared to the marketed drugs Linezolid and Ciprofloxacin.

Full text of DOI:10.1007/s00044-012-0394-2

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res
DOI 10.1007/s00044-012-0394-2
ORIGINAL RESEARCH
Design and synthesis of new N-substituted amino methyl-[1,2,3]
triazolyl moieties of fluoroquinolones as antibacterial agents
•
G. Govinda Rajulu Halehatty S. Bhojya Naik
•
•
Abhilash Viswanathan Devesh S. Agarwal
•
•
Ganesh Sambasivam Kesavan Poonimangadu Koppolu
Received: 11 August 2012 / Accepted: 4 December 2012
Ó Springer Science+Business Media New York 2012
Abstract A series of twenty new N-substituted amino
methyl-[1,2,3] triazolyl derivatives at C-7 position of
fluoroquinolones were designed and synthesized through
multistep synthesis. The synthesized compounds were
characterized by 1H NMR, 13C NMR, ESI–MS, and IR. The
antibacterial activities of these new fluoroquinolones were
evaluated using a standard broth micro dilution technique.
Out of the twenty derivatives, aryl substituted amino deriv-
atives (6m to 6q) exhibited very good potency in inhibiting
the growth of Methicillin-sensitive Staphylococcus aureus
(MSSA), Methicillin-resistant Staphylococcus aureus
(MRSA), and Vancomycin-Resistant Enterococcus faecalis
(VRE faecalis) (MIC: 0.25–4.00 lg/mL) as compared to the
marketed drugs Linezolid and Ciprofloxacin.
extremely successful antibiotics that are potent, broad-
spectrum antibacterial activity, and have relatively few side
effects (Mitscher, 2005). These antibiotics exert their
antimicrobial activity by binding to two type II bacterial
topoisomerase enzymes, DNA gyrase (subunits encoded by
gyrA and gyrB) and topoisomerase IV (subunits encoded
by grlA and grlB for Staphylococcus aureus). This binding
induces permanent double-stranded DNA breaks, and
results in cell death (De Souza, 2005; Hooper, 2001).
Most of the quinolones currently in the market or under
development are generally characterized by a broad anti-
bacterial spectrum, but their activity against clinically
important Gram-positive cocci, including Staphylococci,
Streptococci, and Enterococci, is relatively moderate. This
insufficient activity has not only limited their use in infec-
tions caused by these organisms, but has also contributed to
the rapidly developing quinolone resistance. Thus, recent
efforts have been directed toward the synthesis of new
quinolones that can provide improved Gram-positive anti-
bacterial activity, while retaining the Gram-negative activ-
ity of early fluoroquinolones, such as ciprofloxacin (Piddock
et al, 1994).
Keywords Synthesis Á [1,2,3] triazolyl derivatives Á
Fluoroquinolones Á Antibacterial activity
Introduction
Fluoroquinolones are class of quinolone compounds and
known as first made broad-spectrum antibiotics. The flu-
oroquinoles such as Ciprofloxacin and Norfloxacin are
Structure–activity relationship (SAR) studies of quino-
lone antibacterial agents showed that the basic group at the
C-7 position is the most adaptable site for chemical change
and an area that greatly influences their potency, spectrum,
and safety (Bryskier and Chantot, 1995; Koga et al, 1980).
In general, 5- and 6-membered nitrogen heterocycles have
been proven to be the optimal substituents (Domagala,
1994).
G. Govinda Rajulu (&) Á A. Viswanathan Á
D. S. Agarwal Á G. Sambasivam Á K. P. Koppolu
Anthem Biosciences Pvt. Ltd., 49 Bommasandra Industrial Area,
Bangalore 560099, Karnataka, India
e-mail: govinda_iitd@yahoo.com;
govindarajulu.g@anthembio.com
As part of an ongoing program to identify novel, potent,
and broad-spectrum antibacterial agents, we have intro-
duced 5-memebered nitrogen containing heterocycle such
as [1,2,3] triazole derivatives at C-7 position of fluoro-
quinolones. Also, the [1,2,3] triazoles are known to be
H. S. Bhojya Naik
Department of PG Studies and Research in Industrial Chemistry,
School of Chemical Sciences, Kuvempu University,
Shankaraghatta, Karnataka 577451, India
123

Med Chem Res
Fig. 1 Chemical structure of
Ciprofloxacin and compound 6o
O
N
O
O
N
O
F
F
OH
OH
N
N
N
N
HN
H
N
Compound 6o
Ciprofloxacin
Cl
good building blocks in antimicrobial drug discovery
(Patpi et al., 2012; Shanmugavelan et al., 2011; Sumangala
et al., 2010). To the best of our knowledge, there is no
literature available to reveal the effect of [1,2,3] triazole
group at C-7 position of fluoroquinolones on their anti-
bacterial activity. The design strategy of [1,2,3] triazolyl
derivative with a representative example (compound 6o) is
shown in Fig. 1.
mass was allowed to reach room temperature and poured
into crushed ice to obtain pale yellow precipitate. The
precipitate formed was filtered and dried to give compound
2 as off-white solid 2.3 g (85 %).
MP: 237.0–238.0 °C; IR (ATR, cm-1) t: 3089 (ArH), 2119
(–N3), 1718 (ester –C=O), 1615 (quinolone –C=O), 1594
(–C=C), 1478 (ester –C–O), 1050 (–C–F); 1H NMR
(300 MHz, DMSO-d6) d (ppm): 1.11–1.13 (2H, m, cyclopro-
pyl), 1.21–1.24 (2H, m, cyclopropyl), 1.27 (3H, t, J =6.0 Hz,
OCH2CH3), 3.64–3.69 (1H, m, cyclopropyl), 4.22 (2H, q,
J = 6.0 Hz, OCH2CH3), 7.79 (1H, d, J = 6.9 Hz, ArH), 7.90
(1H, d, J = 11.4 Hz, ArH), 8.45 (1H, s, C2–H); LC–MS (ESI,
m/z): 317.2 (M?H).
Experimental
Chemistry
Chemicals were obtained from Sigma-Aldrich Co. Final
purifications were carried out using Merck silica gel 230–400
mesh. TLC experiments were performed on alumina-backed
silica gel 40 F254 plates (Merck, Darmstadt, Germany). The
plates were illuminated under UV (254 nm) and KMnO4.
Melting points were determined using Buchi B-540 and are
uncorrected. All 1H and 13C NMR spectra were recorded on a
Procedure for the synthesis of 1-cyclopropyl-6-fluoro-7-
(4-hydroxymethyl-[1,2,3] triazol-1-yl)-4-oxo-1,4-dihydro-
quinoline-3-carboxylic acid ethyl ester (3)
To a solution of compound 2 (3.0 g, 9.48 mmol) in N,
N-dimethylformamide (20.0 mL) propargyl alcohol (632 mg,
11.02 mmol), sodium ascorbate (586 mg, 2.3 mmol), copper
iodide (893 mg, 4.7 mmol), and N-ethyl diisopropyl amine
(3.2 mL, 18.9 mmol) were added at ice bath temperature
under nitrogen atmosphere. After stirring at ice bath tem-
perature for 10 min, the reaction mixture was allowed to stir
at room temperature over a period of 2 h. After completion of
reaction, the reaction mass was quenched with 5 % aqueous
ammonia (2 mL), poured into crushed ice, and the precipitate
formed was filtered and dried to obtain product 3 as off-white
solid 2.4 g (68 %).
Bruker AM-300 (300 MHz for 1H NMR and 75 MHz for 13
C
NMR), Bruker BioSpin Corp., Germany. Molecular weights
of unknown compounds were checked by LCMS 6200 series
Agilent Technology. Chemical shifts are reported in ppm (d)
with reference to internal standard TMS. The signals are
designated as follows: s, singlet; d, doublet; t, triplet; m,
multiplet; brs, broad singlet. IR Spectra were recorded using a
Bruker Alpha FTIR spectrometer using a diamond ATR
single reflectance module (24 scans).
MP: 237.0–238.0 °C; IR (ATR, cm-1) t: 3474 (–OH);
3042 (ArH), 1668 (ester –C=O), 1614 (quinolone –C=O),
1477 (ester –C–O), 1025 (–C–F); 1H NMR (300 MHz,
DMSO-d6) d (ppm): 1.17–1.18 (2H, m, cyclopropyl),
1.24–1.32 (5H, m, cyclopropyl and OCH2CH3), 3.72–3.78
(1H, m, cyclopropyl), 4.25 (2H, q, J = 7.2 Hz, OCH2CH3),
4.67 (2H, d, J = 5.7 Hz, CH2OH), 5.42 (1H, t, J = 5.7 Hz,
CH2OH), 8.16 (1H, d, J = 10.8 Hz, ArH), 8.53 (1H, d,
J = 6.0 Hz, ArH), 8.56 (1H, s, triazole H), 8.62 (1H, d,
J = 2.4 Hz, ArH); LC–MS (ESI, m/z): 373.1 (M?H).
Procedure for the synthesis of 7-azido-1-cyclopropyl-6-
fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid ethyl
ester (2)
To a solution of compound 1 (2.5 g, 8.5 mmol) in N,
N-dimethylformamide (25 mL) sodium azide (0.6 g,
9.3 mmol) was added at room temperature (25 °C) under
nitrogen atmosphere. Then reaction mixture was allowed to
stir at 50 °C over a period of 16 h. The resulting reaction
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Med Chem Res
Procedure for the synthesis of 7-(4-Chloromethyl-[1,2,3]
triazol-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-
quinoline-3-carboxylic acid ethyl ester (4)
3.76 (1H, bs, cyclopropyl), 4.25 (2H, q, J = 6.6 Hz,
OCH2CH3), 8.15 (1H, d, J = 10.8 Hz, ArH), 8.53–8.56
(2H, m, ArH & triazole H), 8.63 (1H, s, ArH); 13C NMR
(75 MHz, DMSO-d6) d: 8.21, 14.51, 36.86, 42.81, 53.62,
60.24, 108.27, 113.22, 115.82, 126.70, 129.56, 138.12,
138.58, 149.79, 150.41, 153.51, 165.21, 172.29; LC–MS
(ESI, m/z): 400.0 (M?H).
To a solution of compound 3 (3.0 g, 8.02 mmol) in dichlo-
romethane (15.0 mL) pyridine (0.79 mL, 12.08 mmol) and
thionyl chloride (0.70 mL, 9.6 mmol) were added at ice bath
temperature. After stirring at ice bath temperature for 10 min,
then reaction mixture was allowed to stir at room temperature
over a period of 2 h. After completion of the reaction, the
reaction mixture was diluted with dichloromethane (50 mL),
washed with water (2 9 20 mL), and dried over sodium
sulfate. The residue obtained upon evaporation of the solvent
was washed with diethyl ether to obtain product 4 as a pale
yellow solid 3.0 g (96 %).
MP: 217.3–218.0 °C; IR (ATR, cm-1) t: 3183 (ArH),
1733 (ester –C=O), 1620 (quinolone –C=O), 1500 (–C=C),
1477 (ester –C–O), 1027 (–C–F); 1H NMR (300 MHz,
DMSO-d6) d (ppm): 1.16–1.18 (2H, m, cyclopropyl),
1.25–1.32 (5H, m, cyclopropyl and OCH2CH3), 3.72–3.78
(1H, m, cyclopropyl), 4.25 (2H, q, J = 7.2 Hz, OCH2CH3),
4.99 (2H, s, CH2Cl), 8.17 (1H, d, J = 10.8 Hz, ArH),
8.56–8.58 (2H, m, ArH and triazole H), 8.87 (1H, d,
J = 2.4 Hz, ArH); LC–MS (ESI, m/z): 391.0 (M?H).
1-Cyclopropyl-7-(4-diethylaminomethyl-[1,2,3]triazol-1-yl)-
6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid
ethyl ester (5b)
Compound 5b was obtained as white solid; MP: 171.8–
172.1 °C; IR (ATR, cm-1) t: 2968 (ArH), 1726 (ester –C=O),
1699 (quinone –C=O), 1617 (–C=C), 1481 (ester –C–O), 1034
(–C–F); 1H NMR (300 MHz, DMSO-d6) d (ppm): 1.06–1.08
(6H, m, diethyl amine–CH3), 1.16–1.32 (7H, m, cyclopropyl &
OCH2CH3), 2.50–2.57 (4H, m, diethyl amine-NCH2), 3.76
(2H, s, –CH2-), 3.89 (1H, bs, cyclopropyl), 4.24 (2H, q,
J = 6.9 Hz, OCH2CH3), 8.15 (1H, d, J = 11.1 Hz, ArH), 8.53-
8.56 (2H, m, ArH & triazole H), 8.65 (1H, s, ArH); 13C NMR
(75 MHz, DMSO-d6) d: 8.21, 14.52, 14.71, 35.57, 60.24, 60.48,
110.44, 113.72, 115.85, 125.05, 128.87, 137.91, 145.40, 147.36,
149.79, 153.51, 164.51, 170.10; LC–MS (ESI, m/z): 428.2
(M?H).
General procedure for the synthesis of 1-cyclopropyl-7-
(4-substituted aminomethyl-[1,2,3] triazol-1-yl)-6-fluoro-
4-oxo-1,4-dihydro-quinoline-3-carboxylic acid ethyl esters
(5a–t)
1-Cyclopropyl-7-(4-dipropylaminomethyl-[1,2,3] triazol-
1-yl)-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic
acid ethyl ester (5c)
To a solution of compound 4 (200 mg, 0.48 mmol) in N,
N-dimethylformamide (5.0 mL) triethylamine (230 lL,
1.60 mmol), potassium iodide (42.5 mg, 0.25 mmol), and
the corresponding amine (0.69 mmol) were added at ice
bath temperature. After stirring at ice bath temperature for
10 min, the reaction mass was allowed to stir at room
temperature over a period 4–6 h. After completion of
reaction, reaction mass was diluted with ethyl acetate
(500 mL), washed with water (3 9 25 mL), and dried over
sodium sulfate. The residue obtained upon evaporation of
the solvent was further purified by silica gel column
chromatography using methanol/chloroform as the eluent.
Compound 5c was obtained as off-white solid; MP:
117.7–118.8 °C; IR (ATR, cm-1) t: 2959 (ArH), 1724
(ester –C=O), 1695 (quinone –C=O), 1616 (–C=C), 1481
1
(ester –C–O), 1024 (–C–F); H NMR (300 MHz, DMSO-
d6) d (ppm): 0.86 (6H, t, J = 7.2 Hz, dipropyl amine–
CH3), 1.16–1.32 (7H, m, cyclopropyl & OCH2CH3), 1.50
(4H, bs, dipropyl amine–CH2), 2.40 (4H, bs, dipropyl
amine-NCH2), 3.88 (3H, m, –CH2- & cyclopropyl), 4.24
(2H, q, J = 6.9 Hz, OCH2CH3), 8.15 (1H, d, J = 11.1 Hz,
ArH), 8.53–8.56 (3H, m, ArH & triazole H); 13C NMR
(75 MHz, DMSO-d6) d: 8.24, 11.41, 14.55, 17.18, 36.84,
45.84, 53.90, 60.25, 108.84, 113.51, 115.86, 126.72,
129.54, 138.09, 138.58, 149.84, 150.41, 153.48, 164.52,
172.11; LC–MS (ESI, m/z): 456.2 (M?H).
1-Cyclopropyl-7-(4-dimethylaminomethyl-[1,2,3] triazol-
1-yl)-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic
acid ethyl ester (5a)
1-Cyclopropyl-6-fluoro-4-oxo-7-(4-pyrrolidin-1-ylmethyl-
[1,2,3]triazol-1-yl)-1,4-dihydro-quinoline-3-carboxylic
acid ethyl ester (5d)
Compound 5a was obtained as off-white solid; MP:
187.1–188.6 °C; IR (ATR, cm-1) t: 2925 (ArH), 1725
(ester –C=O), 1698 (quinone –C=O), 1615 (–C=C), 1480
Compound 5d was obtained as off-white solid; MP:
214.4–214.9 °C; IR (ATR, cm-1) t: 3182 (ArH), 3022
(ArH), 1730 (ester –C=O), 1617 (–C=C), 1475 (ester –C–O),
1
(ester –C–O), 1024 (–C–F); H NMR (300 MHz, DMSO-
d6) d (ppm): 1.16–1.32 (7H, m, cyclopropyl & OCH2CH3),
2.22 (6H, s, dimethyl amine-NCH3), 3.64 (2H, s, –CH2-),
1
1023 (–C–F); H NMR (300 MHz, DMSO-d6) d (ppm):
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Med Chem Res
1.16–1.32 (7H, m, cyclopropyl & OCH2CH3), 1.74 (4H, bs,
pyrrolidine–CH2), 2.65 (4H, bs, pyrrolidine-NCH2), 3.76
(1H, bs, cyclopropyl), 3.91 (2H, s, –CH2-), 4.25 (2H, q,
J = 6.9 Hz, OCH2CH3), 8.16 (1H, d, J =10.8 Hz, ArH),
1694 (quinone –C=O), 1615 (–C=C), 1482 (ester –C–O), 1028
(–C–F); 1H NMR (300 MHz, DMSO-d6) d (ppm): 1.08–1.33
(7H, m, cyclopropyl & –OCH2CH3), 2.63 (4H, m, piperazine),
2.98 (4H, bs, piperazine), 3.76 (3H, bs, cyclopropyl & –CH2-),
4.24 (2H, q, J = 7.2 Hz, –OCH2CH3), 8.17 (1H, d,
J = 10.8 Hz, ArH), 8.51–8.54 (2H, m, ArH & triazole H), 8.71
(1H, s, ArH); 13C NMR (75 MHz, DMSO-d6) d: 8.22, 14.54,
36.83, 47.41, 49.62, 60.27, 108.31, 113.61, 116.22, 126.86,
129.70, 137.62, 138.56, 149.92, 150.38, 153.28, 164.82,
172.12; LC–MS (ESI, m/z): 441.3 (M?H).
8.53–8.56 (2H, m, ArH & triazole H), 8.68 (1H, s, ArH); 13
C
NMR (75 MHz, DMSO-d6) d: 8.24, 14.54, 25.61, 36.79,
53.89, 60.25, 108.27, 113.55, 115.87, 126.70, 129.59,
138.12, 138.61, 149.85, 150.39, 153.54, 165.49, 172.21;
LC–MS (ESI, m/z): 426.1 (M?H);
1-Cyclopropyl-6-fluoro-4-oxo-7-(4-piperidin-1-ylmethyl-
[1,2,3]triazol-1-yl)-1,4-dihydro-quinoline-3-carboxylic
acid ethyl ester (5e)
1-Cyclopropyl-6-fluoro-7-[4-(isopropylamino-methyl)-
[1,2,3]triazol-1-yl]-4-oxo-1,4-dihydro-quinoline-3-
carboxylic acid ethyl ester (5h)
Compound 5e was obtained as pale yellow solid; MP: 182.4–
183.7 °C; IR (ATR, cm-1) t: 2935 (ArH), 1700 (ester –C=O),
1640 (quinone –C=O), 1617 (–C=C), 1475 (ester –C–O), 1022
(–C–F); 1H NMR (300 MHz, DMSO-d6) d (ppm): 1.16–1.40
(9H, m, cyclopropyl, OCH2CH3 & piperadine–CH2), 1.52–1.53
(4H, m, pyrrolidine–CH2), 2.55–2.56 (4H, bs, pyrrolidine-
NCH2), 3.72-3.76 (3H, m, cyclopropyl & –CH2-), 4.24 (2H, q,
J = 6.9 Hz, OCH2CH3), 8.16 (1H, d, J = 10.8 Hz, ArH),
Compound 5h was obtained as yellow solid; MP: 186.2-
187.1 °C; IR (ATR, cm-1) t: 2964 (ArH), 1726 (ester –C=O),
1696 (quinone –C=O), 1616 (–C=C), 1482 (ester –C–O), 1021
(–C–F); 1H NMR (300 MHz, DMSO-d6) d (ppm): 1.07 (6H, d,
J = 6.3 Hz, isopropyl–CH3), 1.17–1.32 (7H, m, cyclopropyl
& –OCH2CH3), 2.85-2.89 (1H, m, isopropyl –CH), 3.76 (1H,
m, cyclopropyl), 3.95 (2H, s, –CH2-), 4.24 (2H, q, J = 6.9 Hz,
–OCH2CH3), 8.16 (1H, d, J = 10.8 Hz, ArH), 8.53 (1H, d,
J = 6.3 Hz, ArH), 8.56 (1H, s, triazole H), 8.63 (1H, s, ArH);
13C NMR (75 MHz, DMSO-d6) d: 8.21, 14.54, 18.95, 36.77,
49.65, 60.26, 60.54, 108.30, 113.50, 113.80, 115.89, 128.13,
138.60, 140.58, 149.85, 150.37, 153.21, 164.84, 172.11;
LC–MS (ESI, m/z): 414.2 (M?H).
8.54–8.56 (2H, m, ArH & triazole H), 8.65 (1H, s, ArH); 13
C
NMR (75 MHz, DMSO-d6) d: 8.21, 14.52, 25.41, 27.70. 36.80,
49.70, 54.31, 60.28, 109.10, 113.58, 115.80, 126.72, 129.54,
138.21, 138.61, 149.10, 150.43, 153.45, 165.51, 172.13;
LC–MS (ESI, m/z): 440.1 (M?H).
1-Cyclopropyl-6-fluoro-7-(4-morpholin-4-ylmethyl-
[1,2,3]triazol-1-yl)-4-oxo-1,4-dihydro-quinoline-3-
carboxylic acid ethyl ester (5f)
1-Cyclopropyl-7-(4-cyclopropylaminomethyl-[1,2,3]triazol-
1-yl)-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid
ethyl ester (5i)
Compound 5f was obtained as pale yellow solid; MP: 192.6–
193.5 °C; IR (ATR, cm-1) t: 2914 (ArH), 1693 (ester –C=O),
1641 (quinolone –C=O), 1617 (–C=C), 1482 (ester –C–O),
1005 (–C–F); 1H NMR (300 MHz, CDCl3) d (ppm):
1.22–1.23 (2H, m, cyclopropyl), 1.41–1.48 (5H, m, cyclo-
propyl and OCH2CH3), 2.68 (4H, bs, morpholine-NCH2),
3.55-3.59 (1H, m, cyclopropyl), 3.80 (4H, t, J = 4.5 Hz,
morpholine–OCH2), 3.88 (2H, s, –CH2-), 4.43 (2H, q,
J = 6.9 Hz, OCH2CH3), 8.34 (1H, d, J = 2.7 Hz, ArH), 8.39
(1H, d, J = 11.0 Hz, ArH), 8.67 (1H, s, triazole H), 8.72 (1H,
d, J = 6.0 Hz, ArH); 13C NMR (75 MHz, DMSO-d6) d: 8.22,
14.55, 36.89, 53.62, 55.81, 60.28, 72.24, 108.27, 113.55,
115.85, 126.71, 129.50, 138.27, 138.57, 149.80, 150.44,
153.51, 164.82, 172.12; LC–MS (ESI, m/z): 442.3 (M?H).
Compound 5i was obtained as off-white solid; MP:
214.9–215.0.6 °C; IR (ATR, cm-1) t: 2966 (ArH), 1722
(ester –C=O), 1692 (quinone –C=O), 1617 (–C=C), 1484
(ester –C–O), 1022 (–C–F); 1H NMR (300 MHz, DMSO-d6)
d (ppm): 0.66–0.73 (4H, m, cyclopropyl), 1.69–1.32 (7H, m,
cyclopropyl & –OCH2CH3), 2.63 (1H, bs, –NH), 3.06–3.08
(1H, m, cyclopropyl), 3.76 (1H, m, cyclopropyl), 4.25 (2H, q,
J = 6.6 Hz, –OCH2CH3), 4.34 (2H, s, –CH2-), 8.19 (1H, d,
J = 10.8 Hz, ArH), 8.53–8.57 (2H, m, ArH & triazole H),
8.83 (1H, s, ArH); 13C NMR (75 MHz, DMSO-d6) d: 4.04,
8.22, 14.53, 30.01, 35.61, 60.24, 60.52, 110.48, 113.72,
114.01, 115.21, 128.39, 137.96, 141.24, 149.36, 149.90,
152.71, 164.23, 170.82; LC–MS (ESI, m/z): 412.2 (M?H).
1-Cyclopropyl-6-fluoro-4-oxo-7-(4-piperazin-1-ylmethyl-
[1,2,3]triazol-1-yl)-1,4-dihydro-quinoline-3-carboxylic
acid ethyl ester (5g)
7-(4-Cyclopentylaminomethyl-[1,2,3]triazol-1-yl)-1-
cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-
carboxylic acid ethyl ester (5j)
Compound 5g was obtained as yellow solid; MP: 192.6–
193.5 °C; IR (ATR, cm-1) t: 2919 (ArH), 1717 (ester –C=O),
Compound 5j was obtained as off-white solid; MP:
193.3–194.2 °C; IR (ATR, cm-1) t: 3306 (–NH), 2955 (ArH),
123

Med Chem Res
1-Cyclopropyl-6-fluoro-4-oxo-7-(4-phenylaminomethyl-
[1,2,3]triazol-1-yl)-1,4-dihydro-quinoline-3-carboxylic
acid ethyl ester (5m)
1727 (ester –C=O), 1695 (quinone –C=O), 1615 (–C=C), 1482
(ester –C–O), 1024 (–C–F); 1H NMR (300 MHz, DMSO-d6) d
(ppm): 1.17–1.32 (7H, m, cyclopropyl & –OCH2CH3), 1.46-
1.49 (4H, m, cyclopentyl), 1.66 (2H, bs, cyclopentyl),
1.81–1.83 (2H, m, cyclopentyl), 3.05 (1H, bs, cyclopentyl),
3.76 (1H, bs, cyclopropyl), 4.00 (2H, s, –CH2-), 4.24 (2H, q,
J = 6.9 Hz, –OCH2CH3), 8.16 (1H, d, J = 11.1 Hz, ArH),
Compound 5m was obtained as yellow solid; MP:
260.6–261.2 °C; IR (ATR, cm-1) t: 3060 (ArH), 1715 (ester
–C=O & quinone –C=O), 1612 (–C=C), 1490 (ester –C–O),
1023 (–C–F); 1H NMR (300 MHz, DMSO-d6) d (ppm):
1.15–1.35 (7H, m, cyclopropyl & –OCH2CH3), 3.75 (1H, bs,
cyclopropyl), 4.24 (2H, q, J = 6.9 Hz, –OCH2CH3), 4.43
(2H, d, J = 5.7 Hz, –CH2-), 6.21 (1H, t, J = 5.7 Hz, –NH–),
6.55 (1H, t, J = 7.2 Hz, ArH), 6.70 (2H, t, J = 7.5 Hz, ArH),
7.08 (2H, t, J = 7.5 Hz, ArH), 8.14 (1H, d, J = 10.8 Hz,
ArH), 8.52–8.55 (2H, m, ArH & triazole H), 8.64 (1H, s,
ArH); 13C NMR (75 MHz, DMSO-d6) d: 8.22, 14.53, 38.31,
58.22, 60.50, 108.30, 113.52, 113.81, 115.78, 128.18, 129.31,
132.42, 132.55, 138.60, 140.60, 142.32 149.85, 150.44,
153.20, 164.54, 172.11; LC–MS (ESI, m/z): 448.5 (M?H).
8.53–8.56 (2H, m, ArH & triazole H), 8.67 (1H, s, ArH); 13
C
NMR (75 MHz, DMSO-d6) d: 8.22, 14.54, 24.07, 29.45,
31.15, 36.78, 58.38, 60.52, 108.30, 113.52, 113.80, 115.88,
128.17, 138.58, 140.52, 149.81, 150.39, 153.19, 164.25,
172.12; LC–MS (ESI, m/z): 440.2 (M?H).
7-(4-Cyclohexylaminomethyl-[1,2,3]triazol-1-yl)-1-
cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-
carboxylic acid ethyl ester (5k)
Compound 5k was obtained as pale yellow solid; MP:
154.4–154.9 °C; IR (ATR, cm-1) t: 3311 (–NH), 2932
(ArH), 1727 (ester –C=O), 1694 (quinone –C=O), 1613
(–C=C), 1481 (ester –C–O), 1023 (–C–F); 1H NMR
(300 MHz, DMSO-d6) d (ppm): 1.07–1.32 (13H, m,
1-Cyclopropyl-6-fluoro-7-{4-[(4-fluoro-phenylamino)-
methyl]-[1,2,3]triazol-1-yl}-4-oxo-1,4-dihydro-quinoline-
3-carboxylic acid ethyl ester (5n)
cyclopropyl, cyclohexyl
& –OCH2CH3), 1.56–1.58
Compound 5n was obtained as yellow solid; MP: 255.3–
256.2 °C; IR (ATR, cm-1) t: 2939 (ArH), 1720 (ester –C=O),
1695 (quinone –C=O), 1611 (–C=C), 1491 (ester –C–O),
(1H, m, cyclohexyl), 1.68 (2H, bs, cyclohexyl), 1.88-
1.92 (2H, m, cyclohexyl), 3.76 (1H, bs, cyclopropyl),
3.96 (2H, s, –CH2-), 4.25 (2H, q, J = 6.9 Hz,
–OCH2CH3), 8.15 (1H, d, J = 11.1 Hz, ArH), 8.53-8.60
(3H, m, ArH & triazole H); 13C NMR (75 MHz, DMSO-
d6) d: 8.22, 14.54, 24.40, 25.22, 28.80, 36.78, 38.29,
56.11, 60.51, 108.40, 113.52, 113.80, 115.87, 128.20,
138.60, 140.60, 149.85, 150.44, 153.20, 164.24, 172.13;
LC–MS (ESI, m/z): 454.2 (M?H).
1
1026 (–C–F); H NMR (300 MHz, DMSO-d6) d (ppm):
1.09–1.31 (7H, m, cyclopropyl & –OCH2CH3), 3.75 (1H, bs,
cyclopropyl), 4.24 (2H, q, J = 7.2 Hz, –OCH2CH3), 4.41
(2H, d, J = 5.4 Hz, –CH2-), 6.14 (1H, t, J = 5.4 Hz, –NH–),
6.70 (2H, d, J = 4.5 Hz, ArH), 6.93 (2H, t, J = 8.7 Hz,
ArH), 8.15 (1H, d, J = 10.8 Hz, ArH), 8.51–8.55 (2H, m,
ArH & triazole H), 8.64 (1H, s, ArH); 13C NMR (75 MHz,
DMSO-d6) d: 8.24, 14.61, 38.87, 57.02, 60.48, 108.31,
113.56, 113.81, 115.75, 117.80, 121.41, 128.20, 138.61,
140.59, 142.64, 149.83, 150.44, 153.20, 154.98, 164.53,
172.11; LC–MS (ESI, m/z): 466.1 (M?H).
7-(4-Cycloheptylaminomethyl-[1,2,3]triazol-1-yl)-
1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-
3-carboxylic acid ethyl ester (5l)
7-{4-[(4–Chloro-phenylamino)-methyl]-[1,2,3]triazol-
1-yl}-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-
3-carboxylic acid ethyl ester (5o)
Compound 5l was obtained as pale yellow solid; MP:
229.3–230.5 °C; IR (ATR, cm-1) t: 2921 (ArH), 1726
(ester –C=O), 1694 (quinone –C=O), 1617 (–C=C), 1483
(ester –C–O), 1010 (–C–F); 1H NMR (300 MHz,
DMSO-d6) d (ppm): 1.27–1.63 (18H, m, cyclopropyl,
cycloheptyl & –OCH2CH3), 1.84–1.88 (2H, m, cyclo-
heptyl), 2.71 (1H, bs, cycloheptyl), 3.76 (1H, bs,
cyclopropyl), 3.91 (2H, s, –CH2-), 4.24 (2H, q,
J = 6.9 Hz, –OCH2CH3), 8.15 (1H, d, J = 11.1 Hz,
ArH), 8.52-8.63 (3H, m, ArH & triazole H); 13C NMR
(75 MHz, DMSO-d6) d: 8.21, 14.53, 24.08, 28.53, 34.20,
39.20, 41.79, 57.80, 60.51, 110.38, 113.72, 114.97,
128.70, 137.89, 147.98, 149.34, 149.78, 152.66, 164.11,
170.10; LC–MS (ESI, m/z): 468.2 (M?H).
Compound 5o was obtained as pale yellow solid; MP:
261.4–262.0 °C; IR (ATR, cm-1) t: 3060 (ArH), 1716 (ester
–C=O & quinone –C=O), 1612 (–C=C), 1490 (ester –C–O),
1
1023 (–C–F); H NMR (300 MHz, DMSO-d6) d (ppm):
1.15–1.31 (7H, m, cyclopropyl & –OCH2CH3), 3.75 (1H, bs,
cyclopropyl), 4.23 (2H, q, J = 6.9 Hz, –OCH2CH3), 4.43
(2H, d, J = 4.8 Hz, –CH2-), 6.45 (1H, bs, –NH–), 6.70 (2H,
d, J = 8.4 Hz, ArH), 7.10 (2H, d, J = 8.1 Hz, ArH), 8.14
(1H, d, J = 10.8 Hz, ArH), 8.51–8.55 (2H, m, ArH & tria-
zole H), 8.66 (1H, s, ArH); 13C NMR (75 MHz, DMSO-d6) d:
8.21, 14.62, 38.87, 57.04, 60.49, 108.30, 113.51, 113.81,
123

Med Chem Res
115.72, 117.81, 121.42, 128.20, 138.65, 140.58, 141.66,
149.86, 150.44, 152.26, 154.91, 164.52, 172.11; LC–MS
(ESI, m/z): 482.3 (M?H).
1710 (ester –C=O), 1691 (quinone –C=O), 1611 (–C=C),
1479 (ester –C–O), 1022 (–C–F); 1H NMR (300 MHz,
DMSO-d6) d (ppm): 1.16-1.35 (7H, m, cyclopropyl &
–OCH2CH3), 3.77 (2H, bs, cyclopropyl & –CH2-), 3.87
(2H, s, –CH2-), 4.24 (2H, q, J = 6.9 Hz, –OCH2CH3),
7.21–7.39 (5H, m, ArH), 8.16 (1H, d, J = 11.1 Hz, ArH),
8.53–8.56 (2H, m, ArH & triazole H), 8.62 (1H, s, ArH);
13C NMR (75 MHz, DMSO-d6) d: 8.23, 14.64, 36.79,
56.32, 57.20, 60.50, 108.27, 113.50, 113.81, 115.84,
128.11, 128.34, 129.46, 129.52, 138.25, 139.66, 140.52,
149.84, 150.39, 153.22, 164.52, 172.12; LC–MS (ESI, m/
z): 462.1 (M?H).
1-Cyclopropyl-6-fluoro-7-{4-[(4-methoxy-phenylamino)-
methyl]-[1,2,3]triazol-1-yl}-4-oxo-1,4-dihydro-quinoline-
3-carboxylic acid ethyl ester (5p)
Compound 5p was obtained as white solid; MP:
261.5–262.6 °C; IR (ATR, cm-1) t: 3058 (ArH), 2978 (ArH),
1716 (ester –C=O & quinone –C=O), 1612 (–C=C), 1490
(ester –C–O), 1024 (–C–F); 1H NMR (300 MHz, DMSO-d6)
d (ppm): 1.16-1.29 (7H, m, cyclopropyl & –OCH2CH3), 3.63
(3H, s, –OMe), 3.75 (1H, bs, cyclopropyl), 4.24 (2H, q,
J = 6.3 Hz, –OCH2CH3), 4.38 (2H, d, J = 4.8 Hz, –CH2-),
5.80 (1H, bs, –NH–), 6.69 (4H, d, J = 12.0 Hz, ArH), 8.15
(1H, d, J = 10.5 Hz, ArH), 8.51–8.55 (2H, m, ArH & triazole
H), 8.62 (1H, s, ArH); 13C NMR (75 MHz, DMSO-d6) d:
8.22, 14.63, 38.30, 56.22, 57.25, 60.50, 108.31, 113.54,
113.80, 115.75, 118.12, 121.29, 128.22, 138.64, 140.60,
141.66, 143.51, 149.86, 150.45, 153.21, 164.52, 172.10;
LC–MS (ESI, m/z): 478.1 (M?H).
1-Cyclopropyl-6-fluoro-7-{4-[(4-fluoro-benzylamino)-
methyl]-[1,2,3]triazol-1-yl}-4-oxo-1,4-dihydro-quinoline-
3-carboxylic acid ethyl ester (5s)
Compound 5s was obtained as white solid; MP:
156.7–157.3 °C; IR (ATR, cm-1) t: 3322 (–NH), 3041
(ArH), 1725 (ester –C=O), 1695 (quinone –C=O), 1612
(–C=C), 1482 (ester –C–O), 1023 (–C–F); 1H NMR
(300 MHz, DMSO-d6) d (ppm): 1.16–1.32 (7H, m, cyclo-
propyl & –OCH2CH3), 2.93 (bs, 1H), 3.76 (1H, bs, cyclo-
propyl & –CH2-), 3.86 (2H, s, –CH2-), 4.24 (2H, q,
J = 6.6 Hz, –OCH2CH3), 7.14 (2H, t, J = 7.0 Hz, –ArH),
7.40 (2H, t, J = 7.8 Hz, –ArH), 8.16 (1H, d, J = 10.8 Hz,
ArH), 8.53–8.56 (2H, m, ArH & triazole H), 8.61 (1H, s,
ArH); 13C NMR (75 MHz, DMSO-d6) d: 8.21, 14.64, 36.77,
56.32, 58.12, 60.51, 108.28, 113.54, 113.77, 115.86, 128.21,
128.70, 129.72, 138.57, 139.42, 140.48, 149.82, 150.41,
153.21, 154.53, 164.49, 171.99; LC–MS (ESI, m/z): 480.2
(M?H).
1-Cyclopropyl-6-fluoro-4-oxo-7-[4-(p-tolylamino-methyl)-
[1,2,3]triazol-1-yl]-1,4-dihydro-quinoline-3-carboxylic
acid ethyl ester (5q)
Compound 5q was obtained as off-white solid; MP:
211.2–211.7 °C; IR (ATR, cm-1) t: 3333 (–NH)), 2936 (ArH),
1721 (ester –C=O), 1684 (quinone –C=O), 1608 (–C=C), 1478
(ester –C–O), 1021 (–C–F); 1H NMR (300 MHz, DMSO-d6) d
(ppm): 1.16–1.31 (7H, m, cyclopropyl & –OCH2CH3), 2.14
(3H, s, –ArMe), 3.75 (1H, bs, cyclopropyl), 4.24 (2H, q,
J = 6.3 Hz, –OCH2CH3), 4.40 (2H, d, J = 6.0 Hz, –CH2-),
5.96 (1H, t, J = 5.7 Hz, –NH–), 6.61 (2H, d, J = 8.1 Hz,
ArH), 6.90 (2H, d, J = 10.8 Hz, ArH), 8.14 (1H, d,
J = 10.8 Hz, ArH), 8.52 (1H, d, J = 6.0 Hz, ArH), 8.55 (1H,
s, triazole H), 8.61 (1H, s, ArH); 13C NMR (75 MHz, DMSO-
d6) d: 8.22, 14.64, 23.26, 38.30, 56.12, 60.52, 108.30, 113.53,
113.81, 114.78, 115.82, 126.82, 127.96, 130.21, 138.61,
140.52, 140.92, 149.86, 150.40, 153.22, 164.51, 172.12;
LC–MS (ESI, m/z): 462.2 (M?H).
1-Cyclopropyl-6-fluoro-7-(4-imidazol-1-ylmethyl-
[1,2,3]triazol-1-yl)-4-oxo-1,4-dihydro-quinoline-3-
carboxylic acid ethyl ester (5t)
Compound 5t was obtained as white solid; MP:
178.4–179.8 °C; IR (ATR, cm-1) t: 2979 (ArH), 1720 (ester
–C=O & quinone –C=O), 1614 (–C=C), 1482 (ester –C–O),
1032 (–C–F); 1H NMR (300 MHz, DMSO-d6) d (ppm): 1.15-
1.13 (7H, m, cyclopropyl & –OCH2CH3), 3.73 (1H, bs,
cyclopropyl), 4.24 (2H, q, J = 6.9 Hz, –OCH2CH3), 5.44
(2H, s, –CH2-), 6.92 (1H, s, Imidazole H), 7.29 (1H, s,
Imidazole H), 7.80 (1H, s, Imidazole H), 8.16 (1H, d,
J = 11.1 Hz, ArH), 8.54-8.56 (2H, m, ArH & triazole H),
8.80 (1H, s, ArH); 13C NMR (75 MHz, DMSO-d6) d: 8.22,
14.65, 36.80, 54.64, 60.50, 108.24, 113.54, 115.84, 124.52,
126.72, 128.51, 129.54, 138.14, 138.57, 140.25, 149.82,
150.34, 153.50, 164.51, 172.11; LC–MS (ESI, m/z): 423.2
(M?H).
7-[4-(Benzylamino-methyl)-[1,2,3]triazol-1-yl]-1-
cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-
carboxylic acid ethyl ester (5r)
Compound 5r was obtained as off-white solid; MP: 120.2–
121.9 °C; IR (ATR, cm-1) t: 3324 (–NH), 3044 (ArH),
123

Med Chem Res
1H NMR (300 MHz, DMSO-d6) d (ppm): 0.92 (6H, t,
J = 7.2 Hz, dipropyl amine–CH3), 1.27–1.35 (4H, m,
cyclopropyl), 1.82–1.83 (4H, bs, dipropyl amine–CH2), 3.02
(4H, bs, dipropyl amine-NCH2), 3.95 (1H, bs, cyclopropyl),
4.59 (2H, s, –CH2-), 8.42 (1H, d, J = 10.5 Hz, ArH),
8.82–8.85 (2H, m, ArH & triazole H), 9.13 (1H, s, ArH),
10.92 (1H, bs, –COOH); 13C NMR (75 MHz, DMSO-d6) d:
8.20, 11.41, 17.16, 36.80, 45.80, 53.91, 108.26, 113.55,
115.85, 126.77, 129.55, 138.09, 138.58, 149.80, 150.41,
153.51, 165.71, 177.01; LC–MS (ESI, m/z): 428.1 (M?H).
General procedure for the synthesis of 1-cyclopropyl-7
-(4- substituted amino methyl-[1,2,3]triazol-1-yl)-6-fluoro-
4 -oxo-1,4-dihydro-quinoline-3-carboxylic acids (6a–t)
To a solution of 6N hydrochloric acid (10.0 mL) substi-
tuted ester 5a–t (0.5 mmol) was added at room tempera-
ture. The resulting suspension was allowed to stir at 60 °C
over a period of 12 h. The completion of the reaction was
monitored by TLC. The solid obtained upon evaporation of
the volatiles under reduced pressure was washed with
diethyl ether (2 9 5 mL).
1-Cyclopropyl-6-fluoro-4-oxo-7-(4-pyrrolidin-1-ylmethyl-
[1,2,3]triazol-1-yl)-1,4-dihydro-quinoline-3-carboxylic
acid (6d)
1-Cyclopropyl-7-(4-dimethylaminomethyl-[1,2,3]triazol-
1-yl)-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic
acid (6a)
Compound 6d was obtained as pale yellow solid; IR (ATR,
cm-1) t: 3168 (–OH), 2923 (ArH), 2544 (acid –OH), 1707
(acid –C=O & quinolone –C=O), 1611 (–C=C), 1486 (acid
Compound 6a was obtained as pale yellow solid; IR (ATR,
cm-1) t: 2942 (ArH), 2537 (acid –OH), 1722 (acid –C=O &
quinolone –C=O), 1617 (–C=C), 1479 (acid –C–O), 1024
(–C–F); 1H NMR (300 MHz, DMSO-d6) d (ppm): 1.26–1.32
(4H, m, cyclopropyl), 2.80(6H, s, dimethylamine–CH3), 3.95
(1H, bs, cyclopropyl), 4.56 (2H, s, –CH2-), 8.41 (1H, d,
J = 9.0 Hz, ArH), 8.83–8.85 (2H, m, ArH & triazole H), 9.08
(1H, s, ArH), 11.16 (1H, bs, –COOH); 13C NMR (75 MHz,
DMSO-d6) d: 8.19, 36.87, 42.81, 53.62, 108.27, 113.64,
115.85, 126.69, 129.56, 138.12, 138.58, 149.82, 150.42,
153.51, 165.77, 177.29; LC–MS (ESI, m/z): 372.1 (M?H).
1
–C–O), 1021 (–C–F); H NMR (300 MHz, DMSO-d6) d
(ppm): 1.27–1.35 (4H, m, cyclopropyl), 1.91–2.03 (4H, m,
pyrrolidine–CH2), 3.19 (2H, bs, pyrrolidine-NCH2), 3.48
(2H, bs, pyrrolidine-NCH2), 3.95 (1H, bs, cyclopropyl),
4.64 (2H, s, –CH2-), 8.41 (1H, d, J = 10.8 Hz, ArH), 8.80
(1H, d, J = 5.7 Hz, ArH), 8.84 (1H, s, triazole H), 9.08
(1H, s, ArH), 11.45 (1H, bs, –COOH); 13C NMR (75 MHz,
DMSO-d6) d: 8.17, 25.62, 36.80, 53.89, 108.27, 113.56,
115.88, 126.69, 129.58, 138.12, 138.61, 149.81, 150.41,
153.54, 165.69, 177.22; LC–MS (ESI, m/z): 398.1 (M?H).
1-Cyclopropyl-7-(4-diethylaminomethyl-[1,2,3]triazol-
1-yl)-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic
acid (6b)
1-Cyclopropyl-6-fluoro-4-oxo-7-(4-piperidin-1-ylmethyl-
[1,2,3]triazol-1-yl)-1,4-dihydro-quinoline-3-carboxylic
acid (6e)
Compound 6b was obtained as pale yellow solid; IR (ATR,
cm-1) t: 2942 (ArH), 2538 (acid –OH), 1720 (acid –C=O
& quinolone –C=O), 1617 (–C=C), 1479 (acid –C–O),
Compound 6e was obtained as pale yellow solid; IR (ATR,
cm-1) t: 2942 (ArH), 2541 (acid –OH), 1725 (acid –C=O &
quinolone –C=O), 1611 (––C=C), 1494 (acid –C–O), 1033
(–C–F); 1H NMR (300 MHz, DMSO-d6) d (ppm): 1.07–1.15
(9H, m, cyclopropyl, OCH2CH3 & piperadine–CH2), 1.74–1.81
(4H, m, pyrrolidine–CH2), 2.96–2.99 (2H, m, pyrrolidine-
NCH2), 3.37–3.46 (2H, m, pyrrolidine–NCH2), 3.94 (1H, m,
cyclopropyl), 4.54 (2H, s, –CH2-), 8.41 (1H, d, J = 10.2 Hz,
ArH), 8.80–8.85 (2H, m, ArH & triazole H), 9.08 (1H, s, ArH),
10.85 (1H, bs, –COOH); 13C NMR (75 MHz, DMSO-d6) d:
8.21, 25.43, 27.69. 36.81, 49.69, 54.32, 109.12, 113.56, 115.78,
126.72, 129.54, 138.22, 138.61, 149.08, 150.44, 153.42, 165.62,
177.13; LC–MS (ESI, m/z): 412.1 (M?H).
1
1030 (–C–F); H NMR (300 MHz, DMSO-d6) d (ppm):
1.16–1.27 (4H, m, cyclopropyl), 1.34 (6H, t, J = 6.9 Hz,
diethyl amine–CH3), 3.14 (4H, q, J = 6.9 Hz, diethyl
amine-NCH2), 3.95 (1H, bs, cyclopropyl), 4.57 (2H, s,
–CH2-), 8.41 (1H, d, J = 10.8 Hz, ArH), 8.81 (1H, d,
J = 6.0 Hz, ArH), 8.84 (1H, s, triazole H), 9.13 (1H, s,
ArH), 11.03 (1H, bs, –COOH); 13C NMR (75 MHz,
DMSO-d6) d: 8.08, 14.72, 35.57, 60.49, 110.44, 113.72,
115.85, 125.00, 128.88, 137.93, 145.39, 147.36, 149.80,
153.51, 164.56, 171.81; LC–MS (ESI, m/z): 400.1 (M?H).
1-Cyclopropyl-7-(4-dipropylaminomethyl-[1,2,3]triazol-
1-yl)-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic
acid (6c)
1-Cyclopropyl-6-fluoro-7-(4-morphol in-4-ylmethyl-
[1,2,3]triazol-1-yl)-4-oxo-1,4-dihydro-quinoline-3-
carboxylic acid (6f)
Compound 6c was obtained as yellow solid; IR (ATR, cm-1
)
t: 2968 (ArH), 2492 (acid –OH), 1718 (acid –C=O & quin-
olone –C=O), 1611 (–C=C), 1452 (acid –C–O), 1043 (–C–F);
Compound 6f was obtained as pale yellow solid; IR (ATR,
cm-1) t: 2958 (ArH), 2541 (acid –OH), 1720 (acid –C=O),
123

Med Chem Res
1
1610 (–C=C), 1489 (acid –C–O), 1007 (–C–F); H NMR
cyclopropyl), 3.05–3.08 (1H, m, cyclopropyl), 3.96 (1H, m,
cyclopropyl), 4.50 (2H, s, –CH2-), 8.41 (1H, d, J = 10.5 Hz,
ArH), 8.76 (1H, d, J = 5.7 Hz, ArH), 8.85 (1H, s, triazole H),
9.01 (1H, s, ArH), 9.77 (2H, bs,–NH2?), 14.48 (1H, bs,
–COOH); 13C NMR (75 MHz, DMSO-d6) d: 4.04, 8.10,
30.01, 35.60, 60.52, 110.48, 113.72, 114.01, 115.21, 128.39,
137.94, 141.24, 149.36, 149.89, 152.69, 164.50, 171.79;
LC–MS (ESI, m/z): 384.2 (M?H).
(300 MHz, DMSO-d6) d (ppm): 1.26–1.32 (4H, m, cyclo-
propyl), 2.49–2.51 (4H, m, morpholine-NCH2), 3.31
(4H, bs, morpholine–OCH2), 3.72 (2H, s, –CH2-), 3.94
(1H, m, cyclopropyl), 8.37 (1H, d, J = 10.2 Hz, ArH),
8.72–8.77 (2H, m, ArH and triazole H), 8.83 (1H, s, ArH),
14.59 (1H, bs, –COOH); 13C NMR (75 MHz, DMSO-d6) d:
8.21, 36.91, 53.62, 55.81, 72.23, 108.27, 113.55, 115.85,
126.71, 129.49, 138.23, 138.57, 149.82, 150.44, 153.51,
165.72, 177.00; LC–MS (ESI, m/z): 414.1 (M?H).
7-(4-Cyclopentylaminomethyl-[1,2,3]triazol-1-yl)-1-
cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-
carboxylic acid (6j)
1-Cyclopropyl-6-fluoro-4-oxo-7-(4-piperazin-1-ylmethyl-
[1,2,3]triazol-1-yl)-1,4-dihydro-quinoline-3-carboxylic
acid (6g)
Compound 6j was obtained as pale yellow solid; IR (ATR,
cm-1) t: 3154 (–NH), 2956 (ArH), 2662 (acid –OH), 1713
(acid –C=O & quinolone –C=O), 1610 (––C=C), 1467
Compound 6g was obtained as yellow solid; IR (ATR, cm-1
)
1
t: 3059 (ArH), 2647 (acid –OH), 1710 (acid –C=O & quino-
lone –C=O), 1610 (–C=C), 1491 (acid –C–O), 1004 (–C–F);
1H NMR (300 MHz, DMSO-d6) d (ppm): 1.26–1.35 (4H, m,
cyclopropyl), 3.46 (8H, m, piperazine), 3.94 (1H, bs, cyclo-
propyl), 4.67 (2H, s, –CH2-), 8.42 (1H, d, J = 10.5 Hz, ArH),
8.80–8.84 (2H, m, ArH & triazole H), 9.09 (1H, s, ArH), 9.91
(2H, bs,–NH2?), 14.57 (1H, bs, –COOH); 13C NMR (75 MHz,
DMSO-d6) d: 8.23, 36.83, 47.40, 49.60, 108.30, 113.61,
116.19, 126.85, 129.65, 137.64, 138.56, 149.92, 150.38,
153.28, 165.73, 177.00; LC–MS (ESI, m/z): 413.2 (M?H).
(acid –C–O), 1012 (–C–F); H NMR (300 MHz, DMSO-
d6) d (ppm): 1.26–1.34 (4H, m, cyclopropyl), 1.54 (2H, bs,
cyclopentyl), 1.74–1.76 (4H, m, cyclopentyl), 2.00–2.02
(2H, m, cyclopentyl), 3.55 (1H, bs, cyclopentyl), 3.96
(1H, bs, cyclopropyl), 4.41 (2H, s, –CH2-), 8.41 (1H, d,
J = 10.5 Hz, ArH), 8.77 (1H, d, J = 5.7 Hz, ArH), 8.84
(1H, s, triazole H), 9.06 (1H, s, ArH), 9.68 (2H, bs,–NH2?),
14.47 (1H, bs, –COOH); 13C NMR (75 MHz, DMSO-d6) d:
8.18, 24.07, 29.45, 31.15, 36.78, 58.38, 108.28, 113.51,
113.80, 115.88, 128.17, 138.60, 140.52, 149.84, 150.39,
153.20, 165.70, 177.00; LC–MS (ESI, m/z): 412.2 (M?H).
1-Cyclopropyl-6-fluoro-7-[4-(isopropylamino-methyl)-
[1,2,3]triazol-1-yl]-4-oxo-1,4-dihydro-quinoline-3-
carboxylic acid (6h)
7-(4-Cyclohexylaminomethyl-[1,2,3]triazol-1-yl)-1-
cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-
carboxylic acid (6k)
Compound 6h was obtained as pale yellow solid; IR (ATR,
cm-1) t: 2967 (ArH), 2509 (acid –OH), 1715 (acid –C=O &
quinolone –C=O), 1610 (–C=C), 1452 (acid –C–O), 1007
(–C–F); 1H NMR (300 MHz, DMSO-d6) d (ppm): 1.26–1.34
(10H, m, isopropyl–CH3 & cyclopropyl), 3.38 (1H, m, iso-
propyl –CH), 3.95 (1H, bs, cyclopropyl), 4.42 (2H, s, –CH2-),
8.42 (1H, d, J = 10.5 Hz, ArH), 8.77 (1H, d, J = 5.4 Hz,
ArH), 8.85 (1H, s, triazole H), 9.04 (1H, s, ArH), 9.48 (2H, bs,
–NH2?), 14.49 (1H, bs, –COOH); 13C NMR (75 MHz,
DMSO-d6) d:8.19, 18.96,36.78,49.65,60.54,108.30,113.50,
113.79, 115.90, 128.13, 138.60, 140.58, 149.85, 150.37,
153.21, 165.70, 176.98; LC–MS (ESI, m/z): 386.1 (M?H).
Compound 6k was obtained as pale yellow solid; IR (ATR,
cm-1) t: 3155 (–NH), 2941 (ArH), 2691 (acid –OH), 1717
(acid –C=O & quinolone –C=O), 1613 (–C=C), 1466 (acid
–C–O), 997 (–C–F); 1H NMR (300 MHz, DMSO-d6) d
(ppm): 1.34–1.42 (10H, m, cyclopropyl & cyclohexyl),
1.77–1.81 (2H, m, cyclohexyl), 2.14–2.17 (2H, m, cyclo-
hexyl), 3.08 (1H, bs, cyclohexyl), 3.95 (1H, bs, cyclopro-
pyl), 4.44 (2H, s, –CH2-), 8.42 (1H, d, J = 10.8 Hz, ArH),
8.77 (1H, d, J = 5.7 Hz, ArH), 8.85 (1H, m, triazole H),
9.04 (1H, s, ArH), 9.48 (2H, bs,–NH2?), 14.58 (1H, bs,
–COOH); 13C NMR (75 MHz, DMSO-d6) d: 8.19, 24.40,
25.23, 28.80, 36.78, 38.29, 56.09, 108.30, 113.52, 113.80,
115.87, 128.18, 138.60, 140.59, 149.85, 150.40, 153.20,
165.70, 177.00; LC–MS (ESI, m/z): 426.2 (M?H).
1-Cyclopropyl-7-(4-cyclopropylaminomethyl-
[1,2,3]triazol-1-yl)-6-fluoro-4-oxo-1,4-dihydro-quinoline-
3-carboxylic acid (6i)
7-(4-Cycloheptylaminomethyl-[1,2,3]triazol-1-yl)-1-
cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-
carboxylic acid (6l)
Compound 6i was obtained as pale yellow solid; IR (ATR,
cm-1) t: 2974 (ArH), 2513 (acid –OH), 1722 (acid –C=O),
1692 (quinolone –C=O), 1617 (–C=C), 1484 (acid –C–O),
1022 (–C–F); 1H NMR (300 MHz, DMSO-d6) d (ppm):
0.79–0.93 (4H, m, cyclopropyl), 1.17–1.34 (4H, m,
Compound 6l was obtained as pale yellow solid; IR (ATR,
cm-1) t: 2926 (ArH), 2357 (acid –OH), 1727 (acid –C=O),
123

Med Chem Res
1682 (quinolone –C=O), 1624 (–C=C), 1478 (acid –C–O),
1
quinolone –C=O), 1618 (–C=C), 1491 (acid –C–O), 1046
(–C–F); 1H NMR (300 MHz, DMSO-d6) d (ppm):
1.24–1.32 (4H, m, cyclopropyl), 3.94 (1H, bs, cyclopro-
pyl), 4.45 (2H, 2, –CH2-), 6.73 (2H, d, J = 8.4 Hz, ArH),
7.12 (2H, d, J = 8.4 Hz, ArH), 8.36 (1H, d, J = 10.5 Hz,
ArH), 8.73-8.74 (2H, m, ArH & triazole H), 8.82 (1H, s,
ArH); 13C NMR (75 MHz, DMSO-d6) d: 8.18, 38.88,
57.04, 108.33, 113.54, 113.81, 115.72, 117.81, 121.42,
128.20, 138.66, 140.58, 141.66, 149.86, 150.45, 152.26,
154.99, 165.73, 177.33; LC–MS (ESI, m/z): 454.6 (M?H).
1022 (–C–F); H NMR (300 MHz, DMSO-d6) d (ppm):
1.26–1.70 (14H, m, cyclopropyl & cycloheptyl), 2.12–2.15
(2H, m, cycloheptyl), 3.39 (1H, bs, cycloheptyl), 3.96
(1H, bs, cyclopropyl), 4.43 (2H, s, –CH2-), 8.41 (1H, d,
J = 10.5 Hz, ArH), 8.77 (1H, d, J = 5.7 Hz, ArH), 8.85
(1H, s, triazole H), 9.05 (1H, s, ArH), 9.46 (2H, bs,–NH2?);
14.57 (1H, bs, –COOH); 13C NMR (75 MHz, DMSO-d6) d:
8.09, 24.08, 28.52, 34.19, 39.20, 41.79, 57.80, 110.39,
113.73, 114.97, 128.70, 137.91, 147.98, 149.35, 149.78,
152.68, 164.54, 171.77; LC–MS (ESI, m/z): 440.1 (M?H).
1-Cyclopropyl-6-fluoro-7-{4-[(4-methoxy-phenylamino)-
methyl]-[1,2,3]triazol-1-yl}-4-oxo-1,4-dihydro-quinoline-
3-carboxylic acid (6p)
1-Cyclopropyl-6-fluoro-4-oxo-7-(4-phenylaminomethyl-
[1,2,3]triazol-1-yl)-1,4-dihydro-quinoline-3-carboxylic
acid (6m)
Compound 6p was obtained as off-white solid; IR (ATR,
cm-1) t: 2998 (ArH), 2358 (–NH), 1729 (acid –C=O &
quinolone –C=O), 1610 (–C=C), 1512 (acid –C–O), 1015
(–C–F); 1H NMR (300 MHz, DMSO-d6) d (ppm):
1.25–1.31 (4H, m, cyclopropyl), 3.72 (3H, s, –OMe), 3.94
(1H, bs, cyclopropyl), 4.64 (2H, 2, –CH2-), 6.94 (2H, bs,
ArH), 7.19 (2H, bs, ArH), 8.38 (1H, d, J = 9.9 Hz, ArH),
8.73–8.83 (3H, m, ArH & triazole H); 13C NMR (75 MHz,
DMSO-d6) d: 8.20, 38.30, 56.22, 57.23, 108.31, 113.54,
113.80, 115.75, 118.12, 121.29, 128.22, 138.66, 140.58,
141.66, 143.51, 149.86, 150.45, 153.21, 165.71, 177.01;
LC–MS (ESI, m/z): 450.1 (M?H).
Compound 6m was obtained as pale yellow solid; IR (ATR,
cm-1) t: 3057 (ArH), 2357 (acid –NH), 1713 (acid –C=O &
quinolone –C=O), 1611 (–C=C), 1490 (acid –C–O), 1024
(–C–F); 1H NMR (300 MHz, DMSO-d6) d (ppm):
1.24–1.31 (4H, m, cyclopropyl), 3.94 (1H, bs, cyclopropyl),
4.57 (2H, d, J = 5.4 Hz, –CH2-), 6.84 (1H, bs, ArH), 6.98
(2H, d, J = 6.6 Hz, ArH), 7.21 (2H, t, J = 6.9 Hz, ArH),
8.37 (1H, d, J = 10.5 Hz, ArH), 8.73–8.82 (3H, m, ArH &
triazole H); 13C NMR (75 MHz, DMSO-d6) d: 8.19, 38.30,
58.22, 108.30, 113.52, 113.81, 115.78, 128.18, 129.31,
132.42, 132.55, 138.60, 140.59, 142.32 149.85, 150.40,
153.20, 165.70, 177.01; LC–MS (ESI, m/z): 420.4 (M?H).
1-Cyclopropyl-6-fluoro-4-oxo-7-[4-(p-tolylamino-methyl)-
[1,2,3]triazol-1-yl]-1,4-dihydro-quinoline-3-carboxylic
acid (6q)
1-Cyclopropyl-6-fluoro-7-{4-[(4-fluoro-phenylamino)-
methyl]-[1,2,3]triazol-1-yl}-4-oxo-1,4-dihydro-quinoline-
3-carboxylic acid (6n)
Compound 6q was obtained as off-white solid; IR (ATR,
cm-1) t: 2998 (ArH), 2359 (–NH), 1728 (acid –C=O &
quinolone –C=O), 1617 (––C=C), 1511 (acid –C–O), 1023
(–C–F); 1H NMR (300 MHz, DMSO-d6) d (ppm):
1.25–1.33 (4H, m, cyclopropyl), 2.22 (3H, s, –ArMe), 3.94
(1H, bs, cyclopropyl), 4.59 (2H, 2, –CH2-), 7.01 (2H, bs,
ArH), 7.08–7.10 (2H, m, ArH), 8.37 (1H, d, J = 10.8 Hz,
ArH), 8.73 (1H, d, J = 5.7 Hz, ArH), 8.82 (2H, m, ArH &
triazole H); 13C NMR (75 MHz, DMSO-d6) d: 8.20, 23.26,
38.31, 56.12, 108.31, 113.53, 113.82, 114.78, 115.82,
126.82, 127.96, 130.21, 138.61, 140.54, 140.96, 149.86,
150.41, 153.22, 165.69, 177.00; LC–MS (ESI, m/z): 434.5
(M?H).
Compound 6n was obtained as yellow solid; IR (ATR,
cm-1) t: 3058 (ArH), 2553 (acid –OH), 1726 (acid –C=O
& quinolone –C=O), 1612 (–C=C), 1492 (acid –C–O),
1
1022 (–C–F); H NMR (300 MHz, DMSO-d6) d (ppm):
1.25–1.33 (4H, m, cyclopropyl), 3.94 (1H, bs, cyclopro-
pyl), 4.51 (2H, d, J = 5.4 Hz, –CH2-), 6.88 (2H, bs, ArH),
7.02 (2H, t, J = 8.4 Hz, ArH), 8.37 (1H, d, J = 10.5 Hz,
ArH), 8.73–8.75 (2H, m, ArH & triazole H), 8.82 (1H, s,
ArH); LC–MS (ESI, m/z): 438.1 (M?H); 13C NMR
(75 MHz, DMSO-d6) d: 8.20, 38.89, 57.02, 108.31, 113.56,
113.81, 115.77, 117.82, 121.41, 128.20, 138.61, 140.59,
142.64, 149.85, 150.44, 153.21, 154.98, 165.71, 177.01;
LC–MS (ESI, m/z): 438.1 (M?H).
7-[4-(Benzylamino-methyl)-[1,2,3]triazol-1-yl]-1-
cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-
carboxylic acid (6r)
7-{4-[(4-Chloro-phenylamino)-methyl]-[1,2,3]triazol-
1-yl}-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-
3-carboxylic acid (6o)
Compound 6r was obtained as pale yellow solid; IR (ATR,
cm-1) t: 3058 (ArH), 2709 (acid –OH), 1717 (acid –C=O
& quinolone –C=O), 1611 (–C=C), 1492 (acid –C–O),
Compound 6o was obtained as pale yellow solid; IR (ATR,
cm-1) t: 3051 (ArH), 2354 (–NH), 1728 (acid –C=O &
123

Med Chem Res
1
1022 (–C–F); H NMR (300 MHz, DMSO-d6) d (ppm):
Gram-negative strains, by means of standard twofold serial
dilution method using agar media. Minimum inhibitory
concentration (MIC) is defined as the minimum concen-
tration of the compound required to give complete inhibi-
tion of bacterial growth after incubation at 35 °C for 24 h.
1.26–1.33 (4H, m, cyclopropyl), 3.96 (1H, bs, cyclopro-
pyl), 4.27 (2H, s, –CH2-), 4.42 (2H, s, –CH2-), 7.43
(3H, bs, ArH), 7.60 (2H, bs, ArH), 8.41 (1H, d,
J = 10.5 Hz, ArH), 8.78 (1H, d, J = 5.1 Hz, ArH), 8.84
(1H, s, triazole H), 9.05 (1H, s, ArH), 10.09 (2H, bs,
–NH2?); 13C NMR (75 MHz, DMSO-d6) d: 8.20, 36.77,
56.32, 57.21, 108.27, 113.50, 113.81, 115.84, 128.14,
128.34, 129.46, 129.51, 138.25, 139.66, 140.52, 149.84,
150.39, 153.20, 165.70, 177.00; LC–MS (ESI, m/z): 434.0
(M?H).
Result and discussion
Chemistry
The new fluoroquinolone derivatives described herein were
synthesized as shown in Schemes 1. The quinolone ester 1
was conveniently synthesized from the commercially
available 2,4,5-trifluoro-benzoic acid in four steps as per
the reported procedure (Ledoussal et al, 1992) and the
spectral data of the compound was in agreement with the
reported data (Dubar et al, 2009). After having synthesized
known compound 1, reaction of compound 1 with sodium
azide at 50 °C yielded selectively 7-azido derivate 2 in
good yield. After having synthesized compound 2, our
initial efforts to convert compound 2–4 by reacting the
compound 2 with propargyl chloride as per our earlier click
chemistry protocol (Selvakumar Natesan et al, 2011) did
not result the desired compound 4. Unfortunately, similar
reaction conditions with propargyl bromide also did not
result the corresponding bromo analog of compound 4.
At this juncture, we have planned to synthesize com-
pound 4 in two steps from compound 2. Then reaction of
compound 2 with propargyl alcohol as per standard click
chemistry conditions (Selvakumar Natesan et al, 2011)
smoothly resulted in the compound 3 in good yield. Then
the key intermediate 4 readily obtained in excellent yield
(96 %) by reacting the compound 3 with thionyl chloride at
room temperature. The amino alky derivatives 5a–t
smoothly obtained by reacting compound 4 with corre-
sponding amines at room temperate. Finally, the target
compounds 6a–t were synthesized in good yields from
their precursors 5a–t by refluxing them with 6N hydro-
chloric acid at 60 °C.
1-Cyclopropyl-6-fluoro-7-{4-[(4-fluoro-benzylamino)-
methyl]-[1,2,3]triazol-1-yl}-4-oxo-1,4-dihydro-quinoline-
3-carboxylic acid (6s)
Compound 6s was obtained as yellow solid; IR (ATR,
cm-1) t: 3012 (ArH), 2357 (acid –NH), 1715 (acid –C=O
& quinolone –C=O), 1611 (–C=C), 1492 (acid –C–O),
1
1001 (–C–F); H NMR (300 MHz, DMSO-d6) d (ppm):
1.26–1.32 (4H, m, cyclopropyl), 3.95 (1H, bs, cyclopro-
pyl), 4.27 (2H, s, –CH2-), 4.42 (2H, s, –CH2-), 7.30 (2H, t,
J = 8.1 Hz, ArH), 7.60 (2H, bs, ArH), 8.42 (1H, d,
J = 10.5 Hz, ArH), 8.77 (1H, d, J = 5.4 Hz, ArH), 8.85
(1H, s, triazole H), 9.02 (1H, s, ArH), 9.97 (2H, bs,–NH2?);
13C NMR (75 MHz, DMSO-d6) d: 8.19, 36.78, 56.32,
58.11, 108.28, 113.54, 113.78, 115.86, 128.21, 128.69,
129.72, 138.57, 139.42, 140.48, 149.82, 150.41, 153.21,
154.53, 165.71, 176.87; LC–MS (ESI, m/z): 452.1 (M?H).
1-Cyclopropyl-6-fluoro-7-(4-imidazol-1-ylmethyl-
[1,2,3]triazol-1-yl)-4-oxo-1,4-dihydro-quinoline-3-
carboxylic acid (6t)
Compound 6t was obtained as yellow solid; IR (ATR,
cm-1) t: 3061 (ArH), 1714 (acid –C=O & quinolone
–C=O), 1611 (–C=C), 1491 (acid –C–O), 1021 (–C–F); 1H
NMR (300 MHz, DMSO-d6) d (ppm): 1.25–1.31 (4H, m,
cyclopropyl), 3.93 (1H, bs, cyclopropyl), 5.75 (2H, s,
–CH2-), 7.74 (1H, s, Imidazole H), 7.88 (1H, s, Imidazole
H), 8.40 (1H, d, J = 10.8 Hz, ArH), 8.77–8.84 (2H, m,
ArH & triazole H), 9.04 (1H, s, ArH), 9.37 (1H, bs,
Imidazole H), 14.75 (1H, bs, –COOH); 13C NMR
(75 MHz, DMSO-d6) d: 8.20, 36.79, 54.64, 108.25, 113.54,
115.87, 124.52, 126.77, 128.51, 129.54, 138.14, 138.57,
140.23, 149.82, 150.34, 153.49, 165.78, 177.00; LC–MS
(ESI, m/z): 395.4 (M?H).
The structures of all the newly synthesized compounds
1
were confirmed by IR, H and 13C NMR, and LC mass
spectral studies. The structure of compound 2 was con-
firmed by their IR and LCMS analyses. The IR spectrum of
2 revealed the presence of –N3 group due to the appearance
of strong band at 2119 cm-1, while that of –C=O of ester
was observed at 1718 cm-1. Further, the LCMS showed its
molecular ion peak at 317.2 (M?H), which is in accor-
dance with its molecular formula C15H15FN4O3. The for-
mation of alcohol 3 from azide 2 was evidenced by its IR,
1HNMR, and LC–MS spectra. Its IR spectrum showed
absorbance bands at 3474 and 1668 cm-1 indicating the
presence of –OH and –C=O groups, respectively, while its
Antibacterial activity
All compounds were screened for their in vitro antibacte-
rial activity against representative Gram-positive and
123

Med Chem Res
Step 2
Step 1
Propargyl alcohol, CuI,
DIPEA, Sodium ascorbate,
0 °C to RT
O
N
O
O
N
O
O
N
1
O
NaN3/DMF,
55 °C, 16 h
F
F
O
F
F
O
O
N
N
N
N3
HO
3
2
X
Propargyl chloride , CuI,
DIPEA, Sodium ascorbate,
0 °C to RT
SOCl2, Py, DCM
0 °C to RT, 2 h
Step 3
Step 4
O
N
O
O
N
O
O
O
Step 5
F
KI, TEA, DMF,
RT, Amine
F
O
F
6N HCl, 60 °C
O
OH
N
N
N
N
N
N
N
N
N
N
Cl
R1
R1
4
6 a-t
5 a-t
R1=Alkyl amine, Aryl amine,
Hetero aryl, Araalkyl amine
Scheme 1 Synthetic route to synthesize compounds 6a–t
1H NMR spectrum showed sharp singlet at d 8.56 clearly
confirming the conversion of –N3 to [1,2,3] triazole. The
LCMS spectrum of 3 showed a molecular ion peak at 373.1
(M?H), which matches with its molecular formula
C18H17FN4O4.
of broad singlet d 11.16 (which disappeared on D2O
exchange) that corresponds to –OH proton of acid. The
C13 NMR signals at 165.7 and 177.29 correspond to the
presence of two different carbonyl fictional groups in the
molecule and also signal at 42.81 confirms the presence of
N(CH3)2. The structure of 6a was further confirmed by
LCMS. It showed the molecular ion peak at m/z 372.1
(M?H), which conforms to its molecular formula C18H18
FN5O3.
The formation of chloro derivative 4 from alcohol 3 was
confirmed by its 1HNMR and LC–MS spectra. Its 1H NMR
spectrum showed sharp singlet at d 4.99 confirming the
formation of the chloro derivative 4. The LCMS spectrum
of 4 showed a molecular ion peak at 391.0 (M?H), which
matches with its molecular formula C18H16ClFN4O3. The
structures of compounds 5–t were interpreted by their IR,
1HNMR, and LCMS analyses. The IR spectrum of 5a
revealed the presence of ester –C=O group due to the
appearance of strong band at 1725 cm-1, while that of
The physicochemical characteristics of the newly syn-
thesized compounds are presented in Table 1.
Antibacterial evaluation
1
–C=O of quinoline was observed at 1698 cm-1. In its H
All the newly synthesized 20 compounds (6a–t) were
evaluated for their in vitro antibacterial activities against
human pathogens by means of standard twofold serial
dilution method using agar media. The in vitro antibacterial
activity were performed against three Gram-positive bac-
terial strains including Methicillin-resistant Staphylococcus
aureus, Vancomycin-Resistant Enterococcus faecalis, and
three Gram-negative strains including Klebsiella pneumoniae
(clinical). Ciprofloxacin and Linezolid were used as reference
drugs.
NMR spectrum the appearance of a singlet at d 2.22 con-
firmed the presence of newly introduced –N(CH3)2 group.
Further, the LCMS showed its molecular ion peaks at 383.1
(M?H) and 400.0 (M?2?H), which is in accordance with
its molecular formula C20H22FN5O3.
The structures of compounds 6a–t were elucidated by
1
their IR, H and 13C NMR, and LCMS analyses. The IR
spectrum of 6a revealed the presence of acid –OH group
due to the appearance of absorbance bands at 2537 cm-1
,
.
while that of –C=O of acid was observed at 1712 cm-1
The data generated from this study (Table 2) showed
that some of the target compounds exhibit good potency in
inhibiting the growth of Gram-positive bacteria such as
1
The H NMR spectrum of 6a showed singlet at d 2.80, for
six protons which correspond to –N(CH3)2 and appearance
123

Med Chem Res
Table 1 Physicochemical characteristics of N-substituted amino methyl-[1,2,3] triazolyl derivatives at C7 position of fluoroquinolones (6a–o)
O
O
F
OH
N
N
N
N
R1
Compound
R1
MF/M.Wt.
Yield (%)
92
Mpa (°C)
6a
C18H18FN5O3./
371.37
179.1–180.2 °C
N
6b
6c
C20H22FN5O3/
399.43
93
92
209.3–209.8 °C
180.0–180.9 °C
N
C22H26FN5O3/
427.48
N
6d
6e
C20H20FN5O3/
397.41
87
87
252.4–253.9 °C
188.1–189.1 °C
N
C21H22FN5O3/
411.44
N
6f
C20H20FN5O4/
413.41
79
87
250.5–251.5 °C
212.7–213.1 °C
O
N
6g
C20H21FN6O3/
412.43
N
N
6 h
6i
C19H20FN5O3/
385.40
82
84
86
82
84
83
85
83
91
285.2–286.7 °C
221.4–222.9 °C
280.4–282.3 °C
202.1–203.4 °C
161.7-162.2 °C
200.6–201.4 °C
213.9–215.2 °C
193.2–194.6 °C
225.4–226.1 °C
NH
C19H18FN5O3/
383.39
NH
6j
C21H22FN5O3/
411.44
NH
6 k
6l
C22H24FN5O3/
425.47
NH
NH
C23H26FN5O3/
439.49
6m
6n
6o
6p
C22H18FN5O3/
419.42
NH
C22H17F2N5O3/
437.41
F
NH
C22H17ClFN5O3/
453.86
Cl
O
NH
C23H20FN5O4/
449.45
NH
123

Med Chem Res
Table 1 continued
Compound
R1
MF/M.Wt.
Yield (%)
89
Mpa (°C)
6q
6r
6s
6t
a
C23H20FN5O3/
433.45
213.2–214.0 °C
NH
C23H20FN5O3/
433.45
81
82
86
259.0–259.6 °C
249.7–250.2 °C
129.2–131.0 °C
NH
C23H19F2N5O3/
451.44
F
NH
C19H15FN6O3/
394.37
N
NH
Melting point of compounds at their decomposition
Table 2 Antibacterial activity of new fluoroquinolones 6a–t
Compound
Gram positive panel MIC (lg/mL)
Gram negative panel MIC (lg/mL)
AB 356 Klebsiella BAA 747
ATCC 29213
Staphylococcus
aureus (MSSA)
ATCC 33591
Staphylococcus
aureus (MRSA)
ATCC 700802
Enterococcus
faecalis (VR)
ATCC 25238
Moraxella
catarrhalis
pneumoniae
(Clinical)
Acinetobacter
baumannii
6a
4
8
16
32
32
16
16
16
32
16
16
16
32
32
2
2
8
1
6b
6c
8
32
32
8
16
8
16
16
8
16
8
2
6d
6e
2
2
1
4
16
16
16
16
16
16
32
32
0.5
1
2
8
1
6f
8
16
8
16
32
16
32
16
8
4
6g
6h
6i
16
16
16
16
16
32
0.25
0.25
0.25
0.5
0.5
2
8
4
1
32
4
32
6j
1
6k
6l
2
1
16
1
16
1
8
6m
6n
6o
6p
6q
6r
0.125
0.25
0.125
0.5
0.125
1
4
2
2
0.25
0.5
0.5
2
1
1
0.5
8
2
4
2
4
8
4
1
8
6s
2
2
4
2
8
1
6t
32
4
32
2
32
2
32
[32
0.125
32
[32
0.5
8
Linezolid
4
Ciprofloxacin 0.5
0.5
0.5
0.25
Staphylococci aureus including MRSA and VRE faecalis
(0.25–8.00 lg/mL). The in vitro activity of compound
6o against Gram-positive bacteria such as Methicillin-
resistant Staphylococcus aureus and Vancomycin-Resistant
E. faecalis are superior to the marketed drugs Linezolid
and Ciprofloxacin.
The in vitro activity of compound 6o against Gram-
negative bacteria such as Klebsiella pneumonia, Acinetobacter
baumannii, and Moraxella catarrhalis are superior to the
marketed drug Linezolid and comparable to Ciprofloxacin.
The antibacterial activity of compounds 6m to 6q sug-
gested that introduction of N-aryl amino methyl-[1,2,3]
123

Med Chem Res
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Acknowledgments We are thankful to Anthem biosciences man-
agement, Anthem biosciences, Bangalore, India, for their invaluable
support and allocation of resources for this work. We would like
thank Analytical chemistry team, Department of analytical chemistry,
Anthem biosciences, Bangalore, India, for having carried out all the
analytical work.
123