New trifluoromethyl quinolone derivatives: Synthesis and investigation of antimicrobial properties

Article abstract of DOI:10.1016/j.bmcl.2013.03.120

A series of quinolone derivatives, containing different heterocyclic amines were prepared. Synthesized compounds were evaluated for their in vitro antimicrobial activities against two Gram-positive bacteria, three Gram-negative bacteria as well as four fungi. All the derivatives showed good activity towards Gram-positive bacteria and less activity towards Gram-negative bacteria. They also showed moderate to comparable activity against Aspergillus niger and Candida albicans and low to moderate antifungal activity against Aspergillus fumigatus and Aspergillus flavus.

Full text of DOI:10.1016/j.bmcl.2013.03.120

Bioorganic & Medicinal Chemistry Letters 23 (2013) 3225–3229
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
New trifluoromethyl quinolone derivatives: Synthesis and
investigation of antimicrobial properties
⇑
Siva S. Panda, Subhash C. Jain
Department of Chemistry, University of Delhi, Delhi 110 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of quinolone derivatives, containing different heterocyclic amines were prepared. Synthesized
compounds were evaluated for their in vitro antimicrobial activities against two Gram-positive bacteria,
three Gram-negative bacteria as well as four fungi. All the derivatives showed good activity towards
Gram-positive bacteria and less activity towards Gram-negative bacteria. They also showed moderate
to comparable activity against Aspergillus niger and Candida albicans and low to moderate antifungal
activity against Aspergillus fumigatus and Aspergillus flavus.
Received 14 March 2013
Revised 25 March 2013
Accepted 27 March 2013
Available online 3 April 2013
Keywords:
Quinolone
Ó 2013 Elsevier Ltd. All rights reserved.
Trifluoromethyl
Antimicrobial
Lipophilicity
Molar refractivity
The increasing incidence of infection caused by the rapid devel-
opment of bacterial resistance to most of the known antibiotics is a
serious health problem.1 Consequently, there is an urgent need
for the development of novel types of antimicrobial agents
targeting unique mechanisms and pathways. Bacteria and fungi
generally develop drug resistance in three ways: producing metab-
olizing enzymes for the degradation of the drugs, modifying their
targets to render the drugs ineffective, and expressing a high level
of efflux proteins that ‘pump’ the drug out in order to lower its con-
antibacterial activity thereby improving overall the therapeutic
efficiency. Also, substitution of hydrogen by a trifluoromethyl
group could also result in increasing the therapeutic efficiency. In
this case, the size is no doubt much larger (the volume of a trifluo-
romethyl group is close to that of an isopropyl group),16 but it is
the enhanced volume that contributes to the hydrophobicity,
which is higher than in the case fluorine is present. The trifluoro-
methyl have been reported to possess biological activities being
–3
1
7
18
19
20
herbicides,
fungicides,
analgesic,
antipyretic,
and good
2
–7
21
centration.
As multidrug-resistant bacterial strains proliferate,
inhibitors of platelet aggregation.
the necessity for effective therapy has stimulated research into
the design and synthesis of novel antimicrobial molecules.
Quinolone moiety is of great importance to chemists as well as
biologists as it is found in a large variety of naturally occurring
compounds possessing diverse biological activities. Quinoline
Prompted by the varied biological activities of quinolone deriv-
atives and understanding the importance of trifluoromethyl com-
pounds, we envisaged the synthesis of potential antimicrobial
2
2,23
agents,
containing two biodynamic moieties that is, trif-
luromethylquinolone and a heterocyclic amine, separated by a
suitable alkyl/alkenyl spacer. All the synthesized compounds were
screened for antibacterial and antifungal activity and also deter-
mined their logP and molar refractivity (MR).
8
9
derivatives have been used as antimalarial, anti-inflammatory,
1
0
11
12
13,14
anticancer, antibiotic, antihypertensive, anti HIV
and as
tyrokinase PDGF-RTK inhibiting agents.15 Additionally, some
known fluoroquinolone antibiotics such as Ciprofloxacin, Levoflox-
acin, Gatifloxacin and Norfloxacin are well known drugs.
6-Substituted-2-(trifluoromethyl)quinolin-4(1H)-ones (3a–d)
2
4
were prepared in 79–85% yield by cyclocondensation of substi-
tuted aniline with ethyl 4,4,4-trifluoro-3-oxobutanoate (2) in poly-
phosphoric acid at 150 °C for 2 h. (Scheme 1, Table 1).
Thus, the presence of fluorine a highly electronegative centre,
enhances lipophilicity, and can alter the physico-chemical proper-
ties of the molecule significantly (such as solubility or the logP) in
a predictable way. This could result in increasing the stability,
reducing the toxicity to eukaryotic cells, besides improving the
Compound 3a–d, on reaction with 2-(4-bromobutyl)isoindo-
2 3
line-1,3-dione (4) in presence of K CO in DMF at 25 °C for 6 h gave
2
5
a mixture of N- and O-substituted quinolines . Both N- and O-
substituted compounds were isolated by column chromatography.
It was observed that the ratio of N- and O-substituted compounds
depends on the substituents on the quinoline ring. In case of
methoxy substituent, only N-substituted product was formed.
(Scheme 2, Table 2).
⇑
Corresponding author. Tel.: +91 11 27667725x1387; fax: +91 11 27666605.
E-mail addresses: sspanda12@gmail.com (S.S. Panda), jainsc48@hotmail.com
(
S.C. Jain).
0
960-894X/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2013.03.120

3
226
S. S. Panda, S. C. Jain / Bioorg. Med. Chem. Lett. 23 (2013) 3225–3229
O
R
O
O
R
PPA
+
NH2
F3C
O
o
150 C, 2 h
N
H
a-d
CF3
1
a-d
2
3
Scheme 1. Synthesis of 2-(trifluoromethyl)quinolin-4(1H)-ones.
Table 1
MTCC 441), three Gram-negative bacteria (Escherichia coli MTCC
43, Salmonella typhi MTCC 733, and Klebsiella pneumoniae MTCC
432) as well as four fungi (Aspergillus niger MTCC 282, Aspergillus
Synthesis of trifluoromethylquinolones
4
R
Product 3
Yield (%)
Mp (°C)
Lit. mp (°C)
H
F
CH
OCH
3a
3b
3c
3d
85
82
84
79
208–210
249–251
252–253
152–154
206–20824
250–2512
251–25324
—
fumigatus MTCC 343, Aspergillus flavus MTCC 277, and Candida albi-
4
27,28
cans MTCC 227) using Cup plate method
where inoculated
3
Muller–Hilton agar for bacteria and Sabouraud dextrose agar for
fungi was separately poured onto the sterilized petri dishes (25–
3
3
0 mL: each petri dish). The poured material was allowed to set
(
30 min.) and thereafter the ‘CUPS’ (08 mm diameter) was made
O
O
N
Br
by punching into the agar surface with a sterile cork borer and
scooping out the punched part of the agar. Into these cups, the test
compound solution (0.1 mL) was added with the help of a micro
pipette. The plates were incubated at 37 °C for 14 h for bacteria
and 30 h for fungi and the results were noted. The test solution
was prepared using DMSO as solvent. Minimum Inhibitory Con-
centration (MIC) of all the compounds were also studied by serial
R
+
N
H
CF3
O
4
3
a-d
K CO , DMF
2
5
3
o
2
C, 6 h
O
N
29
dilution method. Clinically antimicrobial drugs Ciprofloxacin
R
and Miconazole were used as the positive control and DMSO was
used for blank.
O
CF3
N
On comparison, the antimicrobial activity of the above synthe-
sized compounds, it was found that the tested compounds are
more effective against the Gram-positive bacteria. It looks that
the strong lipophilic character of the molecule plays an essential
role in producing antimicrobial effect. This property is seen as an
important parameter related to membrane permeation in biologi-
cal system. Many processes of drug disposition depend on the
capability to cross membranes and hence there is a high correla-
tion with measures of lipophilicity. Hydrophobic drugs with high
partition coefficients are preferentially distributed to hydrophobic
compartments such as lipid bilayers of cells while hydrophilic
drugs (low partition coefficients) preferentially are found in hydro-
philic compartments such as blood serum. Hydrophobicity/lipo-
philicity plays a major role in determining where drugs are
distributed within the body after adsorption and as a consequence,
how rapidly they are metabolized and excreted. In this context the
presence of the hydrophobic moiety would be important for such
activity. Moreover, many of the proteins involved in drug disposi-
tion have hydrophobic binding sites thereby further adding to the
N
+
O
O
O
O
N
R
5a-d
6a-c
CF3
Scheme 2. Reaction of 2-(trifluoromethyl)quinolin-4(1H)-ones (3a–d) with 2-(4-
bromobutyl)isoindoline-1,3-dione (4).
6
-Fluoro-2-(trifluoromethyl)quinolin-4(1H)-one (3b) was re-
acted with excess of 1,4-dibromobutane (7) in presence of K CO
2
3
in DMF at 25 °C for 4 h to obtain crude 1-(4-bromobutyl)-6-flu-
oro-2-(trifluoromethyl)quinolin-4(1H)-one (8) which was purified
by column chromatography. Similarly (E)-1-(4-bromobut-2-en-1-
yl)-6-fluoro-2-(trifluoromethyl)quinolin-4(1H)-one (11) was pre-
pared from 6-fluoro-2-(trifluoromethyl)quinolin-4(1H)-one (3b)
and (E)-1,4-dibromobut-2-ene (10). Compounds 8 and 11, when
reacted separately with different heterocyclic secondary amines
gave corresponding desire products in good yields26. (Scheme 3,
Table 3)
All the newly synthesized compounds 5a–d, 6a–c, 9a–d and
2a–d were screened for their in vitro antimicrobial activities to
determine zone of inhibition at 100 g/mL against two Gram-posi-
tive bacteria (Staphylococcus aureus MTCC 096 and Bacillus subtilis
3
0
importance of lipophilicity.
The lipophilicity of the compounds, expressed as logP, explains
the main predictor for the activity. The octanol/water partition
coefficient ClogP being a measure of hydrophobicity/lipophilicity
was calculated using ChemDraw Ultra 13.0 software integrated
with Cambridgesoft Software (Cambridgesoft Corporation).31 The
results obtained are given in Table 4. The calculated values of logP
for 2-(4-((6-substituted-2-(trifluoromethyl)quinolin-4-yl)oxy)bu-
tyl) isoindoline-1,3-diones 6a–c were higher than that of 2-(4-(6-
substituted-4-oxo-2-(trifluoromethyl)quinolin-1(4H)-yl)butyl)iso-
indoline-1,3-diones 5a–d. The lipophilic power of compounds has
increased with increasing logP. The antimicrobial activity observed
of O-substituted compounds 6a–c are slightly higher than that of
N-substituted compounds 5a–d.
1
l
Table 2
Synthesis of N- and O-substituted trifluoromethylquinolines
R
Product 5
Product 6
Yield (%)
Yield (%)
Mp (°C)
Mp (°C)
H
F
CH
OCH
72
81
74
92
100–101
125–127
106–108
104–105
14
10
22
0
92–94
98–99
84–86
—
The molar refractivity (MR), which represents size and polariz-
ability of a molecule describing steric effects, was also calculated
3
(
using ChemDraw Ultra 13.0 software) to explain the activity
3
behavior of the synthesized compounds. From Tables 5 and 6, it

S. S. Panda, S. C. Jain / Bioorg. Med. Chem. Lett. 23 (2013) 3225–3229
3227
Br
O
N
O
N
F
F
K CO , DMF,
HN
Br
7
CF3
CF3
K CO , DMF,
2
3
2
3
o
o
25
C, 4 h
8
Br 25 C, 4 h
N
9a-d
O
F
N
H
CF3
3b
Br
O
O
N
F
HN
F
10
Br
N
CF3
K CO , DMF,
CF3
K CO , DMF,
2
3
2
3
o
o
Br
25 C, 4 h
25
C, 4 h
11
N
1
2a-d
Scheme 3. Synthesis of compounds 9a–d and 12a–d.
Table 3
Table 4
Synthesis of compounds 9a–d and 12a–d
Calculated logP and molar refractivity (MR) of compounds 5a–d, 6a–c, 9a–d and
2a–d
1
o
Compound
Yield (%)
Mp ( C)
Compound
logP
MR
O
5
a
3.35
3.51
3.84
3.23
4.64
4.80
5.13
3.50
2.37
2.52
3.08
3.21
2.08
2.23
2.79
1.32
5.09
107.47
107.87
113.37
114.72
103.37
103.78
109.27
96.44
93.57
100.71
91.85
96.47
93.59
F
5b
9
9
9
8
7
4
2
1
6
0
40–42
84–85
42–43
71–73
69–71
5c
5d
6a
N
CF3
N
N
N
N
9
a
O
6
6
9
b
c
a
F
F
F
9b
9c
9d
N
CF3
O
N
9
b
O
1
1
1
2a
2b
2c
100.73
91.87
89.39
12d
Ciprofloxacin
Miconazole
N
O
CF3
CF3
CF3
CF3
102.57
9c
can be inferred that the higher value of molar refractivity favors
the activity ratio.
The values of the MIC against microorganisms tested are re-
ported in Tables 5 and 6. The investigations showed significant
inhibitory effects, with the majority of the compounds having
N
9d
O
F
F
MIC values 6.25–50 lg/mL. The antibacterial data indicated that
N
all the synthesized compounds showed significant antibacterial
activity against all the Gram-positive strains. Among them com-
pounds 6a–c, 5c, 9c, 9d and 12c were found to be more potent.
As shown in Table 5, none of the compounds have inhibitory effect
against E. coli. Less activity was noted against S. typhi and K. pneu-
monia. According to the investigations, compounds containing
phthalimide and N-methyl piperazine have shown enhanced
activity.
The antifungal activity of synthesized quinolone derivatives
in vitro are summarized in Table 6. All the compounds showed
good to comparable activity against A. niger and C. albicans. Some
compounds were endowed with a medium activity against A.
fumigatus. For A. flavus, the tested compounds showed low to mod-
erate antifungal activity.
N
N
12a
O
6
5
93–95
N
O
N
1
2b
O
F
F
6
6
8
2
68–69
73–75
N
O
CF3
N
N
1
2c
In conclusion, several quinolones derivatives were synthesized
in good yields. The pharmacological study was undertaken to eval-
uate the effects of substituents on the antibacterial and antifungal
activities. All the synthesized compounds exhibited good antibac-
terial activity towards Gram-positive bacteria and some of the
N
CF3
1
2d

3
228
S. S. Panda, S. C. Jain / Bioorg. Med. Chem. Lett. 23 (2013) 3225–3229
Table 5
Antibacterial activity data of 5a–d, 6a–c, 9a–d and 12a–d.
Compound
MIC in
l
g/mL and zone of inhibitiona (in mm)
S. aureus
B. subtilis
E. coli
S. typhi
K. pneumonia
5
5
5
5
6
6
6
9
9
9
9
1
1
1
1
a
b
c
d
a
b
c
a
b
c
d
2a
2b
2c
2d
12.5 (13–16)
6.25 (15–18)
6.25 (15–18)
6.25 (16–18)
6.25 (16–19)
6.25 (15–18)
6.25 (15–20)
12.5 (12–15)
6.25 (15–18)
6.25 (15–19)
6.25 (14–20)
12.5 (13–15)
12.5 (12–14)
6.25 (15–18)
6.25 (15–20)
6.25 (17–22)
12.5 (12–14)
12.5 (13–16)
6.25 (15–20)
12.5 (13–16)
6.25 (16–18)
6.25 (15–17)
6.25 (15–18)
25 (<10)
12.5 (13–15)
6.25 (15–18)
6.25 (15–18)
12.5 (12–14)
6.25 (14–18)
6.25 (14–18)
12.5 (12–16)
6.25 (18–21)
50 (<10)
50 (<10)
25 (<10)
50 (<10)
50 (<10)
25 (<10)
50 (<10)
50 (<10)
50 (<10)
50 (<10)
50 (<10)
50 (<10)
25 (<10)
50 (<10)
50 (<10)
6.25 (18–22)
25 (<10)
12.5 (13–16)
12.5 (13–16)
12.5 (13–16)
6.25 (16–20)
12.5 (12–15
12.5 (12–15)
6.25 (15–19)
12.5 (12–15)
25 (<10)
12.5 (13–16)
12.5 (13–16)
25 (<10)
25 (<10)
12.5 (12–15)
12.5 (12–15)
50 (<10)
25 (<10)
50 (<10)
12.5 (12–14)
25 (<10)
50 (<10)
12.5 (12–14)
25 (<10)
12.5 (14–16)
25 (<10
12.5 (13–16)
12.5 (12–15)
25 (<10
12.5 (12–15)
12.5 (12–16)
6.25 (18–20)
Ciprofloxacin
Table 6
Antifungal activity data of 5a–d, 6a–c, 9a–d and 12a–d
4. Kohler, T.; Kok, M.; MicheaHamzehpour, M.; Plesiat, P.; Gotoh, N.; Nishino, T.;
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Compound MIC in
g/mL and zone of inhibitiona (in mm)
l
A. niger
A. fumigatus
A. flavus
C. albicans
5
5
5
5
6
6
6
9
9
9
9
1
1
1
1
a
b
c
d
a
b
c
a
b
c
d
2a
2b
2c
2d
12.5 (13–16)
6.25 (17–20)
12.5 (12–14)
12.5 (12–15)
6.25 (17–20)
6.25 (17–20)
6.25 (17–20)
12.5 (12–14)
12.5 (13–15)
6.25 (14–18)
12.5 (12–15)
6.25 (17–20)
6.25 (17–20)
12.5 (12–14)
12.5 (12–15)
6.25 (17–22)
25 (<10)
12.5 (12–14)
25 (<10)
25 (<10)
25 (<10)
12.5 (12–14)
25 (<10)
25 (<10)
12.5 (12–14)
50 (<10)
12.5 (12–14)
25 (<10)
25 (<10)
12.5 (12–14)
25 (<10)
6.25 (17–20)
6.25 (17–20)
6.25 (15–17)
6.25 (15–20)
6.25 (17–20)
6.25 (15–18)
6.25 (15–17)
6.25 (15–19)
6.25 (15–17)
12.5 (12–14)
6.25 (16–20)
12.5 (12–14)
6.25 (15–19)
6.25 (15–20)
6.25 (15–18)
6.25 (17–22)
8. Nasveld, P.; Kitchener, S. Trans. R. Soc. Trop. Med. Hyg. 2005, 99, 2.
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Inflamm. 1983, 6, 209.
10. Denny, W. A.; Wilson, W. R.; Ware, D. C.; Atwell, G. J.; Milbank, J. B.; Stevenson,
25 (<10)
R. J. U.S Patent, 7064117, 2006.
12.5 (12–14)
12.5 (12–14)
12.5 (12–14)
25 (<10)
1
1
1
1. Mahamoud, A.; Chevalier, J.; Davin-Regli, A.; Barbe, J.; Pages, J.-M. Curr. Drug
Targets 2006, 7, 843.
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25 (<10)
12.5 (12–14)
12.5 (12–15)
25 (<10)
14. Strekowski, L.; Mokrosz, J. L.; Honkan, V. A.; Czarny, A.; Cegla, M. T.; Patterson,
S. E.; Wydra, R. L.; Schinazi, R. F. J. Med. Chem. 1991, 34, 1739.
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25 (<10)
25 (<10)
12.5 (12–14)
12.5 (12–14)
12.5 (14–17)
12.5 (12–14)
12.5 (12–14)
6.25 (17–20)
Miconazole
1
1
1
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synthesized compounds showed good to moderate antifungal
activity. These compounds however did not show any promising
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2
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5. Preparation
isoindoline-1,3-dione (5a) and 2-(4-((2-(trifluoromethyl)quinolin-4-yl)oxy)
butyl)isoindoline-1,3-dione (6a), representative procedure: mixture of 2-
trifluoromethyl-4-quinolinone 3a (0.20 g, 0.93 mmol), N-(4-bromobutyl)
phthalimide (0.26 g, 0.93 mmol) and anhydrous K CO (0.19 g, 1.34 mmol) in
mL DMF was stirred in a round bottom flask for 6–8 h at room temperature.
of
2-(4-(4-oxo-2-(trifluoromethyl)quinolin-1(4H)-yl)butyl)
Acknowledgment
A
Author (S.S.P.) is thankful to UGC, New Delhi for research
fellowship.
2
3
5
The reaction mixture showed two spots on TLC and hence was subjected to
column chromatography. The column was packed in petroleum ether and
eluted with petroleum ether:ethylacetate mixture. Both the compounds were
Supplementary data
isolated and identified as compounds 5a and 6a. Compound 5a: Colorless solid.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2013.03.
1
Yield: 0.17 g (72%), mp 100–101 °C; H NMR (400 MHz, CDCl
3
) d 8.21 (d,
J = 8.4 Hz, 1H), 8.10 (d, J = 8.8 Hz, 1H), 7.82 (m,2H), 7.76 (d, J = 7.6 Hz, 1H),
7
3
1
9
.71–7.61 (m, 2H), 7.59 (d, J = 7.6 Hz, 1H), 7.01 (s, 1H), 4.30 (t, J = 5.4 Hz, 2H),
.84 (t, J = 6.2 Hz, 2H), 2.03 (br s, 4H); 13C NMR (100 MHz, CDCl
) d 168.4,
62.9, 149.1, 148.0, 134.0, 131.9, 130.9, 129.5, 127.5, 123.2, 122.9, 121.6, 102.1,
6.6, 68.2, 37.4, 29.7, 26.2, 25.2. Anal. Calcd for C22 : C, 63.77; H, 4.13;
1
20.
3
17 3 2 3
H F N O
References and notes
N, 6.76. Found: C, 63.88; H, 4.06; N, 6.45. Compound 6a: Colorless solid, Yield:
1
0
3
.03 g (14%), mp 92–94 °C; H NMR (400 MHz, CDCl ) d 7.96 (d, J = 8.0 Hz, 1H),
1
.
(a) Chu, D. T. W.; Plattner, J. J.; Katz, L. J. Med. Chem. 1996, 39, 3853; (b) Beovic,
B. Int. J. Food Microbiol. 2006, 112, 280; (c) Finch, R.; Hunter, P. A. J. Antimicrob.
Chemother. 2006, 58, i3; (d) Suree, N.; Jung, M. E.; Clubb, R. T. Mini-Rev. Med.
Chem. 2007, 7, 991.
7.88–7.85 (d, J = 8.4 Hz, 1H), 7.84–8.81 (m, 2H), 7.72–7.70 (m, 2H), 7.69–7.65
(m, 1H), 7.46 (m, 1H), 7.20 (s, 1H), 4.54 (t, J = 5.6 Hz, 2H), 3.72 (t, J = 6.6 Hz, 2H),
1.90 (br s, 4H); 13C NMR (100 MHz, CDCl
) d 168.1, 166.8, 147.5, 137.1, 136.8,
134.0, 133.9, 132.0, 130.2, 128.0, 125.2, 124.0, 123.2, 121.7, 119.7, 111.7, 111.6,
3
2
.
.
Mitscher, L. A.; Pillai, S. P.; Gentry, E. J.; Shankel, D. M. Med. Res. Rev. 1999, 19,
65.7, 36.9, 29.7, 26.2, 25.3. Anal. Calcd for C22
6.76. Found: C, 64.01; H, 4.50; N, 6.87.
17 3 2 3
H F N O : C, 63.77; H, 4.13; N,
4
77.
3
Nikaido, H.; Zgurskaya, H. I. Curr. Opin. Infect. Dis. 1999, 12, 529.
26. Preparation
of
6-fluoro-1-(4-(piperidin-1-yl)butyl)-2-(trifluoromethyl)
quinolin-4(1H)-one (9a) and (E)-6-Fluoro-1-(4-(piperidin-1-yl)but-2-en-1-yl)-

S. S. Panda, S. C. Jain / Bioorg. Med. Chem. Lett. 23 (2013) 3225–3229
3229
2
-(trifluoromethyl)quinolin-4(1H)-one (12a), representative procedure:
7.10 (s, 1H), 6.00–5.89 (m, 2H), 4.97–4.86 (br s, 2H), 3.05 (br s, 2H), 2.72 (br s,
4H), 2.39 (br s, 4H), 1.59 (m, 2H); 13C NMR (75.47 MHz, CDCl
) d 162.2, 159.3,
148.3, 145.0, 133.1, 132.0, 125.6, 123.1, 122.7, 121.2, 106.1, 105.8, 97.5, 69.1,
Piperidine (0.06 g, 0.66 mmol) was dissolved in DMF (5 mL) along with
anhydrous potassium carbonate (0.14 g, 0.99 mmol) The bromo compound (8
and 11) (0.66 mmol) was added to the solution, and the mixture was stirred at
room temperature for 4 h. After completion of the reaction, the mixture was
poured in ice cold water. The precipitate was washed with water and dried
3
20 4 2
60.8, 54.4, 25.7, 24.1. Anal. Calcd for C19H F N O: C, 61.95; H, 5.47; N, 7.60.
Found: C, 62.23; H, 5.55; N, 7.22.
27. Barry, A. L. The Antimicrobic Susceptibility Test: Principles and Practices; Lea &
Febiger: Philadelphia, 1976. p 180.
28. Reddy, P. M.; Ho, Y. P.; Shanker, K.; Rohini, R.; Ravinder, V. Eur. J. Med. Chem.
2009, 44, 2621.
29. Mackie; McCartney Practical Medical Microbiology In Colle, J. G., Duguid, J. P.,
Fraser, A. G., Marmion, B. P., Eds., 13th ed.; Churchill Livingstone: London,
1989.
30. Ansari, K. F.; Lal, C. Eur. J. Med. Chem. 2009, 44, 4028.
31. ChemDraw Ultra 13.0, CambridgeSoft Corporation, Cambridge.
under vacuum to get the desired product 9a and 12a in good yield. Compound
1
9
a: Colorless solid. Yield: 0.19 g (94%), mp 40–42 °C; H NMR (300 MHz, CDCl
3
)
d 8.16–8.11 (m, 1H), 7.85–7.81 (m, 1H), 7.57–7.53 (m, 1H), 7.04 (s, 1H), 4.29 (t,
J = 6.3 Hz, 2H), 2.44–2.41 (m, 4H), 2.02 (m, 2H), 1.82–1.77 (m, 2H), 1.63–1.61
1
3
(
m, 4H), 1.55–1.44 (m, 2H); C NMR (75.47 MHz, CDCl
3
) d 162.8, 159.4, 145.1,
32.3, 126.9, 122.7, 121.2, 120.9, 119.6, 105.8, 97.0, 69.2, 58.9, 54.6, 26.9, 24.4,
3.5. Anal. Calcd for C19 O: C, 61.61; H, 5.99; N, 7.56. Found: C, 62.02; H,
.76; N, 7.93. Compound 12a: Colorless solid. Yield: 0.14 g (70%), mp 69–71 °C;
1
2
5
H
22
F
4
N
2
1
3
H NMR (300 MHz, CDCl ) d 8.15–8.12 (m, 1H), 7.87–7.84 (m, 1H), 7.55 (m, 1H),