Synthesis of N-aryl-2,2,2-trifluoroacetimidoyl piperazinylquinolone derivatives and their antibacterial evaluations

Article abstract of DOI:10.1016/j.jfluchem.2011.02.002

N-substituted trifluoroacetimidoyl chlorides were used for the synthesis of new piperazinylquinolone derivatives. These reactions provided N-aryl-2,2,2-trifluoroacetimidoyl piperazinylquinolone derivatives in good yields. Two selected compounds were evalu

Full text of DOI:10.1016/j.jfluchem.2011.02.002

Journal of Fluorine Chemistry 132 (2011) 263–268
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Synthesis of N-aryl-2,2,2-trifluoroacetimidoyl piperazinylquinolone derivatives
and their antibacterial evaluations
Ali Darehkordi a, , Mahmood Javanmiri a,b, Somayeh Ghazi a,b, Shokrollah Assar b
*
a Department of Chemistry, Faculty of Science, Vali-e-Asr University of Rafsanjan, Rafsanjan 77176, Iran
b Department of Microbiolog, Immunology and Biology, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
A R T I C L E I N F O
A B S T R A C T
Article history:
N-substituted trifluoroacetimidoyl chlorides were used for the synthesis of new piperazinylquinolone
derivatives. These reactions provided N-aryl-2,2,2-trifluoroacetimidoyl piperazinylquinolone deriva-
tives in good yields. Two selected compounds were evaluated for their antibacterial activities. These
compounds displayed good antibacterial activities.
Received 9 December 2010
Received in revised form 1 February 2011
Accepted 2 February 2011
Available online 4 March 2011
ß 2011 Elsevier B.V. All rights reserved.
Keywords:
Organofluorine
Trifluoroacetimidoyl chloride
Piperazinylquinolone
Norfloxacin
Ciprofloxacin
1. Introduction
mentarium to treat the serious gram-positive bacterial infections
[10,11]. The excellent pharmacokinetic properties, high antimi-
One particularly important area of medicinal researches is the
synthesis and application of organofluorine compounds. Organo-
fluorine chemistry has received extensive attention especially in
the pharmaceutical industry and in materials science due to the
unique properties of fluorinated compounds [1]. Some of the most
well known fluorine containing drugs are Prozac1 (anti-depres-
sant), Diflucan1 (anti-fungal agent), Casodex1 (anti-cancer agent)
and Desflurane (inhalation anesthetic) [1]. Recently, new applica-
tion of organofluorine compounds is including their use as
potential therapeutics for HIV, cancer or Alzheimer’s disease.
Accordingly, the synthesis of these molecules is in great demand
[2] and the search for new biologically active fluorinated
compounds is in the forefront of organic and medicinal chemistry
[3]. Trifluoromethylated imines are particularly important as
precursor products or as building blocks for the synthesis of
biologically active molecules [4].
crobial activities, and few side effects that most quinolones
demonstrate explain widespread use of oxazolidinones in clinical
practice [12]. These compounds have been effective against gram-
negative bacteria, while the gram-positive pathogens, such as
Staphylococcus aureus which resist their effects have become a
problem [13–19]. Thus, despite many advances in the fluoroquin-
olone field, there exists a continuous need for novel quinolones to
overcome the limitations of existing drugs. From an SAR viewpoint,
antibacterial compounds of both classes feature a heterocyclic
amine presented as a popular C-ring in oxazolidinones [5–7] and a
mandatory cyclic amine in position 7 of quinolones [20]. In the past
few years organofluorine chemistry has returned as an expanding a
productive area of research, as can be seen by the increasing
number of recent publications, reviews, topics, and monographs
[21]. Furthermore, organofluorine chemicals have found a wide
range of applications in medicine and agriculture due, in part, to
the unique biological properties imparted by the fluorine atom
[22].
A new class of synthetic antibacterial agents is oxazolidinones
that have a unique mechanism in inhibition of bacterial protein
synthesis [5–9].
The first drug in this class, Zybox (linezolid), has been widely
accepted as a valuable addition to the chemotherapeutic arma-
The 1,4-dihydro-4-oxopyridine-3-carboxylic acids associated
with a 5,6-fused aromatic ring is the common chemical feature of
bactericidal quinolones (Fig. 1).
In the resulting bicyclic ring, the 1-, 5-, 6-, 7-, and 8-positions
are the major targets of chemical variation but, synthetic efforts for
improved potency the main focus have been on 7-position [23–25].
Both activity spectrum and pharmacokinetic profiles can be
controlled at C-7. The most common substituents are cyclic amino
* Corresponding author. Tel.: +98 3913202147; fax: +98 3913202260.
E-mail addresses: adarehkordi@yahoo.com, darehkordi@mail.vru.ac.ir
(A. Darehkordi).
0022-1139/$ – see front matter ß 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2011.02.002

264
A. Darehkordi et al. / Journal of Fluorine Chemistry 132 (2011) 263–268
Fig. 1. Common pharmacophore of quinolones and structure of some piperazinylquinolones.
Fig. 2. N1-linked tosufloxacin A (inactive against gram-positive strains), lactam B oxazolidinones C, and D incorporating ciprofloxacin, ofloxacin, and levofloxacin quinolone
substructures linked via a piperazine group (highly potent against gram-positive strains).
groups, for example, piperazine and pyrrolidine rings and other
groups have been less successful. Piperazine rings are particularly
common (e.g., ciprofloxacin, norfloxacin or enoxacin) and confer
potency against gram-negative bacteria [25–29].
In this research N-aryltrifluoroacetimidoyl chlorides were
selected as an N-link to quinolones derivatives in order to improve
antibacterial properties.
According to this information N-aryltrifluoroacetimidoyl chlor-
ides were selected as an N-link to quinolone derivatives in order to
improve antibacterial properties of them. N-aryltrifluoroacetimi-
doyl chlorides can be prepared by several procedures [29]. In this
research a one-pot synthesis of imidoyl halides was described
which consists of refluxing a mixture of trifluroacetic acid and a
primary amine in carbon tetrachloride in the presence of
triethylamine and triphenylphosphine. Work up and distillation
provided the desired imidoyl chlorides in good to excellent yields
[29]. We also reported the synthesis of N-aryltrifluoroacetimidoyl
phthalimide and succcinimide by using imidoyl chlorides [30].
2. Results and discussion
2.1. Chemistry
Trifluoromethylated compounds are of particular interest as the
strong electron-withdrawing effect of CF3 group contributes to a
number of biologically important molecular properties. For
example it results in significant increase in lipophilicity of the
molecule, which is a very important feature in drug delivery. The
different medicinal applications of fluorinated organic molecules
are widespread [1].
Despite of many advances in the fluoroquinolone field, there
exist continuous needs for novel quinolones to overcome the
limitations of available drugs.
Design of a tether connecting the oxazolidinone and quinolone
pharmacophores is critical for antibacterial activity. Thus, N1-linked
tosufloxacin analogue A (Fig. 2) is inactive. In contrast, oxazolidi-
nones B, C, and D (Fig. 2) incorporating ciprofloxacin, ofloxacin, and
levofloxacin quinolone substructures linked via a piperazine group
are highly potent against gram-positive strains [27].
The results of MIC tests against both gram-positive and gram-
negative bacteria revealed that ciprofloxacin derivatives
(R = cyclopropyl and X = CH) were more active than norfloxacin
and enoxacin derivatives (R = ethyl and X = CH or N). These data
confirm that the effect of changes in the side-chain of the 7-
piperazinyl ring mainly depends on the substituent at N À 1
position [28].
Scheme
1.
Substitution
reaction
of
acetimidoyl
chlorides
with
piperazinylquinolones.

A. Darehkordi et al. / Journal of Fluorine Chemistry 132 (2011) 263–268
265
Table 1
Synthesis of piperazinylquinolone derivatives.
Entry
Product
Acetimidoyl chloride
Yield (%)
5a
86
5b
83
5c
80
5d
85
5e
5f
72
70
5g
60

266
A. Darehkordi et al. / Journal of Fluorine Chemistry 132 (2011) 263–268
Table 2
Chemicals and solvents were purchased from Merck AG and
Aldrich Chemical companies. The trifluoroacetimidoyl chloride 3
was prepared according to the literature. Melting points were
determined with a Bammstead electrothermal. IR spectra (KBr)
were obtained on a Matson-1000 FT-IR spectrometer. The proton
and carbon-13 NMR spectra were recorded by a BRUKER DRX-500
AVANCE spectrometer at 500 and 125.7 MHz, respectively, using
Antibacterial activity of ciprofloxacin, vancomycin, 5a and 5c.
Type of bacteria
reagents
Staphylococcus
aureus
Escherichia
coli
Klebsiella
pneumonia
5c
39 mm
31 mm
–
30 mm
32 mm
26 mm
–
33 mm
30 mm
27 mm
–
5a
Ciprofloxacin
Vancomycin
17 mm
Me4Si as an internal standard (chemical shifts in d
, ppm). 19F NMR
spectra were taken on Brucher AM-300 (282 MHz) spectrometer
using CFCl3 as external standard. Element analyses (C, H, and N)
were performed by a Heracus CHN-O-Rapid analyzer. The mass
spectra were run on a Finnigan TSQ-70 spectrometer (Finnigan,
USA) at 70 eV. Merck silica gel 60 F254 plates were used for
analytical TLC.
Here, we describe preparation of N-aryl-2,2,2-triflouroacety-
midoyl piperazinylquinolone derivatives from N-substituted tri-
fluoroacetimidoyl chlorides which chlorine is replaced with
nitrogen.
Thus, the reaction of equimolar quantities of norfloxacin or
ciprofloxacin with N-substituted trifluoroacetimidoyl chlorides
and K2CO3 under reflux for 18–20 h resulted in the formation of N-
aryl-2,2,2-trifluoroacetymidoyl piperazinylquinolone derivatives
5 in 60–86% yields (Scheme 1 and Table 1).
4.1.2. General procedure for synthesis of N-aryl-2,2,2-
trifluoroacetimidoyl piperazinylquinolone derivative
A mixture of piperazinylquinolone 4 (1 mmol) and K2CO3
(26 mg, 1 mmol) in DMF (10 mL) was stirred at room temperature
for 10 min and then a solution of N-aryl-2,2,2-trifluoroacetimidoyl
chloride 3 (1 mmol) in DMF (10 mL) were added successively. The
mixture was refluxed for 18–24 h. After consumption of piper-
azinylquinolone (monitored by TLC), NaHCO3 (20 mL, 10%) was
added and the resulting solids were washed with water and
recrystallised from DMF to give N-aryl-2,2,2-trifluoroacetimidoyl
piperazinylquinolone compounds.
In trifluoroacetimidoyl norfloxacin, trifluoroacetimidoyl cipro-
floxacin and trifluoroacetimidoyl enoxacin compounds, hydroxyl
(OH), carbonyl (C55O), and imino (C55N) groups, in IR spectra
appeared in 3409–3429, 1718–1724, and 1620–1631 cmÀ1
,
respectively. The 1H NMR spectra of these compounds showed a
singlet signal at 15.07–15.15 (COOH) and multiplet signals at 3.20–
3.57 ppm assigned for the protons of piperazine ring. 19F NMR
spectra of trifluoroacetimidoyl norfloxacin, ciprofloxacin and
enoxacin showed peaks at À73.85 to À76.15 ppm for CF3 imidoyl
groups, and at À121.80 to À125.29 ppm corresponding to fluorine
atom of quinoline rings, while CF3 group attached to the
trifluoroacetimidoyl aromatic rings appeared at À58.79 to
À60.41 and À66.21 ppm.
4.1.3. N-4-methyl (phenyl)-2,2,2-trifluoroacetimidoyl ciprofloxacin
(5a)
Yellow-brownish solid; mp: 186 8C, IR KBr (n
max, cmÀ1): 3424
(–COOH), 3043–2929 (C–H aromatic), 2849–2795 (CH-aliphatic),
1720 (C55O), 1624, 1527 (C55N, C55C). 19F NMR (DMSO-d6,
2.2. Biology
282 MHz);
(DMSO-d6, 500 MHz);
d
(ppm): À123.16 (1F, s), À73.41(3F, CF3, s). 1H NMR
d (ppm): 1.26–1.31 (m, 4H,), 2.20 (s, 3H,
Ciprofloxacin and vancomycin are both specific drugs which are
routinely used as antibacterial drugs. Therefore, growth restriction
zones of the bacterial such as Escherichia coli, Klebsiella pneumoniae
and S. aureus indicate sensitive to N-4-methyl (phenyl)-2,2,2-
trifluoroacetimidoyl ciprofloxacin and N-(5-chloro-2-(trifluoro-
methyl) phenyl)-2,2,2-trifluoroacetimidoyl norfloxacin. As shown
in Table 2 among the synthesized compounds, 5a and 5c were
found to be effective against the growth of these bacteria with a
CH3), 3.30 (br, 4H, piperazine ring), 3.37 (m, br, 4H, piperazine
ring), 3.76–3.81 (m, 1H, cyclopropyl ring), 6.69 (br, 2H, H phenyl
ring) 7.07 (d, 2H, H phenyl ring), 7.51 (s, 1H, H8-quinoline), 7.80 (d,
1H, H5-quinoline, JH,F = 13.1 Hz), 8.59 (s, 1H, H2-quinoline), 15.07
(s, 1H, COOH). 13C NMR (DMSO-d6 300 MHz);
d (ppm): 7.48 (CH2
cyclopropyl ring), 20.28 (CH3), 35.74 (CH cyclopropyl), 48.70,
49.11 (CH2 piperazine ring), 104.28, 106.37, 110.74, 117.64,
118.73, 119.27 (CF3, q, JC–F = 277.2 Hz), 119.99, 129.12, 131.80
(CF3-ring, q, JC–F = 274.31 Hz), 138.93 (C55N, q, JC–C–F = 42.2 Hz),
142.51, 147.75, 151.73, 153.72, 165.68, 176.14. Anal. calcd. for
concentration of 10–15
mg/mL.
These compounds would have promising antibacterial effects,
although more experiments to examine reproducibility and
effective dose are required.
C
26H24F4N4O3: C, 60.46; H, 4.68; N, 10.85. Found: C, 60.37; H, 4.59;
N, 10.69%.
3. Conclusion
4.1.4. N-4-methyl (phenyl)-2,2,2-trifluoroacetimidoyl norfloxacin
(5b)
In conclusion,
a
series of N-aryl-2,2,2-trifluoroacetimidoyl
Yellow-brownish solid; mp: 194 8C, IR KBr (n
max, cmÀ1): 3409
piperazinylquinolone derivatives were synthesized by the reaction
of N-aryltrifluoroacetimidoyl chlorides with norfloxacin, ciproflox-
acin and enoxacin, under mild conditions. We selected N-aryltri-
fluoroacetimidoyl chloride as an N-link to quinolone derivatives in
order to improve their antibacterial properties. The selected
compounds were evaluated for their antibacterial activities. These
compounds displayed good antibacterial activities. Further studies
on biological activities of these compounds are in progress.
(–COOH), 2922–3048 (C–H aromatic), 2853–2798 (CH-aliphat-
ic), 1718 (C55O), 1620, 1579 (C55N, C55C). 19F NMR (DMSO-d6,
282 MHz);
(DMSO-d6, 500 MHZ);
d
(ppm): À123.13 (1F, s), À73.26 (3F, CF3, s). 1H NMR
d (ppm): 1.53 (t, 3H, J = 7.2 Hz, –CH3
ethyl), 2.24 (s, 3H, CH3), 3.55 (br, 4H, piperazine), 3.58 (m, br,
4H, piperazine), 4.40 (q, 2H, J = 7.2 Hz, –CH2– ethyl), 6.67 (br, 2H,
H phenyl ring) 7.07 (d, 2H, H phenyl ring), 7.38 (s, 1H, H8-
quinoline), 7.54 (d, 1H, H5-quinoline, JH,F = 13.1 Hz), 8.63 (s, 1H,
H2-quinoline), 15.07 (s, 1H, COOH). 13C NMR (DMSO-d6
4. Experimental
300 MHz); d (ppm): 14.21 (–CH3 ethyl), 20.34 (1C, CH3), 52.14
(CH2 ethyl), 45.54, 49.00 (CH2 piperazine ring), 104.32, 106.37,
110.90, 116.96, 118.85, 119.48 (CF3, q, JC–F = 277.2 Hz), 122.55,
123.15, 129.19, 131.76, 138.93, 144.49 (C55N, q, JC–C–F = 43.1 Hz),
147.78, 151.78, 154.51, 165.80, 180.59. Anal. calcd. for
4.1. Chemistry
4.1.1. General experimental procedures
All reactions were performed with magnetic stirring in flame-
dried glassware with dry and distilled solvents.
C
25H24F4N4O3: C, 59.52; H, 4.80; N, 11.11. Found: C, 59.50; H,
4.79; N, 11.15%.

A. Darehkordi et al. / Journal of Fluorine Chemistry 132 (2011) 263–268
267
4.1.5. N-(5-chloro-2-(trifluoromethyl) phenyl)-2,2,2-
1H NMR (DMSO-d6, 500 MHz);
d
(ppm): 1.24 (m, 2H, CH2-
trifluoroacetimidoyl norfloxacin (5c)
cyclopropyl), 1.36 (m, 2H, CH2-cyclopropyl), 2.87 (m, br, 4H,
piperazine), 3.59 (m, br, 4H, piperazine), 3.78 (m, 1H, cyclopropyl)
7.43–7.45 (br, 6H, H phenyl ring), 7.94 (s, 1H, H8-quinoline), 8.10 (s,
1H, H phenyl ring), 7.82 (d, 1H, H5-quinoline, JH,F = 13.0 Hz), 8.52 (s,
1H, H2-quinoline), 15.12 (s, 1H, COOH). 13C NMR (DMSO-d6
Yellow-brownish solid; mp: 206 8C, IR KBr (n
max, cmÀ1): 3429
(–COOH), 2922–3055 (C–H aromatic), 2886–2783 (CH-aliphatic),
1720 (C55O), 1631, 1583 (C55N, C55C). 19F NMR (DMSO-d6,
282 MHz);
d
(ppm): À127.17 (1F, s), À76.47 (3F, CF3, s), À-58.79
(ppm): 1.56 (t, 3H,
(3F, CF3, s). 1H NMR (DMSO-d6, 500 MHz);
d
300 MHz); d (ppm): 7.56 (CH2 cyclopropyl ring), 35.87 (CH
J = 7.2 Hz, –CH3 ethyl), 3.43 (br, 4H, piperazine), 3.66 (m, br, 4H,
piperazine), 4.47 (q, 2H, J = 7.2 Hz, –CH2– ethyl), 7.31 (br, 2H, H
phenyl ring), 7.59 (s, 1H, H8-quinoline), 7.94 (s, 1H, H phenyl ring)
7.60 (d, 1H, H5-quinoline, JH,F = 13.0 Hz), 8.66 (s, 1H, H2-quinoline),
cyclopropyl), 46.34, 47.78 (CH2 piperazine ring), 105.01, 108.73,
113.04, 113.23, 115.16, 117.95, 120.44 (CF3, q, JC–F = 278.1 Hz),
120.82, 125.17, 128.19, 128.66, 129.97, 133.87, 139.93, 144.09,
144.72, 144.99, 146.78 (C55N, q, JC–C–F = 43.3 Hz), 146.96, 148.85
152.83, 155.09, 167.02 (C55O), 177.19 (C55O), 198.55 (C55O), Anal.
calcd. for C32H25ClF4O4: C, 59.96; H, 3.93; N, 8.74. Found: C, 60.12;
H, 4.03; N, 8.42%.
15.14 (s, 1H, COOH). 13C NMR (DMSO-d6 300 MHz);
d (ppm): 14.25
(–CH3 ethyl), 52.18 (CH2 ethyl), 49.12, 52.32 (CH2 piperazine ring),
105.82, 109.17, 112.31, 118.76, 118.85, 120.44 (CF3, q, JC–
F = 278.0 Hz), 122.75, 123.55, 129.89, 132.48, 139.63 (C55N, q, JC–
C–F = 44.0 Hz), 144.87 (C55N, q, JC–C–F = 44.0 Hz), 148.78, 155.74,
156.65, 165.97, 179.19. Anal. calcd. for C25H20ClF7N4O3: C, 50.65;
H, 3.40; N, 9.45. Found: C, 50.69; H, 3.52; N, 9.46%.
4.1.9. N-(3,5-bistrifluoromethyl (phenyl))-2,2,2-trifluoroacetimidoyl
enoxacin (5g)
Yellow-brownish solid; mp: 141–145 8C, IR KBr (n
max, cmÀ1):
3419 (–COOH), 2920–3047 (C–H aromatic), 2881–2776 (CH-
4.1.6. N-(5-chloro-2-(trifluoromethyl)phenyl)-2,2,2-
aliphatic), 1732 (C55O), 1636, 1582 (C55N, C55C). 19F NMR
trifluoroacetimidoyl ciprofloxacin (5d)
(DMSO-d6, 282 MHz);
d
(ppm): À128.14 (1F, s), À78.63 (3F, CF3,
Yellow-brownish solid; mp: 214 8C, IR KBr (
(–COOH), 2929–3043 (C–H aromatic), 2795–2849 (CH-aliphatic),
1720 (C55O), 1624, 1527 (C55N, C55C). 19F NMR (DMSO-d6,
n
max, cmÀ1): 3424
s), À66.21 (6F, 2CF3, s). 1H NMR (DMSO-d6, 500 MHz);
d (ppm):
1.57 (t, 3H, J = 7.2 Hz, –CH3 ethyl), 3.50 (br, 4H, piperazine), 3.67
(m, br, 4H, piperazine), 4.43 (q, 2H, J = 7.2 Hz, –CH2– ethyl), 7.31
(br, 2H, arom), 7.56 (s, 1H, H8-quinoline), 7.62 (s, 1H, arom), 7.58
(d, 1H, H5-quinoline, JH,F = 13.0 Hz), 8.64 (s, 1H, H2-quinoline),
282 MHz);
d
(ppm): À127.32 (1F, s), À76.53 (3F, CF3, s), À60.41
1.22–1.30 (m, 4H, CH2
(3F, CF3, s). 1H NMR (DMSO-d6, 500 MHz);
d
cyclopropyl), 3.20 (br, 4H, piperazine), 3.29 (m, br, 4H, piperazine),
3.55–3.85(m, 1H, cyclopropyl), 7.57 (br, 2H, H phenyl ring) 7.90
(br, 2H, H phenyl ring), 7.59 (s, 1H, H8-quinoline), 7.94 (s, 1H, H
phenyl ring) 8.65 (d, 1H, H5-quinoline, JH,F = 13.1 Hz), 8.97 (s, 1H,
15.13 (s, 1H, COOH). 13C NMR (DMSO-d6 300 MHz);
d (ppm): 14.23
(–CH3 ethyl), 53.08 (1C, CH2 ethyl), 49.65, 52.53 (CH2 piperazine
ring), 105.82, 109.17, 113.45, 115.60, 118.76, 120.85 (CF3-imidoyl,
q, JC–F = 278.1 Hz), 122.75, 123.55, 124.35, 127.00 (CF3-ring, q, JC–
F = 272.1. Hz), 129.89, 132.88 (C–CF3-attached the ring, q, JC–C–
F = 33.1 Hz), 136.41, 138.96, 139.63, 145.87 (C55N, q, JC–C–
F = 43.3 Hz), 148.78, 151.74, 155.74, 165.53, 175.17 (C55O). Anal.
calcd. for C25H19F10N5O3: C, 47.86; H, 3.05; N, 11.16. Found: C,
47.67; H, 2.98; N, 11.21%.
H2-quinoline), 15.10 (s, 1H, COOH). 13C NMR (DMSO-d6 300 MHz)
d
(ppm): 7.54 (CH2 cyclopropyl ring), 35.89 (CH cyclopropyl), 46.27,
47.29 (CH2 piperazine ring), 103.04, 106.79, 111.00, 117.92,
119.23, 119.89 (CF3, q, JC–F = 277.6 Hz), 124.70,130.47, 139.03,
144.01, 146.26 (C55N, q, JC–C–F = 43.0 Hz) 148.05 151.80, 153.79,
165.72, 176.30. Anal. calcd. for C26H20ClF7N4O3: C, 51.63; H, 3.33;
N, 9.26. Found: C, 51.46; H, 3.32; N, 9.19%.
4.2. Biology
4.1.7. N-(3,5-dimethyl (phenyl))-2,2,2-trifluoroacetimidoyl
4.2.1. Material and method
ciprofloxacin (5e)
The 0.01 g of synthesized powder (anti-bacterial compounds
Yellow-brownish solid; mp: 203–205 8C, IR KBr (
n
max, cmÀ1):
tested) was dissolved in 200
mL DMSO and then blank discs were
3425 (–COOH), 2956–3054 (C–H aromatic), 2884–2780 (CH-
soaked with 40 L of the above solution containing different
m
aliphatic), 1715 (C55O), 1628, 1588 (C55N, C55C). 19F NMR
compounds. Discs were put at 60 8C for 30 min to get dried. E. coli,
K. pneumonia as gram-negative bacteria and S. aureus as gram-
positive were obtained from Persian Type Culture Collection
(PTCC) with 1037, 1290 and 1189 codes respectively and cultured.
Antibiogram test performed according to Kirby-Bauer method on
Mueller Hinton Agar (Merck, Germany). In case of Staphylococcus,
vancomycin and in cases of Klebsiella and Escherichia we used
ciprofloxacin as positive controls (Padtan Teb, Iran). Two prepared
(5c, 5a, as mentioned) discs with positive controls tested. After
18 h, the diameter of inhibition zones were measured (mm) and
reported as shown in Table 2.
(DMSO-d6, 282 MHz);
d
(ppm): À122.19 (1F, s), À74.37 (3F, CF3,
(ppm): 1.16 (m, 2H, CH2-
s), 1H NMR (DMSO-d6, 500 MHz);
d
cyclopropyl), 1.30 (m, 2H, CH2-cyclopropyl), 2.87 (br, 4H, pipera-
zine), 3.32 (m, br, 4H, piperazine), 3.78 (m, 1H, H-cyclopropyl), 6.55
(s, 2H, H phenyl) 6.90 (s, 1H, H phenyl ring), 7.54(s, 1H, H8-
quinoline), 7.93 (s, 1H, H phenyl ring), 7.85 (d, 1H, H5-quinoline,
JH,F = 13.1 Hz), 8.62 (s, 1H, H2-quinoline), 15.12 (s, 1H, COOH). 13
NMR (DMSO-d6 300 MHz); (ppm): 7.56 (CH2 cyclopropyl ring),
C
d
35.87 (CH cyclopropyl), 46.34, 47.78 (CH2 piperazine ring), 105.01,
108.73, 113.23, 115.16, 117.95, 119.43 (CF3, q, JC–F = 276.2 Hz),
120.82, 124.81 (CF3-ring, q, JC–F = 271.4 Hz), 125.17, 128.19,
129.97, 133.87 (C–CF3-attached the ring, q, JC–C–F = 33.1 Hz),
139.93, 144.09, 144.99, 145.01 (C55N, q, JC–C–F = 42.2 Hz), 148.85,
152.83, 155.09, 168.12 (C55O), 173.62 (C55O). Anal. calcd. for
Acknowledgment
We gratefully acknowledge, the Vali-e-Asr University of
Rafsanjan Faculty Research Grant for financial support.
C27H20F10N4O3: C, 50.79; H, 3.16; N, 8.78. Found: C, 50.88; H, 3.23;
N, 8.61%.
4.1.8. N-(5-chlorobenzophenone)-2,2,2-trifluoroacetimidoyl
References
ciprofloxacin (5f)
Yellow-brownish solid; mp: 198–200 8C, IR KBr (n
max, cmÀ1):
3430 (–COOH), 2925–3056 (C–H aromatic), 2889–2788 (CH-
aliphatic), 1760, 1727 (C55O), 1630, 1587 (C55N, C55C). 19F NMR
[1] (a) G.A. Olah, R.D. Chambers, G.K.S. Prakash (Eds.), Synthetic Fluorine Chemistry,
Wiley, New York, 1992;
(b) I. Ojima, J.R. McCarthy, J.T. Welch, Biomedical Frontiers of Fluorine Chemistry,
American Chemical Society, Washington, DC, 1996;
(DMSO-d6, 282 MHz);
d
(ppm): À125.29 (1F, s), À73.85(3F, CF3, s).
(d) T. Hiyama, Organofluorine Compounds, Springer, Berlin, 2001.

268
A. Darehkordi et al. / Journal of Fluorine Chemistry 132 (2011) 263–268
[2] (a) J. Fried, E.F. Sabo, J. Am. Chem. Soc. 76 (1954) 1455–1456;
[16] S. Schaefler, J. Clin. Microbiol. 27 (1989) 335–336.
[17] D.C. Hooper, Lancet Infect. Dis. 2 (2002) 530–538.
[18] D.T. Bearden, L.H. Danziger, Pharmacotherapy 21 (2001) 224S–232S.
[19] L.J.V. Piddock, Drugs 58 (Suppl. 2) (1999) 11–18.
[20] T.D. Gootz, K.E. Brighty, in: Andriole, V.T. (Ed.), The Quinolones, 2nd ed., Academic,
San Diego, 1998, pp. 29–80.
(b) J. Begue, D. Bonnet-Delpon, Tetrahedron 47 (1991) 3207–3258;
(c) B. Imperiali, R.H. Abeles, Biochemistry 25 (1986) 3767;
(d) P.R. Bernstein, B.C. Gomes, B.J. Kosmider, E.P. Vacek, J.C. Williams, J. Med.
Chem. 38 (1995) 212–215;
(e) J.T. Welch, Tetrahedron 43 (1987) 3123–3197.
[3] M. Torok, M. Abid, S.C. Mhadgut, B. Torok, Biochemistry 45 (2006) 5377–5383.
[4] (a) G.K.S. Prakash, A. Yudin, Chem. Rev. 97 (1997) 757–786;
(b) G.K.S. Prakash, J.B. Hu, G.A. Olah, J. Fluorine Chem. 112 (2001) 355–360;
(c) G.K.S. Prakash, M. Mandal, G.A. Olah, Angew. Chem. Int. Ed. 40 (2001) 589–590;
(d) B. Torok, G.K.S. Prakash, Adv. Synth. Catal. 345 (2003) 165–168;
(e) B. Torok, M. Abid, G. London, J. Esquibel, M. Torok, S.C. Mhadgut, P. Yan, G.K.S.
Prakash, Angew. Chem. Int. Ed. 44 (2005) 3086–3089.
[21] P.M. Hershberger, T.P. Demuth Jr., Adv. Exp. Med. Biol. 456 (1998) 239.
[22] (a) G. Resnati, V.A. Soloshonok, Tetrahedron 52 (1) (1996) 319–330;
(b) R.E. Banks, J.C. Tatlow, B.E. Smart, Organofluorine Chemistry: Principles and
Commercial Applications, Plenum Press, New York, 1994;
(c) G.K.S.A.K. Prakash, Chem. Rev. 97 (1997) 757–786.
[23] (a) T. Kitazume, J.T. Lin, T. Yamamoto, T. Yamazaki, J. Am. Chem. Soc. 113 (1991)
8573–8575;
[5] M.R. Barbachyn, S.J. Brickner, G.J. Cleek, R.C. Gadwood, K.C. Greg, S.K. Hendges,
D.K. Hutchinson, P.R. Manninen, K. Munesada, R.C. Thomas, L.M. Thomasco, D.S.
Toops, D.A. Ulanowicz, in: Bentley, P.H., O’Hanlon, P.J. (Eds.), Anti-infectives:
Recent Advances in Chemistry and Structure–activity Relationships, The Royal
Society of Chemistry, Hartnolls: Bodmin., 1997, pp. 15–26.
[6] C.W. Ford, J.C. Hamel, D. Stapert, J.K. Moerman, D.K. Hutchinson, M.R. Barbachyn,
G.E. Zurenko, Trends Microbiol. 5 (1997) 196–200.
[7] R.C. Gadwood, D.A. Shinabarger, Annual Reports in Medicinal Chemistry, Aca-
demic, San Diego, 2000, pp. 135–143.
[8] G.E. Zurenko, J.K. Gibson, D.L. Shinabarger, P.A. Aristoff, C.W. Ford, W.G. Tarpley,
Curr. Opin. Pharmacol. 1 (2001) 470–476.
[9] M.F. Gordeev, Curr. Opin. Drug Disc. Dev. 4 (2001) 450–461.
[10] D. Clemett, A. Markham, Drugs 59 (2000) 815–827.
(b) J.T. Welch, ACS Symposium Series, vol. 456, American Chemical Society,
Washington, DC, 1991;
(c) R. Filler, Y. Kobayashi, L.M. Yagupolskii, Biomedical Aspects of Fluorine
Chemistry, Elsevier, Amsterdam, 1993;
(d) J.T. Welch, S. Eswarakrishnan, Fluorine in Bioorganic Chemistry, Wiley,
Chichester, 1991.
[24] Y. Asahina, T. Ishizaki, S. Suzue, Prog. Drug Res. 38 (1992) 57–106.
[25] J.M. Domagala, J. Antimicrob. Chemother. 33 (1994) 685–706.
[26] G.S. Tillotson, J.M. Blondeau, in: Adam, D., Finch, R.G., Hunter, P.A. (Eds.), Moxi-
floxacin in Practice, Maxim Medical, 1999, pp. 91–101.
[27] M.F. Gordeev, C. Hackbarth, M.R. Barbachyn, L.S. Banitt, J.R. Gage, G.W. Luehr, M.
Gomez, J. Trias, S.E. Morin, G.E. Zurenko, C.N. Parker, J.M. Evans, R.J. White, D.V.
Patel, Bioorg, Med. Chem. Lett. 13 (2003) 4213–4216.
[11] H.B. Fung, H.L. Kirschenbaum, B.O. Ojofeitimi, Clin. Ther. 23 (2001) 356–391.
[12] V.T. Andriole, Drugs 58 (Suppl. 2) (1999) 1–5.
[28] A. Foroumadi, M. Oboudiat, S. Emami, A. Karimollah, L. Saghaee, M.H. Moshafid, A.
Shafieea, Bioorg. Med. Chem. 14 (2006) 3421–3427.
[13] S. Emami, A. Shafiee, A. Foroumadi, Mini-Rev. Med. Chem. 6 (2006) 375–386.
[14] H.M. Blumberg, D. Rimland, D.J. Carroll, P. Terry, I.K. Wachsmuth, J. Infect. Dis. 163
(1991) 1279–1285.
[15] L.R. Peterson, J.N. Quick, B. Jensen, S. Homann, S. Johnson, J. Tenquist, Arch. Intern.
Med. 150 (1990), pp. 2151–2155.
[29] (a) K. Tamura, K. Uneyama, H. Mizukami, K. Maeda, H. Watanabe, J. Org. Chem. 58
(1993) 32–35;
(b) A. Darehkordi, H. Khabazzadeh, K. Saidi, J. Fluorine Chem. 126 (2005) 1140–
1143.
[30] K. Saidi, A. Darehkordi, J. Fluorine Chem. 105 (2000) 49–51.