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than that of Clinafloxacin. These implied that this new type of cli-
nafloxacin triazoles should be potential as anti-MRSA agents.
In conclusion, a series of new clinafloxacin triazole hybrids were
successfully synthesized from commercially available substituted
benzene, triazole and Clinafloxacin. Their structures were
confirmed by 1H NMR, 13C NMR, IR, MS and HRMS spectra. The
in vitro antibacterial and antifungal evaluation showed that most
of the synthesized clinafloxacin triazole compounds could
effectively inhibit the growth of all tested bacteria and fungi
including methicillin-resistant S. aureus, and some clinafloxacin
triazoles displayed better antimicrobial activities in comparison
with their positive control. Particularly, clinafloxacin triazole 5g
with a 2,4-difluorophenyl group gave the most potent antibacterial
ˇ
13. Škugor, M. M.; Štimac, V.; Palej, I.; Lugaric´, Ð.; Paljetak, H. C.; Filic´, D.; Modric´,
´
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and antifungal efficacy (MIC = 0.25–1 lg/mL) among these tested
compounds including the standard drugs. Importantly, 4-fluoro-
phenyl compound 5d and 2,4-difluorophenyl triazole 5g showed
the strongest activity against drug-resistant MRSA (MIC =
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21. Experimental: Melting points were determined on X-6 melting point apparatus
and were uncorrected. IR spectra were determined on a Bio-Rad FTS-185
0.25
(MIC = 1
l
g/mL), which were superior to their precursor Clinafloxacin
g/mL). These results suggested that this type of clina-
l
floxacin triazole hybrids should have great potential as new type
of antibacterial agents to treat the drug-resistant bacteria infec-
tion. Moreover, these results also confirmed that the hybrid of anti-
bacterial Clinafloxacin with antifungal triazole moiety could not
only remarkably enhance the antimicrobial activity, but also
broaden the antimicrobial spectrum. Further researches, including
the in vivo bioactive evaluation along with toxicity investigation,
the effect factors on antimicrobial activities such as other hetero-
cyclic azole rings (benzotriazole, imidazole, benzimidazole and
their derivatives) and other substituents on skeleton quinolone
ring as well as their corresponding metal complexes and salts
(hydrochloride, nitrate, acetate and lactate) are now in progress.
All these will be discussed in the future paper.
spectrophotometer in the range of 400–4000 cmÀ1 1H NMR and 13C NMR spectra
.
were recorded on a Bruker AV 300 spectrometer using TMS as an internal
standard. The mass spectra were confirmed on FINIGAN TRACE GC/MS and
HRMS. Some synthetic data were given for some representative compounds.
Synthesis of [1-((2-p-tolyloxiran-2-yl)methyl)-1H-1,2,4-triazole] (4a). To
a
solution of 3a (1.00 g, 5 mmol) in toluene (55 mL) was added
trimethylsulfoxonium iodide (2.20 g, 10 mmol) followed by the addition of
20% sodium hydroxide solution (1.89 mL). The reaction mixture was then heated
at 60 °C for 6 h. After the reaction was completed (monitored by TLC, ethyl
acetate/light petroleum (1/1, V/V)), it was diluted with ethyl acetate (3 Â 20 mL).
The organic layer was washed with water (2 Â 30 mL), brine (20 mL), dried over
anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure
and the residue was purified by flash silica gel column eluting with ethyl acetate/
light petroleum (1/1, V/V) to give 4a as light yellow solid (0.44 g). Yield: 41%, mp:
52–53 °C; 1H NMR (300 MHz, CDCl3): d 8.06 (s, 1H, Tri 3-H), 7.91 (s, 1H, Tri 5-H),
Acknowledgments
This work was partially supported by National Natural
Science Foundation of China [No. 21172181, 81250110089 (The
Research Fellowship for International Young Scientists from
International (Regional) Cooperation and Exchange Program)], the
key program from Natural Science Foundation of Chongqing
(CSTC2012jjB10026), the scientific and technological project in
Chongqing (CSTC, 2011AB5001), the Specialized Research Fund for
the Doctoral Program of Higher Education of China (SRFDP
20110182110007) and the Research Funds for the Central
Universities (XDJK2011D007, XDJK2012B026).
7.22 (d, J = 6 Hz, 2H, Ph 2, 6-H), 7.15 (d, J = 6 Hz, 2H, Ph 3, 5-H), 4.61–4.81 (dd, J1
=
45 Hz, J2 = 15 Hz, Tri-CH2), 2.83 (s, 2H, OCH2), 2.33 (s, 3H, Ph-CH3) ppm; 13C NMR
(75 MHz, CDCl3): d 151.8, 144.4, 138.3, 132.9, 129.5, 125.7, 58.6, 53.6, 53.4,
21.1 ppm; MS (m/z): 238 [M+Na]+; HRMS (TOF) calcd for C12H13N3O: [M]+,
215.2511; found, 215.2519. Synthesis of [8-Chloro-1-cyclopropyl-7-(3-(2-(2,4-
difluorophenyl) -2-hydroxy -3-(1H–1,2,4-triazol-1-yl)propylamino)pyrrolidin-
1-yl) -6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid] (5 g). To
a
solution of 4 g (0.323 g, 1.5 mmol) in ethanol (20 mL) was added clinafloxacin
(0.547 g, 1.5 mmol) followed by the addition of sodium bicarbonate (0.126 g,
1.5 mmol). The reaction mixture was stirred at 70 °C for 18 h. After the reaction
was completed (monitored by TLC, methanol/dichloromethane (1/100, V/V)),
the reaction was cooled to room temperature and treated with formic acid to
adjust the pH value to 5.5–6.5. After the ethanol was removed under reduced
pressure, the mixture was purified by flash silica gel column eluting with
methanol/dichloromethane (1/100, V/V) to give the pure target compound 5 g as
white solid (0.322 g). Yield: 36%, mp: 210–211 °C; IR (KBr) : 3419, 3044, 2964,
2924, 2849, 2822, 2725, 1729, 1629, 1614, 1500, 1446, 1382, 1349, 1259, 1136,
References and notes
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;
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