A new efficient route to 7-aryl-6-fluoro-8-nitroquinolones as potent antibacterial agents

Article abstract of DOI:10.1016/j.ejmech.2014.08.065

A series of 7-aryl-6-fluoro-8-nitroquinolones (6a-e) were synthesized through a novel, simple and clean synthetic procedure, through a Suzuki-Miyaura reaction. The target compounds were evaluated in vitro for their antimicrobial properties against bacterial and fungal strains. All of them showed antibacterial activity higher than the activity of ciprofloxacin, both towards Gram positive Bacillus subtilis and Staphylococcus aureus, and Gram negative Haemophilus influenzae strains. Compound 6d, containing the trisubstituted 7-aryl moiety, emerged as the most active quinolone derivative with MIC values ranging from 0.00007 μg/mL to 0.015 μg/mL.

Full text of DOI:10.1016/j.ejmech.2014.08.065

European Journal of Medicinal Chemistry 86 (2014) 364e367
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Preliminary communication
A new efficient route to 7-aryl-6-fluoro-8-nitroquinolones as potent
antibacterial agents
Salah A. Al-Trawneh a, Mustafa M. El-Abadelah b, Mohammad M. Al-Abadleh c,
,
*
Franca Zani d, Matteo Incerti d, Paola Vicini d
a Chemistry Department, Faculty of Science, Mu'tah University, Karak 61710, Jordan
b Chemistry Department, Faculty of Science, The University of Jordan, Amman 11942, Jordan
c College of Pharmacy, Taibah University, Al Madinah 41477, Saudi Arabia
d
ꢀ
Dipartimento di Farmacia, Universita degli Studi di Parma, Parco Area delle Scienze 27/A, Parma 43124, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of 7-aryl-6-fluoro-8-nitroquinolones (6aee) were synthesized through a novel, simple and clean
synthetic procedure, through a SuzukieMiyaura reaction. The target compounds were evaluated in vitro
for their antimicrobial properties against bacterial and fungal strains. All of them showed antibacterial
activity higher than the activity of ciprofloxacin, both towards Gram positive Bacillus subtilis and
Staphylococcus aureus, and Gram negative Haemophilus influenzae strains. Compound 6d, containing the
trisubstituted 7-aryl moiety, emerged as the most active quinolone derivative with MIC values ranging
Received 2 April 2014
Received in revised form
22 August 2014
Accepted 25 August 2014
Available online 26 August 2014
from 0.00007 mg/mL to 0.015 mg/mL.
Keywords:
© 2014 Elsevier Masson SAS. All rights reserved.
7-Aryl-6-fluoro-8-nitroquinolones
7-Aryl-1-cyclopropyl-6-fluoro-8-nitro-4-
oxo-1,4-dihydroquinoline-3-carboxylic
acids
SuzukieMiyaura reaction
Antibacterial activity
1. Introduction
tolerance for a broad range of functional groups (Scheme 2). The
inorganic boron-containing byproducts are less toxic than those of
organostannanes [4], and they can be readily removed by a simple
workup procedure. By contrast, the complete removal of tin-
containing byproducts is a well-recognized problem, and the
presence of even traces of these compounds in organic products
must be avoided. We also report herein on the antimicrobial
screening of 7-aryl-8-nitro-4-oxo-quinoline-3-carboxylic acids
(6aee, Scheme 2). The results will be compared with those of the
tetracyclic fluoroquinolones (4aee) previously published by us [3]
and of the 7-phenyl analog, unsubstituted at C-8 locus, that was
patented as antibacterial agent [5].
Metal-catalyzed carbonecarbon cross-coupling reactions have
become broadly applied in organic syntheses. Several important
named reactions, such as Stille [1] and Suzuki [2] reactions, have
been developed using this chemistry. Concerns over hazardous
waste generated during the catalytic reaction led to increasing
attention on the use of less toxic and environmentally compatible
materials in the design of synthetic methods.
Quite recently, we have employed the Stille reaction in the
arylation of 7-chloro-8-nitroquinolone 1 for obtainment of 7-aryl-
8-nitroquinolones 2 that were then cyclized and hydrolyzed into
the corresponding novel tetracyclic fluoroquinolones 3 and 4 [3]
(Scheme 1). Compounds 4aee, possessing high antibacterial and
anti-cancer activity, are devoid of cytotoxicity against normal cells
and thus have promising therapeutic potentials [3].
2. Results and discussion
2.1. Chemistry
Herein we sought to adopt the SuzukieMiyaura reaction as an
alternative synthetic route towards 2, precursors of 4, utilizing
readily available organoboron compounds
Ethyl
7-chloro-1-cyclopropyl-6-fluoro-8-nitro-4-oxo-1,4-
5 that also have
dihydroquinoline-3-carboxylate (1), prepared according to a re-
ported methodology [6], was utilized as substrate in the Suzu-
kieMiyaura reaction towards the synthesis of the target
compounds 6aee (Scheme 2). Thus, direct interaction of compound
* Corresponding author.
E-mail addresses: pvicini@ipruniv.cce.unipr.it, paola.vicini@unipr.it (P. Vicini).
http://dx.doi.org/10.1016/j.ejmech.2014.08.065
0223-5234/© 2014 Elsevier Masson SAS. All rights reserved.

S.A. Al-Trawneh et al. / European Journal of Medicinal Chemistry 86 (2014) 364e367
365
O
N
O
CO2R
F
O
N
SnMe3
CO2Et
CO2Et
F
F
(i)
X
+
(ii)
X
N
Cl
NH
X
X
NO2
NO2
R1
R1
R1
X
2a-e
1
X
3a-e (R = Et)
4a-e (R = H)
(iii)
(for X and R1 / 4a-e, see Scheme 2)
(i) Pd(OAc)2, CsF, DMF, 70-100°C; (ii) P(OEt)3, 200°C (MW); (iii) 10% aq. HCl, EtOH, reflux.
Scheme 1. Synthesis of tetracyclic fluoroquinolones 3 aee and 4aee.
both Gram positive Bacillus subtilis and Staphylococcus aureus, and
Gram negative Haemophilus influenzae strains.
In particular, the most active derivative 6d, 4-methoxy-3,5-
dimethylphenyl substituted in C-7 position of the fluoroquinolone
scaffold, showed remarkable inhibition at 0.00007
mg/mL, 0.003 mg/
mL and 0.015 g/mL, respectively. The minimum inhibitory con-
m
centrations (MICs) determined towards the same strains for
phenyl-6a and 4-substituted phenyl-quinolones 6bec and 6e, car-
rying methyl, methoxy or fluorine substituent, were 0.015e0.03
mg/
mL, 0.15 g/mL and 0.03e0.15 g/mL. In general, these compounds
m
m
revealed higher antibacterial activity than ciprofloxacin; especially
6d was many folds more potent than the reference drug against the
two Gram positive bacteria and H. influenzae. B. subtilis was found
to be the most sensitive among the tested microorganism. A good
inhibitory effect was also exhibited on the growth of Gram negative
Escherichia coli by 6a, 6b and 6e at 3 mg/mL and by 6ced at 25 mg/
mL, but lower than that of ciprofloxacin. Interestingly, with the only
exception of compound 6a against H. influenzae and of 6e against
Gram positive bacteria, the novel 7-aryl-8-nitrofluoroquinolones
were more active than their corresponding tetracyclic analogs
4aee, where a fused ring is present as a bridge between the critical
7 and 8 positions of the fluoroquinolone scaffold. Very strong dif-
ferences in effectiveness were detected for 6b towards S. aureus and
H. influenzae and for 6d towards all the sensitive bacteria. However,
compound 6a was less active than the corresponding quinolone
Scheme
2. Synthesis
of
7-aryl-1-cyclopropyl-6-fluoro-8-nitro-4-oxo-1,4-
dihydroquinoline-3-carboxylic acids 6aee.
1 with the proper arylboronic acid 5aee, catalyzed by bis(-
triphenylphosphine)palladium (II) and CsF, produced the corre-
sponding 7-arylderivatives 2aee in good yields. Acid-catalyzed
hydrolysis of the latter esters delivered the corresponding 7-
arylquinoline-3-carboxylic acids 6aee in high yields (Scheme 2).
The new compounds 6aee were characterized by elemental anal-
ysis, MS and NMR spectral data; these data, detailed in the Exper-
imental part, are consistent with the assigned structures. Thus, the
mass spectra display the correct molecular ion peaks for which the
measured high resolution (HRMS-ESI) data are in good agreement
with the calculated values. DEPT and 2D (COSY, HMBC, HMQC)
experiments showed correlations that helped in the 1H and 13C
signal assignments to the different carbons and their attached and/
or neighboring hydrogens (see also Supplementary material).
unsubstituted in C-8 position (MIC ꢀ 0.015e0.062
m
g/mL for
Staphylococci and 0.062
mg/mL for E. coli) [5]. No literature data are
Table 1
In vitro antibacterial activity of 7-aryl-1-cyclopropyl-6-fluoro-8-nitro-4-oxo-1,4-
dihydroquinoline-3-carboxylic acids 6aee (minimum inhibitory concentration in
mg/mL).
Compound
Microorganism
Bacillus
subtilis
ATCC 6633 ATCC 6538
Staphylococcus
aureus
Escherichia Haemophilus
coli influenzae
ATCC 8739 ATCC 19418
2.2. Antimicrobial activity
6a
4a [3]
6b
4b [3]
6c
4c [3]
6d
4d [3]
6e
4e [3]
0.015
0.015
0.015
0.07
0.03
0.07
0.00007
0.07
0.015
0.003
0.15
0.3
0.15
>100
0.15
3
0.003
6
0.15
0.07
0.3
3
50
3
>100
25
>100
25
>100
3
25
0.15
0.03
0.03
>100
0.15
1.5
0.015
6
0.07
0.15
0.15
The in vitro antimicrobial activity of the newly synthesized 7-
aryl-1-cyclopropyl-6-fluoro-8-nitro-4-oxo-1,4-dihydroquinoline-
3-carboxylic acids, 6aee, was detected against four strains of bac-
teria and three strains of fungi.
The results of antibacterial testing are summarized in Table 1,
together with those of the corresponding tetracyclic fluo-
roquinolones 4aee [3], here reported for a useful comparison. All
new compounds exhibited excellent antibacterial activity, against
Ciprofloxacin 0.03
0.015

366
S.A. Al-Trawneh et al. / European Journal of Medicinal Chemistry 86 (2014) 364e367
available to make comparison between the most potent 6d and the
corresponding quinolone unsubstituted in C-8 position.
As concerns antifungal properties, all compounds showed no
activity against Saccharomyces cerevisiae, Candida tropicalis and
reaction mixture was heated at 100 ꢁC under nitrogen atmosphere
for 24 h. The resulting solution was then cooled to rt and quenched
with water (10 mL), whereby a black gummy precipitate was ob-
tained. The latter product was dissolved in CHCl3 and filtered so as
to remove the insoluble matter. The filtrate was dried over anhy-
drous Na2SO4 and evaporated under reduced pressure to give a
brown residue. This crude product was purified by column chro-
matography using silica gel and eluting with chloroform/ethyl ac-
etate (1:1, v/v) (Scheme 2). Yields ranged from 65 to 70%. The
melting points and spectral data of the title compounds (2aee),
thus prepared, were identical to those recently reported [3] using
the Stille-coupling procedure.
Aspergillus niger fungal strains up to the concentration of 100
mL, compared to reference miconazole having MICs of 12 g/mL,
g/mL and 3 g/mL, respectively (data not shown).
mg/
m
6
m
m
3. Conclusion
In summary, we have developed a convenient method to syn-
thesize
7-aryl-1-cyclopropyl-6-fluoro-8-nitro-4-oxo-1,4-
dihydroquinoline-3-carboxylic acids through SuzukieMiyaura re-
action. All of the synthesized compounds show very interesting and
broad spectrum antibacterial properties and derivative 6d shows
4.1.3. General procedure for the synthesis of 7-aryl-1-cyclopropyl-
6-fluoro-8-nitro-4-oxo-1,4-dihydroquinoline-3-carboxylic acids
(6aee)
the most potent levels of activity with MIC values up to 0.00007 mg/
mL against B. subtilis. These compounds exhibit, generally, better
inhibition than the analogous antibacterial tetracyclic fluo-
roquinolones and activity superior to that of ciprofloxacin against
B. subtilis, S. aureus and H. influenzae strains. Despite the small
number of synthesized compounds does not allow to discuss
structureeactivity relationship, it can be observed that the pres-
ence of 4-methoxy-3,5-dimethylphenyl moiety in derivative 6d
strongly increases the antimicrobial activity, relative to the non-
substituted and 4-phenyl substituted analogues. 4-Methoxy-3,5-
dimethylphenyl-6-fluoro-8-nitroquinolone 6d can be considered
a lead compound worthy of further structural optimization and
development as potential antibacterial agent.
A suspension of the suitable ester (2aee) (1 mmol) in 10% aq.
HCl (10 mL) and ethanol (12 mL) was refluxed for 30e36 h. The
solvents were evaporated in vacuo from the reaction mixture and
the residual solid product was soaked with methanol (3e5 mL),
collected by suction filtration and recrystallized from ethanol.
4.1.3.1. 1-Cyclopropyl-6-fluoro-8-nitro-4-oxo-7-phenyl-1,4-
dihydroquinoline-3-carboxylic
acid
(6a). Yield
86%;
mp
299e300 ꢁC. Anal. Calcd for C19H13FN2O5 (368.32): C, 61.96; H, 3.56;
N, 7.61. Found: C, 61.68; H, 3.48; N, 7.42. HRMS ((þ)-ESI): m/
z ¼ 369.08822 (calcd. 369.08813 for C19H14FN2O5, [MþH]þ);
391.07001 (calcd. 391.07007 for C19H13FN2O5Na, [MþNa]þ). 1H
NMR (300 MHz, DMSO-d6):
d
¼ 0.97 (m, 2H) and 1.12 (m, 2H) (H2-
4. Experimental
20/H2-30), 3.72 (m, 1H, H-10), 7.37 (m, 2H, H-200/H-600),7.52 (m, 3H, H-
300 þ H-400 þ H-500), 8.37 (d, 3JHeF ¼ 8.4 Hz,1H, H-5), 8.83 (s,1H, H-2),
4.1. Chemistry
13.89 (br s, 1H, CO2H). 13C NMR (75 MHz, DMSO-d6):
d
¼ 11.0 (C-20/
C-30), 39.7 (C-30),109.3 (C-3),114.7 (d, 2JCeF ¼ 24.8 Hz, C-5),129.1 (C-
200/C-600), 129.2 (C-300/C-500), 129.4 (d, 3JCeF ¼ 5.1 Hz, C-4a), 129.8 (C-
Melting points (uncorrected) were determined on a Stuart sci-
entific melting point apparatus in open capillary tubes (AK Scien-
tific, Inc., USA). Silica gel for column chromatography was
purchased from MachereyeNagel GmbH & Co. 1H and 13C NMR
spectra were recorded on a 300 MHz spectrometer (Bruker DPX-
300) with TMS as the internal standard. Chemical shifts are
2
100), 130.4 (C-400), 130.5 (C-8a), 131.1 (d, JCeF ¼ 23.9 Hz, C-7), 140.6
3
(d, JCeF ¼ 1.4 Hz, C-8), 153.4 (C-2), 156.1 (d, 1JCeF ¼ 247 Hz, C-6),
164.9 (CO2H), 175.8 (d, C-4).
4.1.3.2. 1-Cyclopropyl-6-fluoro-7-(4-methylphenyl)-8-nitro-4-oxo-
1,4-dihydroquinoline-3-carboxylic acid (6b). Yield 88%; mp
287e288 ꢁC. Anal. Calcd for C20H15FN2O5 (382.34): C, 62.83; H, 3.95;
N, 7.33. Found: C, 62.94; H, 4.08; N, 7.21. HRMS ((þ)-ESI): m/
expressed in
d
units; 1He1H, HeF and CeF coupling constants are
given in Hertz. Electron-impact mass spectra (EIMS) were obtained
using a Finnegan MAT TSQ-70 spectrometer at 70 eV; ion source
temperature 200 ꢁC. High resolution mass spectra (HRMS) were
measured in negative ion mode for the acids 6aee by electrospray
ionization (ESI) technique on a Bruker APEX-2 instrument. The
samples were dissolved in acetonitrile, diluted in spray solution
(methanol/water 1:1 v/v þ 0.1% formic acid) and infused using a
z
¼
383.10376 (calcd.383.10378 for
C
20H16FN2O5, [MþH]þ);
405.08577 (calcd.405.08572 for C20H15FN2O5Na, [MþNa]þ). 1H
NMR (300 MHz, DMSO-d6):
d
¼ 0.97 (m, 2H) and 1.13 (m, 2H) (H2-
20/H2-30), 2.36 (s, 3H, CH3), 3.72 (m, 1H, H-10), 7.24 (d, J ¼ 8 Hz, 2H,
H-200/H-600), 7.32 (d, J ¼ 8 Hz, 2H, H-300/H-500), 8.36 (d, 3JHeF ¼ 8.5 Hz,
1H, H-5), 8.83 (s, 1H, H-2), 13.90 (br s, 1H, CO2H). 13C NMR (75 MHz,
syringe pump with a flow rate of 2 mL/min. External calibration was
conducted using Arginine cluster in a mass range m/z 175e871.
Elemental analyses were performed on a Euro Vector Elemental
Analyzer (EA 3000 A).
DMSO-d6):
d
¼ 11.0 (C-20/C-30), 21.4 (C(400)-CH3), 39.7 (C-10), 109.3
(C-3), 114.5 (d, 2JCeF ¼ 24.8 Hz, C-5), 126.3 (C-100), 129.0 (C-200/C-600),
3
129.2 (d, JCeF
¼
5.8 Hz,C-4a), 129.7 (C-300/C-500), 130.5 (d,
2JCeF ¼ 22.8 Hz, C-7), 140.1 (C-400), 141.9 (C-8), 153.3 (C-2), 156.3 (d,
1JCeF ¼ 248 Hz, C-6), 165.0 (CO2H), 175.8 (C-4).
4.1.1. Ethyl 7-chloro-1-cyclopropyl-6-fluoro-8-nitro-4-oxo-1,4-
dihydroquinoline-3-carboxylate (1)
This compound was prepared from 2,4-dichloro-5-fluoro-3-
nitrobenzoic acid and ethyl 3-(N,N-dimethylamino)acrylate, ac-
cording to the literature procedure [6].
4.1.3.3. 1-Cyclopropyl-6-fluoro-7-(4-methoxyphenyl)-8-nitro-4-oxo-
1,4-dihydroquinoline-3-carboxylic acid (6c). Yield 83%; mp
318e319 ꢁC(dec.). Anal. Calcd for C20H15FN2O6 (398.34): C, 60.30; H,
3.80; N, 7.03. Found: C, 60.12; H, 3.63; N, 6.88. HRMS ((þ)-ESI): m/
z ¼ 399.09848. (calcd. 399.09869 for C20H16FN2O6, [MþH]þ). 1H
4.1.2. General procedure (Suzuki-coupling) for the synthesis of ethyl
7-aryl-1-cyclopropyl-6-fluoro-8-nitro-4-oxo-1,4-dihydroquinoline-
3-carboxylates (2aee)
To a stirred solution of compound 1 (0.5 g, 1.4 mmol) in DMF
(4 mL) was successively added the proper arylboronic acid 5aee
(0.22 g, 1.8 mmol), bis(triphenylphosphine)palladium(II) chloride
(0.1 g, 0.14 mmol) and cesium fluoride (0.21 g, 1.4 mmol). The
NMR (300 MHz, CDCl3):
d
¼ 1.08 (m, 2H) and 1.18 (m, 2H) (H2-20/H2-
30), 3.76 (m, 1H, H-10), 3.85 (s, 3H, C(400) eOCH3), 7.00 (d, J ¼ 8.7 Hz,
2H, H-300/H-500),7.24 (d, J ¼ 8.7 Hz, 2H, H-200/H-600), 8.40 (d,
3JHeF ¼ 8.2 Hz, 1H, H-5), 8.93 (s, 1H, H-2), 13.94 (s, 1H, CO2H). 13
C
NMR (75 MHz, CDCl3):
d
¼ 11.2 (C-20/C-30), 38.9 (C-10), 55.4 (C(400)
eOCH3), 109.5 (C-3), 114.5 (C-300/C-500), 114.7 (d, 2JCeF ¼ 25.2 Hz, C-

S.A. Al-Trawneh et al. / European Journal of Medicinal Chemistry 86 (2014) 364e367
367
3
5), 120.1 (C-100), 128.5 (d, JCeF ¼ 5.2 Hz, C-4a), 130.0 (C-200/C-600),
substances, respectively. DMSO was loaded as negative control. The
samples containing bacteria were incubated at 37 ꢁC for 24 h and
the ones containing fungi at 30 ꢁC for 48 h. The lowest concen-
tration of compound that showed inhibition of microbial growth
was registered as the minimum inhibitory concentration value
131.0 (d, 2JCeF ¼ 21.8 Hz, C-7),131.7 (C-8a),142.1 (d, 3JCeF ¼ 1.4 Hz, C-
1
8), 151.7 (C-2), 156.8 (d, JCeF ¼ 251 Hz, C-6), 161.0 (C-400), 165.2
(CO2H), 176.2 (C-4).
4.1.3.4. 1-Cyclopropyl-6-fluoro-7-(4-methoxy-3,5-dimethylphenyl)-
(MIC, mg/mL).
8-nitro-4-oxo-1,4-dihydroquinoline-3-carboxylic
acid
(6d).
Each experiment has been done in triplicate and results were
confirmed by at least three independent experiments.
Yield 85%; mp 308e303 ꢁC. (dec.). Anal. Calcd for C22H19FN2O6
(426.39): C, 61.97; H, 4.49; N, 6.57. Found: C, 62.05; H, 4.61; N, 6.39.
HRMS ((þ)-ESI): m/z
¼
427.13030 (calcd. 427.12999 for
Acknowledgments
C
C
22H20FN2O6, [MþH]þ); 449.11235 (calcd. 449.11194 for
22H19FN2O6Na, [MþNa]þ). 1H NMR (300 MHz, DMSO-d6):
¼ 1.02
d
We wish to thank the Deanship of Scientific Research at The
University of Jordan, Amman, Jordan for financial support.
(m, 2H) and 1.16 (m, 2H) (H2-20/H2-30), 2.28 (s, 6H, C (300)-CH3/C(500)
eCH3), 3.72 (m, 1H, H-10), 3.76 (s, 3H, C(400) eOCH3), 7.06 (s, 2H, H-
200/H-600), 8.40 (d, 3JHeF ¼ 8.3 Hz,1H, H-5), 8.87 (s,1H, H-2), 14.02 (br
s, 1H, CO2H/exchangeable with D2O). 13C NMR (75 MHz, DMSO-d6):
Appendix A. Supplementary data
d
¼ 11.0 (C-20/C-30), 16.3 (s, C (300) eCH3/C (500) eCH3), 39.7 (C-10),
59.9 (C(400) eOCH3), 109.3 (C-3), 114.4 (d, 2JCeF ¼ 24.8 Hz, C-5), 124.2
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.ejmech.2014.08.065.
3
(C-100), 128.9 (d, JCeF ¼ 6.8 Hz, C-4a), 129.5 (C-200/C-600), 130.9 (d,
3JCeF ¼ 2.8 Hz, C-8a), 131.0 (d, JCeF ¼ 23.3 Hz, C-7), 131.5 (C-300/C-
2
500), 142.0 (C-8), 153.3 (C-2), 156.1 (d, 1JCeF ¼ 250 Hz, C-6), 158.3 (C-
400), 165.0 (CO2H), 175.9 (C-4).
References
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1995;
4.1.3.5. 1-Cyclopropyl-6-fluoro-7-(4-fluorophenyl)-8-nitro-4-oxo-
1,4-dihydroquinoline-3-carboxylic acid (6e). Yield 91%; mp
292e293 ꢁC. (dec). Anal. Calcd for C19H12F2N2O5 (386.31): C, 59.07;
H, 3.13; N, 7.25. Found: C, 58.95; H, 3.02; N, 7.14. HRMS ((þ)-ESI): m/
z ¼ 387.07870 (calcd. 387.07855 for C19H13F2N2O5, [MþH]þ);
409.06062 (calcd. 409.06065 for C19H12F2N2O5Na, [MþNa]þ). 1H
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d
¼ 1.02 (m, 2H) and 1.17 (m, 2H) (H2-
(f) S. Kotha, K. Lahiri, K. Dhurke, Tetrahedron 58 (2002) 9633e9695;
3
20/H2-30), 3.77 (m, 1H, H-10), 7.41 (pseudo t (dd), JHeF ¼ 8.6 Hz,
ꢁ
(g) J. Hassan, M. Sevignon, C. Gozzi, E. Schulz, M. Lemaire, Chem. Rev. 102
(2002) 1359e1469;
JHeH ¼ 8.2 Hz, 2H, H-300/H-500), 7.50 (dd, 4JHeF ¼ 5 Hz, JHeH ¼ 8.2 Hz,
(h) A. Suzuki, H.C. Brown, Organic Syntheses Via Boranes, vol. 3, Aldrich
Chemical Co., Inc., Milwaukee, WI, 2003;
3
2H, H-200/H-600), 8.42 (d, JHeF ¼ 8.4 Hz, 1H, H-5), 8.88 (s, 1H, H-2),
13.94 (br s, 1H, CO2H/exchangeable with D2O). 13C NMR (75 MHz,
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evaluation of tetracyclic fluoroquinolones as antibacterial and anticancer
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[4] For discussions concerning the toxicity of organotin compounds, see: (a) S.J. De
Mora, Tributyltin: Case Study of an Environment Contaminant, Cambridge
University Press, New York, 1996;
DMSO-d6):
d
¼ 11.0 (C-20/C-30), 39.7 (C-10), 109.3 (C-3), 114.7 (d,
2JCeF ¼ 24.6 Hz, C-5), 116.4 (d, 2JCeF ¼ 22.1 Hz, C-300/C-500), 125.4 (d,
3JCeF ¼ 3.6 Hz, C-100), 129.2 (d, JCeF ¼ 7.8 Hz, C-4a), 130.0 (d,
3
2JCeF ¼ 23.7 Hz, C-7), 130.9 (d, JCeF ¼ 2.7 Hz, C-8a), 131.7 (d,
4
3JCeF ¼ 8.6 Hz, C-200/C-600), 142.1 (C-8), 153.4 (C-2), 156.1 (d,
1JCeF ¼ 247 Hz, C-6), 163.4 (d, 1JCeF ¼ 245 Hz, C-400), 164.9 (CO2H),
175.8 (d, 4JCeF ¼ 2 Hz, C-4).
(b) I.J. Boyer, Toxicology 55 (1989) 253e298.
[5] T. Himmler, M. Schriewer, U. Petersen, K. Grohe, I. Haller, R. Endermann,
H. Zeiler, J. Eur. Pat. (1988). DE 3816119 A1 (Chem. Abstr. 1990, 112, 216720).
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Offen. (1987), 3601567 (Chem. Abstr. 1987, 107, 236747);
4.2. Antimicrobial activity
(c) J.P. Sanchez, J.M. Domagala, S.E. Hagen, C.L. Heifetz, M.P. Hutt, J.B. Nichols,
A.K. Trehan, J. Med. Chem. 31 (1988) 983;
(d) R.M. Pulla, C.N. Venkaiah, PTC Int. Appl. (2001). WO 085 692 (Chem. Abstr.
2001, 135, 371649);
(e) Y.M. Al-Hiari, I.S. Al-Mazari, A.K. Shakya, R.M. Darwish, R. Abu-Dahab,
Molecules 12 (2007) 1240e1258;
(f) R.A. Al-Qawasmeh, J.A. Zahra, F. Zani, P. Vicini, R. Boese, M.M. El-Abadelah,
ARKIVOC xii (2009) 322.
The antibacterial and antifungal properties of compounds 6aee
were determined in vitro by the two fold broth dilution method [7].
Bacteria (B. subtilis ATCC 6633 and S. aureus ATCC 6538 Gram
positive strains, E. coli ATCC 8739 and H. influenzae ATCC 19418
Gram negative ones) were cultivated on Mueller Hinton medium,
fungi (C. tropicalis ATCC 1369 and S. cerevisiae ATCC 9763 yeasts and
A. niger ATCC 6275 mould) on Sabouraud dextrose broth. Suspen-
sions of the microorganisms were prepared to inoculate 5$105
bacteria/mL and 1$103 fungi/mL. The compounds were dissolved in
[7] National Committee for Clinical Laboratory Standards (NCCLS) (Wayne, PA): (a)
Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow
Aerobically; Approved Standards M7-A7 and 17th Informational Supplement
M100-S17, 2007, p. 27;
(b) Reference Method for Broth Dilution Antifungal Susceptibility Testing of
Yeasts, Approved Standard M27-A2, 2002, p. 22;
(c) Reference Method for Broth Dilution Antifungal Susceptibility Testing of
Filamentous Fungi, Approved Standard M38-A2, 2002, p. 22.
DMSO and tested at the concentration range of 0.000015e100 mg/
mL. Their activity was compared with that of ciprofloxacin and
miconazole used as reference antibacterial and antifungal