Molecular structures of new ciprofloxacin derivatives

Article abstract of DOI:10.1016/S0022-2860(02)00062-5

Two new derivatives from the ciprofloxacin fluoroquinoline family, 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo- quinoline-3-methylcarbamate and 1-cyclopropyl-7-(4-ethyl-1-piperazinyl)-6-fluoro-1,4-dihydro-(3-oxopyrazolo) [4,3-c]quinoline, were synthesised, tested for antibacterial activity and crystallised. Their molecular and crystal structures were determined. Tests in vitro reveal lower activities than for ciprofloxacin. Characteristic structural features of these compounds are comparable to data for other known fluoroquinolines. The bicyclic quinoline ring is planar in both compounds; the carbamate side chain and five-membered pyrazolo ring are almost coplanar with it. A piperazinyl ring exhibits a chair conformation. In the crystal packing of the carbamate analogue, two C-HO interactions form a dimer. The pyrazolo derivative crystallises as solvate with 1.5 water molecules per quinoline molecule. In its crystal structure donor and acceptor functionalities form dimers, via hydrogen bonds, which are connected into an infinite pattern through hydrogen bonded water molecules.

Full text of DOI:10.1016/S0022-2860(02)00062-5

Journal of Molecular Structure 611 52002) 73±81
www.elsevier.com/locate/molstruc
Molecular structures of new cipro¯oxacin derivatives
 Â
Ï
Zrinka Banic Tomisic , Nedjeljko Kujundzic , Mirjana Bukvic Krajacic ,
Ï Âa
Aleksandar Visnjevac , Biserka Kojic-Prodic
Âa
Ï Âa
b
Âb,
*
Ï
Â
a
Â
PLIVA, Pharmaceutical Industry, Incorporated, Research Division, Prilaz baruna Filipovica 25, HR-10000 Zagreb, Croatia
b
Ï Â
Rudjer Boskovic Institute, P.O. Box 180, Bijenicka 54, HR-10002 Zagreb, Croatia
Received 3 October 2001; revised 28 January 2002; accepted 28 January 2002
Abstract
Two new derivatives from the cipro¯oxacin ¯uoroquinoline family, 7-chloro-1-cyclopropyl-6-¯uoro-1,4-dihydro-4-oxo-
quinoline-3-methylcarbamate and 1-cyclopropyl-7-54-ethyl-1-piperazinyl)-6-¯uoro-1,4-dihydro-53-oxopyrazolo)[4,3-c]quino-
line, were synthesised, tested for antibacterial activity and crystallised. Their molecular and crystal structures were determined.
Tests in vitro reveal lower activities than for cipro¯oxacin. Characteristic structural features of these compounds are compar-
able to data for other known ¯uoroquinolines. The bicyclic quinoline ring is planar in both compounds; the carbamate side chain
and ®ve-membered pyrazolo ring are almost coplanar with it. Apiperazinyl ring exhibits a chair conformation. In the crystal
packing of the carbamate analogue, two C±H´´´O interactions form a dimer. The pyrazolo derivative crystallises as solvate with
1.5 water molecules per quinoline molecule. In its crystal structure donor and acceptor functionalities form dimers, via
hydrogen bonds, which are connected into an in®nite pattern through hydrogen bonded water molecules. q 2002 Elsevier
Science B.V. All rights reserved.
Keywords: Fluoroquinolines; Synthesis; Antimicrobial activity; X-ray structure; Hydrogen bonds; C±H´´´F intramolecular interaction
1. Introduction
and multi-resistant Enterobacteriaceae, the develop-
ment of a new class of antimicrobialsЯuoroquino-
lones was initiated.
The 4-quinolones are a class of highly potent and
orally active broad-spectrum antibacterial agents
[1±3] which originate from a 1,8-naphthyridine
precursorÐnalidixic acid 5Scheme 1), synthesised
in the early 1960s [4]. It was the ®rst clinically used
quinolone antibiotic. Numerous quinolones have been
synthesised since then and many are used as drugs
today. To solve the problem of increasing antimicro-
bial resistance, especially the strong demand for
treating drug-resistant Streptococcus pneumoniae
The development from nalidixic acid 51,8-
naphthyridine core, the ®rst generation) to the second
and the third generations of antimicrobial quinolone
drugs involved basically modi®cations including
piperazine substitution at the 7-position, ¯uorination
at the 6-position and replacement of carbon with
nitrogen at the 8-position 5quinolone core). Nor¯ox-
acin 5Scheme 1) was the ®rst member of the ¯uoro-
quinolone series. Modi®cations such as 1-cyclopropyl
substitution 5cipro¯oxacin, Scheme 1) and 1,8-cycli-
sation 5o¯oxacin, levo¯oxacin) produced the second
generation of ¯uoroquinolones. In the next step,
substitutions on the 6-¯uoro-7-piperazinyl compound
* Corresponding author. Tel.: 1385-1-4680126; fax: 1385-1-
4680245.
 Â
E-mail address: kojic@rudjer.irb.hr 5B. Kojic-Prodic).
0022-2860/02/$ - see front matter q 2002 Elsevier Science B.V. All rights reserved.
PII: S0022-2860502)00062-5

Ï Â
Z.B. Tomisic et al. / Journal of Molecular Structure 611 ;2002) 73±81
74
antimicrobials is the enzyme DNAgyrase, an essential
adenosine triphosphate-hydrolyzing topoisomerase,
inhibiting bacterial DNAreplication and transcription
causingrapid celldeath.ThedrugsdirectlybindtoDNA
via hydrogen bonding to unpaired bases. In spite of the
known molecular target and its interactions with these
drugs, there are still open questions.
The most recent research ®ndings on adverse reac-
tion caused by quinolone antimicrobial agents and
their photomutagenic activity [8] call for more atten-
tion to examine further signi®cant tolerability
problems. In this family of drugs, the most striking
case is trovanw 5trova¯oxacin mesylate) which is
associated with serious liver injuries and can hardly
be used. Quite often quinolones interact with other
drugs such as theophylline and non-steroidal antiin-
¯ammatory drugs producing effects on CNS [9]. So
far, the molecular target or a receptor for such effects
has not been known. Most probably, several mechan-
isms are responsible for effects on CNS and the
problem of tolerability is still unresolved.
As part of an ongoing research project in the search
for new pharmacologically active ¯uoroquinolones, we
report synthesis, antimicrobial tests results and discuss
molecular and crystal structures of two ¯uoroquinoline
derivatives 5Scheme 2): 7-chloro-1-cyclopropyl-6-
¯uoro-1,4-dihydro-4-oxo-quinoline-3-methylcarbamate
1 with the new carbamate functionality at position 3,
and 1-cyclopropyl-7-54-ethyl-1-piperazinyl)-6-¯uoro-
1,4-dihydro-53-oxopyrazolo)[4,3-c]quinoline 5named
Scheme 1. Examples of active quinolones.
produced an improved second generation of ¯uoro-
quinolones 5spar¯oxacin and clina¯oxacin). The
third generation, involving a 7-azabicyclo modi®ca-
tion, yielded moxy¯oxacin and gati¯oxacin in the
quinolone series and trova¯oxacin in the 1,8-
naphthyridine series. Cipro¯oxacin, with the broadest
spectrum of infective indications, is presently the
reference agent for the new series of compounds to
be compared with. Structure±activity relationship
studies [5±7] and the known drug target [3 and the
references therein] have facilitated the development
of new more potent quinolone generations with
broader spectrum activity, better pharmacokinetics,
and good tolerability. The functional target of quinolone
Scheme 2. Synthetic routes.

Ï Â
Z.B. Tomisic et al. / Journal of Molecular Structure 611 ;2002) 73±81
75
Table 1
Crystalographic data, structure solution and re®nement of 1 and 2
Compound
1
2
Formula
Mr
C14H12ClFN2O3
310.71
C38H50OF2N10O5
764.88
Crystal system
Space group
Monoclinic
P21/a
Monoclinic
C2/c
Ê
a 5A)
7.166752)
14.166352)
13.738552)
90.57055)
1394.7455)
4
21.858358)
10.663751)
19.577456)
122.70652)
3839.852)
4
Ê
b 5A)
Ê
c 5A)
b 58)
V 5A )
Ê 3
Z
F000
Dx 5mg m23
640
1624
)
1.480
40.38±46.29
2.656
1.323
40.07±45.74
0.802
u range 58) for cell det.
m 5mm21
)
Crystal form and colour
Crystal size 5mm)
Absorption correction
Total data collected
Unique data
Colourless needle
0:18 £ 0:08 £ 0:07
Psi-scan
Yellow prism
0:20 £ 0:11 £ 0:11
Psi-scan
2954
4027
2840
2192[I . 2\s5I)]
0.0218
3906
2949
Observed data 5criterion)
Rint
0.0222
u
max 58) for data collection
74.15
74.13
Range of h, k, l
Re®nement on
R1 [F0 . 4s 5F0)]
wR2 5F2), all data
S
2 8,8; 217,0; 217,0
F2
2 22.27; 0.13; 224,0
F2
0.0783
0.0477
0.2361
0.1460
1.045
192
1.057
Parameters
Weighting schemea
266
w ˆ 1=‰s2ꢀF02† 1
w ˆ 1=‰s2ꢀF02† 1
ꢀ0:0813P†2 1
1:8779PŠ
0.37, 20.36
helena
ꢀ0:1428P†2 1 1:612PŠ
Ê 23
Max. and min. Dr 5eA
Data reduction programme
)
1.53, 20.45
helena [11]
sir97 [12]
Structure solution programme
Structure re®nement programme
Molecular graphics programme
sir92 [13]
shexl97
platon98
shexl97 [14]
platon98 [15]
P ˆ ꢀF02 1 2Fc2†=3:
a
by IUPAC: 5-cyclopropyl-7-54-ethyl-1-piperazinyl)-
8-¯uoro-2,5-dihydro-pyrazolo[4,3-c]quinoline-3-one)
2 with a fused pyrazolo ring at atoms C3 and C4 of the
quinoline moiety.
1 and 2, including their intermediates, is outlined in
Scheme 2. The compounds synthesised were charac-
terised by elemental CHNS/O analysis, mass spectra,
FT-IR, 1H and 13C NMR spectra 5data not shown).
2.1.1. Preparation of compound 1
Amixture of 7-chloro-1-cyclopropyl-6-¯uoro-1,4-
dihydro-4-oxo-quinoline-3-carboxylic acid 5A) 59.8 g,
0.035 mol), methanol 5140 ml) and sulphuric acid
52.2 ml) was re¯uxed for 24 h. The solution was
cooled down to room temperature and the solid
2. Experimental
2.1. The synthesis of compounds 1 and 2
The synthesis of the new ¯uoroquinolone derivatives

Ï Â
Z.B. Tomisic et al. / Journal of Molecular Structure 611 ;2002) 73±81
76
Fig. 1. Molecular structure of 1, ortep plot, with atom numbering. Thermal ellipsoids are drawn at 50% probability level. Intramolecular
hydrogen bonds N31±H31´´´O4 and C2±H2´´´O32 are indicated by dashed lines.
obtained diluted with water 580 ml). Acidic aqueous
solution was neutralised with 10% NaOH to pH 10,
cooled to 5 8C and then stirred for 1 h. The precipitate
was ®ltered, washed with cold water 53 £ 50 ml) and
dried for 1 h at 100 8C to give 7-chloro-1-cyclopropyl-
6-¯uoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic
acid methyl ester 51B) 56.15 g, 59.8%).
Amixture of 1B 56 g, 0.02 mol) and hydrazine-
hydrate 525 ml, 0.514 mol) was stirred at room
temperature for 10 h. The precipitated solid was
collected by ®ltration and washed with water to give
7-chloro-1-cyclopropyl-6-¯uoro-1,4-dihydro-4-oxo-
quinoline-3-carboxylic acid hydrazide 51C) 54.6 g,
93.3%).
To the solution of 1C 52.96 g, 0.01 mol) in 10 ml
3 M sulphuric acid, cooled to 0±5 8C, water solution
of NaNO2 54.14 g, 0.06 mol) was added dropwise.
After 30 min, reaction mixture was ®ltered to give
7-chloro-1-cyclopropyl-6-¯uoro-1,4-dihydro-4-oxo-
quinoline-3-carboxylic acid azide 51D).
2.1.2. Preparation of compound 2
1-Cyclopropyl-7-54-ethyl-1-piperazinyl)-6-¯uoro-
1,4-dihydro-4-oxo-quinoline-3-carboxylic acid 52B)
was synthesised from 1-cyclopropyl-7-chloro-6-
¯uoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid
5A) according to previously described procedure [10].
Asolution of 2B 55 g, 0.0139 mol) in SOCl2 was
re¯uxed for 10 h. The solvent was removed in vacuo
to obtain 1-cyclopropyl-7-54-ethyl-1-piperazinyl)-6-
¯uoro-1,4-dihydro-4-oxo-3-quinolinoyl chloride 52C)
as a dark foam 55.2 g, 95.1%).
Amixture of 2C 55.2 g, 0.0132 mol) and hydrazine-
hydrate 525 ml, 0.514 mol) was stirred at room
temperature for 1 h. The solvent was removed and
the residue was dissolved in 20 ml 96% ethanol.
After concentration of the reaction mixture under
reduced pressure, the residue was recrystallised from
96% ethanol to give 1-cyclopropyl-7-54-ethyl-1-
piperazinyl)-6-¯uoro-1,4-dihydro-53-oxopyrazolo)
[4,3-c]quinoline 52).
Asolution of 1D 51.5 g, 0.0054 mol) in methanol
525 ml) was re¯uxed for 3 h. Reaction mixture was
evaporated to dryness to yield 7-chloro-1-cyclo-
propyl-6-¯uoro-1,4-dihydro-4-oxo-quinoline-3-methyl-
carbamate 51) 51.55 g, 92.3%).
2.2. Activity
For antimicrobial activity tests in vitro, the
following strains were used: Staphylococcus aureus

Ï Â
Z.B. Tomisic et al. / Journal of Molecular Structure 611 ;2002) 73±81
77
Fig. 2. Molecular structure of 2, ortep plot, with atom numbering. Thermal ellipsoids are drawn at 50% probability level. Intramolecular
hydrogen bond C76±H76´´´F7 is indicated by dashed line. For clarity, crystalline water molecules are not shown.
5ATCC29213), Escherichia coli 5ATCC25922),
Enterococcus faecalis 5ATCC29212) and S. pneumo-
niae 5ATCC6305). Cipro¯oxacin was used as a refer-
ence substance. Unfortunately, both compounds
showed lower activities than cipro¯oxacin.
Nonius CAD4 diffractometer using a graphite mono-
chromated Mo Ka radiation. For both compounds,
crystals suitable for the X-ray structure determination
were obtained from ethanol solution 596 vol%) by
slow evaporation at room temperature. Details about
data collection, structure solution, re®nement and
about software used are listed in Table 1 [11±15].
All hydrogen atoms in both compounds, except
hydrogen at N42 and hydrogens of water molecules
2.3. X-ray structure analysis
X-ray measurements were performed on an Enraf
Table 2
Selected geometric parameters for 1
Ê
5a) Bond lengths 5A)
F6±C6
Cl7±C7
N1±C2
N1±C9
1.35155)
1.72954)
1.35555)
1.37854)
N1±C11
C11±C12
C11±C13
C12±C13
1.45955)
1.38959)
1.38758)
1.50359)
5b) Angles 58)
C2±N1±C9
C2±N1±C11
C9±N1±C11
120.653)
C12±C11±C13
C11±C12±C13
C11±C13±C12
65.654)
57.254)
57.354)
118.853)
120.053)
5c) Torsion angles 58)
C2±N1±C11±C12
C2±N1±C11±C13
C9±N1±C11±C12
C9±N1±C11±C13
2113.256)
232.958)
74.957)
C2±C3±N31±C32
C4±C3±N31±C32
7.656)
2174.553)
177.153)
C3±N31±C32±O33
N31±C32±O33±C34
155.255)
2179.854)

Ï Â
Z.B. Tomisic et al. / Journal of Molecular Structure 611 ;2002) 73±81
78
Table 3
Selected geometric parameters for 2
Ê
5a) Bond lengths 5A)
F6±C6
1.35452)
C12±C13
C3±C4
1.49153)
1.42452)
1.31651)
1.40052)
1.35452)
1.44852)
N1±C2
1.34352)
1.41452)
1.45652)
1.48953)
1.48353)
N1±C9
N41±C4
N41±N42
N42±C31
C3±C31
N1±C11
C11±C12
C11±C13
5b) Angles 58)
C2±N1±C9
121.38510)
118.62514)
119.76510)
59.751)
C4±C3±C31
N41±C4±C3
N42±N41±C4
N41±N42±C31
N42±C31±C3
105.551)
C2±N1±C11
C9±N1±C11
C11±C12±C13
C11±C13±C12
C12±C11±C13
112.851)
103.451)
115.451)
103.051)
60.151)
60.251)
5c) Torsion angles 58)
C2±N1±C11±C12
C2±N1±C11±C13
114.252)
44.053)
C9±N1±C11±C12
C9±N1±C11±C13
271.453)
2141.552)
in compound 2, were generated according to stereo-
chemistry and re®ned using a riding model in
shelxl97 [14]. The hydrogen at N42 and the ones
on water molecules 5in compound 2) were located in
difference Fourier map. Crystallographic data have
been deposited with the Cambridge Crystallographic
Data Centre, supplementary publication No. CCDC-
171413 and CCDC-171414. Copies of data may be
obtained free of charge on application to CSD, 12
Union Road, Cambridge CB2 1EZ, UK 5fax: 144-
1223/336033, e-mail: deposit@ccdc.cam.ac.uk).
values found for the corresponding analogues [16±
18]. An asymmetry in nitrogen to carbon C9±N1±
C2 bond lengths is observed in compound 2 5Table
3), whereas in 1 it is less pronounced 5Table 2). Thus,
a bond N1±C9 in 2 5Table 3) is longer than the
Ê
average value for Nsp2±Csp2/aryl value of 1.35552) A
[19]. The cyclopropyl ring of 1 is slightly distorted;
higher values of temperature factors for atoms C11,
C12, C13 and higher residual density than usual
Ê 23
5Drmax ˆ 1.53 eA ) near the cyclopropyl ring have
been observed.
The bicyclic quinoline ring is planar in both
compounds with the maximum displacement from
Ê
the best least-squares plane of 0.02054) A for atom
Ê
C3 of 1 and 0.02852) A for atom N1 of 2. In
both structures, ¯uorine atoms are shifted from the
Ê
quinoline least-squares plane [0.020 A in 1 and
Ê
0.068 A in 2]. The pyrazolo ring of 2 is almost
3. Results and discussion
The molecular structures of the studied compounds
are shown in Figs. 1 and 2. Both molecules are achiral
and crystallise in the centrosymmetric space groups
5Table 1). The values observed for bond lengths and
angles 5Tables 2 and 3) are in agreement with the
coplanar with the quinoline ring plane. The dihedral
angle between these planes is 251)8. The carbonyl
Ê
oxygen O31 is signi®cantly displaced 50.161 A)
Table 4
from the quinoline ring plane as a consequence of
its participation in hydrogen bond network. The
cyclopropyl rings of both compounds are not coplanar
with the quinoline ring; the angles between the quino-
line and cyclopropyl least-squares planes are 46.155)8
in 1 and 54.552)8 in 2. Apiperazinyl ring of 2 is in a
chair conformation NCN with Cramer and Pople puck-
Hydrogen bonding geometry for 1
Ê Ê Ê
D±H 5A) H´´´A 5A) D´´´A 5A) D±H´´´A 58)
D±H´´´A
N31±H´´´O4 0.8651)
C2±H´´´O32 0.9351)
C34±H´´´O4a 0.9651)
2.3351)
2.1851)
2.4552)
2.69054)
2.81255)
3.35252)
10554)
12453)
157.251)
a
Ê
Symmetry operation: 1 2 x; 1 2 y; 1 2 z:
ering parameters Q ˆ 0.58352) A, u ˆ 3.052)8 and

Ï Â
Z.B. Tomisic et al. / Journal of Molecular Structure 611 ;2002) 73±81
79
Fig. 3. In the crystal packing of 1, the centorsymmetric dimer is created by two C±H´´´O interactions. Stacking of aromatic rings is pronounced
along the axis-a.
w ˆ 35254)8 [20]. The carbamate side chain of 1
adopts a zig-zag conformation almost in the plane of
the quinoline ring with a characteristic torsion angle
C3±N31±C32±O33 of 177.052)8. The overall confor-
mation of both compounds is described by selected
torsion angles in Tables 2 and 3.
Molecules of 1 are stabilised by intramolecular
hydrogen bonds 5Fig. 1). The carbonyl oxygen O4
and a hydrogen of the amino N31 group 5N31±
H31´´´O4) form a ®ve-membered ring [graph-set
notation S55)] [21±23]. An intramolecular contact
membered ring [graph-set notation S56)]. In related
3-carboxylic acid analogues selected from the
Cambridge Structural Database [25] carbonyl oxygen
O4 acts as an acceptor of hydrogen from carboxyl
group in formation of intramolecular hydrogen
bond. The crystal packing comprises centrosymmetric
dimers formed by C±H´´´O interactions between
methyl groups and carbonyl oxygen atoms 5Table 4,
Fig. 3) forming the 16-membered ring with graph-set
descriptor R22516). p-Stacking of aromatic rings is
pronounced along the crystallographic a-axis with
Ê
the shortest separation distance of 3.64 A 5Fig. 3).
In the crystal packing of 2 intermolecular hydrogen
C2±H2´´´O32 satis®es criteria for
hydrogen bond 5Table 4) [24] forming a six-
a
C±H´´´O
Table 5
Hydrogen bonding geometry for 2
Ê
D±H 5A)
Ê
H´´´A 5A)
Ê
D´´´A 5A)
D±H´´´A
D±H´´´A 58)
N42±H´´´O31a
0.9452)
1.0154)
0.7757)
0.9754)
0.9752)
1.8752)
1.9254)
2.1657)
1.8654)
2.3154)
2.81052)
2.81752)
2.92153)
2.82652)
2.93452)
17153)
14653)
16655)
16953)
12154)
O1W±H1´´´O2W
O2W±H21´´´N74b
O2W±H22´´´O31c
C76±H76´´´F6
a
Symmetry operation: 3=2 2 x; 1=2 2 y; 1 2 z:
Symmetry operation: x, 2y, 1=2 1 z:
Symmetry operation: x 2 1=2; y 2 1=2; z.
b
c

Ï Â
Z.B. Tomisic et al. / Journal of Molecular Structure 611 ;2002) 73±81
80
Fig. 4. Crystal packing of 2: 5a) Hydrogen bonded dimers of quinoline molecules are interconnected via hydrogen bonds with water molecules;
Ê
5b) stacking is pronounced between the aromatic planes along the axis-a with a centroid distance of two nearest quinoline moieties of 3.525 A.

Ï Â
Z.B. Tomisic et al. / Journal of Molecular Structure 611 ;2002) 73±81
81
bonds N42±H42´´´O31 create centrosymmetric
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hydrogen bonding is completed by cooperation of
crystalline water molecules; compound 2 crystallises
with 1.5 water molecules per quinoline molecule. One
water molecule 5O1W), of the two present in the
asymmetric unit, is in special position at the twofold
axis 54e special position in the C2/c space group).
Water molecules O2W interconnect dimers of
hydrogen bonded quinoline molecules by donating
one of their hydrogen atoms to carbonyl oxygen
O31 of the pyrazolo ring of one quinoline molecule
5O2W±H22W´´´O31) and the other hydrogen to
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[101] of the cell are formed with graph-set descriptor
C22515). Water molecules OW1 form bridges between
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acceptor in one hydrogen bond, a feature which is
commonly observed in the crystal structures of small
molecule hydrates [26]. p´´´p interactions have been
detected between quinoline moieties 5Fig. 4b);
centroids of the two neighbouring rings N1±C2±
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Ï Ï
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Ê
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structure of 2 ¯uorine meets quite well geometrical
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lecular interaction C76±H76A´´´F6 [graph-set nota-
tion S56)]. According to the analysis reported by
Shimoni and Glusker [27] for C±F as an acceptor
group attached to an aromatic system, the mean
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Ê
H´´´F distance is 2.58 A whereas the mean C±
H´´´F angle is 1298. These values were obtained for
a small statistical sample 5seven structures) but they
®t nicely in the ranges obtained by our analysis of
data extracted from Cambridge Structural Database,
version 5.21, April 2001 [25]. The restrictions to
organic compounds and the structures with an R
value ,0.05, while searching met 325 structures
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255±261.
Ê
with the C´´´F range from 2.480 to 3.169 A and
Ê
H´´´F from 2.072 to 2.669 A. Our data for compound
2 5Table 5) are in agreement with these ®ndings and
data reported for analogous compound, cipro¯oxacin
lactate [28].