Metal complexes of the fourth generation quinolone antimicrobial drug gatifloxacin: Synthesis, structure and biological evaluation

Article abstract of DOI:10.1016/j.molstruc.2010.05.041

Three metal complexes of the fourth generation quinolone antimicrobial agent gatifloxacin (GFLX) with Y(ΙΙΙ), Zr(ΙV) and U(VΙ) have been prepared and characterized with physicochemical and spectroscopic techniques. In these complexes, gatifloxacin acts as a bidentate deprotonated ligand bound to the metal through the ketone oxygen and a carboxylato oxygen. The complexes are six-coordinated with distorted octahedral geometry. The kinetic parameters for gatifloxacin and the three prepared complexes have been evaluated from TGA curves by using Coats-Redfern (CR) and Horowitz-Metzeger (HM) methods. The calculated bond length and force constant, F(U=O), for the UO ₂ bond in uranyl complex are 1.7522 A? and 639.46 N m ^-1. The antimicrobial activity of the complexes has been tested against microorganisms, three bacterial species, such as Staphylococcus aureus (S. aureus), Escherichia coli (E. coli) and Pseudomonas aeruginosa (P. aeruginosa) and two fungi species, penicillium (P. rotatum) and trichoderma (T. sp.), showing that they exhibit higher activity than free ligand.

Full text of DOI:10.1016/j.molstruc.2010.05.041

Journal of Molecular Structure 977 (2010) 243–253
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Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstruc
Metal complexes of the fourth generation quinolone antimicrobial drug
gatifloxacin: Synthesis, structure and biological evaluation
*
Sadeek A. Sadeek , Walaa H. El-Shwiniy
Department of Chemistry, Faculty of Science, Zagazig University, Zagazig, Egypt
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 20 April 2010
Received in revised form 27 May 2010
Accepted 27 May 2010
Available online 1 June 2010
Three metal complexes of the fourth generation quinolone antimicrobial agent gatifloxacin (GFLX) with
Y(III), Zr(IV) and U(VI) have been prepared and characterized with physicochemical and spectroscopic
techniques. In these complexes, gatifloxacin acts as a bidentate deprotonated ligand bound to the metal
through the ketone oxygen and a carboxylato oxygen. The complexes are six-coordinated with distorted
octahedral geometry. The kinetic parameters for gatifloxacin and the three prepared complexes have
been evaluated from TGA curves by using Coats–Redfern (CR) and Horowitz–Metzeger (HM) methods.
The calculated bond length and force constant, F(U@O), for the UO2 bond in uranyl complex are
Keywords:
GFLX
1.7522 Å and 639.46 N mꢀ1
.
UV
1H NMR
The antimicrobial activity of the complexes has been tested against microorganisms, three bacterial
species, such as Staphylococcus aureus (S. aureus), Escherichia coli (E. coli) and Pseudomonas aeruginosa
(P. aeruginosa) and two fungi species, penicillium (P. rotatum) and trichoderma (T. sp.), showing that they
exhibit higher activity than free ligand.
Kinetic data
TGA
Antimicrobial activity
Ó 2010 Elsevier B.V. All rights reserved.
1. Introduction
The fluoroquinolones constitute an important class of synthetic
antimicrobial agents. Recent studies indicate an important role of
Bristol-Myers Squibb and Allergon produced Gatifloxacin (For-
mula I) under the brand names Tequin and Zymor. Gatifloxacin
sold under these names is an antibiotic of the fourth generation
fluoroquinolone family, that like other members of that family
inhibits the bacterial enzymes DNA gyrase and topoisomeraseIV.
In many countries, gatifloxacin is also available as tablets and in
various aqueous solutions for intravenous therapy.
metal ions on the mechanism of action of these drugs. The dissoci-
ation and coordination behavior of fluoroquinolone antibiotics
have been studied and published [1]. Metal complex is known to
enhance the biological activities of quinolone antibiotics due per-
haps to resulting higher liposolubilities leading to greater intracel-
lular accumulations [2–5].
Number of studies regarding the interaction between various
quinolones with the metallic cations has been reported in the liter-
ature [6–17]. These studies have been primarily directed towards
the identification of function groups directly linked to the metal
and to establish the structure formed by these coordination
complexes. Infrared spectroscopic and solid state paramagnetic
resonance spectroscopy studies of metallic complexes derived
from these compounds suggest that they are formed by interaction
through ring carbonyl and carboxylate oxygen atoms [2,6–18]. In
basic media the quinolones bearing a piperazinyl ring in position
7 could also form complexes where terminal nitrogen is involved
in the coordination to the metal [19–24].
O
O
F
OH
N
N
HN
O
As a continuation of our work on metal interactions with fluoro-
quinolone derivatives [10,11] we describe the synthesis of gatifloxa-
cin with Y(III), Zr(IV) and U(VI) complexes, with the objective of
better understanding the structures formed by these compounds.
For the characterization of the complexes formed, the following
techniques were employed: 1H NMR, UV spectroscopies, Elemental
analysis, Infrared, conductance measurements and thermal analysis.
Formula I: 1-cyclopropyl-6-fluoro-8-methoxy-7-(3-methylpi-
perazin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid.
* Corresponding author.
E-mail address: sadeek59@yahoo.com (S.A. Sadeek).
0022-2860/$ - see front matter Ó 2010 Elsevier B.V. All rights reserved.
doi:10.1016/j.molstruc.2010.05.041

244
S.A. Sadeek, W.H. El-Shwiniy / Journal of Molecular Structure 977 (2010) 243–253
and Wong [25], against different bacterial species, such as Staphy-
2. Materials and methods
lococcus aureus (S. aureus), Escherichia coli (E. coli) and Pseudomonas
aeruginosa (P. aeruginosa) and antifungal screening was studied
against two species, penicillium (P. rotatum) and trichoderma
(T. sp.). The nutrient agar medium for antibacterial was (0.5% Pep-
tone, 0.1% Beef extract, 0.2% Yeast extract, 0.5% NaCl and 1.5% Agar-
Agar) and for antifungal (3% Sucrose, 0.3% NaNO3, 0.1% K2HPO4,
0.05% KCl, 0.001% FeSO4, 2% Agar-Agar) was prepared and then
cooled to 47 °C and seeded with tested microorganisms. After
solidification 5 mm diameter holes were punched by a sterile
cork-borer. The investigated compounds, i.e., ligand and their com-
plexes, were introduced in Petri-dishes (only 0.1 ml) after dissolv-
ing in DMSO at 1.0 ꢁ 10ꢀ3 M. These culture plates were then
incubated at 37 °C for 20 h for bacteria and for seven days at
30 °C for fungi. The activity was determined by measuring the
diameter of the inhibition zone (in mm). Growth inhibition was
calculated with reference to the positive control, i.e., gatifloxacin.
Metal salts and solvents were purchased from Merck Germany.
Gatifloxacin was obtained from Sigma, these materials used with-
out further purification.
The infrared spectra of the three solid complexes, gatifloxacin
and the final products of the thermogravimetric analysis were re-
corded from KBr discs using FTIR 460 plus, 1H NMR spectra were
recorded on Varian Mercury VX-300 NMR Spectrometer using
DMSO-d6 as solvent. C, H, N and halogen elemental analysis were
carried out on a Perkin Elmer CHN 2400. The percentage of Y(III),
Zr(IV) and U(VI) metal ions were determined gravimetrically by
transforming the solid products into oxide, and also determined
by using atomic absorption method. A spectrometer model PYE-
UNICAM SP 1900 fitted with the corresponding lamp was used
for this purposed. Electronic solid reflection spectra of gatifloxacin
and the isolated solid complexes were obtained in the region of
800–200 nm using UV-3101PC Shimadzu with a 1 cm quartz cell.
Thermogravimetric (TG) and differential (DTG) thermogravimetric
analysis were carried out under N2-atmosphere using detectors
model TGA-50H Shimadzu. The rate of heating of the sample was
3. Results and discussion
Gatifloxacin of Y(III), Zr(IV) and U(VI) were synthesized as solids
of a color characteristics of the metal ion. The molar ratio for all
complexes synthesized is M:GFLX = 1:2 for Y(III) and Zr(IV) and
1:3 for U(VI). The prepared complexes are hydrates with various
degrees of hydration. The structures of the complexes suggested
from the elemental analysis agree well with their proposed for-
mula (Table 1). The found values of elemental analysis agree well
with the calculated percentage of C, H, N and halogen data are in
a well agreement with each other and prove the molecular formu-
las of the prepared complexes. The physical characteristics of these
complexes are given in Table 1. The molar conductance values of
the complexes were found to be in the range from 133.12 to
332.8 S cm2 molꢀ1 at 25 °C.
kept at 10 °C/min. Molar conductivities in DMSO at 1.0 ꢁ 10ꢀ3
M
were measured on CONSORT K410.
2.1. Synthesis of gatifloxacin metal complexes
The yellowish white solid complex [Y(GFLX)2(H2O)Cl]Cl2ꢂ11H2O
was prepared by adding 0.5 mmol (0.0977 g) of Yttrium chloride
(YCl3) in 10 ml bidistilled water drop wisely to a stirred suspended
solution of 1 mmol (0.37516 g) of GFLX in 50 ml ethanol. The reac-
tion mixture was stirred for 48 h at 30 °C in a water bath. The yel-
lowish white precipitate was filtered off and dried in vacuum
over CaCl2. The orange and faint yellow solid complexes of
[ZrO(GFLX)2H2O]Cl2ꢂ14H2O and [UO2(GFLX)3](NO3)2ꢂ6H2O were
prepared in a similar manner described above by using methanol
and acetone as a solvents instead of ethanol and using ZrOCl2ꢂ8H2O
and UO2(NO3)2ꢂ6H2O in 1:2 and 1:3 M ratio. Unfortunately we were
not able to obtained appropriate monocrystals to perform X-ray dif-
fraction analysis. Qualitative black ring test for ionic nitrate using
freshly prepared FeSO4 solution and concentrated sulfuric acid, a
black ring of FeSO4ꢂNO is formed led to the presence of nitrate as
counter ions in the uranyl/GFLX complex and for the other com-
plexes the qualitative reactions revealed the presence of chloride
as counter ions. The three complexes were characterized by their
elemental analysis, infrared, electronic, 1H NMR and thermal
analysis.
3.1. Infrared absorption studies
The infrared spectra of anhydrous gatifloxacin and its com-
plexes are listed in Table 2, Fig. 1. The IR spectra of the complexes
are compared with those of the free ligand in order to determine
the coordination sites that may involved in chelation. All gatiflox-
acin metal complexes exhibit a broad band between 3444 and
3373 cmꢀ1, which corresponds to the vibration
m(OAH) as well as
to NAH vibration of the piperazinyl moity [2,17,26–28]. The
NAH vibration of the piperazinyl appears in the region of 2591–
2343 cmꢀ1, it indicates that the carboxylic group is deprotonated
and the molecules exists in zwitterionic form with two of the
hydrogen atoms attached to N-3 forming donor hydrogen bonds
with water molecules [29]. The valence vibration of the carboxylic
2.2. Antibacterial and antifungal activity
stretch m(C@O) and the pyridone stretch m(C@O) for free gatifloxa-
Antibacterial activity of the ligand and its metal complexes was
investigated by a previously reported modified method of Beecher
cin were found at 1724 and 1635 cmꢀ1 [30]. These bands
disappears in the complexes which indicative of the involvement
Table 1
Elemental analysis and physicochemical parameters data of gatifloxacin and its metal complexes.
Complexes M.Wt. (M.F.)
Yield% mp (°C) Color
Content (calculated) found
% C % H % N
(60.79) (5.91) (11.19)
60.75 5.91 11.17
Yellowish white (39.26) (5.86) (7.23)
39.16 5.80 7.23
(38.06) (6.18) (7.01)
38.00 6.18 7.00
(42.04) (4.79) (9.47)
41.98 4.70 9.46
K )
(S cm2 molꢀ1
%M
–
%Cl
–
GFLX 375.16 (C19H22N3O4F)
–
158
>360
300
White
ꢀ8.32
[Y(GFLX)2(H2O)Cl]Cl2ꢂ11H2O 1161.4 (C38H68N6O20F2Cl3Y)
85.20
(7.66)
7.65
(9.17) 267.28
9.11
[ZrO(GFLX)2H2O]Cl2ꢂ14H2O 1198.22 (C38H74N6O24F2Cl2Zr) 52.48
[UO2(GFLX)3](NO3)2ꢂ6H2O 1627 (C57H78N11O26F3U) 64.66
Orange
(7.61)
7.61
(5.93) 332.8
5.92
260
Faint yellow
(14.63)
14.62
133.12
–

S.A. Sadeek, W.H. El-Shwiniy / Journal of Molecular Structure 977 (2010) 243–253
245
Table 2
Infrared frequencesa (cmꢀ1) and tentative assignmentsb for (A) Gatifloxacin (GFLX) as a ligand; (B) [Y(GFLX)2(H2O)Cl]Cl2ꢂ11H2O; (C) [ZrO(GFLX)2H2O]Cl2ꢂ14H2O and (D)
[UO2(GFLX)3](NO3)2ꢂ6H2O.
A
B
C
D
Assignment
(OAH); H2O, COOH
(CAH); aromatic
3403m,br
3091vw
3022vw
2978vw
2938vw
2842m
2591vw
2475m,br
2366vw
1724s
3373m,br
3080vw
3391m,br
3082vw
3034vw
2938w
3444m,br
3096vw
3009m
2933w
2846m
m
m
2942vw
2841vw
m
(CAH); aliphatic
AðNHþ2 Þ
2846vw
2468ms
2362m
2846vw
2468m
2363m,sh
–
1622ms
1523s
2493m
2361ms
2343sh
–
1619vs
1577w
1519vs
1453vs
m
–
m
m
m
(C@O); COOH
–
1616ms
1572ms
1527vw
1461vs
as(COOꢀ)
1635vs
1547ms
1448vs
1391ms
–
1360ms
1321vs
1278vs
1210ms
1180vw
1143ms
1114vw
1096vw
1061vs
1037vw
995s
(C@O) and phenyl breathing modes
1455vs
ACH; deformations of ACH2
m
s(COOꢀ)
1377s
1323s
1291vs
1383ms
1322vw
1283ms
1383s
1322m
db(ACH2)
1213ms
1178ms
1134ms
1094ms
1059vs
1214m
1179m
1132m
1061s
1281s
m(CAC),
m(CAO),
m(CAN)
1216w
1179w
1137w
1094m
1061s
dr(ACH2)
995s
937s
893ms
820vs
–
995vs
936vs
897s
995s
919w
ACH bend; phenyl
938vs
888s
823vs
–
–
–
895s
813vs
–
m
m
m
as(U@O)
s(U@O)
(Zr@O)
810vs
780m
740s
655s
560m
509sh
499ms
775ms
733s
686ms
651s
596vw
542s
515vw
487m
450vw
734m
775w
736ms
660s
593vw
552m
519m
492w
440w
db(COOꢀ)
653ms
552m
516w
450vw
410vw
m(MAO) + ring deformation
a
s = strong,w = weak, sh = shoulder, v = very, br = broad.
b
m
= stretching, d = bending.
of the carboxylic group in the interaction with metal ion and the
carboxylic group is deprotonated [31,32]. On complexation, the
complexes given a separation [
D
m
=
m
as(COOꢀ) ꢀ
m
s(COOꢀ)] 239–
236 cmꢀ1, suggesting monodentate bonding for the carboxylate
group.
characteristic peak of pyridone stretch
m(C@O) and carboxylic
stretch in all the metal complexes spectra shifted towards lower
For [UO2(GFLX)3](NO3)2ꢂ6H2O complex, the most probably
structure is shown in Formula II, where the six oxygen atoms of
their GFLX ligands occupy equatorial positions around the central
metal atom U(VI), forming a plane containing the six-membered
rings and the two oxygen atoms of the uranyl group occupy axial
frequency region. The m(C@O) of pyridone for free gatifloxacin ap-
pears at 1635 cmꢀ1 as a very strong intensity absorption but in the
spectra of our complexes, this band is effected by the interaction
with the metal ion and appear as a medium strong at around
1560 cmꢀ1. The band around 1619 cmꢀ1 in the spectra of our com-
positions. The data given in Table 2 show that
m
as(U@O) absorption
plexes can be assigned to the asymmetric stretching vibration (mas
)
band occurs as a strong singlet at 895 cmꢀ1 and the
ms(U@O)
of the ligated carboxylato group and the symmetric vibrations oc-
absorption band occurs at 813 cmꢀ1 as a very strong singlet. These
assignments for the stretching vibrations of the uranyl group, UO2,
agree quite well with those known for many dioxouranium (VI)
curs as
a medium or strong intensity absorption around
1380 cmꢀ1, these bands are absent in the spectrum of gatifloxacin.
The spectra of the isolated solid complexes show a group of bands
complexes [36,37]. The ms(U@O) value was used to calculate both
with different intensity which characteristics for
m
(MAO). The
the bond length and force constant, F(U@O), for the UO2 bond in
our complex according to the known method [36,37]. The calcu-
lated bond length and force constant values are 1.7522 Å and
m
(YAO) bands observed at 653, 552 and 410 cmꢀ1 and at 655,
560 and 499 cmꢀ1 for Zr(IV) and at 660, 552, 492 and 440 cmꢀ1
for U(VI) (Table 2), which are absent in the spectrum of gatifloxa-
cin. This shows the coordination of the drug through both its ke-
tone and carboxylic group. A carboxylate ligand can coordinate
to the metal ions either as a monodenate or a bidentate ligand, giv-
ing changes in the relative positions of the asymmetric and sym-
metric stretching vibrations [33–35]. The infrared spectra of the
639.46 N mꢀ1
.
3.2. UV–visible spectra
The formation of the metal complexes was also confirmed by
UV–visible spectra. Fig. 2 shows the electronic solid reflection

246
S.A. Sadeek, W.H. El-Shwiniy / Journal of Molecular Structure 977 (2010) 243–253
Fig. 1. Infrared spectra of: (A) GFLX; (B) [Y(GFLX)2(H2O)Cl]Cl2ꢂ11H2O; (C)
[ZrO(GFLX)2H2O]Cl2ꢂ14H2O and (D) [UO2(GFLX)3](NO3)2ꢂ6H2O complexes.
spectra of the free gatifloxacin and its metal complexes in the
wavelength interval from 200 to 800 nm. The reflection spectrum
of free gatifloxacin (Table 3) shows bands at 260, 280, 308, 326
and 348 nm which is assigned to
p–
pꢃ and n–pꢃ transitions. The
absent of the reflection band at 280 nm in the three mentioned
complexes and the shift of the other reflectance bands kmax to high-
er (bathochromic shift) and to lower values (hypsochromic shift) for
the complexes attributed to complexation behavior of gatifloxacin
towards metal ions. The complexes of Y(III), Zr(IV) and U(VI) show
band around 572 nm, which may be assigned to the ligand–metal
charge transfer.
3.3. Thermogravimetric analysis
Fig. 2. Electronic reflection spectra of: (A) GFLX; (B) [Y(GFLX)2(H2O)Cl]Cl2ꢂ11H2O;
(C) [ZrO(GFLX)2H2O]Cl2ꢂ14H2O and (D) [UO2(GFLX)3](NO3)2ꢂ6H2O complexes.
To make sure about the proposed formula and structure for all
complexes, thermogravimetric (TGA) and differential thermogravi-
metric analysis (DTG) were carried out under N2 flow with heating
rates were controlled at 10 °C/min., Fig. 3. Table 4 reports the max-
imum temperature values, Tmax (°C), together with the correspond-
ing weight losses for each step of the decomposition reactions of
the gatifloxacin and the three complexes. The obtained results

S.A. Sadeek, W.H. El-Shwiniy / Journal of Molecular Structure 977 (2010) 243–253
247
Table 3
UV–visible spectra of gatifloxacin and its metal complexes (200–800 nm).
½ZrOðC19H22N3O4FÞ2H2OꢅCl2 ꢂ 14H2O
50 ꢄ
C
½ZrOðC19H22N3O4FÞ H2OꢅCl2 ꢂ 9H2O þ 6H2O
ƒƒƒ!
2
Assignments (nm)
GFLX
GFLX complex with
½ZrOðC19H22N3O4FÞ2H2OꢅCl2 ꢂ 9H2O
ð3Þ
Y(III)
Zr(IV)
U(VI)
431;501 ꢄ
C
p* transitions
260
280
234
–
235
–
249
–
ZrO þ 16C þ 6C H þ 5C H þ 2NH Cl þ 2HF
ƒƒƒƒƒ!
2
2
4
2
2
4
p–
þ NO þ 3NO2 þ 9H2O
n–p* transitions
308, 326 302, 325 310, 327 308, 328
348
350
354, 367 342, 349
½UO2ðC19H22N3O4FÞ3ꢅðNO3Þ2 ꢂ 6H2O
Ligand–metal charge transfer
–
572
574 569
55 ꢄ
C
½UO ðC19H22N3O4FÞ ꢅðNO3Þ ꢂ 2H2O þ 4H2O
ƒƒƒ!
2
3
2
½UO2ðC19H22N3O4FÞ3ꢅðNO3Þ2 ꢂ 2H2O
ð4Þ
strongly support the structures proposed for the complexes under
investigation. Gatifloxacin is thermally stable in the temperature
range 25–50 °C. Decomposition of the GFLX started at 50 °C and
finished at 800 °C with two stages. The first step of decomposition
occur at maximum temperature 80 °C corresponding to the loss of
C2H2 molecule with a mass loss of 6.921% and the energy of activa-
tion was 56.61 kJ molꢀ1. The second stage of decomposition occur
at two maxima 292 and 566 °C with the total weight loss accompa-
nying these stage was 93.079% and may be attributed to the loss of
CO + 8C2H2 + 3NO + HF + 1.5H2. The hydrated gatifloxacinates of
Y(III), Zr(IV) and U(VI) are decomposed in two steps. The TGA curve
of [Y(C19H22N3O4F)2(H2O)Cl]Cl2ꢂ11H2O shows two stages of
decomposition. The first stage occur at maximum temperature
60 °C corresponds to the loss of nine water molecules with mass
loss of 13.986% (calc. 13.949%) and the energy of activation for this
step was 34.84 kJ molꢀ1. The relatively low value of temperature of
this step may indicate that these water molecules undergoes less
H-bonding. The second step of decomposition occurs at three max-
ima at 317, 394 and 480 °C, is accompanied by a weight loss of
63.900%. This step is associated with the loss of residue hydrated
water molecules and the gatifloxacinate forming Yttrium oxide,
Y2O3, as a final solid product. The actual weight loss from this stage
is very close to calculated (63.932%). The [ZrO(C19H22N3O4F)2-
H2O]Cl2ꢂ14H2O complex decomposes in two steps within the tem-
perature range 30–800 °C with mass loss 73.649% leaving ZrO2 as
residue and the activation energies were 28.32 and 31.71 kJ molꢀ1
(Table 5) corresponding to the two maxima at 323 and 704 K. For
hydrated U(VI) gatifloxacin, the first stage of decomposition occurs
at a maximum temperature 55 °C and is accompanied by a weight
loss of 4.431% associated with the loss of four water molecules and
the activation energy of this step is 29.82 kJ molꢀ1. The second step
of decomposition occurs at three maxima at 253, 356 and 519 °C, is
accompanied by a weight loss of 74.556% associated with the loss
of 12C2H4 + 7C2H2 + 3HF + 7CO + 11NO + 2H2O + 0.5H2. The activa-
tion energies corresponding to the two maxima 526 and 629 K are
253;356;519 ꢄ
C
UO þ 12C þ 12C H þ 7C H þ 3HF þ 7CO
ƒƒƒƒƒƒƒƒ!
2
2
4
2
2
þ 11NO þ 2H2O þ 0:5H2
The proposed structure formula on the basis of the results dis-
cussed in this paper located as shown in Formula (II):
+
NH2
F
N
N
O
O
Cl
O
O
O
O
Y
N
N
O2H
O
O
F
+H2N
+
NH2
55.36 and 71.10 kJ molꢀ1
.
The infrared spectra of the final products of three complexes
obtained at 800 °C, shows the characteristic spectrum for metal oxi-
des and the absence of all bands associated with the gatifloxacinate
group.
According, to these conculsions, the decomposition mechan-
sims proposed for GFLX and thier complexes are summarized as
follows:
F
N
N
O
O
O
O
O
O
O
Zr
80 ꢄ
C
C19H22N O F
C
C
17H20N3O4F þ C2H2
ƒƒƒ!
3
4
ð1Þ
N
N
292;566 ꢄ
O2
H
C17H20N O F
CO þ 8C H þ 3NO þ HF þ 1:5H
ƒƒƒƒƒ!
3
4
2
2
2
O
O
½YðC19H22N3O4FÞ2ðH2OÞClꢅCl2 ꢂ 11H2O
60 ꢄ
C
½YðC19H22N3O4FÞ ðH2OÞClꢅCl2 ꢂ H2O þ 9H2O
½YðC19H22N3O4FÞ2ðH2OÞClꢅCl2 ꢂ H2O
ƒƒƒ!
2
F
ð2Þ
317;394;480 ꢄ
C
YO1:5 þ 12C þ 5C2H2 þ 6C2H4 þ 3NH4Cl þ 2HF
þ 2CO2 þ 2CO þ 3NO þ 0:5H2O þ 0:5H2
ƒƒƒƒƒƒƒ!
+H2
N

248
S.A. Sadeek, W.H. El-Shwiniy / Journal of Molecular Structure 977 (2010) 243–253
Fig. 3. TGA and DTG diagrams of: (A) GFLX; (B) [Y(GFLX)2(H2O)Cl]Cl2ꢂ11H2O; (C) [ZrO(GFLX)2H2O]Cl2ꢂ14H2O and (D) [UO2(GFLX)3](NO3)2ꢂ6H2O complexes.

S.A. Sadeek, W.H. El-Shwiniy / Journal of Molecular Structure 977 (2010) 243–253
249
Table 4
The maximum temperature Tmax (°C) and weight loss values of the decomposition stages for Y(III), Zr(IV), and U(VI) gatifloxacins.
Compounds (M.F.)
Decomposition
Tmax (°C)
Weight loss (%)
Calc.
Lost species
Found
GFLX
First step
80
6.933
6.921
C2H2
(C19H22N3O4F)
Second step
Total loss, residue
292, 566
93.067
93.079
100, 0.0
CO + 8C2H2 + 3NO + HF + 1.5H2
[Y(GFLX)2(H2O)Cl]Cl2ꢂ11H2
First step
Second step
60
13.949
63.932
13.986
63.900
9H2O
O (C38H68N6O20F2Cl3Y)
317, 394, 480
5C2H2 + 6C2H4 + 3NH4Cl + 2HF + 2CO2 + 2CO + 3NO +
0.5H2O + 0.5H2
Total loss, residue
77.881, 22.119
77.886, 22.114
[ZrO(GFLX)2H2O]Cl2ꢂ14H2O
First step
Second step
Total loss, residue
50
431, 501
9.013
64.68
73.693, 26.307
9.042
64.607
73.649, 26.351
6H2O
(C38H74N6O24F2Cl2Zr)
6C2H4 + 5C2H2 + 2NH4Cl + 2HF + NO + 3NO2 + 9H2O
[UO2(GFLX)3](NO3)2ꢂ6H2O
First step
Second step
Total loss, residue
55
4.425
70.129
74.554, 25.446
4.431
70.125
74.556, 25.444
4H2O
(C57H78N11O26F3U)
253, 356, 519
12C2H4 + 7C2H2 + 3HF + 7CO + 11NO + 2H2O + 0.5H2
Table 5
Thermal behavior and kinetic parameters determined using the Coats–Redfern (CR) and Horowitz–Metzger (HM) operated for gatifloxacin and their complexes.
Complexes (M.F.)
Decomposition Ts (K) Method Parameter
r
range (K)
Eꢃꢁ104
A ꢁ 103
D
Sꢃꢁ102
D
Hꢃꢁ104
D
Gꢃꢁ105
(J molꢀ1
)
(sꢀ1
)
(J molꢀ1 Kꢀ1
)
(J molꢀ1
)
(J molꢀ1
)
GFLX (C19H22N3O4F)
302–496
538–685
353
565
CR
HM
CR
5.661
6.745
6.696
6.736
5.45 ꢁ 104
2.94 ꢁ 106
5.754 ꢁ 10
ꢀ0.9805
ꢀ0.6505
ꢀ1.591
5.368
6.452
6.227
6.266
0.8829
0.87483
1.522
0.89363
0.92408
0.86241
0.86015
HM
2.022 ꢁ 102 ꢀ1.487
1.467
[Y(GFLX)2(H2O)Cl]Cl2ꢂ11H2O (C38H68N6O20F2Cl3Y) 302–448
333
590
CR
HM
CR
3.484
3.671
13.362
15.663
2.117 ꢁ 10
ꢀ1.6302
3.207
3.394
12.872
15.173
0.86357
0.83720
1.479
0.94395
0.93219
0.92989
0.94887
1.077 ꢁ 102 ꢀ1.4949
2.482 ꢁ 108 ꢀ0.3244
544–598
HM
1.88 ꢁ 1010
ꢀ0.1218
1.589
[ZrO(GFLX)2H2O]Cl2ꢂ14H2O (C38H74N6O24F2Cl2Zr)
[UO2(GFLX)3](NO3)2ꢂ6H2O (C57H78N11O26F3U)
294–416
462–680
323
704
CR
HM
CR
2.832
2.905
3.171
6.092
1.810
7.866
0.02134
2.31199
ꢀ1.832
ꢀ1.710
ꢀ2.2661
ꢀ1.8765
ꢀ175.375
ꢀ159.5581
ꢀ1.6098
2.563
2.636
2.586
5.507
0.8481
0.8159
1.854
0.97015
0.96244
0.99022
0.99636
HM
1.872
299–353
353–534
549–758
328
526
629
CR
HM
CR
HM
CR
HM
2.982
3.302
5.536
7.486
7.110
8.083
4.7157
31.604
2.7097
3.029
5.098
7.048
6.587
7.559
0.8462
0.82629
1.357
1.352
1.6949
1.6399
0.82098
0.84491
0.82943
0.94916
0.98050
0.97992
4.274 ꢁ 10
4.168 ꢁ 103 ꢀ1.2290
3.252 ꢁ 10
ꢀ1.647
ꢀ1.405
5.98 ꢁ 102
3.4. The kinetic studies
+H2N
+
NH2
Thermodynamic activation parameters of decomposition pro-
cess of gatifloxacin and its complexes namely the energy of activa-
tion, Eꢃ, entropy of activation,
D D
Sꢃ, enthalpy of activation, Hꢃ and
F
F
N
N
Gibbs free energy,
the Coats–Redfern [38] and Horowitz–Metzger equations [39].
The entropy,
Sꢃ, enthalpy, Hꢃ and the free energy change of acti-
vation,
Gꢃ, were evaluated using the following equations:
D
Gꢃ, were calculated graphically by employing
O
O
D
D
D
O
N
O
O
U
O
N
D
D
D
Sꢃ ¼ 2:303½logðAh=KTÞꢅR
Hꢃ ¼ Eꢃ ꢀ RT
O
Gꢃ ¼
D
Hꢃ ꢀ T
D
Sꢃ
H
O
H
O
O
O
The thermal behaviors of the gatifloxacin ligand and the three
O
complexes in terms of stability ranges, peak temperatures and val-
ues of kinetic parameters, are shown in Fig. 4 and Table 5. The acti-
vation energies of decomposition were found to be in the range
28.32–156.63 kJ molꢀ1. The high values of the activation energies
reflect the thermal stability of the complexes.
F
O
H
N
N
+H2N
O
3.5. The 1H NMR studies
The 1H NMR spectra of gatifloxacin molecule in DMSO-d6
(Table 6) showed a multiplet at d: 0.97–1.23 ppm corresponding

250
S.A. Sadeek, W.H. El-Shwiniy / Journal of Molecular Structure 977 (2010) 243–253
Fig. 4. The diagrams of kinetic parameters of gatifloxacin and their complexes using Coats–Redfern (CR) and Horowitz–Metzger (HM) equations.
to cyclopropane protons; doublet at d: 1.44–1.46 ppm for ACH3 of
piperazine ring; multiplet at d: 2.90–3.39 ppm for protons of piper-
azine ring; singlet at d: 3.72 ppm for methoxy group; multiplet at
d: 3.98–4.01 ppm for ANACH2; a weak singlet at 7.5 ppm for +NH2

S.A. Sadeek, W.H. El-Shwiniy / Journal of Molecular Structure 977 (2010) 243–253
251
Fig. 4 (continued)
and at d: 7.84, 8.79 ppm of ACH. The peak in the downfield region
at d: 10.8–11.3 ppm in the spectra of ligand can be assigned to the
proton of carboxylic (COOH). The 1H NMR spectra of [Y(C19H22N3-
O4F)2(H2O)Cl]Cl2ꢂ11H2O and [ZrO(C19H22N3O4F)2H2O]Cl2ꢂ14H2O

252
S.A. Sadeek, W.H. El-Shwiniy / Journal of Molecular Structure 977 (2010) 243–253
Table 6
Table 7
1H NMR values (ppm) and tentative assignments: (A) Gatifloxacin (GFLX) as a ligand;
The inhibition diameter zone values (mm) for GFLX and their complexes.
(B) [Y(GFLX)2(H2O)Cl]Cl2ꢂ11H2O and (C) [ZrO(GFLX)2H2O]Cl2ꢂ14H2O.
Compounds
Microbial species
Bacteria
A
B
C
Assignments
Fungi
0.97–1.23
1.44–1.46
2.90–3.39
3.72
3.98–4.01
–
1.132
1.142–1.273
1.320
3.336
3.523, 3.589
3.717, 3.795
4.171–4.277
7.456
dH, ACH2; cyclopropane
dH, ACH3; piperazine
dH, ANH; piperazine
dH, ACH3; methoxy
dH, ANACH2
E. coli
P. aeruginosa
S. aureus
P. rotatum
T. sp
1.312, 1.326
3.302, 3.367
3.572
3.742
4.088
GFLX
20
31
29.5
28
0
28
37
34
33
0
32
48.5
39
54
0
0
0
0
0
0
0
0
0
0
0
Y(III)/GFLX
Zr (IV)/GFLX
U(VI)/GFLX
Control (DMSO)
dH, H2O
7.5
7.555
dH, A+NH2
7.84, 8.79
10.8, 11.3
8.677
–
7.811, 8.713
–
dH, ACH aromatic
dH, ACOOH
Fig. 6. Statistical representation for biological activity of gatifloxacin and its
complexes.
Table 7. Surprising GFLX–Y, GFLX–Zr and GFLX–U complexes show
excellent activity against three types of bacteria and no antifungal
activity observed for ligand and their metal complexes as show in
Fig. 6.
The enhanced intrinsic activity of complexes can be explained
on the basis of cell permeability, the lipid membrane around the
cell favors the penetration of lipid-soluble materials; liposolubility
is an important factor that controls the antimicrobial activity. On
complexation the polarity of the metal ion will be reduced due
to overlap of ligand orbital and partial sharing of the positive
charge of the metal ion with donor groups [43,44]. It is likely that
the increased liposolubility of the ligand upon metal chelation may
contribute to its facile transport into the bacterial cell which blocks
the metal binding sites in enzymes of microorganisms [40].
Fig. 5. 1H NMR spectra of: (A) [Y(GFLX)2(H2O)Cl]Cl2ꢂ11H2O; (B) [ZrO(GFLX)2-
H2O]Cl2ꢂ14H2O complexes in DMSO, dTMS
.
complexes in DMSO-d6 (Fig. 5) exhibit the OAH proton peak at d:
4.171–4.277 ppm, due to the presence of water molecules in the
complexes. The resonance of the carboxylic proton (COOH) is not
detected in the spectra of the two complexes that suggest the coor-
dination of gatifloxacin through its carboxylato oxygen atoms [40].
Also on comparing main peaks of gatifloxacin with its complexes, it
is observed that all the peaks of the free ligand are present in the
spectra of the complexes with chemical shift upon binding of the
quinolones to the metal ion [41].
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