Pii: s0162-0134(01)00182-9

Journal of Inorganic Biochemistry 84 (2001) 163–170 www.elsevier.nl / locate / jinorgbio Complexes of Ni(II) and Cu(II) with ofloxacin Crystal structure of a new Cu(II) ofloxacin complex Benigno Mac´ıas *, Mar´ıa V. Villa , Inmaculada Rubio , Alfonso Castineiras , Joaqu´ın aDepartamento de Qu´ımica Inorganica, Facultad de Farmacia, Universidad de Salamanca, Campus Unamuno, 37007-Salamanca, Spain bDepartamento de Qu´ımica Inorganica, Facultad de Farmacia, Universidad de Santiago de Compostela, Santiago de Compostela, Spain cDepartamento de Qu´ımica Inorganica, Facultad de Farmacia, Universidad de Valencia, Valencia, Spain Received 6 September 2000; received in revised form 25 January 2001; accepted 29 January 2001 Several coordination compounds formed between Ni(II) or Cu(II) with ofloxacin have been synthesised and characterised. According to elemental chemical analysis and FT-IR spectroscopy data, direct reaction of Ni(II) and Cu(II) salts with ofloxacin leads to formation ofprecipitates for which mass spectrometry demonstrates their polymeric nature. However, crystalline [Cu(oflo) (H O)]?2H O is formed if the reaction is carried out in the presence of ammonia. This complex crystallises in the triclinic system, space group P-1 with a59.2887(12), b511.2376(14), c517.874(2) A, a 592.12(3), b 595.39(3), g591.71(3)8 and Z52. The local geometry around theCu(II) ion is a slightly distorted square base pyramid. Electronic spectra, magnetic susceptibility measurements and EPR spectra of thesynthesised complexes indicate a tetragonal environment.
 2001 Elsevier Science B.V. All rights reserved.
Keywords: Ofloxacin; Quinolones; Nickel complexes; Copper complexes metal cations have been reported in the literature, speciallythose dealing with cinoxacin [2–6], although some studies on coordination compounds between ofloxacin (hereafter oflo) or ciprofloxacin with metal cations commonly found zoxacine-6-carboxilic acid), is a nalidixic acid analog with in several drugs used as antacids have been also reported broad spectrum antibacterial activity (Scheme 1). It [7]. These studies have been mainly directed towards belongs to the fluorquinolones group, which act as specific identifying the groups directly attached to the metal site, inhibitors of the bacterial DNA-gyrase, the enzyme respon- and establishing the structure of the coordination com- sible for converting double-stranded DNA into a negative pounds thus formed. In the present work, we report on the superhelical form [1].
interaction between several Cu(II) and Ni(II) salts with Studies of interaction between several quinolones with oflo, analysing the effect of the counteranion in the startingmetal salt on the nature of the compound finally formed, aswell as the role of such anions on the groups relevant inthe coordination to such a cation, determining by X-raydiffraction (XRD) procedures the molecular structure ofone of the complexes isolated.
2.1. Materials and methods Ofloxacin was provided by Sigma and all reagents used *Corresponding author. Tel.: 134-923-294-524; fax: 134-923-294- were of analytical grade.
E-mail address: bmacias@gugu.usal.es (B. Mac´ıas).
Chemical analyses for carbon, hydrogen, and nitrogen 0162-0134 / 01 / $ – see front matter  2001 Elsevier Science B.V. All rights reserved.
B. Mac´ıas et al. / Journal of Inorganic Biochemistry 84 (2001) 163 –170 were performed on a 2400 elemental analyzer from Perkin- Crystal data and structure refinement for [Cu(oflo) (H O)]?2H O Elmer. Nickel and copper were determined on a ICPspectrometer (Perkin-Elmer model 2380 Plasma 2).
Empirical formula IR spectra were recorded using KBr mulls and a Perkin- Elmer FT-IR instrument. Electronic spectra were recorded on a Shimadzu UV-240 double beam with a diffuse reflectance accessory and a Hewlett-Packard 8452A diode P-1 (No. 2) Unit cell dimensions The room-temperature magnetic moment was measured by the Faraday method on a AZTEC DSM8 pendulum- type susceptometer and electron paramagnetic resonance spectra were recorded at X-band frequencies with a Bruker The water content in the complexes was determined by thermal analysis, using a Perkin-Elmer TGA-7 thermobal- Calculated density (mg / m ) ance and a DTA-7 differential thermal analysis apparatus, Absorption coefficient (mm both operating at a heating rate of 58C / min and under oxygen as the reaction atmosphere.
Crystal size (mm) u range for data collection (8) Molecular masses were measured by Servicio de Masas 2 8 5 h 5 12 Autonoma de Madrid, Spain) by the FAB 2 14 5 k 5 11 method with samples held on a nitrobenzyl alcohol (NBA) 2 23 5 l 5 19 matrix and L-SIMS ionization mode, in a VG Autospec Reflections collected / unique 11012 / 7673 [R apparatus; the source was maintained at 308C and 35 keV, Completeness to u 5 28.06 (%) Max. and min. transmission ion were used.
Data / restraints / parameters Goodness-of-fit on F 2.2. Syntheses of the complexes Final R indices [I . 2s(I )] R 50.0703, wR 5 0.1433 R indices (all data) R 5 0.1617, wR 5 0.1698 The complexes have been prepared by direct reaction Largest diff. peak and hole (e / A ) MS spectra for the compound Cu(oflo)Cl?2.5H O.
B. Mac´ıas et al. / Journal of Inorganic Biochemistry 84 (2001) 163 –170 between oflo with the corresponding metal cations in theform of water-soluble salts, such as chlorides, sulphates ornitrates. Although in preliminary studies 0.1 M NaOH wasadded to the solution in order to improve solubility of oflo,it was observed that addition of the metal cation gave riseto the same effect, the nature of the complexes formedbeing independent on the presence of NaOH. A typicalprocedure was as follows: 0.41 mmol of the metal saltdissolved in 5 ml H O were added to a magnetically stirred solution containing 0.82 mmol oflo suspended in 25ml H O. As the amount of cation added was increased, oflo dissolved, the solution attaining an emerald-greencolour in the case of Ni(II); the concentration of the finalsolution (by elimination of the solvent or by drying in adesiccator with concentrated sulphuric acid) gave rise to abright green precipitate with a sponge-like aspect, whichwas filtered and washed with distilled water. For thecopper salts, the solution becomes deep blue and shortlyafter completing the addition of the salt a greenish-blueprecipitates is formed, which is filtered and washed alsowith distilled water. The solids formed have very lowsolubility in water, probably because of their polymericnature (see below). Yields were greater than 90% in bothcases. Experimental data fit well with the calculatedformula if the presence of crystallization water moleculesis assumed, as checked by thermal analysis. Ni(oflo)(SO ) ?2.5H O. Calc.: C, 42.2; H,4.7; N, 8.2; Ni, 11.5; H O loss, 8.9. Found: C, 42.6; H, 4.9; N, 8.2; Ni, 10.9; H O loss 9.4. Ni(oflo)Cl?2.5H O. Calc.: C, 43.3; H, 4.8; N, 8.4; Ni, 11.8; H O loss, 9.0. Found: C, 43.7; H, 4.9; N, 8.1; Ni, 11.4; H O loss, 9.1. Ni(oflo)(NO )?2.5H O. Calc.: C, 41.1; H, 4.6; N, 10.7; Ni, 11.2; H O loss, 8.6. Found: C, 41.2; H, 4.8; N, 10.9; Ni, 10.9; H O loss, 8.3.
Fig. 2. FT-IR spectra for the compounds: (a) ofloxacin, (b) Ni(oflo)Cl? ?2.5H O. Calc.: C, 41.8; H, 4.7; N, 8.1; 2.5H O, (c) Ni(oflo)(SO ) ?2.5H O, (d) Ni(oflo) (NO )?2.5H O and (e) Cu, 12.3; H O loss, 8.7. Found: C, 42.0; H, 4.9; N, 8.1; Ni(oflo) ?3H O.
Cu, 12.2; H O loss, 8.8. Cu(oflo)Cl?2.5H O. Calc.: C, 42.9; H, 4.8; N, 8.3; Cu, 12.6; H O loss, 8.9. Found: C, Cu(oflo)(NO )?2.5H O. Calc.: N, 40.7; H, 4.6; N, 10.6; Cu, 12.0; H O loss, 8.5. Found: C, 41.1; H, 4.7; N, 10.8; Selected bond lengths (A) and angles (8) for [Cu(oflo) (H O)]?2H O Cu, 12.2; H O loss, 8.5.
Under the experimental conditions used, it was not possible to isolate the compounds in a crystalline form, but single crystals were isolated if the synthesis is carried out in the presence of ammonia as follows: 0.35 mmol of the metal salt are added to 0.7 mmol oflo previously dissolved in 10 ml of 1 M NH . A bright green (in the case of nickel) or deep blue (in the case of copper) solution is formed, although in the case of the copper solution, it turns into emerald-green after a few hours. Crystals, which are separated by filtration, are formed after 2 or 3 days.
Ni(oflo) ?3H O. Calc.: C, 51.8; H, 5.3; N, 10.1; Ni, 7.0, H O loss, 6.5. Found: C, 51.6; H, 5.4; N, 10.2; Ni, 7.4; H O loss, 6.8. [Cu(oflo) (OH )]?2H O. Calc.: C, 51.3; H, 5.3; N, 10.0; Cu, 7.6; H O loss, 6.4. Found: C, 51.4; H, Symmetry transformations used to generate equivalent atoms: [1 5.5; N, 10.2; Cu, 7.9; H O loss, 6.7. The Cu-complex x 1 1, y, z.
B. Mac´ıas et al. / Journal of Inorganic Biochemistry 84 (2001) 163 –170 crystals prepared could be analysed by XRD in order to 3. Results and discussion
determine their crystalline structure; unfortunately, the Nicomplex crystals did not give rise to adequate diffractions.
3.1. Mass spectrometry The results obtained support the assumption above about 2.3. X-ray structure determination of [Cu(oflo) (H O)]? the polymeric nature of the compounds isolated. As shown in Fig. 1 for the Cu complex prepared from the chloride, peaks due to m /z values corresponding to different stoich- A light green block crystal of [Cu(oflo) (H O)]?2H O iometries (depicted in Fig. 1) are recorded, in addition to was mounted on a glass fiber and used for data collection.
the most intense signal at m /z 5784.2, corresponding to Crystal data were collected at 291 K using a Bruker Smart the molecular ion, [Cu(oflo) ] , and that at m /z 5424.1, corresponding to [Cu(oflo)] . Similar results were also MoKa radiation ( l50.71073 A) was used throughout. The obtained for the Ni complexes, although in this case they data were processed with SAINT [8] and corrected for are associated with the NBA matrix. It can be tentatively absorption using SADABS (transmissions factors: 1.000– concluded that the original polymer is broken into different 0.644) [9]. The structure was solved by direct methods fragments, with different sizes, in the ionization chamber.
using the program SHELXS-86 [10] and refined by full- Both the water molecules and the counteranions seem to be matrix least-squares techniques against F using SHELXL-97 absent in the detected ionic fragments, so we may conclude [11]. Positional and anisotropic atomic displacement pa- they are only weakly bonded to the main fragments.
rameters were refined for all nonhydrogen atoms. Hydro-gen atoms were located from difference syntheses andrefined isotropically. The H atoms of two water molecules, 3.2. IR spectra O(2) and O(3) in the next tables, were not located. Atomicscattering factors were from the International Tables for Although the counteranions are not detected by MS, X-ray Crystallography [12]. Molecular graphics were from their presence in the solids isolated is definitively con- PLATON [13]. A summary of the crystal data, experimental cluded from the FT-IR spectra. So, bands are detected at details and refinement results are listed in Table 1.
(sulphate) or 1351 cm Fig. 3. ORTEP diagram for [Cu(oflo) ?H O]?2H O with the atom-labelling scheme.
B. Mac´ıas et al. / Journal of Inorganic Biochemistry 84 (2001) 163 –170 in Fig. 2. The band at 1713 cm due to the carboxylic Atomic coordinates ( 310 ) and equivalent isotropic displacement param- group is not detected in the spectra of any of the complexes, indicating that this moiety participates in the bonding to the metal ion [15]. However, the techniquedoes not permit a definitive conclusion about the participa- tion of the ketonic group in the bonding to the metal; the corresponding band is recorded at 1622 cm spectrum of oflo, and a band close to this position in the spectra of the complexes could be due to the ketonic group or to the carboxylate group bonded to the metal ion. If this band is due to the ketonic group, the antisymmetric and symmetric modes of the carboxylate group would account for the bands recorded at 1575 and 1570 cm ly. However, if the ketonic group participates in the bonding to the metal we would expect a shift of its stretching band towards lower wavenumbers, thus corre- sponding to the band recorded at 1575 cm bands at 1620 ad 1470 cm would correspond to the carboxylate group. We should conclude that FT-IR spec- troscopy, by itself, does not permit a definitive answer to the way the ligand is bonded to the metal cation. Finally, the band at 508 cm could be ascribed to the Ni–O stretching mode [2,4]. The IR spectra of the Cu(II) complexes are similar to that Ni(II) complexes.
3.3. Crystal structure of [Cu(oflo) (H O)]?2H O An ORTEP diagram of the complex [Cu(oflo) (H O)]? 2H O including the atomic numbering scheme is shown in Fig. 3 and selected bond distances and angles are presented in Table 2. Atomic coordinates and equivalent isotropic displacement coefficients are shown in Table 3.
The crystalline structure data definitively demonstrates the participation of the ketonic group of the oflo molecule in the bonding to the metal cation, the Cu(II) cation becoming five coordinated in a square base pyramidal structure. The copper atom is located 0.205 A above the average plane defined by oxygens O11, O31, O13 and O33, which deviate from such average plane 0.039 A above (O11 and O31) and 0.039 A below (O13 and O33).
The apical position would be occupied by a water mole- cule and the four corners of the base would be occupied by four oxygen atoms, two from the carboxylate groups and the two remaining from the ketonic groups (from two oflo molecules). The metal atom placed in a crystallographic inversion centre relates the two bidentate oflo ligands that bind through one oxygen of the carboxylate group and the exocyclic carbonyl oxygen. The Cu–O distances are similar to those reported previously for the corresponding complex with cinoxacin [5]. The geometry is not totally regular, although distortions are not too severe. The Cu–O (carboxylate) distances are slightly lower than the Cu–O (ketonic) distances. The O–Cu–O angles of a given oflo molecule are larger than the O–Cu–O angles with oxygen is defined as one third of the trace of the orthogonalised U atoms from different oflo molecules, although this effect could also arise from the intrinsic structure of the oflo

B. Mac´ıas et al. / Journal of Inorganic Biochemistry 84 (2001) 163 –170 molecule. In addition two water molecules (shown in Fig.
suggesting the same chromophore in both states. A broad 4, pertinent crystallographic information given in Tables 2 band is recorded at 650 nm (e 5 12 M and 3) provide additional crystalline stability through a shoulder at 740 nm. This band is characteristic of regular network of hydrogen bond interactions.
or distorted octahedral structures; the main absorption is associated to transition n ( A → T (F)) and the shoul- 3.4. Electronic spectra der to the spin-forbidden transition A → E , which is usually recorded close to the main absorption, specially in The electronic spectra recorded in solid state and in complexes where Dq / B is close to 1, where the energies of aqueous solution of the Ni(II) complexes are similar, states T (F) and E are very close [16,17]. Other bands Fig. 4. Stereoscopic view of the unit cell showing the molecular packing and the intermolecular hydrogen bonding (dashed).
B. Mac´ıas et al. / Journal of Inorganic Biochemistry 84 (2001) 163 –170 Fig. 5. Electronic spectra in the solid state for: (top) Cu(oflo)Cl?2.5H O; (middle) Cu(oflo) (NO )?2.5H O and (bottom) Cu(oflo)(SO ) in the ultraviolet region at 332, 290, and 258 nm (e 5 35 000–65 000 M ) are due to transitions between energy levels of the ligands.
The solid spectra of the polymeric Cu(II) complexes (Fig. 5) show a broad asymmetric band with splittings thattentatively correspond to the splitting expected for thelocal C4v symmetry of these cations in the square pyramid Fig. 6. EPR spectra for the compounds: (a) Cu(oflo)Cl?2.5H O; (b) ?2.5H O and (c) [Cu(oflo) ?H O]?2H O.
3.5. Magnetic susceptibility and EPR spectra The magnetic moment measured at room temperature EPR values was obtained by simulation [20]. The EPR for the Ni complexes is similar in all cases, with m 53.12 spectrum of polycrystalline Cu(oflo)Cl?2.5H O complex BM, which can be related to an octahedral (regular or were g 52.11, g 52.17, g 52.41 and A 5150 G, rather distorted) environment [18]. The value measured is larger close to those reported for a square base pyramid structure than the spin-only magnetic moment, 2.83 BM, and such [21]. The value for the R parameter [R 5 ( g g ) /( g g )] an increase should be due to contributions from the orbital is 0.25, i.e. lower than 1, thus indicating that the unpaired electron is located in orbital dx y . The EPR spectrum of The value measured for the Cu complexes was m 5 the Cu(oflo)(SO ) ?2.5H O is axial slightly rhombic with 1.98 BM, also larger than the spin-only value, 1.73 BM.
g parameters according to the simulation programme, g 5 Such divergence is not uncommon in mononuclear Cu(II) 2.04, g 5 2.07, g 5 2.27 and A 5170 G. Finally, the complexes due to the mixing-in of some angular moment values for the crystalline complex [Cu(oflo) (H O)]?2H O from the closely lying excited states via spin–orbit cou- were g 5 2.22, g 5 2.00 and A 5 160 G, very close to those reported in the literature for a square base pyramid EPR spectroscopy is more sensitive to the chemical structure, in agreement with the structure concluded for environment of the metal cation, and thus permits discrimi- this complex from the XRD data discussed above (Fig. 3).
nation between the properties of the different complexes Nevertheless, according to all these data, the local geome- isolated, as shown in Fig. 6 for the Cu complexes. The try around copper should be close to tetragonal in all cases.
B. Mac´ıas et al. / Journal of Inorganic Biochemistry 84 (2001) 163 –170 [10] G.M. Sheldrick, Acta Cryst. A46 (1990) 467.
[11] G.M. Sheldrick, SHELXL-97. Program for the Refinement of Crystal Structures, University of Goettingen, Goettingen, 1997.
The authors thank CICYT (grant PM97-0105-C02-02 [12] International Tables for X-ray Crystallography, Vol. C, Kluwer, and IN96-0252) for financial support. Critical reading of Dordrecht, 1995.
the manuscript by Professor V. Rives is also acknowledged.
[13] A.L. Spek, PLATON. A Multipurpose Crystallographic Tool, Ut- recht University, Utrecht, 2000.
[14] K. Nakamoto, in: Infrared and Raman Spectra of Inorganic and Coordination Compounds, Part B: Applications in Coordination, Organometallic and Bioinorganic Chemistry, 5th Edition, Wiley,New York, 1997.
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