Synthesis, spectroscopic and thermogravimetric interpretations of UO 2 (II), ZrO(II), Zr(IV), VO(II) and V(V) cipro ﬂ oxacin antibiotic drug complexes

New ﬁ ve cipro ﬂ oxacin (CIP) complexes of dioxouranium(II), oxozirconium(II), zirconium(IV), oxovanadium(II) and vanadium(IV) in the proportion 1:2 have been prepared using CIP as a drug chelate with UO 2 (NO 3 ) 2 . 6H 2 O, ZrOCl 2 . 8H 2 O, ZrCl 4 , VOSO 4 . xH 2 O and V 2 O 5 respectively. The CIP complexes have been characterized based on the elemental analysis, molar conductance, magnetic, (FTIR & 1 HNMR) spectral and thermal studies. The molar conductance studies of the synthesized complexes in DMSO solvent with concentration of 10 –3 M indicate their non-electrolytic properties. At room temperature, the magnetic moment measurements revealed a diamagnetic behavior for all CIP prepared complexes. The different formulas of the new complexes can be represented as [UO 2 (CIP) 2 (NO 3 ) 2 ] ( I ), [VO(CIP) 2 (SO 4 )(H 2 O)] ( II ), [V 2 (O)(O 2 ) 2 (CIP) 2 ] ( III ), [Zr(O)(CIP) 2 (Cl) 2 ] ( IV ), and [Zr(CIP) 2 (Cl) 4 ] ( V ). The thermal analysis data of the complexes indicates the absence of coordinated water molecules except for vanadyl(II) complex ( II ). The CIP chelate is a uni-dentate ligand coordinated to the mentioned metal ion through terminal piperazinyl nitrogen. The transmission electron microscopy (TEM) investigation con ﬁ rms the nano-structured form of the complexes.


INTRODUCTION
Many drugs and active pharmaceutical agents included metal sites or metallo-pharmaceuticals binding, that can be coordinated or reacted with various metal ions and potentially infl uence their bioactivities and might also cause damages to their target biomolecules. Ciprofl oxacin (CIP) antibiotic drug belongs to the fl uoroquinolones family, which are bacteriostatic at low concentration and bactericidal at high concentrations 1-4 . The CIP drug has highly active against most Gram-negative pathogens including Pseudomonas aeruginosa and the Enterobacteriaceae. Fluoroquinolones are used to treat upper and lower respiratory infections, gonorrhea, bacterial gastroenteritis, skin and soft tissue infections and both uncomplicated and complicated urinary tract infections, especially those caused by Gram-negative than Gram-positive infections 2, 4 . Quinolones form metal chelates due to their ability to coordinated with different metal ions. In its metal complexes, the quinolones were reacted as a bi-dentate, unidentate and bridging bidentate ligand. Often, the quinolones are chelated in a bi-dentate manner via one of the oxygen atoms of deprotonated carboxylic group and the oxygen atom of carbonyl group. In rare cases, the quinolones can be chelated as bi-dentate ligand through oxygen atoms of carboxylic group or via two nitrogen atoms of piperazinyl ring. On the other hand, the quinolone drug can acts as a uni-dentate ligand towards the metal ion via the nitrogen atom of the terminal piperazinyl ring 5- 25 [25]. The preparation and characterization of new metal complexes with ciprofl oxacin antibacterial agents are of great importance for understanding the drug-metal interaction and taking into account their potential pharmacological use. The aim of this article is the isolation and spectroscopic characterization of the UO 2 (II), ZrO(II), Zr(IV), VO(II) and V(V) complexes, as well as their structural using spectroscopic and thermal analysis techniques.

Synthesis of CIP complexes
The dioxouranium(II), oxozirconium(II), zirconium(IV), oxovanadium(II) and vanadium(IV) ciprofl oxacin complexes were synthesized by utilizing a 1:2 stoichiometry between metal ions and CIP ligand. A solution of 1.0 mmol of a metal ions UO 2 (NO 3 ) 2 · 6H 2 O, ZrOCl 2 · 8H 2 O, ZrCl 4 , VOSO 4 · xH 2 O and V 2 O 5 that previously soluble in 20 mL of distilled water was mixed to 2.0 mmol of ciprofl oxacin drug suspended in 50 of acetone solvent. The mixtures were continuously stirring with heated at ~ 60 o C under refl ux on a hotplate for about 15 hrs and then cooling overnight. The associated solid complexes were isolated by fi ltration, washed several times with 20 mL boiling water and 10 mL acetone then dried under vacuum over anhydrous CaCl 2 . After the dissolved of oxozirconium(II), zirconium(IV), oxovanadium(II) complexes in concentrated nitric acid, the presence of Cl − and SO 4 − − ions inside the coordination sphere of CIP complexes were investigated by using the AgNO 3 and BaCl 2 reagents. The yield of the products was about 71-78%. The solid complexes have a higher melting point above 250 o C. The elemental analyses (Calc./Found) and physical meaning of the CIP complexes can be listed in Table 1.

Elemental analysis and conductance measurements
The elemental analysis vales and some of the physical meaning (color and molar conductance), as well as the magnetic susceptibility of the dioxouranium(II), oxozirconium(II), zirconium(IV), oxovanadium(II) and vanadium(IV) ciprofl oxacin complexes (I-V), are introduced in Table 1. All synthesized CIP complexes are colored, slightly hygroscopic and thermally stable with high melting points, indicating a strong metal-ligand interaction. The fi ve solid CIP complexes are insoluble in most common organic solvents like ethyl alcohol, chloroform, diethyl ether, benzene, cyclohexan, carbon tetrachloride, but are partially soluble in DMSO and DMF solvents. The elemental analysis data (Table 1) 4 ] (V). The molar conductance data of the complexes in DMSO with gently heating at 10 -3 M concentration are found to be (Λ m = 7−24) ohm -1 · cm 2 · mol -1 , that indicating their non-electrolytic behavior 26 . Because of failed to isolate a pure single crystal, the X-ray crystal structure was not performed. Therefore, the solid complexes were interpreted based on the elemental analysis, FTIR, 1 H-NMR, TG/DTG analysis.

Infrared spectra
FTIR spectra of the fi ve CIP complexes are shown in Fig. 1a−c. The infrared frequencies of ciprofl oxacin drug and UO 2 (II), ZrO(II), Zr(IV), VO(II) and V(V) complexes ( Table 2) were assigned.

i. [UO 2 (CIP) 2 (NO 3 ) 2 ] (I) complex
The FTIR spectrum of the [UO 2 (CIP) 2 (NO 3 ) 2 ] (I) complex (Fig. 1a) shows distinguish frequencies at 1731 cm -1 and 1628 cm -1 which are assigned to ν(C=O) of carboxylic and carbonyl groups. These vibration bands are occur at the same or shifted to higher frequencies in Table 1. Elemental analysis and physical properties of CIP complexes comparison with the free CIP drug (1707 cm -1 and 1627 cm -1 ) 19-25 . These results confi rmed that the oxygen atoms of carboxylic and carbonyl groups didn't participate in the coordination towards UO 2 (II) metal ions. Therefore, ciprofl oxacin ligand acts as a neutral mono-dentate and coordinated to UO 2 (II) metal ion through -N atom of piperazinyl ring. This coordination mode rarely took place and, to this knowledge, unprecedented in quinolone drug interactions toward metal ions. The presence of four new absorption bands at 1568, 1298, 1037, and 747 cm -1 corresponding to ν 4 , ν 1 , ν 2 and ν 3 vibrations agree with frequencies reported for bi-dentate nitrate group 27 . These frequencies values confi rmed that the nitrate group is located inside the coordination sphere 27 . If the difference between (ν 4 − ν 1 ) is near to ~200 cm -1 , it's favored that the nitrate group has a covalency character 27 for the metal-nitrate chelating. The separation of highest frequency bands ν 1 and ν 4 (180-140 cm -1 ) in the complexes favors bidentate character of the nitrate group 27 . Accordingly, the most probable geometrical structure of this complex is shown in Formula A, where the two nitrato groups act as bidentate chelates while the two CIP molecules exhibit as mono-dentate ligands. The

ii. [VO(CIP) 2 (SO 4 )(H 2 O)] (II) and [V 2 (O)(O 2 ) 2 (CIP) 2 ] (III) complexes
The infrared spectra of the [VO(CIP) 2 Fig. 1b and their band assignments are given in produced in Table 2. The FTIR spectra of these complexes have two distinct bands at 1707 cm -1 and ~1620 cm -1 attributed to   Figure 1c show the infrared spectra of [Zr(O) (CIP) 2 (Cl) 2 ] (IV) and [Zr(CIP) 2 (Cl) 4 ] (V) complexes. By comparison between the vibration frequencies of free CIP drug ligand and two zirconium(IV/V) complexes, it was found that there are two absorption bands in the case of free CIP ligand at 1707 cm -1 and 1627 cm -1 . The fi rst band at 1707 cm -1 is assigned to the carboxylic group, this band was observed in the spectra of the zirconium(IV/V) complexes with shifted to the higher frequency at ~ 1730 cm -1 , indicating that the carboxylic group didn't share in the coordination towards metal ion. The other stretching vibration band presence at 1627 cm -1 is assigned to the ketone group, this band existed at 1628 cm -1 in the spectra of zirconium(IV/V) complexes in the same position of the CIP ligand, so it could be assigned to the uncoordinated of the ketone group towards metal ion. Similar to the UO 2 (II), VO(II) and V(V) complexes, the nitrogen atom of the piperazinyl ring is involved in the coordination to zirconium metal ion as shown in Formula D&E. The ν(Z=O) vibration in the [Zr(O)(CIP) 2 (Cl) 2 ] (IV) complex is observed as the expected frequency at 955 cm -1 is a good agreement with those known for many zirconyl(II) complexes 27,30 .

Electronic spectra and magnetic susceptibility
The electronic absorption spectra of the UO 2 (II), ZrO(II), Zr(IV), VO(II) and V(V) ciprofl oxacin complexes dissolved in DMSO solvent were scanned within the UV-Vis (200-800 nm) region. In the case of the CIP free ligand, there are two distinguish bands that were present at 275 and 325 nm due to n→π* and π→π* electronic transitions of the hydrocarbons, carboxylic and ketonic moieties. The absorption spectra of all synthesized complexes are similar to the free CIP ligand with slightly shifted, these can be confi rmed that the CIP ligand didn't change to the zwitterionic structure and both carboxylic and carbonyl groups not involved in the complexation towards metal ions. The magnetic susceptibility values of the dioxouranium(II), oxozirconium(II), zirconium(IV), oxovanadium(II) and vanadium(IV) ciprofl oxacin com-plexes (I-V) were calculated and revealed a diamagnetic nature of the complexes 32, 33 .

HNMR spectra
The 1 HNMR spectral assignments of CIP free ligand and UO 2 (II), ZrO(II) and V(V) complexes are listed in Table 3  The proton of the -COOH group didn't change and present at the same chemical shift, this meaning that the carboxylic group not participated in coordination process. The structures of the complexes of ciprofl oxacin with UO 2 (II), ZrO(II), Zr(IV), VO(II) and V(V) ions have been confi rmed from the elemental analyses, FTIR, molar conductance, UV-Vis and thermal analysis data. Thus, from the FTIR spectra, it is concluded that ciprofl oxacin behaves as a neutral unidentate ligand coordinated to the metal ions via the piperazine N atom. From the molar conductance data, it was found that the complexes are non-electrolytes. As a general formula, the investigated complexes structures can give as shown in Formulas A-E.

Thermo gravimetric analysis
In the present study, the heating rate was 10 o C/min under N 2 atmosphere and the mass loss was scanned from room temperature to 800 o C ( Fig. 2A-E). The thermal cracking of [UO 2 (CIP) 2 (NO 3 ) 2 ] (I) complex takes place through three DrTGA steps. The fi rst occurs at 118 o C and it corresponds to the mass loss of 17.71% with the elimination of nitrato coordinated groups and other terminal groups. The second step presence at 268 o C due to the start decomposition of CIP molecules with a mass loss 20.90%. The third decomposition step at 410 o C is assigned to the contentious decomposition of CIP molecule with a mass loss 15.21%. The UO 2 oxide which was polluted with few un-oxidized carbon atoms is the fi nal residual solid product at 800 o C. The [VO(CI-P) 2  ) respectively. These degradation peaks correspond to the decomposition of ciprofl oxacin and chlorine molecules with mass loss of 67.14 and 58.88% for complexes IV and V respectively. In both zirconium complexes, the ZrO 2 oxide polluted with few carbon atoms is the fi nal remaining product at 800 o C.

TEM investigation
The transmission electron microscopy images of the [UO 2 (CIP) 2