Cu(II) COMPLEXATION WITH LEVOFLOXACIN: RTT AND DIFFERENTIAL-THERMAL ANALYSIS

ABSTRACT

In this paper  we studied a new complex compound based on (LEVH₂) ₂[Cu₃Cl₉(H₂O) ₂] Cl, derived from levofloxacin (LEV) and Cu (II) ions. This complex compound structure  is studied by X-ray diffraction analysis (X-ray DA) of LEV and its complex revealed that the molecule (LEVH₂) ₂ [Cu₃Cl₉(H₂O) ₂] Cl consists of a pentahedral [Cu₃Cl₉(H₂O) ₂] ³⁻ anion, two like-charged (LEVH₂) ²⁺ cations, and one chloride anion and confirmed that the synthesized complex. Also, differential thermal analysis (DTA) of the complex demonstrated that the thermal decomposition of its organic component occurs in distinct stages, beginning at 75°C and concluding at 370°C.

АННОТАЦИЯ

В данной научной работе описывается изучение нового комплексного соединения (LEVH₂)₂[Cu₃Cl₉(H₂O)₂]Cl, образованного левофлоксацином (LEV) и ионом Cu (II). В результате исследования LEV и его комплексного соединения методом PCA установлено, что молекула вещества (LEVH₂)₂[Cu₃Cl₉(H₂O)₂]Cl образует комплексное соединение, состоящее из пентаэдрического [Cu₃Cl₉(H₂O)₂]^3-, двух одноименно заряженных катионов (LEVH₂)²⁺ и одного хлорид-аниона. Установлено, что синтезированный комплекс имеет пентаэдрическую структуру.

Анализ комплекса методом ДСК показал, что термическое разложение органического компонента в его составе происходит по-разному, начиная с 75°С и заканчивая 370°С.

Keywords: Levofloxacin, chloride anion, pentagonal pyramid, Hirschfeld surface.

Ключевые слова: левофлоксацин, хлорид-анион, пентагональная пирамида, поверхность Гиршфельда.

Introduction.

According to the results of Levofloxacin (LEV) fluoroquinolone complexes are the most effective fluoroquinolones, which is a biologically active compound used in medical practice. In addition, an antibacterial agent against even very small amount of its gram-negative and some gram-positive bacteria [2.3.15] and is used in the clinical treatment of many infections, such as chronic prostatitis, skin and soft tissue infections, pulmonary and urinary tract infections [4-6]. Such types of compounds are studied by many scientists such as Golovnev N.N[16], Vasiliev A.D[14] and they have shown that it has certain bioactive properties, Metal complexes of LEV containing a pyridine ring have been synthesized and studied [7-8]. In addition, scientists such as Bijay Lakhmi Pradhan, Jai Prakash Yadav, Lekhan Lodhi [9,10,11,12,13] have also carried out  several research works in this area.

All chemicals and solvents were purchased from commercial sources (Sigma-Aldrich) and used without further purification. Mass spectra were obtained using a 6420 triple quadrupole mass spectrometer (Agilent Technologies, USA). Ionization was performed using electrospray ionization, and mass spectra were recorded under the following experimental parameters: m/z range 300-1350, drying gas (nitrogen) flow rate of 3 ml/min, temperature of 300°C, gas pressure at the nebulizer needle of 20 psi, fragmentation voltage of 35 V, and capillary voltage of 3500 V. Mass spectra of some of the synthesized compounds are provided in the appropriate sections of the discussion of the results.

During the research, the results of elemental analysis were determined using the EuroVector EA3000 Series CHNS-O elemental analyzer installed at the Institute of Bioorganic Chemistry of the Uzbek Academy of Sciences in Uzbekistan [106; pp. 1094-1106]. The analyzer is designed to simultaneously determine the amounts of carbon, hydrogen, nitrogen, and sulfur in powdered substances. The operation of the device is based on the principle of dynamic combustion in an oxygen atmosphere, followed by the separation of the resulting gaseous products (CO2, H2O, N2) by chromatographic methods. [17]

Experimental part.

In the experimental part of the research, a solution of LEV in dilute hydrochloric acid and solutions of copper (II) chloride were used. The resulting solutions were heated and mixed using a mechanical stirrer at a temperature of 30–35°C for 20–25 minutes. They were then left at room temperature with the container partially uncovered for further observation. As a result, green crystals formed at the bottom of the vessel after 8–12 days. The structure of the complex was determined using the RTD method. The reaction equation for the formation of the complex was proposed as follows: (Figure 1).

Figure 1. Synthesis reaction of metalcomplex containing (LEVH₂)₂[Cu₃Cl₉(H₂O)₂] Cl

Based on the IR spectrum and RTT data of the obtained complex, Hirshfeldsirt analysis was also studied.

Analysis of the results obtained.

As a result of the reaction of levofloxacin with CuCl2∙2H2O, the synthesis of the complex compound (LEVH2)2[Cu3Cl9(H2O)2] Cl was carried out. The structures of the obtained complex compounds are presented in Figure 2.

Figure 2. Scheme of the structure of the complex compound (LEVH₂)₂[Cu₃Cl₉(H₂O)₂] Cl

The molecular structure and crystallographic data of the (LEVH₂)₂[Cu₃Cl₉(H₂O)₂] Cl complex are presented in Figure 3 and Table 1. The molecular structure of the complex, which has a cluster-type crystal structure (LEVH₂)₂[Cu₃Cl₉(H₂O)₂] Cl (1), consists of a truncated pentagonal pyramidal [Cu₃Cl₉(H₂O)₂]₃- anion, two similarly charged (LEVH₂)²⁺ cations, and one chloride anion.

Table 1.

 Molecular structure and crystallographic data of (LEVH₂)₂[Cu₃Cl₉(H₂O)₂] Cl complex

Figure 3. Intramolecular hydrogen bonds in (LEVH₂)₂[Cu₃Cl₉(H₂O)₂] Cl are shown as solid lines

The Cu2+ ions have a cluster-type pentagonal pyramidal coordination: the average Cu1-O5 distance is 1.991Å, the average Cu1-Cl1, Cu1-Cl2 and Cu1-Cl4 distances are 2.265Å, 2.235Å, 2.373Å, respectively. The average Cu1-Cl3 distance is 2.654Å. The bond lengths and most of the angles of the LEV2+ cations are very similar to those of LEV∙HCL. The piperazine ring has an armchair conformation: the dihedral angles of N(3)C(17)C(16)N(2) and N(3)C(15)C(14)N(2) are -58.57 and 56.750, respectively. The dihedral angle of the -CH3 group attached to the N(3) atom in the piperazine ring is C(18)N(3)C(15)C(17) equal to 124.830, while the angles of C15-N3-C18 and C17-N3-C18 are 111.64 and 112.300, respectively. The quinolone ring is in a fully flattened state.

Figure 4. Interaction energies of the corresponding molecules in the (LEVH₂)₂[Cu₃Cl₉(H₂O)₂]Cl complex (kJ/mol)

Hydrogen bonds and supramolecular properties in the crystal structure, neighboring (LEV)²⁺ cations are oriented antiparallel to each other (Figures 3 and 5). The aromatic part of the two (LEV)²⁺ cations is displaced relative to each other, and the arrangement of the aromatic rings does not allow for the formation of π-π interactions in the crystal.

Figure 5. Intermolecular hydrogen bonds in (LEVH₂)₂[Cu₃Cl₉(H₂O)₂]Cl are shown as solid lines

To investigate the thermal properties of the crystal form of (LEVH2)2[Cu3Cl9(H2O)2]Cl, a Differential Scanning Calorimetry (DSC) study was conducted (Fig. 6). The DSC analysis revealed that the thermal decomposition of the organic component in the complex occurred between 75°C and 370°C. The DSC curves illustrate this process through endothermic and exothermic effects, indicating the cleavage of existing chemical bonds and the formation of new ones. The nature of the DSC curves for the (LEVH₂)₂[Cu₃Cl₉(H₂O)₂]Cl complex is practically the same. The first curve shows endothermic effects at 63.40C and ∆Q = -728J/g, and the second curve shows endothermic effects at 288.20C and ∆Q = -579.7 J/g, with expansion at 347.10C, ∆Q = 1127 J/g, leading to the melting of the substance and subsequent destruction, that is, decomposition, of the substance upon heating.

Figure 6. DSK analysis of the (LEVH₂)₂[Cu₃Cl₉(H₂O)₂]Cl complex

As a result, it begins to decompose into water and the (LEVH2)2+ ion. Copper (II) chloride is formed as a thermolysis product.

Conclusion. As a result of the study of LEV and its complex compound by the RTT method, the following conclusion can be drawn: the substance molecule (LEVH₂)₂[Cu₃Cl₉(H₂O)₂]Cl (1) formed a complex compound consisting of [Cu₃Cl₉(H₂O)₂]^3- in the pentahedral form, two similarly charged (LEVH₂)²⁺ cations, and one chloride anion. It was found that the synthesized complex has a pentahedral structure and that water is located in the inner sphere in the complex compounds. It was concluded that the complex compounds synthesized on the basis of levofloxacin are in the form of crystal hydrates.

References:

1. Maouche N., Meskine D., Alamir B., Koceir E. A. Trace elements profile is associated with insulin resistance syndrome and oxidative damage in thyroid disorders: manganese and selenium interest in Algerian participants with dysthyroidism // Journal of Trace Elements in Medicine and Biology. – 2015. – Vol. 32. – PP.112-121.
2. Gouaref I., Bellahsene Z., Zekri S., Alamir B., Koceir E.A. The link between trace elements and metabolic syndrome/oxidative stress in essential hypertension with or without type 2 diabetes // Annales de Biologie Clinique (Paris) – 2016. – Vol.74. – PP. 233-243.
3. Agay D., Anderson R.A., Sandre C. Alterations of antioxidant trace elements (Zn, Se, Cu) and related metal-enzymes in plasma and tissues following burn injury in rats // Burns. – 2005.–Vol.31. – PP. 366-371.
4. Rayssiguier Y., Gueux E., Nowacki W., Rock E., Mazur A. High fructose consumption combined with low dietary magnesium intake may increase the incidence of the metabolic syndrome by inducing inflammation // Magnesium Research. – 2006. – Vol. 19. – PP. 237-243.
5. Daniele S., Katalin V., Sarolta T., Giovanni M., Eugenio G. VO²⁺ Complexation by Bioligands Showing Keto–Enol Tautomerism: A Potentiometric, Spectroscopic, and Computational Study // Inorg. Chem. – 2011. – №50 (20). – PP. 10328-10341.
6. Frost L., Osman A., Geipel G., Viehweger K., Moll H., Bernhard G. The Interaction of U (VI) with Some Bioligands or the Influence of Different Functional Groups on Complex Formation // The New Uranium Mining Boom. – 2011. – PP. 595-606.
7. Mohamed M.M., Shoukry M.M. Interaction of diphenyltin (IV) dichloride with some selected bioligands // Chem Pharm Bull (Tokyo). – 2001. – № 49(3). – РP. 253-257.
8. Warren M. J., Raux E., Schubert H. L., Escalante-Semerena J. C. The biosynthesis of adenosyl cobalamin vitamin B12 // Nat. Prod Rep. – 2002. – Vol.19. – PP. 390-412.
9. Gad N. Role and Importance of Cobalt Nutrition on Groundnut (Arachis hypogaea) Production // World Applied Sciences Journal. –2012. – №20 (3). – PP. 359-367.
10. Hokin B., Adams M., Ashton J., Louie H. Comparison of the dietary cobalt intake in three different Australian diets // Asia Pac. J. Clin. Nutr. – 2004. – №13 (3). – PP. 289-291.
11. Salih B.M., Satyanarayana S. Vitamin B12 models: Synthesis and characterization of cyano-bridged dicobaloximes and antimicrobial activity // African Journal of Pure and Applied Chemistry. – 2009. – №.3 (9). – PP.170-176.
12. Kennedy D.G., Kennedy S., Blanchflower W.J., Scott J.M., Weir D.G., Molloy A.M., Young P.B. Cobalt-vitamin B12 deficiency causes accumulation of odd-numbered, branched-chain fatty acids in the tissues of sheep // Br. J. Nutr. – 1994. – №86 (1). – PP. 67-76.
13. Liu L., Zhang H., Meng X., Yin J., Li D., Liu C. Dinuclear metal (II) complexes of polybenzimidazole ligands as carriers for DNA delivery // Biomaterials. – 2010. – Vol.31. – P/p. 1380-1391.
14. Bouchard L.S., Anwar M.S., Liu G.L., Hann B., Xie Z.H. Picomolar sensitivity MRI and photoacoustic imaging of cobalt nanoparticles // Proc. Nat. Acad. Sci. USA. –2009. – Vol.106. – PP. 4085-4089.
15. Jiang R., Yin J., Hu S., Meng X., Liu C. Cobalt (II)-polybenzimidazole complexes as a nonviral gene carrier: effects of charges and benzimidazolyl groups // Curr Drug Deliv. –2013. – Vol.10. – PP. 122-133.
16. Artetxe B., Reinoso S., San Felices L., Martin-Caballero J., Gutierrez-Zorrilla J.M. Trans-Di-aqua-bis-(pyridazine-3-carboxylato-[kappa]2N₂O)-cobalt (II) dehydrate // Acta Crystallogr., Sect. E. – 2013. – №69. – PP. 420-421.
17. Bozarova M.I. Cu (II) with levofloxacin complex: hirshfeld surface and in spectrum analysis // Scientific bulletin of Namangan state university. №-4 2024 - PP. 188-191.