SYNTHESIS AND STRUCTURE OF A MONOLIGAND COMPOUND BASED ON Mn2+ AND CEFOTAXIME

ABSTRACT

Synthesis method studiedmonoligand complex compound of manganese (II) chloride with cefotaxime and its structure was determined. Elemental analysis was carried out to determine the composition of the resulting compound. The resulting compounds were studied by IR spectroscopy and thermal TG/DSC analysis. The resulting complexes have a chelate structure. In order to prove the individuality of the crystal lattice of the synthesized coordination compound, X-ray phase analysis of the starting substances and the synthesized coordination compound was carried out.

АННОТАЦИЯ

Изучен метод синтеза монолигандного комплексного соединения хлорида марганца (II) с цефотаксимом и определена его структура. Для определения состава полученного соединения был проведен элементный анализ. Полученные соединения исследованы методами ИК- спектроскопии и термического ТГ/ДСК анализа. Полученные комплексы имеют хелатную структуру. С целью доказательства индивидуальности кристаллической решетки синтезированного координационного соединения был проведен рентгенофазовый анализ исходных веществ и синтезированного координационного соединения.

Keywords: manganese coordination compounds, cefotaxime, cefotaxime complex, cephalosporins

Ключевые слова: координационные соединения марганца, цефотаксим, комплекс цефотаксима, цефалоспорины

Introduction. Research has shown that intermediate metal complexes with antibiotics are used as drugs to treat a number of human diseases. These metals exhibit varying states of oxidation and are capable of reacting with a number of negatively charged molecules. This activity of metal intermediates may provide unique therapeutic opportunities in the development of metal-based drugs with promising pharmacological applications. Advances in inorganic chemistry open up good opportunities for the use of metal complexes as therapeutic agents. The effect of metal complexes on living organisms differs from the effect of non-metals. Medicinal inorganic chemistry exploits the unique properties of metal ions to develop new drugs [1].

Analysis of literature on the topic. Cefotaxime is an antibiotic of the third-generation cephalosporin group, with a wide spectrum of action. It belongs to the amphoteric type of antibiotics [2] and contains aminothiazole and carboxyl groups. In an acidic environment it exists as a cation or zwitterion, in a neutral and alkaline environment it exists as an anion. In medicine it is used in the form of sodium salt NaCxm [3].

Cephalosporin molecules contain electron-donating functional groups, which enable interaction with metal cations to form complex compounds [4]. Every year, the study of complex compounds of beta-lactam antibiotics with metal cations, primarily the preparation and study of the properties of solid complexes, is becoming more and more relevant [5 – 7]. In medicine, zinc complexes look the most promising due to its low toxicity.

There is little literature data on zinc complexes of cefazolin. The preparation and study of complexes with the composition [ZnClCzl] have been reported [8; 9]. The authors of both studies suggest tetradentate coordination of the cefazolin anion with the participation of the nitrogen atoms of the side chain heterocycles and the oxygen atoms of the carboxylate and amide or beta-lactam groups.

However, these results contradict stoichiometry, which raises doubts about the reliability of the results of the work as a whole.

Zinc complex of cefotaxime composition [Zn (Cxm)₂)] ⋅3H₂O was obtained and studied in [10], but the authors of the work did not draw any conclusions about the structure of the coordination sphere of the complex. In [11], the preparation of a complex with the composition [Zn (Cxm)Cl₂(H₂O)₂] is reported with molecules rather than anions of cefotaxime.

Thus, according to the analyzed literature, information about the manganese complex of cefotaxime is insufficient, and it requires clarification, which was the goal of our study.

Research methodology. The complexes were obtained in the form of precipitation as a result of the interaction in a neutral aqueous solution of manganese chloride and cefotaxime sodium salt in a molar ratio of 1:2. After washing with water cooled to 5 ºC on the filter, the sediments were dried in air, first at room temperature, then in an oven for 3 hours at 80 °C. Subsequently, the obtained samples were stored in a desiccator over a layer of silica gel in a closed cabinet to avoid exposure to light [1].

The resulting manganese-containing cefotaxime compound is slightly soluble in water, but highly soluble in alcohol. The solubility of the resulting compound in water is 0.51 g/100 ml, and in 96% ethyl alcohol - 0.98 g/10 ml.

Analysis and results. Analysis of the synthesized complex for metal content was carried out on a 3030B atomic absorption spectrophotometer from Perkin-Elmer (USA), and elemental analysis for the content of carbon, hydrogen, nitrogen and sulfur was determined on an EA-1108 elemental analyzer from Carlo Erba (Italy) . The results of elemental analysis are given in Table 1.

Table 1.

Elemental analysis of a complex compound with the composition [MnC₃₂H₃₂N₁₀O₁₄S₄]∙H₂O

IR absorption spectra were recorded in the region of 400-4000 cm^-1 on an Avatar System 360 FT-IR and Protege 460 Magna-IR technology spectrophotometer from Nicolet Instrument Corporation (USA), using samples in the form of tablets with KBr diameter7 mm and with a resolution of 4 cm^-1.

IR spectroscopic examination of the resulting sample showed that the chemical structure of cefotaxime did not change during the preparation of the complex. The IR spectrum of the manganese complex and the corresponding sodium salt of cefotaxime (Fig. 1, 2) is similar. In this case, a shift occurs in the absorption bands of the C=O stretching vibrations of beta-lactam, amide and carboxylate groups (Table 2), which can be considered as the coordination of these groups with the manganese ion.

Figure 1. IR spectrum of NaCxm

Figure 2. IR spectrum of the complex compound [Mn(Cxm)₂]∙H₂O

Table 2.

Wave numbers of characteristic absorption bands of the sodium salt of cefotaxime and the manganese complex compound

To confirm the individuality of the crystal lattice of the synthesized coordination compound, X-ray phase analysis of the starting materials and the synthesized coordination compound was carried out and the diffraction patterns were compared. It was found that the interplanar distances and the intensity of the synthesized compound do not coincide [12].

Figure 3. X-ray diffraction pattern of the complex compound and cefatoxime

In the derivatogram of the [Mn(Cxm)₂]·H₂O complex presented in Figure 4, four endothermic effects were observed at temperatures of 84, 119, 184, 290 ^oC and one exothermic effect at 243 ^oC. The first endoeffect at a temperature of 84 ^oC is associated with the exit of hygroscopic water in the complex. The endoeffect at the temperature of 184 ^oC corresponds to the decomposition of primary radicals in the ligand, and at 290 ^oC to the decomposition of the heteroring in the ligand. At these temperatures, the total reduction in ligand mass is 55.8%. The exoeffect at 243 ^oC corresponds to the combustion of thermolysis products. In the temperature range of 60-400 ^oC, the decrease in total mass was 63.59%.

Figure 4. Derivatogram of [Mn(Cxm)₂]·H₂O complex

Conclusion. A single-ligand complex of manganese(II) with cefotaxime was synthesized. Based on thermal analysis data, it was concluded that the resulting complex has the composition [Mn(Cxm)₂]·H₂O, and water does not enter the coordination sphere of the complex, since it evaporates at 84 °C. Together with the results of IR spectroscopy, an approximate structural formula of the complexes was established, in which the cefotaxime anion is coordinated by a manganese ion, beta-lactam, amide and carboxylate groups are coordinated equally by the closure of chelate rings through oxygen atoms. It has been proven that the coordination number of the manganese atom is 6.

References:

1. Mayakova M.N., Alekseev V.G., Ivanova A.I., Ryasensky S.S. Tverdyye kompleksy tsinka(II) s tsefazolinom i tsefotaksimom [Solid complexes of zinc(II) with cefazolin and cefotaxime] // Bulletin of TVGU. Series "Chemistry". 2015. No. 3. P. 5–13[In Russian]
2. Alekseev V.G. Metallokompleksy penitsillinov i tsefalosporinov [Metal complexes of penicillins and cephalosporin] // Pharm. Chem. magazine 2010. T.44, No. 1. P. 16–26. [In Russian]
3. J. R.Anacona, J. Estacio. Synthesis and antibacterial activity of cefixime metal complexes // Transition Metal Chemistry, - 2006. - №2. - pp. 227–231.
4. J. R. Anacona, J. J. Santaella. In vitro, antibacterial activity of metal complexes containing a cephaclor derivative ligand // Latin American Journal of Pharmacy, - 2013. - №1. - pp. 101–106.
5. J. R. Anacona, M. Lopez. Mixed-ligand nickel(II) complexes containing sulfathiazole and cephalosporin antibiotics synthesis, characterization, and antibacterial activity // International Journal of Inorganic Chemistry, - 2012, - Article ID106187. - рр.8.
6. K. Singh, Y. Kumar, P. Puri, and G. Singh. Spectroscopic, thermal, and antimicrobial studies of Co(II), Ni(II), Cu(II) and Zn(II) complexes derived from bidentate ligands containing N and S donor atoms // Bioinorganic Chemistry and Applications. - 2012. - Article ID729708. - 9 p.
7. M. R. Karekal, V. Biradar, M. B. H. Mathada. Synthesis, characterization, antimicrobial, DNA cleavage, and antioxidant studies of some metal complexes derived from Schiff base containing indole and quinoline moieties // Bioinorganic Chemistry and Applications, - 2013. - Article ID 315972. - 16 p.
8. Ming L.J. Structure and function of “metalloantibiotics”// Med. Res. Rev. 2003. V. 23, № 6. P. 697–762.
9. Chen D., Milacic V., Frezza M., Dou Q.P. Metal complexes, their cellular targets and potential for cancer therapy// Curr. Pharm. Des. 2009. V.15, № 7. P.777–791
10.  Mashkovsky M.D. Lekarstvennyye sredstva [Medicines]. 16th ed., revised, corrected. and additional M.: New Wave, 2021. 1216 p. [In Russian]