The Synthesis And Biological Activity Of Chlortetracycline With Metal Ions

Chlortetracycline(CTC), as a kind of natural tetracyclines antibiotics, is produced by the streptomyces aureofaciens. Chlortetracycline has been widly employed for antibacterial and growth promoting in the clinical aspects because of its broad antibacterial spectrum and low price. Recently, the main production of the chlortetracycline is its calcium complex which is popular among the livestock industry, However, its further development is confined by its low bioavailability and unsatisfactory effects. Accordingly, CTC, in this study, is termed as a leading compound, in order to obtain the excellent and novel pharmacological activity compounds, it is essential to explore the structural modification of CTC. Based on the electronic property of metal ions and the structure effects of ligand compound, the study is conducted as following statement. The chlortetracycline was synthesized with different bivalent metal ions, which was followed by structure characterization with the IR spectrum?UV-vis and 1H-NMR methods as well as the basic study on the biological and pharmacological character. In addition, the stability and safety estimation of the complexes were also been performed in this study. The main contents and results are as follows:(1) In this study,4 metal ions(Zn2+?Mg2+?Co2+?Cu2+) were selected as the metal ligand in the coordination of the chlortetracycline complexes. The characterization method(e.g. metal elemental analysis) indicated that the metal ions were coordinated with chlortetracycline molecule in the carbonyl cyclopentadienyl methane system(C1-C3), with which the oxygen of amide group and oxygen of hydroxyl group at ring A were important coordination sites. In addition, phenol two ketone system(C10-C11) could also be involved in the coordination, and formed the stable chemical structure finally. The structure analysis demonstrated that the molar ratio of metal complexes(Zn2+?Mg2+?Co2+) were all the 1:1 with two water molecule in coordination. The molecule ratio of copper complex(Cu2+), however, was the 1:2 formation(chlortetracycline: metal), and 4 water molecule were involved in the coordination.(2) The stability of metal complexes and CTC against high temperature, humidity and illumination test were compared, as the quantitative regulation of derives in samples could be acquired. The results showed that the stability of complexes in the high humidity and illumination was improved, especially the zinc and cobalt groups. While the abnormal conditions induced the epimerization in the control group(CTC) with an increasement of impurity contents and toxicity.(3) In terms of the antibiotic experiment, the minimal inhibitory concentration(MIC) of both complexes and CTC was investigated in Staphylococcus aureus, Escherichia coli and Bacillus sp strains. The results indicated that the complexes and CTC shared a similar antibiotic activity. While, comparing with other groups, the magnesium complex showed higher activity against the Staphylococcus aureus strain, with the lower MIC value(0.18 ?g/m L). The copper complex, with higher MIC value(0.36 ?g/m L), tended to a negative activity against Bacillus sp strains. The results indicated the inhibitory ability of chlortetracycline could be adjusted with different metal ions.(4) According to the safety assessment of the complexes via the oral test, the LD50 value of complexes were generally higher than 2000 mg/kg, which could be classified as the No.5 category according to “Classification and Labelling of Chemical”. The classification proved that the low oral toxicity of the metal complexes in the normal clinic dose. In the animal test, the pharmacokinetics character of chlortetracycline complexes were compared with the calcium control group. The results indicated that the internal process of the medicines was similar and consistent with the one compartment model. The group of zinc complex, with higher absorption rate(Ka) and lower plasma clearance rate, ensured the drug had higher CTC concentration in the internal blood, and the relative bioavailability(F) was 138% compared with the control group. Consequently, It has a bright future in clinic and application effect.