Sulfate tetra-[1--oxyethyl)-2-methyl-5-nitroimidazol] zinc (ii) hydrate exhibiting bacteriostatic activity

 

(57) Abstract:

Usage: in medicine as a means of having bacteriostatic activity. The inventive sulfate Tetra-[1 - b-oxyethyl/-2-methyl-5-nitroimidazol] zinc (II) hydrate. BF C24H16N12O21SZn, output 0,1092 g (72%). Tpl148 - 150oC. the Reagent is 1: 1 - b-oxyethyl/-2-methyl-5-nitroimidazol. Reagent 2: ZnSO7HO. Reaction conditions: in the midst of methyl alcohol. table 4.

The invention relates to new derivatives of metronidazole [1-(-oxyethyl)-2-methyl-5-nitroimidazol] with bacteriostatic action and finds application in medicine.

Known use as antimicrobial agent metronidazole [1,3] found that the complexes of trace elements with lekarstvennymi substances often exhibit higher activity compared to the original substances [2]

The disadvantages of metronidazole are: low solubility in water, volatile effectiveness against anaerobic and aerobic microflora, a number of toxic reactions [3] Data on antimicrobial activity of complexes of copper (II) and platinum (II) with metronidazole are missing.

It is known, is therefore metronidazol taken as equivalent when determining the biological activity of the target product.

The structure of the target product was proposed on the basis of research and calculations by the method of Hackelia formal charge around molecules metronidazole presented in the paper [5] the Positive charge 0,0374 around N-1 and the negative (-1,0012) around the N-3 suggests that the coordination of IU-1 is carried out on the nitrogen atom in position 3. Similar structure confirmed by x-ray diffraction analysis, was installed at the complex metronidazole with platinum (II).

The purpose of the invention increase bacteriostatic activity and expansion steps.

This goal is achieved the target product sulfate Tetra-[1-( -oxyethyl)-2-methyl-5-nitroimidazol] zinc (II) hydrate. Gross formula: C24H46N12O21SZn, molecular weight 936,08. The resulting complex is a cheesy white precipitate.

The formula of the target product:

-

The method of obtaining the target product based on the reaction of 1-( -oxyethyl)-2-methyl-5-intorimidazole with zinc sulfate in the environment of methanol.

P R I m e R 1. 0,120 g [0,0007 M] 1-(-oxyethyl)-2-methyl-5-intorimidazole dissolved in an organic solvent in the flask with a glass stopper. To the resulting solution was added 0.1 Buechner, washed, air-dried at room temperature and stored in a desiccator over CaCl2or MgSO4. The complex of 1-( -oxyethyl)-2-methyl-5-intorimidazole with zinc sulfate.

Yield 72% 0,1092 g, TPL. 148-150aboutC.

The data of elemental analysis, AAS and thermogravimetry are shown in table. 1.

The structure of the obtained compounds was confirmed by IR and UV spectroscopy.

When comparing the IR spectra of 1-( -oxyethyl)-2-methyl-5-intorimidazole and the target product, the appearance of bands, indicating the presence of water of crystallization (3450 and 1640 cm-1), as well as bands, characteristic for the ion SO42-1120, 1090, 1070, 1050 cm-1asymmetric stretching motion; 610 cm-1asymmetric deformation oscillation and is forbidden by the symmetry of the valence fluctuation 978 cm-1that indicates the distortion of the symmetry of SO42-in the coordination complex. IT is a group of the ligand participate in the complexation does not accept, as the absorption band at 3200 cm-1saved. The change in low-frequency region of the spectrum the appearance of the bands at 310 cm-1can be attributed to the formation of ties Me-n

When comparing the camping decrease in the intensity of the bands of the electronic transitions. The presence of zinc in a complex also confirmed by qualitative x-ray fluorescence analysis.

P R I m m e R 2. The bacteriostatic activity of the claimed compounds was studied against strains of Staphylococcus aureus was ATSS 25920, Escherichia coli was ATSS 1247 "Crimea", the Bacillus subtilis ADS 6633 when compared to metronidazole in vitro by the method of diffusion in ohar. The tests were performed at a dose of 0.1 LD50obtained data are presented in table. 2.

P R I m e R 3. The activity of the complex with metronidazole zinc sulfate was studied on the model of salmonellosis in mice weighing 18-20 g were infected intraperitoneally suspension of the daily culture of Salmonella typhimurium N 7 number of 8.75 103a MIC.tel/ml, caused the death of 50% of mice within 7 days. One day after infection for 7 days daily, the mice were injected intramuscularly with 0.1 ml of the study drug. The concentration of drugs 100 mg/kg Control group animals were injected with sterile saline in an amount of 0.1 ml (within 7 days). It is established that the survival rate of mice in the control group was 40% with the introduction of metronidazole 50% and the introduction of the target product on day 7 after infection, 100%

P R I m e R 4. The bacteriostatic activity of the new compounds were studied in vitro on CLASS="ptx2">

P R I m e R 5. The study of the toxicity of complex metronidazole with zinc sulfate conducted on nonlinear white mice with intraperitoneal route of administration.

The analyte was injected once in 2-4% of freshly heated water solutions. Using the method of probit analysis according to Litchfield and Wilcoxon signed was determined the exact values of LD50and other parameters of toxicity (LD50, LD16, LD84).

It is established that metronidazole and its complex compound with zinc sulfate is characterized by relatively low toxicity and in accordance with the classification of the toxicity belong to the class of low-toxic substances (see table. 4).

P R I m e R 6. The effect on the system of the coupled transport of ions in the membranes of human erythrocytes was determined by red blood cell model to study the effect of pharmacological agents on the coupled transfer of anions and cations on the parameters changing the activity of potassium and pH isotonic medium with low ionic strength.

It is established that the complex metronidazole with zinc sulfate caused an optimal pH in suspensions of red blood cells only at concentrations of 10-3M Received republics with zinc sulfate and allow you to recognize the absence of negative side effect of the complex with metronidazole zinc sulfate by the action of the system of the coupled transport of ions in the membranes of human erythrocytes.

P R I m e R 7. Study of the influence of compensatory-adaptive reactions in the cells of the liver, kidneys, spleen were carried out on outbred mice-males weighing 18, Two groups of animals once daily was administered intragastrically metronidazole and its complex with zinc sulfate for 7 days at a dose of 6 mg/kg of the Third group of control animals. In all groups of animals were killed by decapitation under ether anesthesia on the first, third and fifth day. As objects for study at the light-optical level climbed organs: liver, kidney, spleen.

It is established that the complex metronidazole with zinc sulfate in comparison with metronidazole contributes to the development of compensatory-adaptive reactions in the liver, kidney, spleen.

P R I m e R 8. To study the mechanism of reducing the toxicity of metronidazole at its complexation with zinc sulfate used model of the process of fat absorption in the small intestine by electron microscopy.

According to the results of electron microscopic studies found that the introduction of complex metronidazole with zinc sulfate does not cause damaging effects on the processes of absorption of fatty acids in thin kishechnika.posle does not cause disturbances in the structural and functional properties of enterocytes.

Thus, the claimed compound has a high bacteriostatic activity, low toxicity and a broader spectrum of activity than metronidazole.

Sulfate Tetra-[1-( b-oxyethyl)-2-methyl-5-nitroimidazol] zinc (II) hydrate formula

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exhibiting bacteriostatic activity.

 

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