6-nitro-2-iminocoumarin 3-carboxylic acid 4-toluidide silver salt eliciting antibacterial activity

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to new compounds of coumarone class, namely, to 6-nitro-2-iminocoumarin 3-carboxylic acid 4-toluidide silver salt of the formula (1): that elicits an antibacterial effect and can be used in medicine. Invention provides preparing a new compound eliciting an antibacterial effect with respect to S. aureus, E. coli, and C. albicans with mononuclear cells values 0.25; 0.5 and 7.8 mcg/ml, respectively, and with acute toxicity value LD50 for these compounds 2 460 ± 230 mg/kg.

EFFECT: valuable properties of compound.

1 cl, 1 tbl, 2 ex

 

The invention relates to new biologically active compounds of class coumarins, particularly, to a silver salt of 4-toluidine 6-nitro-2-iminocoumarin-3-carboxylic acid of the formula (I)

exhibiting antimicrobial activity. The closest analogue to the structure of compound I is 2,4-xylidide 2-acetylaminofluorene-3-carboxylic acid (U.S. Pat. RU # 2193559 C1. Publ. 27.11.2002. Bull. No. 33) of the formula

having anticoagulant activity. As a benchmark comparison we have selected antimicrobial drugs dioxidine (Mashkovsky PPM Medicines. - M.: New wave, 2000, Vol.2, s-299) and fluconazole (ibid SS-362), widely used in medical practice.

The aim of the invention is the finding of new coumarin derivatives having antimicrobial activity.

This goal is achieved silver salt of 4-toluidine 6-nitro-2-iminocoumarin-3-carboxylic acid (II), which is obtained by the interaction of 5-nitrosalicylic aldehyde with 4-toluidino tsianuksusnogo acid formed at this 4-toluidin 6-nitro-2-iminocoumarin-3-carboxylic acid (II), is treated with an equivalent amount of silver nitrate.

The invention is illustrated by the following examples.

Example 1. 4-Toluidin 6-nitro-2-iminocoumarin-3-carboxylic acid (II). SMEs,67 g (0.01 mol) of 5-nitrosalicylic aldehyde, of 1.74 g (0.01 mol) 4-toluidine tsianuksusnogo acid, 5 drops of piperidine is boiled in 15 ml of ethanol for 1 h Precipitated after cooling the reaction mixture the precipitate was separated, washed with ether, and crystallized from dioxane. Get 2,98 g (92.3 per cent) II. So pl. 235-237°C. Found, %: With 63.4; H 4,3; N 13,2. With17H13N3O4. Calculated, %: From 63.1; H 4,0; N 13,0.

Example 2. The silver salt of 4-toluidine 6-nitro-2-iminocoumarin-3-carboxylic acid (I). Dissolving 0.32 g (0.001 mol) 4-toluidine 6-nitro-2-iminocoumarin-3-carboxylic acid in 80 ml of a mixture of isopropanol - dioxane (2:1) at low heat. To the warm solution with continuous stirring of the reaction mixture was added 0.17 g (0.001 mol) of silver nitrate in a minimum amount of water. The residue is filtered off, washed with alcohol on the filter and dried at room temperature. Obtain 0.25 g (58%) of compound I. T. pl.>300°C. Found, %: C Of 47.8; H 3,1; N and 10.0. C17H12N3O4Ag. Calculated, %: C 47,4; 2.8; N 9,8.

The structure of compounds I and II confirmed by the data of IR, PMR spectroscopy. In IR-spectra of compound I are the bands at 1670 cm-1(CO), 3310 cm-1(CONH). In the PMR spectra of compound I present: a singlet at 2,30 ppm (SN3), multiplet with the center of 7.60 ppm (M, aromatic rings).

The IR spectrum II exhibits bands at 1670 cm-1(CO), 3330 cm-1(=NH), 3420 cm (NH).

The claimed compound was tested for the presence he has antimicrobial activity.

Determination of the bacteriostatic activity was performed by the method of twofold serial dilutions in liquid nutrient medium (Manual on experimental (preclinical) study of new pharmacological substances. - M., 2000, s-273). For all the studied compounds were determined IPC in respect of pharmacopoeial strains: S.aureus was ATSS 6538-P, E. coli ATCC 25922, C. albicans ATCC 885-653, P. aeruginosa ATCC 9027. Crops produced in mesopotania broth, pH 7.0 with different concentrations of the tested compounds. The cultures were grown in test tubes on a beveled apparitional environment (mastopathy agar). To determine the antimicrobial activity was used 18-20-hour culture. For preparation of the working suspension of microbes produced washout grown culture isotonic solution of sodium chloride, and set the density of the microbial suspension according to the turbidity standard 5 units. Next, from the obtained microbial suspension (500 million MT/ml) were prepared working solution of bacteria with a concentration of 5 million MT/ml of This suspension of microbes was made in the amount of 0.1 ml in tubes with serial dilutions of study drug. Thus, microbial load when determining the ACA was 250000 MT/ml of the Studied compound in the amount of 0.05 g was dissolved in 5 ml of dimethyl who formamide; 1 ml of the prepared dilution of 1:100 was combined with 4 ml mycopathologia broth (1:500). Next was preparing a series of serial dilutions of the compounds twice with decreasing concentration.

Records of the results produced after 18-20 h of exposure control and experimental tubes in the incubator at 37 ° °C. Minimal inhibitory concentration (MIC) was determined by the absence of signs of microbial growth on nutrient medium: the last tube of stunting (clear broth) corresponds to the IPC of the drug in relation to this strain. Bacteriostatic effect of the studied compounds was compared with the action dioksidina (Adaska E.N., INF. and antimicrob, terap., 2001, No. 5, p.150-155). Antifungal activity was compared with the action of fluconazole (Rex J.Y., Walsh T.J., Sobel J.D. et all, Clin. Infect. Dis, 2000, V. 30, No. 4, R-678).

Acute toxicity (LD50) the claimed compounds was studied on white laboratory mice of both sexes weighing 19-20, Investigational compound was administered once in the stomach in the form of starch mucus in the amount of 1580, 2500, 3160 mg/kg, respectively, the observation of the animals was performed within 10 days. Statistical processing of results was carried out according to Prozorovsky CENTURIES (Prozorovsky CENTURIES, Prozorovsky BTW, Demchenko V.M. Pharmacol. and toxicol., 1978, No. 4, s-502).

The results are shown in the table.

As can be seen from the people, the connection I exceeds the activity dioxidine against S. aureus at least 250 times, E. coli is not less than 7.8 times, P. aeruginosa is not less than 250 times. The connection I also exceeds antifungal activity of fluconazole against C. albicans is not less than 2.1 times. Compound I according to the classification Izmerov NF (Izmerov NF Parameters toxicometric industrial poisons in a single, M.: Medicine, 1977, s) belongs to the class of moderately toxic substances.

Thus, a silver salt of 4-toluidine 6-nitro-2-iminocoumarin-3-carboxylic acid I shows a pronounced antimicrobial activity and is moderately toxic. Therefore, the claimed compound can be used in medicine as an antimicrobial drug.





Antimicrobial activity and acute toxicity of compounds I

Table
ConnectionS.aureus, ug/mlE. coli, ug/ml.aeruginosa, ug/l.albicans, ug/mlLD50mg/kg
I0,250,50,57,82460±230
dioxidineat 62.5-10003,9-62,5125-1000- -
fluconazole---16-32-

The silver salt of 4-toluidine 6-nitro-2-iminocoumarin-3-carboxylic acid of the formula I

possessing antimicrobial activity.



 

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