2-(2,4-dichloranilino)-1,4-bis(4-methylphenyl)-2-buten-1,4-dion, possessing antimicrobial activity

FIELD: chemistry.

SUBSTANCE: invention relates to field of organic chemistry, to derivatives of 1,4-diketones, namely to novel biologically active substance -2-(2,4-dichloranilino)-1,4-bis(4-methylphenyl)-2-buten-1,4-dione of formula 1 , which possesses antimicrobial activity and can be applied in medicine.

EFFECT: obtaining novel biologically active substance which possesses antimicrobial activity.

1 cl, 1 ex, 1 tbl

 

The invention relates to the field of organic chemistry, derivatives of 1,4-diketones, namely a previously unknown new biologically active compound is 2-(2,4-dichloraniline)-1,4-bis(4-were)-2-butene-1,4-dione of formula 1:

which can find application in medicine as an antimicrobial drug.

The closest structural analogues of the claimed compounds are aminopenicillanic 2, which have claimed compounds 1 same aminopenicillanic fragment [Ehitatava, Lddevelop, Relbopaserca, Lioresal. Journal of organic chemistry, 1969, vol 5, VIP, s-2119].

Structural analogs of compounds 1 can also be considered as substituted 2-amino-4-aryl-4-oxo-2-butenova acids and their esters 3, exhibiting antimicrobial and analgesic activity [Antonimina, Ahomelae5v, Woosley, Rod, Tradeshow. Chemical and pharmaceutical journal, 2002, T.36, No. 11, p.28-30. Nevkritova, Woosley, Avialbility, Antonimina, Waikola, Sagulenko. Chemical and pharmaceutical journal, 1998, 32, No. 9, p.32-35].

All these analogues 2, 3 contain common with the claimed compounds 1 aminophenylamino fragment. The differences consist in the fact that as the substituents R and R' claimed in the x compounds is n-colligny Deputy, R"=H, as R"' - 2,4-dichloroaniline Deputy.

As a benchmark comparison, we have used antimicrobials - cefepime [Yakovlev S.V., eng. the honey. journal, 1998, Vol.6, No. 22, s-1457] and chlorhexidine digluconate [Padalka E.N., INF. and antimicrob. terap., 2001, No. 5, s-155], widely used in medical practice antibiotic and disinfectant.

The purpose of this invention is the synthesis of previously undescribed 2-(2,4-dichloraniline)-1,4-bis(4-were)-2-butene-1,4-dione, having antimicrobial action.

This goal is achieved by obtaining 2-(2,4-dichloraniline)-1,4-bis(4-were)-2-butene-1,4-dione and a study of its antimicrobial action.

Example obtain the claimed compound 1:

A mixture of equimolar amounts of getaway.location and 2,4-dichloraniline boiled in benzene for 5 minutes the Solvent was evaporated. The precipitate was recrystallized from carbon tetrachloride. A yield of 75%. TPL 147-148°C. IR spectrum, cm-1: 1668 (C(1)=0), 1605 (C(4)=0, C=C). An NMR spectrum1N, ppm: 2.36 (s, 6N, me); 6.13 (s, 1H, CH); 6.97 (m, 7H, Ar); 7.76 (d, 4H, N(2), N(6),3J=8.4); 12.35 (s, 1H, NH). Found, %: C 66.72; H 3.80; Cl at 17.85; N, 3.50. C22H15Cl2NO2. Calculated, %: C 66.68; H 3.82; Cl 17.89; N, 3.53.

The obtained compound 1 is a yellow crystalline substance, soluble in alcohols, chloroform, toluene, dimethyl sulfoxide and dimethyl mamide, insoluble in alkanes and water.

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), 2000., s-273]. For all the studied compounds were determined IPC in respect of pharmacopoeial strains: S. aureus was ATSS 6538-P, E. coli was ATSS 25922, C. albicans was ATSS 885-653, P. aerugenosa ADS 9027, B. cereus was ATSS 8035, B. subtilis was ATSS 6633, S. epidermidis was ATSS 14990. 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 sodium chloride solution, 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 stood the sludge 250000 m so/ml. of the Studied compound in the amount of 0.05 g was dissolved in 5 ml of DMSO, 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 hours of exposure control and experimental tubes in the incubator at 37°C. the Minimum inhibitory concentration (MIC) was determined by the absence of signs of 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 effect of cefepime [Yakovlev ST., Eng. the honey. journal, 1998, Vol.6, No. 22, s-1457], chlorhexidine digluconate [Padalka E.N., INF. and antimicrob, terap., 2001, No. 5, s-155].

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 volume 1480, 2960, 4440, 5920, 7400 mg/kg, respectively, the observation of the animals was performed within 10 days. Statistical processing of results was carried out according to Prozorovsky CENTURIES comparison of median lethal dose (LD50) at P=0.05 [Prozorovsky CENTURIES, Prozorovsky BTW, Demchenko V.M. Pharmacol. and toxicol, 1978, No. 4, s-502]. The results are shown in table 1.

As can be seen from table 1, compound 1 on antimicrobial activity comparable with the activity of chlorhexidine digluconate against S.aureus and E.coli. Connection 1 with respect to .albicans, spore-forming rods, S.epidermidis inferior to Comparators. In relation to P.aerugenosa activity is not. Connection 1 according to the classification Izmerov NF [Izmerov NF Parameters toxicometric industrial poisons in a single, M, Medicine, 1977, s] belongs to the class of practically non-toxic drugs.

Thus, 2-(2,4-dichloraniline)-1,4-bis(4-were)-2-butene-1,4-dione 1 shows a pronounced antimicrobial activity and is practically non-toxic. Therefore, the claimed compound 1 can be used in medicine as an antimicrobial drug.

Table 1
Antimicrobial activity (μg/ml) and acute toxicity of compounds 1
ConnectionS.aureusE. coliRegID..albic.S.epid..cereus .subt.LD50mg/kg
12,0-1,02,0-1,0-31-62125312502700-3800
Cefepime0,125-160,015-2,00,03-16-0,5-62---
Chlorhexidine Beagle-t1-21-510-5007-15-1-21-3-

Sources of information

1. Izmerov NF Parameters toxicometric industrial poisons in a single, M, Medicine, 1977, s.

2. Kozminykh E.N., Belyaev S.A., Kozminykh V.O., Makhmudov P.P., Odegova TF Chemical and pharmaceutical journal, 2002, T.36, No. 11, p.28-30.

3. Kolotov, NV, Kozminykh V.O., Devilkin EV, Kozminykh E.N., Call WE, Shelenkov S.A. Chemical and pharmaceutical journal, 1998, 32, No. 9, p.32-35.

4. Padalka E.N., And the F. and antimicrob, terap., 2001, No. 5, s-155.

5. Prozorovskiy CENTURIES, Prozorovsky M. P., Demchenko V.M. Pharmacol. and toxicol., 1978, No. 4, s-502.

6. Manual on experimental (preclinical) study of new pharmacological substances - M., 2000, s-273.

7. Titova H., Gavrilova L.D., Bladework R.L., Vereshchagin LI the Journal of organic chemistry, 1969, vol 5, VIP, s-2119.

8. Yakovlev S.V. Russian journal of medicine in 1998. - V.6, №22. - s-1457.

2-(2,4-dichloraniline)-1,4-bis(4-were)-2-butene-1,4-dione of formula 1:

possessing antimicrobial activity.



 

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