2,2,5,5-tetrabromo-1,6-di-(41-methylphenyl)-1,3,4,6-hexanetetraone possessing antibacterial activity

FIELD: organic chemistry, chemical technology, microbiology.

SUBSTANCE: invention relates to novel 2,2,5,5-tetrabromo-1,6-di-(4'-methylphenyl)-1,3,4,6-hexanetetraone of the formula (I): that possesses antibacterial activity. Compound of the formula (I) is synthesized by interaction of 3,4-dihydroxy-1.6-di-(4'-methylphenyl)-2,4-hexadiene-1,6-dione with bromine in chloroform medium. Compound of the formula (I) possesses antibacterial activity with respect to Staphylococcus aureus with MAC (maximum allowable concentration) value = 0.0075-0.06 mcg/ml and to colon bacillus with MAC value = 0.12-0.32 mcg/ml and with the acute toxicity value LD50 = 2960 mg/ml.

EFFECT: valuable activity of compound.

1 tbl, 1 ex


The invention relates to the field of organic chemistry, derivatives polycarboxylic compounds, namely to new biologically active substances of,6-di-(41-were)-1,3,4,6-hexanetriol formula (I):

which can find application in medicine as an antimicrobial drug.

The closest structural analogue of the claimed compound is 1,6-di-(41-were)-2,2,5,5-tetrachloro-1,3,4,6-hexane-tetraen (II) [Kasatkina US, V.V. Lapin, Hidow NM, Kozminykh V.O., Novikov V.V., Odegova TF Synthesis and bacteriostatic activity of 1,6-disubstituted of,3,4,6-hexane-Ronov. // Proc. Dokl. Actual problems of formats. science and education: results and prospects. Perm, 2001 - P.44-45]

possessing antimicrobial activity.

As a benchmark comparison, we have used antimicrobials - dioxidine [Mashkovsky PPM Medicines. M: New wave, 2000, Vol.2, s-299] and fluconazole [ibid, s-362], widely used in medical practice.

The purpose of this invention is the synthesis is not described previously of,6-di-(41-were)-1,3,4,6-hexanetriol having antimicrobial action.

This goal is achieved by the receipt of,6-di-(41-m is terphenyl)-1,3,4,6-hexanetriol reaction of 3,4-dihydroxy-1,6-di-(4 1-were)-2,4-hexadien-1,6-dione (III) [Hidow NM, Kozminykh E.N., Sofina O.A., Shironina T.M., Kozminykh V.O. Synthesis of 1,6-diaryl-3,4-dihydroxy-2,4-hexadiyn-1,6-diones and their derivatives of 2,3-furandione. // Chemistry of heterocycle. connect. - 1999. No. 11. - S-1475] with bromine in the environment of chloroform:

Example obtain the claimed compound (I)

To a mixture of 0.64 g (0.002 mol) of 3,4-dihydroxy-1,6-di-(41-were)of 2,4-hexadiyn-1,6-dione and 1 g of sodium carbonate in 80 ml of chloroform was added dropwise 1.28 g (0,008 mol) of bromine in 20 ml of chloroform. Stirred on a magnetic stirrer for 2 h prior to the bleaching solution. The solution is filtered and evaporated. The dry residue is recrystallized from toluene. Get 0,82 g (64%) of crystalline compound (I) with Tpl.203-204 (decomp). C18H8Br6About4. IR spectrum, νcm-1(the crystals): 1760 (CO), 1710 (CO). Range of TMR, δ, M. D. CBCl3: 2.44 (6N, 2CH3), 7.23 D., 7.92 D. (8H, 2C6H4).

The obtained compound (I) is a yellow crystalline substance, soluble in dimethyl sulfoxide and dimethylformamide, sparingly soluble in chloroform, toluene, insoluble in hexane and water.

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

Determination of the bacteriostatic the th 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 ATCC 6538-P, E. coli ATCC 25922, C. albicans ATCC 885-653, P. aerugenosa 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 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 M.L./ml were prepared working solution of bacteria with a concentration of 5 million M.L./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 250 000 M.L./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 h of exposure control and experimental tubes in the incubator at 37 °C. Minimum noise reduct the expansion of the 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 action dioksidina [Padalka E.N., INF. and antimicrob, terap., 2001, No. 5, s-155]. Antifungal activity was compared with the action of fluconazole [Rex J.Y., Wals T.J., Sobel J.D. et all, Clin. Infect/ Dis., 2000, V.30, No.4, R-668].

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 the table.

As can be seen from the table, the compound (I) exceeds antimicrobial activity dioxidine to S.aureus not less than 8330 times, E.coli is not less than 32.5 times, P.aerugenosa the same. The compound (I) antifungal activity of C. albicans is comparable with the activity of fluconazole. The 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 practically non-toxic drugs.

Thus, of who rubrum-1,6-di-(4 1-were-1,3,4,6-hexane-tetraen) (I) exerts pronounced antibacterial activity and is practically non-toxic. Therefore, the claimed compound (I) can be used in medicine as an antimicrobial drug.


Antimicrobial activity and acute toxicity of compounds I.
ConnectionS.aureus,ug/mlE. coli mg/mlP.aeruginosa, ug/mlC.albicans, ug/mlLD50mg/kg
dioxidineat 62.5-10003,9-62,5125-1000--

of,6-di-(41-were)-1,3,4,6-hexanetriol formula

possessing antimicrobial activity.


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