RU2303025C2 - 2,2,5,5-tetrabromo-1,6-di-(41-methylphenyl)-1,3,4,6-hexanetetraone possessing antibacterial activity - Google Patents

Abstract

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

Description

The invention relates to the field of organic chemistry, to derivatives of polycarbonyl compounds, namely to new biologically active substances - 2,2,5,5-tetrabrom-1,6-di- (4 ^1- methylphenyl) -1,3,4,6 -hexantetraone of the formula (I):

which may find application in medicine as an antimicrobial drug.

The closest structural analogue of the claimed compound is 1,6-di- (4 ^1- methylphenyl) -2,2,5,5-tetrachloro-1,3,4,6-hexane-tetraone (II) [Kasatkina Yu.S., Lapina V.V., Igidov N.M., Kozminykh V.O., Novikova V.V., Odegova T.F. Synthesis and bacteriostatic activity of 1,6-disubstituted 2,2,5,5-tetrachloro-1,3,4,6-hexantetra-raons. // Abstract. doc. Actual problems of pharmacy. science and education: results and prospects. Perm, 2001 - S.44-45]

possessing antimicrobial activity.

As a reference standard, we took antimicrobials - dioxidine [Mashkovsky M.D. Medicines M .: New wave, 2000, T.2, p. 298-299] and fluconazole [ibid, p. 361-362], widely used in medical practice.

The purpose of this invention is the synthesis of previously not described 2,2,5,5-tetrabromo-1,6-di- (4 ^1- methylphenyl) -1,3,4,6-hexantetraone having an antimicrobial effect.

The goal is achieved by obtaining 2,2,5,5-tetrabromo-1,6-di- (4 ^1- methylphenyl) -1,3,4,6-hexantetraone by reaction of 3,4-dihydroxy-1,6-di- ( 4 ^1- methylphenyl) -2,4-hexadiene-1,6-dione (III) [Igidov N.M., Kozminykh E.N., Sof'ina O.A., Shironina T.M., Kozminykh V.O. Synthesis of 1,6-diaryl-3,4-dihydroxy-2,4-hexadiene-1,6-diones and their derivatives 2,3-furandiones. // Chemistry heterocycle. connection - 1999. - No. 11. - S.1466-1475] with bromine in the medium of chloroform:

An example of the preparation of the claimed compound (I)

To a mixture of 0.64 g (0.002 mol) of 3,4-dihydroxy-1,6-di- (4 ^1- methylphenyl) 2,4-hexadiene-1,6-dione and 1 g of sodium carbonate in 80 ml of chloroform is added dropwise 1 , 28 g (0.008 mol) of bromine in 20 ml of chloroform. Stirred on a magnetic stirrer for 2 hours until the solution discolored. The solution was filtered and evaporated. The dry residue is recrystallized from toluene. Obtain 0.82 g (64%) of crystalline compound (I) with T _pl. 203-204 (decomp.). C ₁₈ H ₈ Br ₆ O ₄ . IR spectrum, ν, cm ^-1 (crystals): 1760 (СО), 1710 (СО). ₁ H-NMR spectrum, δ, ppm CBCl ₃ : 2.44 s (6H, 2CH ₃ ), 7.23 d., 7.92 d. (8H, 2C ₆ H ₄ ).

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 its antimicrobial activity.

The determination of bacteriostatic activity was carried out by the method of two serial dilutions in a liquid nutrient medium [Guide to the experimental (preclinical) study of new pharmacological substances. - M., 2000, p. 264-273]. For all tested compounds, MICs were determined for pharmacopoeial strains: S. aureus ATCC 6538-P, E.coli ATCC 25922, C. albicans ATCC 885-653, P. aerugenosa ATCC 9027. Crops were made in meat and peptone broth, pH 7.0 with different concentrations of test compounds. The cultures were grown in test tubes on a beveled agar medium (meat peptone agar). An 18-20 hour culture was used to determine antimicrobial activity. To prepare a working suspension of microbes, the grown culture was washed off with an isotonic sodium chloride solution and the microbial suspension density was set according to the turbidity standard of 5 units. Next, from the obtained microbial suspension (500 million mt / ml., A working solution of bacteria with a concentration of 5 million mt / ml was prepared. This suspension of microbes was introduced in an amount of 0.1 ml into test tubes with serial dilutions of the studied drug. Thus, the microbial load in the determination of PMA was 250,000 mt / ml, The studied compound in the amount of 0.05 g was dissolved in 5 ml of dimethyl sulfoxide, 1 ml of the resulting dilution of 1: 100 was combined with 4 ml of meat-peptone broth (1: 500) Next, a series of serial dilutions of the compound with a doubling concentration was prepared.

The results were taken into account after 18-20 h of exposure of control and experimental tubes in a thermostat at a temperature of 37 ° C. The minimum inhibitory concentration (MIC) was determined by the absence of signs of growth on a nutrient medium: the last tube with growth retardation (clear broth) corresponds to the MIC of the drug for this strain. The bacteriostatic effect of the studied compounds was compared with the action of dioxidine [Padeiskaya EN, Inf. and antimicrobial, therapist., 2001, No. 5, p.105-155]. 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, p. 662-668].

Acute toxicity (LD ₅₀ ) of the claimed compound was studied on white laboratory mice of both sexes weighing 19-20 g. The test compound was administered once into the stomach in the form of starch mucus in the amount of 1480, 2960, 4440, 5920, 7400 mg / kg, respectively, observation of animals carried out for 10 days. Statistical processing of the results was carried out according to V. Prozorovsky. by comparing the average lethal dose (LD ₅₀ ) at P = 0.05 [Prozorovsky V.V., Prozorovskaya M.P., Demchenko V.M. Farmakol. and toxicol., 1978, No. 4, p.497-502]. The research results are presented in the table.

As can be seen from the table, compound (I) exceeds the dioxidine to S.aureus by antimicrobial activity by no less than 8330 times, E. coli by not less than 32.5 times, P.aerugenosa is the same. Compound (I) has an antifungal activity against C. albicans comparable to that of fluconazole. Compound (I) according to the classification of Izmerov N.F. [Izmerov N.F. The toxicometry parameters of industrial poisons with a single injection, M., Medicine, 1977, p.197] belongs to the class of practically non-toxic drugs.

Thus, 2,2,5,5-tetrabromo-1,6-di- (4 ^1- methylphenyl-1,3,4,6-hexane-tetraone) (I) exhibits pronounced antimicrobial activity and is practically non-toxic. Therefore, the claimed compound (I) may find application in medicine as an antimicrobial drug.

Table
Antimicrobial activity and acute toxicity of compound I. Compound S.aureus, mcg / ml E.coli, mcg / ml P.aeruginosa, μg / ml C.albicans, mcg / ml LD ₅₀ mg / kg one 0.0075-0.06 0.12-0.25 125-1000 16-32 2960 dioxidine 62.5-1000 3.9-62.5 125-1000 - - fluconazole - - - 16-32 -

Claims (1)

2,2,5,5-tetrabromo-1,6-di- (4 ^1- methylphenyl) -1,3,4,6, -hexantetraone of the formula

possessing antimicrobial activity.