RU2809098C1 - Use of n-(4-(trifluoromethyl)phenyl)-[1,1':3',1''-terphenyl]-5'-amine as antibacterial agent against gram-positive microorganisms - Google Patents

Abstract

FIELD: organic chemistry and pharmaceuticals.

SUBSTANCE: invention relates to the use of N-(4-(trifluoromethyl)phenyl)-[1,1':3',1''-terphenyl]-5'-amine of formula 1 as an antibacterial agent against gram-positive microorganisms.

EFFECT: invention provides an effective antibacterial effect against gram-positive microorganisms with low toxicity.

1 cl, 1 tbl, 3 ex

Description

The invention relates to the field of organic chemistry, to new biologically active substances of the class of substituted terphenyls, namely to N -(4-(trifluoromethyl)phenyl)-[1,1':3',1''-terphenyl]-5'-amine 1 formula:

Compound 1 has antibacterial activity, which suggests its use in medicine as a drug with antibacterial properties.

The structural analogues of the claimed compound are 4-(3-(4-((4-(trifluoromethyl)phenyl)amino)phenyl)-1,2,4-oxodiazol-5-yl)phenol 2 , which has antibacterial activity against gram-positive microorganisms [ Bioorganic & Medicinal Chemistry Letters 2015 , 4854-4857, doi: 10.1016/j.bmcl.2015.06.044], formulas:

The standard of comparison was phenyl salicylate with the formula:

which is widely used in medical practice and is analogous in action [Mashkovsky M.D. Medicines. - 16th ed., revised, corrected. and additional - M.: New Wave, 2012.- p. 950].

The objective of the invention is to search for substances with a pronounced antibacterial effect and low toxicity in the series of substituted terphenyls.

This objective is achieved by obtaining N -(4-(trifluoromethyl)phenyl)-[1,1':3',1''-terphenyl]-5'-amine, which has antibacterial activity.

The claimed compound 1 is synthesized by the reaction of 4-trifluoromethylaniline, 4-phenylbut-3-en-2-one and 1-(2-oxo-2-phenylethyl) pyridinium iodide in acetonitrile under heating, followed by isolation of the target product using known methods according to the following scheme:

Example 1. Preparation of compound 1 . To a solution of 4-phenylbut-3-en-2-one (1 mmol, 146 mg) and 1-(2-oxo-2-phenylethyl)pyridinium iodide (1 mmol, 325 mg) in 1,4-dioxane (5 ml ) add 4-trifluoromethylaniline (1 mmol, 161 mg). The resulting mixture is stirred at 90 °C for 24 hours. After 24 hours, the resulting mass is concentrated under vacuum. The residue after concentration is subjected to column chromatography using silica gel as a sorbent, petroleum ether/dichloromethane as an eluent, to purify compound 1 . Yield 54% (210 mg). ^1H NMR spectrum (400 MHz, CDCl ₃ ) δ, ppm: 7.76 – 7.70 (m, 4H), 7.67 – 7.57 (m, 4H), 7.55 – 7.53 (m, 3H), 7.49 – 7.45 (m , 2Н), 7.389 – 7.386 (m, 2Н), 7.17 – 7.15 (m, 2Н), 6.02 (br. s, 1Н). ¹³ C NMR spectrum (100 MHz, CDCl ₃ ), δ, ppm: 146.7, 143.3 (2C), 142.3, 140.8 (2C), 129.0 (4C), 127.8 (2C), 127.3 (4C), 126.9 ( k, ⁴ J _CF = 4 Hz, 2C), 124.8 (k, ² J _CF = 271 Hz), 122.1 (k, ³ J _CF = 33 Hz), 120.9, 120.8, 117.5 (2C), 115.9 (2C). The resulting compound 1 is a yellow oil, soluble in chloroform, toluene, acetone, insoluble in water.

Example 2. To characterize the antibacterial activity, standard parameters were used: the minimum inhibitory concentration (MIC), which was determined by a modified method of two-fold serial dilutions (MUK 4.2.1890-04 Determination of the sensitivity of microorganisms to antibacterial drugs) and the minimum bactericidal concentration (MBC) (Medical Laboratory Technologies : Guide to clinical laboratory diagnostics, p/r Kaprishchenko, 2013, T.2, p. 407). Tests were carried out using cultures of model microorganisms Escherichia coli MC4100 and Staphylococcus epidermidis ATCC29887 on Luria-Bertani nutrient medium in 96-well polystyrene plates. The final concentration of microorganisms in the wells was 5*10 ⁵ CFU/ml. Cultivation was carried out at 37 °C without stirring. Determination of MIC and inoculations to determine MBC were carried out after 24 hours. At the first stage, the compounds under study were dissolved in dimethyl sulfoxide (DMSO), further dilutions were made in methanol. The initial concentrations used in the tests were those that, when added to the Luria-Bertani nutrient medium, did not form a precipitate (from 0.2 to 4 mg/ml).

Example 3. Acute toxicity (LD ₅₀ , mg/ml) of compound 1 was determined according to the method of G. N. Pershin [Pershin G. N. Methods of experimental chemotherapy // M., S. 100, 109-117 (1971)]. Compound 1 was administered intraperitoneally to white mice weighing 16-18 g in the form of a suspension in 2% starch mucus, and the behavior and death of the animals were observed for 10 days. For test compound 1, the LD ₅₀ is > 1500 mg/kg.

According to the classification of drug toxicity, compound 1 belongs to class V of practically non-toxic drugs [Izmerov N.F., Sanotsky I.V., Sidorov K.K. Parameters of toxicometry of industrial poisons with a single exposure: Handbook. M., 1977. – p. 196]. The test results are presented in the table:

Antibacterial activity and acute toxicity of compound 1 .

Compound LD ₅₀ mg/kg Antibacterial activity (µg/ml) St. epidermidis (ATCC29887) E. coli (MC4100) MIC* MBK** MIC MBK 1 >1500 75.0 500.0 >600.0 >600.0 Phenyl salicylate 750.0 2000.0 - -

MIC* - minimum inhibitory concentration,

MBC** is the minimum bactericidal concentration.

As can be seen from the table, the claimed compound 1 exceeds the antibacterial activity of the reference drug (Phenyl salicylate) by 10 times relative to St. epidermidis . N -[(3,5-diphenyl]phenyl)proline methyl ester 1 exhibits higher activity compared to the reference standard against gram-positive microorganisms, which makes it possible to use it to create new drugs with antibacterial action.

Claims (3)

Application of N -(4-(trifluoromethyl)phenyl)-[1,1':3',1''-terphenyl]-5'-amine as an antibacterial agent against gram-positive microorganisms.