RU2791704C1 - Application of 4-(4,7-dimethoxy-3-phenylbenzofuran-2-yl)butane-2-one as an antibacterial agent against gram-positive microorganisms - Google Patents

Abstract

FIELD: pharmaceuticals.

SUBSTANCE: invention relates to an application of 4-(4,7-dimethoxy-3-phenylbenzofuran-2-yl)butane-2-one by the formula I

.

EFFECT: creation of a compound exhibiting significant antibacterial activity against gram-positive microorganisms and low toxicity.

1 cl, 1 tbl, 3 ex

Description

The invention relates to the field of organic chemistry - new biologically active compounds - substituted benzofurans, namely 4-(4,7-dimethoxy-3-phenylbenzofuran-2-yl)butan-2-one I formula:

compound I has antibacterial activity, which suggests its use in medicine as a potential drug with antibacterial properties.

The structural analogue of the claimed compound is 3-{2-(benzo[d][1,3]dioxol-5-yl)-7-methoxybenzofuran-5-yl}propan-1-ol, which has antibacterial activity [Phytochemistry, 2000, 55, 597; doi: 10.1016/S0031-9422(00)00225-9] formulas:

Phenyl salicylate III of the formula was chosen as the reference standard:

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 benzofurans.

The task is achieved by obtaining 4-(4,7-dimethoxy-3-phenylbenzofuran-2-yl)butan-2-one, which has antibacterial activity.

The claimed compound I is synthesized by the interaction of 2-(hydroxy(phenyl)methyl)-3,6-dimethoxyphenol and 2-methylfuran in 1,2-dichloroethane in the presence of catalytic amounts of trifluoromethanesulfonic acid at a temperature of 85°C and the isolation of the target product by standard methods of synthetic organic chemistry according to scheme:

Example 1. 2-(hydroxy(phenyl)methyl)-3,6-dimethoxyphenol (0.5 mmol), 2-methylfuran (0.75 mmol) and 1,2- dichloroethane (1.7 ml). Then, TfOH (4.4 μl, 10 mol.%) was added to the solution in one portion at room temperature with vigorous stirring. The vial was placed in a preheated (up to 80°C) aluminum block and the reaction mixture was stirred for 1 h (TLC monitoring). After completion of the reaction, the resulting solution was concentrated in vacuo. The target product is isolated by column chromatography (silica gel, gradient elution with a mixture of petroleum ether/ethyl acetate from 99:1 to 20:1). Yield 66%. ^1Н NMR spectrum, (400 MHz, DMSO-d ₆ ), d, ppm: 7.47-7.45 (m, 2Н, H _Ar ), 7.42-7.39 (m, 2Н, H _Ar ), 7.35-7.32 ( m, 1Н, H _Ar ), 6.70 (d, ³ J=8.6 Hz, 1Н, H _Ar ), 6.54 (d, ³ J=8.6 Hz, 1Н, H _Ar ), 3.98 (s, 3Н, OCH ₃ ), 3.63 (s, 3H, OCH ₃ ), 3.07 (t, ³ J=7.6 Hz, 2H, CH ₂ ), 2.89 (t, ³ J=7.6 Hz, 2H, CH ₂ ), 2.12 (s, 3H, CH ₃ ). ^13C NMR spectrum (100 MHz, DMSO-d ₆ ), d, ppm: 206.7; 152.7; HRMS (ESI/TOF): m/z [M+H] ⁺ calculated for C ₂₀ H ₂₁ O ₄ : 325.1434; found: 325.1436. The resulting compound I is a light yellow oil, soluble in chloroform, toluene, acetone, ethyl acetate and insoluble in petroleum ether.

Example 2. To characterize the antibacterial activity, standard parameters were used: the minimum inhibitory concentration (MIC), which was determined by the 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 : Guidelines for clinical laboratory diagnostics, p / r Kaprischenko, 2013, V.2, p. 407]. Tests were performed 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 the MIC and seeding for the determination of MBC was carried out after 24 hours. At the first stage, the test compound was dissolved in dimethyl sulfoxide (DMSO), further dilutions were made in methanol. As the initial concentrations in the tests, we used concentrations 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 I was determined by the method of G.N. Pershin [Pershin G.N. Methods of experimental chemotherapy // M., S. 100, 1971, 109-117]. Compound I was administered intraperitoneally to white mice weighing 16-18 g as a suspension in 2% starch mucus, and the behavior and death of the animals were observed for 10 days. For test compound I, the LD ₅₀ is >1500 mg/kg.

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

As can be seen from the table, the claimed compound I exceeds the reference drug (Phenylsalicylate) in antibacterial activity by 5 times in relation to St. epidermidis. Thus, 4-(4,7-dimethoxy-3-phenylbenzofuran-2-yl)butan-2-one I exhibits higher activity compared to the reference standard against gram-positive microorganisms, which makes it possible to use it to create new drugs purposeful action.

Claims (3)

Application of 4-(4,7-dimethoxy-3-phenylbenzofuran-2-yl)butan-2-one

as an antibacterial agent against gram-positive microorganisms.