RU2803747C1 - Use of (z)-2-(2-oxopropyliden)indolin-3-one as an antifungal agent against yeasts - Google Patents

Abstract

FIELD: organic chemistry.

SUBSTANCE: new biologically active compounds - substituted indolin-3-ones, namely (Z)-2-(2-oxopropylidene)indolin-3-one Formula 1, which has antimycotic activity, which suggests its use in medicine as a potential drug with antimycotic properties. The use of (Z)-2-(2-oxopropylidene)indolin-3-one of Formula 1 as an antifungal agent against yeast fungi is presented.

EFFECT: invention provides (Z)-2-(2-oxopropylidene)indolin-3-one of Formula 1, which has a pronounced antimycotic effect and low toxicity.

1 cl, 1 tbl, 3 ex

Description

The invention relates to the field of organic chemistry - new biologically active compounds - substituted indolin-3-ones, namely (Z)-2-(2-oxopropylidene)indolin-3-one 1 of the formula:

compound 1 has antimycotic activity, which suggests its use in medicine as a potential drug with antimycotic properties.

The structural analogue of the claimed compound is (E)-[2,3'-bindolinylidene]-2',3-dione (indirubin) 2, which has antimycotic activity [J. Ethnopharmacol. 2010, 132, 349-354 Phytochemistry, 1999, 52, 2, 271-274; doi: 10.1016/j.jep.2010.07.050] formulas:

Ketoconazole 3 formulas were chosen as the standard of comparison:

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. 918; Med. Chem. Res. 2013, 22, 211 - 218; doi:10.1007/s00044-012-0021-2].

The objective of the invention is to search for substances with a pronounced antimycotic effect and low toxicity in a series of substituted indolin-3-ones.

This goal is achieved by obtaining (Z)-2-(2-oxopropylidene)indolin-3-one, which has antimycotic activity.

The claimed compound 1 is synthesized by treating 2-(2-oxopropyl)-1-tosylindolin-3-one with a NaHCO ₃ solution at 50°C with further isolation of the target product using standard methods of synthetic organic chemistry according to the scheme:

Example 1. Preparation of compound 1. To a solution of 0.343 g (1 mmol) of 2-(2-oxopropyl)-1-tosylindolin-3-one in 4 ml of ethanol add 0.168 g (2 mmol) of NaHCO ₃ dissolved in 2 ml of H ₂ O, and stirred at 50°C for 5 hours. The reaction mixture is then cooled and extracted with dichloromethane (3×10 ml). The combined organic layers are washed with water and saturated NaCl solution, dried over anhydrous Na ₂ SO ₄ and concentrated to dryness. The residue is purified by column chromatography on silica gel using petroleum ether/ethyl acetate as eluent. Yield 85%. T. pl. 162-164°C. ^1H NMR spectrum, (400 MHz, CDCl ₃ ), δ, ppm: 9.73 (s, 1H), 7.66 (d, J=7.5 Hz, 1H), 7.49 (t, J=7.7 Hz, 1H) , 7.00 (t, J=7.5 Hz, 1H), 6.93 (d, J=8.0 Hz, 1H), 6.18 (s, 1H), 2.35 (s, 3H). ¹³ C NMR spectrum, (100 MHz, CDCl ₃ ), δ, ppm: 200.7, 188.5, 153.2, 142.7, 137.2, 125.4, 122.0, 119.9, 111.8, 98.5, 30.9. The resulting compound 1 is a dark red crystalline substance, soluble in chloroform, acetone, ethyl acetate, and ethanol.

Example 2. To characterize the antimycotic activity of compounds, standard parameters were used: minimum inhibitory concentration (MIC), which was determined by a modified method of two-fold serial dilutions [Methodological recommendations: Fungi of the genus Candida. Methods of isolation, identification at the species level and determination of sensitivity to antifungal drugs, Moscow, 2009; MUK 4.2.1890-04 Determination of the sensitivity of microorganisms to antibacterial drugs] and minimum fungicidal concentration (MFC).

Tests were performed using a culture of model microorganisms Candida albicans ATCC 10231 on Mueller-Hinton nutrient medium supplemented with 2% glucose in 96-well polystyrene plates. The concentration of microorganisms in the wells before the start of cultivation was 2.5*105 CFU/ml. Cultivation was carried out at 37°C without stirring. MIC determination and inoculations to determine MPA were carried out after 24 hours. The test compounds were dissolved in dimethyl sulfoxide (DMSO) until complete dissolution at a concentration of 20 mg/ml and lower, depending on solubility. Added to the nutrient medium so that the amount of DMSO did not exceed 5%.

Example 3. Acute toxicity (LD ₅₀ , mg/ml) of compound 1 was determined according to the method of G.N. Pershina [Pershin G.N. Methods of experimental chemotherapy // M., S. 100, 1.971, 109-11.7]. 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 _LD50 is >500 mg/kg.

According to the classification of drug toxicity, compound 1 belongs to class IV of low-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:

How. It can be seen from the table that the claimed compound 1 is one and a half times higher in antimycotic activity than the reference drug (ketoconazole) in relation to C albicans. Thus, (Z)-2-(2-oxopropylidene)indolin-3-one 1 exhibits higher activity compared to the reference standard, which makes it possible to use it to create new drugs with targeted action.

Claims (3)

Applications of (Z)-2-(2-oxopropylidene)indolin-3-one: as an antifungal agent against yeast fungi.