RU2759008C1 - 4-(aroyl)-3-hydroxy-1-(2-hydroxyphenyl)-5-(phenylthio)-1,5-dihydro-2h-pyrrol-2-ones exhibiting antimicrobial activity - Google Patents

Abstract

FIELD: chemistry.SUBSTANCE: invention relates to 4-(aroyl)-3-hydroxy-1-(2-hydroxyphenyl)-5-(phenylthio)-1,5-dihydro-2H-pyrrole-2-ones exhibiting antimicrobial activity.EFFECT: synthesis of new compounds exhibiting antimicrobial activity, usable in pharmacology as potential medicinal products with antimicrobial properties.1 cl, 4 ex, 1 tbl

Description

The invention relates to the field of organic chemistry, namely to new biologically active 4- (aroyl) -3-hydroxy-1- (2-hydroxyphenyl) -5- (phenylthio) -1,5-dihydro-2H-pyrrol-2-ones formulas:

possessing antimicrobial activity, which suggests their use in pharmacology and medicine as drugs with antimicrobial effect.

Known structural analogs of the claimed compounds - 3-hydroxy-1-N-phenyl-1,5-dihydro-2H-pyrrol-2-ones (Kocharyan S.T., Churkina NP, Razina T.L., Karapetyan V.E. , Ogandzanyan S. M., Voskanyan VS, Babayan AT New method for synthesis of 3-perrolin-2-one derivatives // Chemistry of Heterocyclic Compounds. - 1994. - T. 30. - No. 10. - P. 1165- 1169) formulas:

where R = Me, Ph

The standards for comparison of antimicrobial efficacy are the antibacterial drug dioxidin [Padeyskaya E.N. Antibacterial drug dioxidine: features of biological action and significance in the treatment of various forms of purulent infection // Infections and antimicrobial therapy. - 2001. - No. 5. - S. 105-155] and the antifungal drug fluconazole [Shilova I.B., Gus'kova TA, Glushkov R.G. Modern drugs for treating dermatomycosis // Pharmaceutical Chemistry Journal. - 2004. - T. 38. - No. 4. - C. 175-180.], Which are widely used in medical practice and are analogous in action.

The objective of the invention is to search among the derivatives of 1,5-dihydro-2H-pyrrol-2-ones for substances with a pronounced antimicrobial effect and to expand the arsenal of means of influencing a living organism.

The task is achieved by obtaining 4- (aroyl) -3-hydroxy-1- (2-hydroxyphenyl) -5- (phenylthio) -1,5-dihydro-2H-pyrrol-2-ones, which have antimicrobial activity.

The claimed compounds are synthesized by reacting 3-aroyl-2,4-dihydro-1H-pyrrolo [2,1-c] [1,4] benzoxazine-1,2,4-triones (I) with thiophenol in a 1: 1 ratio in medium of anhydrous solvent, followed by the addition of 5 equiv of H ₂ O and the isolation of the target products (II) according to the presented scheme:

where R = H (a), OEt (b), NO ₂ (c).

The process is carried out by boiling, and anhydrous acetonitrile is used as a solvent.

The invention is illustrated by the following examples.

Example 1. Obtaining (4- (benzoyl) -3-hydroxy-1- (2-hydroxyphenyl) -5- (phenylthio) -1,5-dihydro-2H-pyrrol-2-one (IIa).

To a solution of 1.0 mmol of 3-benzoyl-1H-benzo [6] pyrrolo [1,2-d] [1,4] oxazine-1,2,4-trione (Ia) in 2 ml of anhydrous acetonitrile was added 1.0 mmol of thiophenol. The reaction mixture was boiled for 2 minutes. 5.0 mmol of water was added, the precipitate formed after a day was filtered off. Yield 83%, m.p. 176-178 ° C. Compound (IIa) C ₂₃ H ₁₇ NO ₄ S.

Found,%:

Calculated,%: C 68.47; H 4.25; N 3.47; About 15.86; S 7.95.

Compound (IIa) is a yellow crystalline substance, readily soluble in DMSO, DMF, hardly soluble in dichloromethane, chloroform, acetone, alcohols, and insoluble in water and alkanes. Stable under normal storage conditions.

In the IR spectrum of compound (IIa), recorded as a paste in liquid paraffin, there are bands of stretching vibrations of hydroxyl groups of hydroxyphenyl and pyrrol-2-one 3147, 3081 cm ^-1 , carbonyl groups of pyrrol-2-one and benzoyl 1694, 1661 cm ^{- 1} .

¹ H NMR spectrum (400 MHz, DMSO-d ₆ , δ, ppm): 11.63 s (1H), 9.97 s (1H), 7.63-7.56 m (1H), 7.56-7.51 m (2H), 7.48 -7.39 m (3H), 7.38-7.32 m (1H), 7.28-7.20 m (3H), 7.18-7.09 m (2H), 7.06-6.89 m (2H), 6.47 s (1H).

Example 2. Obtaining (4- (4-ethoxybenzoyl) -3-hydroxy-1- (2-hydroxyphenyl) -5- (phenylthio) -1,5-dihydro-2H-pyrrol-2-one (IIb).

1.0 mmol of 3- (4-ethoxybenzoyl) -1H-benzo [6] pyrrolo [1,2-d] [1,4] oxazine-1,2,4-trione Ib mmol of thiophenol. The reaction mixture was boiled for 5 minutes.

5.0 mmol of water was added, the precipitate formed after a day was filtered off. Yield 68%, m.p. 177-179 ° C. Compound (IIb) C ₂₅ H ₂₁ NO ₅ S.

Found,%:

Calculated,%: C 67.10; H 4.73; N 3.13; S 7.16

Compound (IIb) is a yellow crystalline substance, readily soluble in DMSO, DMF, hardly soluble in dichloromethane, chloroform, acetone, alcohols, insoluble in water and alkanes. Stable under normal storage conditions.

In the IR spectrum of compound (IIb), recorded as a paste in liquid paraffin, there are bands of stretching vibrations of hydroxyl groups of pyrrol-2-one and hydroxyphenyl 3186, 3085 cm ^-1 , carbonyl groups of pyrrol-2-one and benzoyl 1685, 1626 cm ^{- 1} .

¹ H NMR (400 MHz, DMSO-d _5, δ, ppm): 11.70 s (1H), 9.94 s (1H), 7.62-7.53 m (2H), 7.42-7.30 m (2H), 7.23 qd (J = 7.5, 6.7, 1.6 Hz, 3H), 7.11 dt (J = 7.1, 1.3 Hz, 2H), 6.99-6.90 m (2H), 6.46 s (1H), 4.14 q (J = 6.9 Hz, 2H), 1.36 t (J = 6.9 Hz, 3H)

Example 3. Obtaining 3-hydroxy-1- (2-hydroxyphenyl) - (4- (4-nitrobenzoyl) -5- (phenylthio) -1,5-dihydro-2H-pyrrol-2-one (IIc).

1.0 mmol of 3- (4-nitrobenzoyl) -1H-benzo [b] pyrrolo [1,2-d] [1,4] oxazine-1,2,4-trione (Ic) mmol of thiophenol. The reaction mixture was boiled for 10 minutes. 5.0 mmol of water was added, the precipitate formed after a day was filtered off. Yield 56%, m.p. 182-184 ° C. Compound (Ps) C ₂₃ H ₁₆ N ₂ O ₆ S.

Found,%:

Calculated,%: C 61.60; H 3.60; N 6.25; About 21.41; S 7.15. Compound (IIc) is a yellow crystalline substance, readily soluble in DMSO, DMF, hardly soluble in dichloromethane, chloroform, acetone, alcohols, insoluble in water and alkanes. Stable when stored under normal conditions

In the IR spectrum of compound (IIc), recorded as a paste in liquid paraffin, there are bands of stretching vibrations of hydroxyl groups of hydroxyphenyl and pyrrol-2-one 3107, 3090 cm ^-1 , carbonyl groups of pyrrol-2-one and benzoyl 1686, 1634 cm ^{- 1} .

¹ H NMR (400 MHz, DMSO-d _6, δ, ppm): 11.65 s (1H), 10.00 (1H), 8.32-8.21 m (2H), 7.67-7.62 m (2H), 7.49 -7.34 m (2H), 7.32-7.22 m (3H), 7.17 d (J = 7.4 Hz, 2H), 7.03-6.91 m (2H), 6.45 s (1H).

Example 4. Pharmacological study of 4- (aroyl) -3-hydroxy-1- (2-hydroxyphenyl) -5- (phenylthio) -1,5-dihydro-2H-pyrrol-2-ones (IIa-c) for the presence of antimicrobial activity.

The antimicrobial properties of chemicals were studied on 2 collectible opportunistic strains of microorganisms: Staphylococcus aureus (strain 906) and Candida albicans, 1353.

To study the antimicrobial action used the generally accepted method of two-fold serial dilutions in a liquid nutrient medium by the micro method [Khabriev R.U. Guidelines for experimental (preclinical) study of new

pharmacological substances. - M .: Institute of Medicine, 2005. - 832 p.]. Initial dilutions of microorganisms were prepared in physiological solution from an overnight agar culture according to an optical turbidity standard (OSS) at 5 IU using a densitometer. After a series of dilutions, the final concentration of cells in the experiment was 2.5 × 10 ⁵ cells / ml. In the wells of a sterile 96-well flat-bottomed microplate, two parallel rows of two-fold serial dilutions of chemical compounds in RPB broth, Sabouraud were prepared. Each well contained 150 μl of a certain concentration of the test substance and 150 μl of culture inoculum. The last rows contained the nutrient medium and culture in equal volumes (control). The maximum tested concentration corresponded to 1000.0 μg / ml, the minimum - 1.0 μg / ml. The fact of inhibition (growth inhibition) of microbial cells in dilutions of preparations was noted after 20 hours of incubation at 37 ° C, followed by sowing on a solid nutrient medium. The final results were recorded 7 days after plating on agar slant. Antimicrobial activity was assessed by the minimum effective concentration.

The results were evaluated using the Gen 5 spectrophotometer software for Epoch microplates. The last well of the row with growth retardation and OD values equal to the optical density of the control well corresponds to the minimum inhibitory concentration of the compound.

Studies have shown (see table) that compounds (IIa-c) exhibit an inhibitory effect against the Staphylococcus aureus strain in the concentration range - 31.2-62.5 μg / ml, bactericidal action occurs at concentrations of 125.0-250.0 μg / ml. In relation to the culture of Candida albicans, compounds (IIa-c) exhibit a fungistatic effect at concentrations of 125.0-500.0 μg / ml, the destructive effect occurs from a concentration of 1000.0 μg / ml.

4- (aroyl) -3-hydroxy-1- (2-hydroxyphenyl) -5- (phenylthio) -1,5-dihydro-2H-pyrrol-2-ones, previously undescribed in the literature, can find application in pharmacology as potential medicines with antimicrobial properties.

Claims (4)

4- (Aroyl) -3-hydroxy-1- (2-hydroxyphenyl) -5- (phenylthio) -1,5-dihydro-2H-pyrrol-2-ones of general formula

where R = Н (a), OEt (b), NO ₂ (с), having antimicrobial activity.