RU2806038C1 - Application of 3'-(4-bromobenzoyl)-4'-hydroxy-1'-(2-hydroxyethyl)spiro[benzo[b][1,4]thiazine-2,2'-pyrrole]-3,5'(1 'h,4h)-dione as agent with antimicrobial activity against s. aureus culture - Google Patents

Abstract

FIELD: organic chemistry.

SUBSTANCE: use of individual compounds of the spiro[benzo[b][1,4]thiazine-2,2 class' -pyrrole]-3.5' -dione. Application of 3'-(4-bromobenzoyl)-4'-hydroxy-1'-(2-hydroxyethyl)spiro[benzo[b][1,4]thiazine-2,2' -pyrrole]-3.5' (1' H,4H)dione of the general formula

as a product with antimicrobial activity against S. aureus cultures is suggested.

EFFECT: production of new compounds that can be used as starting products for the synthesis of new heterocyclic systems and in pharmacology.

1 cl, 1 tbl, 2 ex

Description

The invention relates to the field of organic chemistry, namely to the use of individual compounds of the class of spiro[benzo[b][1,4]thiazin-2,2'-pyrrole]-3,5'-diones as agents with antimicrobial activity, which can be used as starting products for the synthesis of new heterocyclic systems and in pharmacology.

The claimed compounds are 3'-aroyl-4'-hydroxy-1'-(2-hydroxyethyl)spiro[benzo[b][1,4]thiazine-2,2'-pyrrole]-3,5'(1'H, 4H)-diones and the method for their synthesis are known from the prior art. The claimed compounds are products of the interaction of 8-aroyl-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-1,6,7-triones with o-aminothiophenol (“Synthesis of spiro[benzothiazine- 2,2'-pyrroles] by the reaction of pyrrolo[2,1-с][1,4]oxazinetriones with o-aminothiophenol", Tretyakov N.A., Dmitriev M.V., Maslivets A.N., ZhORKh, 2020, 56, No. 5, 802-806. [Synthesis of Spiro[1,4-benzothiazine-2,2'-pyrroles] by the Reaction of Pyrrolo[2,l-c][l,4]oxazinetriones with 2-Aminobenzenethiol. Tretyakov N.A. , Dmitriev M.V., Maslivets A.N. Russ. JOC, 2020, 56(5), 935-938. doi: 10.1134/S1070428020050292]), formed according to the following scheme:

Antimicrobial activity of 3'-aroyl-4'-hydroxy-1'-(2-hydroxyethyl)spiro[benzo[b][1,4]thiazine-2,2'-pyrrole]-3,5'(1'H, 4H)-diones has not been studied previously.

The objective of the invention is to find new compounds with antimicrobial activity and expand the arsenal of means of influencing a living organism.

The problem is solved by the fact that the compound 3'-(4-bromobenzoyl)-4'-hydroxy-1'-(2-hydroxyethyl)spiro[benzo[b][1,4]thiazine-2,2'-pyrrole]- 3,5'(1'H,4H)-dione exhibits high antimicrobial activity at a concentration of 1000 μg/ml against S. aureus cultures.

The claimed compound is synthesized by reacting 8-(4-bromobenzoyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-1,6,7-trione with o-aminothiophenol in a solvent environment followed by isolation of target products according to the following scheme:

The process is carried out at room temperature, and anhydrous dioxane is used as a solvent.

The invention is illustrated by the following examples.

Example 1. 3'-(4-Brombenzoyl)-4'-hydroxy-1'-(2-hydroxyethyl)spiro[benzo[b][1,4]thiazine-2,2'-pyrrole]-3,5' (1'H,4H)-dione (4)

To a solution of 1.5 mmol 8-(4-bromobenzoyl)-3,4-dihydro-1H-pyrrolo[2,1-с][1,4]oxazine-1,6,7-trione (3) in 15 ml 1, 4-dioxane was added to a solution of 1.5 mmol o-aminothiophenol in 5 ml of 1,4-dioxane at room temperature, the solvent was evaporated. Yield 87%, mp. 195-197°C.

Compound (4) C ₂₀ H ₁₅ BrN ₂ O ₅ S.

Found, %: C 50.79; H 3.02; N 5.47; S 6.87

Calculated, %: C 50.54; H 3.18; N 5.89; S 6.75.

Compound (4) is a light yellow crystalline substance, readily soluble in DMSO and DMF, sparingly soluble in less polar organic solvents, insoluble in water and alkanes. Stable when stored under normal conditions.

The IR spectrum of compound (4), recorded as a paste in petroleum jelly, contains bands of stretching vibrations of the alcohol group OH in the form of a narrow peak at 3450 cm ^-1 , the enol group OH in the form of a broad band at 3147 cm ^-1 , and two lactam carbonyl groups at 1712 and 1661 cm ^-1 , and the aroyl carbonyl group at 1633 cm ^-1 .

In the ^1H NMR spectrum of compound (4), recorded in solution in DMSO-d _6, in addition to the signals of the protons of the aromatic rings, there is a group of 4 methylene protons of the ethoxy substituent at: 3.28-3.58 ppm. (m, 4H, NC H ₂ C H ₂ OH), a broadened singlet of the proton of the OH ethoxy group at 4.98 ppm, and a singlet of the proton of the NH group of the thiazine fragment at 11.11 ppm.

Example 2 Pharmacological study of compound (4) for antimicrobial activity

For research, we used the generally accepted method of two-fold serial dilutions in a liquid nutrient medium using the micromethod [Guide to the experimental (preclinical) study of new pharmacological substances - M.: Institute of Medicine, 2005]. Initial dilutions of microorganisms were prepared in physiological solution from a daily agar culture according to the optical turbidity standard (OTS) at 5 IU using a densitometer. After a series of dilutions, the final cell concentration in the experiment was 2.5×10 ⁵ cells/ml.

The antimicrobial properties of the chemical substance were studied on 3 collection opportunistic strains of microorganisms: Staphylococcus aureus (strain 906), Escherichia coli (strain 1257), Candida albicans (RKPGU 1353/1277), obtained at the Federal State Budgetary Institution "Scientific Center for Expertise of Medical Products" Ministry of Health and Social Development of Russia. The fact of inhibition (growth inhibition) of microbial cells in drug dilutions was noted after 20 hours of thermostatting at 37°C. The final results were recorded 7 days after seeding on RPA agar slants. The maximum concentration of compounds tested was 1000.0 μg/ml. Antimicrobial (inhibitory, bactericidal) activity was assessed based on the minimum effective concentration.

Analysis of the data obtained showed:

• compound 4 has an inhibitory effect against S. aureus cultures at a concentration of 1000.0 μg/ml.

The proposed substance is 3'-(4-bromobenzoyl)-4'-hydroxy-1'-(2-hydroxyethyl)spiro[benzo[b][1,4]thiazin-2,2'-pyrrole]-3,5'( 1'H,4H)-dione (4) has pharmacological activity, namely antimicrobial activity against S. aureus cultures, and can be used in pharmacology as a potential drug.

Claims (3)

Application of 3′-(4-bromobenzoyl)-4′-hydroxy-1′-(2-hydroxyethyl)spiro[benzo[ b ][1,4]thiazin-2,2′-pyrrole]-3,5′(1 ′ H , 4H )-dione of the general formula as a agent with antimicrobial activity against S. aureus cultures.