Copolymers of diallylaminophosphonium salts with sulphur dioxide demonstrating anti-microbial activity

FIELD: chemistry.

SUBSTANCE: claimed invention relates to copolymers of diallylaminophosphonium salts with sulphur dioxide demonstrating antimicrobial activity with respect to a number of bacteria, as well as to yeast-like fungi and spores, and can be applied as antiseptic and disinfecting means. Claimed copolymers of diallylaminophosphonium salts with sulphur dioxide aree characterised by general formula where A=Cl- or BF4-. They are soluble in methanol, DMSO, DMFA or if A=Cl- are soluble in water. They are obtained by copolymerisation of equimolar amounts of sulphur dioxide and diallylaminophosphonium salt, selected from tris(diethylamino)diallylaminophosphonium chloride or tris(diethylamino)diallylaminophosphonium tetrafluoroborate.

EFFECT: obtaining novel efficient and low-toxic compounds which do not cause corrosion of processed metals.

2 cl, 3 tbl, 4 ex


The invention relates to copolymers diallylammonium salts with sulfur dioxide exhibiting antimicrobial activity, and can be used as an antiseptic and disinfectant.

Description of the claimed compounds, their properties and their application as an antiseptic and disinfectant in the sources of information not found.

Analogues of the claimed compounds for biological activity are different antiseptics and disinfectants.

So, are widely used for disinfection of traditional chlorine-based tools, such as chloramine-B (sodium salt of N-chloramide benzosulfimide

C6H5SO2NNaCl·3H2O) [Efimov K.M., Gembicki P.A., Snezhko A.G. Oligoimide - class low-toxic disinfectants prolonged action // Disinfection, 2000, No. 4]. At a moderate antimicrobial activity of this drug is highly toxic, irritating to skin and mucous membranes. In addition, he has a pronounced odor and corrosive.

Known as disinfectants Quaternary ammonium compounds, for example, the drug "Alumina" (alkyldimethylbenzylammonium chloride) phosphate [ibid]. This drug also exerts toxicity and irritating effect on the skin and mucous membranes, albeit more moderate than the s with the above means. The disadvantage is its low activity against spore cultures of microorganisms.

Closest on the achieved effects similar to the proposed solutions are polyguanidine, such as postbag-polyhexamethylene guanidine phosphate [ibid].

Postbag has a high biocidal effect against a number of microorganisms and belongs to the 4th class of toxicity in skin flow in the body and to the 3rd class of admission through the stomach, indicating the presence of low toxicity. However, no data about the activity of postopera against Micrococcus luteus, Staphylococcus saprophyticus, a number of dispute.

Worldwide great danger lies in the spread of germs that are resistant to all known antimicrobial agents. It is therefore extremely important is the search for new chemical compounds with biocidal properties against a broad range of opportunistic and pathogenic microorganisms.

Object of the invention is to provide new compounds possessing a wide spectrum of antimicrobial activity with low toxicity for expanding the resource base and range of antiseptic and disinfectants.

To solve the problem of the synthesized copolymers diallylammonium salts with sulfur dioxide General formula

where A=CL-what does BF 4-soluble in methanol, dimethylsulfoxide, dimethylformamide, or if A=CL-soluble in water, obtained by copolymerization equimolar quantities of sulfur dioxide and diallylammonium salt selected from Tris(diethylamino)diallylamine chloride or Tris(diethylamino)diallyldimethylammonium.

The copolymers of the General formula (1) exhibit antimicrobial activity.

Getting diallylammonium salts

Tris(diethylamino)diallylamine chloride (EAAF-CL) are obtained by the following method.

To Tris(diethylamino)phosphatidate with vigorous stirring freshly poured chloride allyl and continue stirring the reaction mixture until the termination of spontaneous growth temperature. Next, while stirring, the reaction mixture is dosed sodium hydroxide in the form of a 50%aqueous solution, the temperature when this support is not above 38°C. At the end of the dosing reaction mixture is stirred for another 30-45 minutes and then under stirring withstand 10-12 hours low boiling. Upon cooling the reaction mixture to separate the middle layer and extracted with AAAF-CL dichloromethane. The extract is evaporated on a rotary evaporator at a temperature of 100°C speed: first water-jet vacuum pump, and then in a vacuum oil pump(5-7 mm Hg).

To obtain Tris(diethylamino)diallylamine of tetrafluoroborate (EAAF-F4) use the following method.

AAAF-CL dissolved in distilled water and with vigorous stirring was added dropwise a 20%aqueous solution of tetrafluoroborate sodium. The reaction mixture is stirred for 15-20 minutes and incubated for a day at room temperature. Next, the precipitate is filtered off, washed with distilled water and dried in a vacuum at a temperature of 80°C to constant weight.

The purity of the obtained compounds was controlled by elemental analysis and NMR13C. the value of the chemical shifts (δ, ppm) and multipletness of the NMR spectrum

13With AAAF-CL and AAAF-BF4shown in table 1.

The copolymerization diallylammonium salts with sulfur dioxide

The copolymerization diallylammonium salts with SO2conducted by well-known methods [Vorobyov A.I., Vasilieva E.V., gaysina HA, Puzin SCI, Liplianin GV Copolymerization of N,N-dialkyl-N,N-diallylammonium halide with sulfur dioxide // high-Molecular compounds. - 1996, v.38, №10. - S-1667].

Sulfur dioxide was dried by passing through concentrated H2SO4and svezhepoymannyh l2. As initiator used DINITROL asuitable acid (DAK). The copolymerization was carried out at a temperature of 80°C for 7 hours. On emery was purified twice presidenial from a solution in an appropriate solvent (methanol) in the precipitator (tetrahydrofuran) and dried in vacuum to constant weight at 50°C.

The composition of the copolymers of the General formula (1) was calculated according to the results of the elemental analysis.

The NMR spectra of13With copolymers AAAF-CL and AAAF-BF4with SO2are shown in table 2.

NMR spectra were recorded on a spectrometer "Bruker AM-300" with an operating frequency of carbon nuclei 75.5 MHz. Spectra were recorded in the modes with broadband decoupling the protons in the JMOD. As a solvent used DMSO-d6and D2O; internal standard tetramethylsilane was (TMS) and 2,2-dimethyl-2-silapentane-5-acid, respectively.

The analysis of the spectra shows that AAAF-CL and AAAF-BF4copolymerized with SO2with the participation of both double bonds via intramolecular cyclization with the formation of pyrrolidinone structures (table 2).

The possibility of obtaining diallylammonium salts and their copolymers with sulfur dioxide the following examples.

Example 1. AAAF-CL was obtained by the described method.

The source materials were taken in the following amounts:

Tris(diethylamino)phosphatidic - 392 g (1.5 mol)

chloride allyl - 600 g (7.5 mol)

a 50%aqueous solution of sodium hydroxide - 255 g (6.4 mol)

Got 490 g AAAF-CL. The output is 86.5% of theoretical.

Found, %: C 56,82; N 11,06; N 14,55. C18H40ClN4P.

Calculated, %: 57,07; N 10,57; N 14,79.

Example 2. AAAF-BF4had the op is pulling method.

The source materials were taken in the following amounts:

AAAF-Cl - 490 g (1.3 mol)

distilled water - 2,0 l

20%aqueous solution of tetrafluoroborate sodium - 960 g

Received 390 g AAAF-BF4. Output - 70.1 percent of theoretical.

Found, %: C 49,72; N There Is A 10.03; N 12,83. C18H40F4N4PB.

Calculated, %: C 50,23; N. Of 9.30; N 13,02.

Example 3. AAAF-Cl with SO2received by the given method.

The source materials were taken in the following amounts:

AAAF-Cl - 1,8925 g (50 mol%)

SO2- 0.32 g (50 mol%)

DUCK 0,066375 g (3 wt%)

Output - 1.45 g (58,7%)

Example 4. AAAF-BF4with SO2received by the given method.

The source materials were taken in the following amounts:

AAAF-BF4- 2,149 g (50 mol%)

SO2- 0.32 g (50 mol%)

DUCK 0,07407 g (3 wt%)

Output - 1.45 g (58,7%)

Study of toxicity and antimicrobial activity

Parameters of acute toxicity copolymers diallylammonium salts with sulfur dioxide was determined on outbred mice of both sexes weighing 18-22 g by a known method [Prozorovsky V.B. have been, Prozorovsky BTW, Demchenko V.M. rapid method for the determination of effective dose and its error // Pharmacology and toxicology, - 1978, No. 4, s-502].

Toxicological tests showed that the claimed copolymers belong to the 4th class of toxicity [Hodge H.E., Sterner L.H. CIT. according to Spector. Spector W.S. (Ed.) Handbook of Toxicology. V.1, 1956]by introduction through the stomach (LD 50>>1000 mg/kg) and can be used for medical purposes.

Determination of antimicrobial activity was performed by the method of twofold serial dilutions [Methods of experimental chemotherapy / edited Hendersen. - M.: 1971. pp.109] at the Museum of test cultures of Escherichia coli St; Staphylococcus aureus, St; Staphylococcus saprophyticus, ATCC 15305; Micrococcus luteus, ATCC 4698; Bacillus antracoides, 1312; Bacillus subtilis ATCC 6633; Bacillus proteus, pc. "Flowers"; Candida albicans, 264/624; Salmonella spp. (STATE research Institute of Standardization and control of medical biological preparations. Laurasia). In the experiments used the 18-hour agar culture (2,5×105microbial cells in 1 ml of medium). We studied the solutions of the compounds in water or dimethyl sulfoxide. The maximum of the tested concentrations 1000,0 µg/ml test Tubes were incubated at 37°C, followed by seeding in 24 hours in tubes with beveled mesopartner agar. Analysis was performed according to the presence and nature of crop growth on a nutrient medium.

It is established that the claimed copolymers inhibit the growth of Staphylococcus and Micrococcus in the concentration range of 7.8 to 31.2 µg/ml of the death of the yeast-like fungus Candida albicans observed when exposed to concentrations of calimero to 31.2 µg/ml Copolymers also cause the death of Escherichia coli at a concentration of 62.5 µg/ml; Salmonella spp. concentrate 125,0 µg/ml; Bacillus subtilis in the concentration range of 15.6 to 31.2 µg/ml; Bacillus proteus and str is s Bacillus antracoides - within the concentration range of 250.0-500,0 mg/ml

The research results of antimicrobial activity are presented in table 3.

The proposed copolymers diallylammonium salts with sulfur dioxide have the following advantages.

1. Have a high biocidal effect against a range of bacteria and yeast-like fungi and spore cultures.

2. Belong to the 4th class of toxicity when injected into the stomach, which allows their use for medical purposes.

3. Does not cause corrosion of materials.

Table 1
Chemical shifts and multipletness of the NMR signals13With AAAF-CL and AAAF-F4
49,27132,54119,5840,58to 13.09
td ttto

Table 2
The NMR spectra of13With copolymers AAAF-CL and AAAF-F4with SO2(DMSO-d6, TMS)
No.ConnectionChem. shifts and multipletness signals, ppm
1C52,6036,7151,9841,27 13,94
Note: t - triplet, d - doublet, Quartet; * - stereoisomers.

Table 3
Antimicrobial activity of copolymers AAAF-the l SO 2and AAAF-F4with SO2
№ p/pThe name of the species (strain) of the microorganismAntimicrobial activity (MIC)ug/ml
AAAF-CL with SO2AAAF-F4with SO2
1Escherichia coli, Ps. 2592262,562,5
2Staphylococcus aureus, PCs 9067,8<31,2>the 15.6
3Micrococcus luteus, ATCC 4698>7,8<a 15.6<15,6>7,8
4Staphylococcus saprophyticus, ATCC 15305<31,2>the 15.6the 15.6
5Candida albicans, 264/62431,2<62,5>31,2
6Bacillus antracoides, 131<500,0>250,0500,0
7Bacillus proteus, pc. "Flowers"<1000,0>500,0 >250,0<500,0
8Bacillus subtilis ATCC 6633<15,6>7,8<62,5>31,2
9Salmonella spp.<125,0125,0

1. Copolymers diallylammonium salts with sulfur dioxide General formula

where A=CL-or BF4-soluble in methanol, dimethylsulfoxide, dimethylformamide, or if A=CL-soluble in water, obtained by copolymerization equimolar quantities of sulfur dioxide and diallylammonium salt selected from Tris(diethylamino)diallylamine chloride or Tris(diethylamino)diallyldimethylammonium.

2. The copolymers according to claim 1, exhibiting antimicrobial activity.


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