3-(5-nitrofuryl)-7-(5-nitrofurfurylidene-3,3a,4,5,6,7-hexahydro-2h-indazole eliciting antibacterial activity with respect to bacterium of genus staphylococcus

FIELD: organic chemistry, antibacterial agents.

SUBSTANCE: invention relates to a novel heterocyclic compound, in particular, 3-(5-nitrofuryl)-7-(5-nitrofurfurylidene-3,3a,4,5,6,7-hexahydro-2H-indazole of the formula (1): that elicits an antibacterial activity with respect to bacterium of genus Staphylococcus and can be used in medicine. The compound of the formula 91) is prepared by reaction of 2,6-di-(5-nitrofurfurylidene)-cyclohexanone with hydrazine hydrate in propanol-2 medium. The yield is 80%, m. p. at 193-195°C, empirical formula is C16H14N4O6, LD50 value at intraperitoneal administration is 500 mg/kg. This compound exceeds activity of furacilinum and furazolidone by 16 and 2-31 times, respectively. Invention provides preparing compound possessing the higher and selective antibacterial activity and low toxicity.

EFFECT: valuable properties of compound.

1 cl, 3 tbl, 1 ex

 

The invention relates to new biologically active organic compound is 3-(5-nitrophenyl)-7-(5-nitrofurfurylidene)-3,3A,4,5,6,7-hexahydro-2H-indazole exhibiting antimicrobial activity against bacteria of the genus Stapylococcus, which may find application in medical practice as a drug for the treatment of staphylococcal infections.

In medical practice for the treatment of infections caused by gram-positive and gram-negative microorganisms used furazolidone (1) (N-(5-nitro-2-furfurylamine)-3-aminoquinoline-2) and furatsilin (2) (5-nitrofurfural semicarbazone)

Furazolidone is active against bacteria of the genus Staphylococcus in a concentration of 1.6 and 6.6 µg/ml [see L. Alekseeva. Antibacterial drugs are derivatives of 5-nitrofuran. Riga. 1963, of lat. SSR, s.219] and belongs to the class of low-toxic substances (LD501758 mg/kg).

Furatsilin exhibits antimicrobial activity against bacteria of the genus Staphylococcus in a concentration of ˜ 20 mcg/ml [see Kresmer L.V. Nitrofuranovye drugs in the fight against staphylococcal infection. Riga. 1964, of lat. SSR, 117 S.], but has a high toxicity (DL50of 82.5 mg/kg), and therefore applies only locally [Mashkovsky PPM Medicines. - M.: Medicine, 2004, Vol.2, s].

However, their long and wide application in medical practice led to the formation and circulation of resistant strains of staphylococci [Venison N.A. Some mechanisms of nitrofurantoine in gram-negative bacteria: author. dis... Kida. the honey. Sciences / Nailtini - Saratov, 1965. - 12 S.; Torlopova so-CALLED. Change the biological properties of Staphylococcus under the influence nitrofuranovye drugs in the experiment and in the body of patients // abstract. dis.... Kida. the honey. Sciences / Teetulpa - Saratov, 1974. - 15 S.].

Object of the invention is the search number nitrofuranov new compounds with high antimicrobial activity against bacteria of the genus Staphylococcus that is resistant to other nitrofurans.

The problem is solved in that a new substance (compound): 3-(5-nitrophenyl)-7-(5-nitrofurfurylidene)-3,3A,4,5,6,7-hexahydro-2H-indazol exhibiting antimicrobial activity against bacteria of the genus Staphylococcus.

The synthesized compound has the formula

The connection is produced by boiling for 10 min a solution of 2,6-di-(5-nitrofurfurylidene)-cyclohexanone in propanol-2 hydrazinehydrate taken in the ratio of 1:14 to reaction

This antimicrobial activity against bacteria of the genus Staphylococcus synthetic substances increases by 16 times compared to practice furatsilinom and 2-31 times compared to furazolidone, not only in relation to the standard is Tim strains of microorganisms, but clinical (table 1, 2, 3). MICK503-(5-nitrophenyl)-7-(5-nitrofurfurylidene)-3,3A,4,5,6,7-hexahydro-2H-indazole against clinical strains of bacteria of the genus Staphylococcus is at 1.17 µg/ml, while the MIC50furazolidone of 3.60 ág/ml

Comparative analysis with analogues shows that the claimed compound is fundamentally different in that it contains in the molecule two 5-nitrofuranovye fragment and azomethine chain =C-C=N-NH - is part of the heterocyclic - hexahydropyrazino structure.

Example preparation of 3-(5-nitrophenyl)-7-(5-nitrofurfurylidene)-3,3A,4,5,6,7-hexahydro-2H-indazole: 0.5 g (1.5 mmol) of 2,6-di-(5-nitrofurfurylidene)-cyclohexanone are dissolved in 250 ml of propanol-2 under heat and add 1 ml (20 mmol) of hydrazine hydrate is added. The mixture is boiled for 10 minutes and leave for the day. The precipitated crystals filtered off. The yield of 0.54 g (80%).

The melting temperature TPL193-195° (propanol-2).

The data of elemental analysis

Found, %: C 54,09; N 4,13; N 15,27.

C16H14N4O6

Calculated, %: 54,08; N 3,91; N 15,64.

The spectral characteristics of the connection:

IR spectrum, cm-1: νNH 3348; νCH(Fu) 3140; νCH22952, 2876; vibrations of C=C-C=N 1676; NO21352, 1500.

An NMR spectrum1H (CDCl3that δ, M. D.): 4,58 d (14 Hz, 1H,3-H); 1.60 m (2N, WITH5H2-), 2.09 m (2N, WITH4H2 -), 3.18 m (2N, WITH6-H2-); 6,80 and 6,86 Shostakovich (2N, Nβ, Nβ' furan cycle 5-nitropyridine fragment); 7,58 and 7,63 Shostakovich (2N, Nβ, Nβ' furan cycle 5-nitropyrimidine fragment); 6,92 S. (1H, CH=); of 7.90 broadened singlet (1H, N-H).

Determination of antimicrobial activity of 3-(5-nitrophenyl)-7-(5-nitrofurfurylidene)-3,3A,4,5,6,7-hexahydro-2H-indazole was carried out using a twofold serial dilution in meat-peptone broth in the range of pH of 7.2 to 7.4, containing different concentrations of the studied compounds and Comparators. Prepared a number of serial twofold dilutions containing from 160,0 to 0.08 µg substance in 1 ml of pre-dissolving the sample substance in a minimum amount of dimethylformamide (DMF). Additionally prepared environment containing compounds at a concentration of 100 μg/ml Of the daily agar culture of bacteria on the optical the turbidity standard was prepared by a suspension concentration of 2·106M.L./ml In each tube containing a specific concentration of study drug were made in 0.1 ml of this suspension. The mixture was shaken and incubated in a thermostat at 37°C for 24 hours after which take into account the results of the experiment, noting the last test tube with clearly marked growth retardation. The amount of substance in the test tube was regarded as minimum inhibitory concentration (MIC) for COI is tiemogo strain, determining the level of susceptibility to this connection.

The experience was accompanied by two controls. The first - sowing culture in BCH no drug, second planting culture broth containing the maximum amount of DMF (3.2 percent), used in several breeding. The results of the comparison of antimicrobial activity of 3-(5-nitrophenyl)-7-(5-nitrofurfurylidene)-3,3A,4,5,6,7-hexahydro-2H-indazole with furazolidone and furatsilinom are shown in table 1.

An important characteristic of antimicrobial agents is their activity not only in relation to the standard test cultures, but also against clinical strains circulating in hospitals at the present time, since the latter can vary in sensitivity to chemotherapeutic agents from the standard strains. In this regard, a study was made protivostoyaschej activity of 3-(5-nitrophenyl)-7-(5-nitrofurfurylidene)-3,3A,4,5,6,7-hexahydro-2H-indazole in respect of 105 clinical strains of staphylococci. The results of the comparison of antimicrobial activity of 3-(5-nitrophenyl)-7-(5-nitrofurfurylidene)-3,3A,4,5,6,7-hexahydro-2H-indazole and furazolidone used in medical practice, against clinical strains of staphylococci are shown in tables 2 and 3.

Acute toxicity 3-(5-nitrophenyl)-7-(5-nitrofurfurylidene)-3,3A,4,5,6,7-hexahydro-2H-indazole was determined on the white bat is of both sexes weighing 20± 2 g of 40 animals in each series of experiments. LD50intraperitoneal injection was 500 mg/kg of the Claimed compound less toxic than furatsilin. As can be seen from the data tables described in connection with low toxicity is more pronounced protivostoyaschej activity than the counterparts, and that activity is superior to the furatsilin 16 times and furpsemide in 2-31 times.

Detected properties of the synthesized compounds are of interest from the point of view of the reserve funds chemotherapy staphylococcal infections.

The method of obtaining the claimed matter is simple in execution, the original substance is available, the output is 80% of theoretically calculated. It is stable in air, easily soluble in dimethylformamide and dimethylsulfoxide, little soluble in aliphatic alcohols, acetone, water, practically insoluble in ether, hexane.

The proposed substance has low toxicity and high antimicrobial activity against bacteria of the genus Staphylococcus.

Table 1.

Comparison of antimicrobial activity of the described connections and analogies in structure and action
ConnectionLD50(mg/kg intraperitoneally MIC, mcg/ml
S.aureus woodS.aureus 209 PS.aureus 23OS.aureus 31CS.epidermidis AS.epidermidis AE.coli was ATSS 25922P.mirabilis 20P.aeruginosa ADS 27835
3-(5-nitrophenyl)-7-(5-nitrofurfurylidene)-3,3A,4,5,6,7-hexahydro-2H-indazol5001,251,250,620,620,080,16100100100
furazolidone17582,52,510202,52,50,076,6
furatsilin82,52020No data

Table 2.

The sensitivity of clinical strains of staphylococci to 3-(5-nitrophenyl)-7-(5-nitrofurfurylidene)-3,3A,4,5,6,7-hexahydro-2H-indazole
The number of strains
MICK mg/mlS.aureusS. epidermidisOnly
The absolute quantity%Σ%abs %Σ%abs%Σ%
8022,5100---21,9100
401113,697,5---1110,598,1
2011,283,9---10,987,6
1044.982,7---4the 3.886,7
556,277,8312,510087,682,9
2,51619,871,6416,687,52019,175,3
1,253037,051,81041,770,94038,1
0,621113,614,814,229,21211,518,1
0,31--14,814,22510,96,6
0,16--14,8416,620,84the 3.8the 5.7
0,0811,21.214,24,221,91.9
Total81100-24100-105100-
MICK501,191,151,17

Table 3.

The sensitivity of clinical strains of staphylococci to furazolidone
MICK mg/mlS. aureusS. epidermidisOnly
Abs%(%abs%(%abs(%2%
8022,5100---21,9100
404a 4.997,5---4the 3.898,1
2033,792,6312,51006the 5.794,3
101012,388,9416,687,51413,388,6
52328,476,61041,770,933of 31.475,3
2,53543,248,262529,24139,143,9
1,2545514,24,254,84,8
0,62 ---------
0,31--------'-
0,16---------
0,08------
Total81100-24100-105100-
MICK503,333,753,60

3-(5-nitrophenyl)-7-(5-nitrofurfurylidene)-3,3A,4,5,6,7-hexahydro-2H-indazol formula

showing antimicrobial activity against the bacteria of the genus Staphylococcus.



 

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12 ck, 19 ex, 3 tbl

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EFFECT: valuable medicinal properties of new compounds.

8 cl, 3 tbl, 4 ex

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3 cl, 4 tbl, 3 ex

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EFFECT: enhanced and valuable properties of preparation.

3 tbl, 3 ex

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EFFECT: improved preparing method, valuable medicinal properties of derivatives.

16 cl, 2 tbl, 14 ex

FIELD: medicine.

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Modified chitosan // 2269542

FIELD: organic chemistry of natural compounds, chemical technology, medicine.

SUBSTANCE: invention relates to the group of chitosan-containing compounds. Invention relates to synthesis of modified chitosan of the following structure: wherein n = 150-1400. The modified chitosan possesses the bactericidal activity, in particular, antituberculosis activity.

EFFECT: valuable medicinal properties of modified chitosan.

1 tbl, 1 dwg, 3 ex

FIELD: medicine.

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EFFECT: higher efficiency of revaccination.

7 ex

FIELD: medicine, obstetrics.

SUBSTANCE: one should conduct antibacterial therapy 3 mo before planned pregnancy consisting of preparations of tetracyclinic group or macrolides in combination with nystatin and metronidasol to continue it since the first day of menstrual cycle and, also, it is necessary to perform correction of vaginal biocenosis, and about 3-4 wk after therapy carried out for 2 next mo before planned pregnancy starting, also, since the first day of menstrual cycle - metabolic therapy; At the onset of pregnancy one should conduct courses for preventing placental deficiency dealing with introduction of preparations that improve uterine-placental circulation, and preparations that improve rheological properties of blood and vitamin-metabolic therapy or the same preparations, and additionally - introduction of macrolides ad viferon rectally in case of activation of chlamydial infection. The present innovation enables to sanitize uterine cavity, improve uterine-placental circulation, restoration of placental tissue structure that, in its turn favors the birth of healthy generation.

EFFECT: higher efficiency of prophylaxis.

1 cl, 9 tbl

FIELD: medicine, pharmacy.

SUBSTANCE: medicinal formulation possessing the bacteristatic effect consists of a core comprising the following components, wt.-%: clarithromycin, 40.0-80.0; polyvinylpyrrolidone, 3.0-10.0; sodium lauryl sulfate, 2.0-5.0; sodium croscarmelose, 4.0-10.0; aerosil, 0.5-2.0; magnesium stearate, 0.5-2.0, and microcrystalline cellulose, 10.0-31.0. Also, the medicinal formulation consists of envelope comprising the following components, wt.-%: hydroxypropylmethylcellulose, 30.0-70.0; polyethylene glycol, 12.0-22.0; titanium dioxide, 11.0-20.0, hydroxypropylcellulose, 2.0-10.0, dye yellow quinoline, 1.0-4.0, and vanillin, 1.0-4.0. Also, invention describes a method for preparing the medicinal formulation by wet granulation followed by tableting and applying the envelope from an aqueous suspension. Prepared tablets show the necessary mechanical strength, insignificant scattering index by mass (± 3.5%) and dissolving 88-91% for 30 min.

EFFECT: improved and valuable properties of medicinal formulation.

3 cl, 2 tbl

FIELD: medicine, gynecology, surgery.

SUBSTANCE: one should introduce 3.5%-chitosan ascorbate gel into fistulous channel that contains metronidasol at the dosage of 2 mg/ml, at the volume up to 20 ml once/2 d till complete fistula's closing. The present innovation enables to activate reparative processes and fistulous epithelization that favors for closing fistulous channel in earlier terms.

EFFECT: higher efficiency of therapy conducted.

2 ex

FIELD: medicine, surgery.

SUBSTANCE: one should apply a polycompositional film onto donor's wounds after autodermoplasty performed. This film contains the following components in weight proportions: chitosan 78.3-89.4; polyvinyl alcohol 9.8-19.8; antibiotic of aminoglycoside group 0.5-2.0; anesthetic 0.1-0.2. It is perforated at tension coefficient being 1:4. The innovation enables to decrease wound's traumatization, improves prophylaxis of suppuration and increases cosmetic effect even at a single application of the film suggested.

EFFECT: higher efficiency of therapy.

2 ex

FIELD: pharmacy.

SUBSTANCE: invention relates to metronidazol-base antiprotozoan preparation possessing broad spectrum of action with respect to protozoa. Proposed agent is made as tablets based on metronidazol and comprises polyvinylpyrrolidone, filling agent and powdering agent also. Microcrystalline cellulose is used as a filling agent, and a mixture of cross-linked homopolymer of N-vinyl-2-pyrrolidone with the nitrogen content 11-12.8% and poly-(2-oxypyrrolidine-1-ylethylene) with K- viscosity value 22.5-26.7 and taken in the ratio = (1-5):1, respectively, is used as polyvinylpyrrolidone. Invention provides enhancing strength of tablet in combination with its rapid degradation in water.

EFFECT: improved pharmaceutical properties of agent.

1 tbl

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