RU2478106C2 - COMPOUNDS OF HYPERBRANCHED POLYMER Boltorn H COMPLEXES POSSESSING ANTI-CANDIDA ACTIVITY AND METHOD FOR PREPARING THEM - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention refers to compounds of hyperbranched polymer Boltorn H complexes which may be used as substances, bases, ingredients and other biologically active substances in preparing chemopreparations for treating and preventing human fungoid diseases, particularly Candida mycosis, as well as to a method for preparing said compounds. The compounds of hyperbranched polymer Boltorn H complexes contains 10 to 14 groups of propionic or acrylic acids and 10 to 14 metal ions. The given compounds possess anti-candida activity on Candida albicans, Candida krusei, Candida tropicalis, Candida parapsilosis and provides action on the Candida proteinase system and the cell wall components. The method for preparing said compounds consists in synthesis of the compounds containing 10 to 14 groups of propionic or acrylic acids and 10 to 14 metal ions with the use of consecutive reactions of etherification, substitution and addition.

EFFECT: higher preventive and clinical effectiveness in the disease.

2 cl, 3 tbl, 5 dwg

Description

The invention relates to medicine, namely to fundamentally new types of compounds based on complexes of hyperbranched polymers Boltorn H, which can be used as substances, bases, components and other biologically active substances in the manufacture of chemotherapeutic agents for the treatment and prevention of human fungal diseases, in particular mycoses Candida, and methods for their preparation.

At present, it is clear enough that an increase in the number of patients with weakened immune status will be characteristic of the coming decades. In particular, immunodeficiency is due to the increasing capabilities of medicine - the increasing use of cytostatics (a means to reduce the permeability of the cell membrane) and immunosuppressants (cf-va to suppress the body's immunity). Fungal infections are favored by invasive, surgical, instrumental interventions, examination of patients, the introduction into medicine of new materials and coatings for prosthetics, etc. Mycoses are the main cause of death in patients in intensive care units, especially emaciated patients with weakened immunity [1-3].

According to medical statistics, up to 50% of fungal diseases are associated with the pathogenic activity of yeast-like fungi of the genus Candida, with 95% of candidiasis caused by a culture of Candida albicans. The high pathogenic activity of the fungal allergen Candida albicans (hereinafter C.alb.) Is directly related to the number and variety of functions of secretory aspartic proteinases produced by it (international name - secretory aspartic proteinase, short for SAP C.alb.) [4].

The literature describes the results of medical and biochemical studies that conclusively prove the effect of Candida secretory aspartic proteases on the development and activation of diseases such as gastritis, stomatitis, fungal infections of the mucous membranes and skin. Also, the greatest study of the methods of influence of secretory aspartic proteases was obtained in connection with the study of the progression of the human immunodeficiency virus [4-9].

To date, secretory aspartic proteases of various pathogenic fungi of the genus Candida have been isolated: Candida albicans, Candida tropicalis, Candida parapsilosis, Candida lusitaniae. The greatest variety of substrate specificity is observed for Candida albicans. The specificity of SAP Candida lusitaniae is comparable to the specificity of Candida parapsilosis [9, 10].

Of greatest interest from the point of view of pathogenicity and impact on the human body is the protease system of Candida albicans (C.alb.). Pathogenic for humans type of yeast - C.alb. It affects the outer integument and internal organs, causing deep mycoses [11, 12]. Favorable conditions for the manifestation of the disease is a general depletion of the body or artificial dysbiosis due to the improper use of antibiotics. Macdonald and Odds published in 1980 [13] for the first time presented the results of studies on the isolation and characterization of C.alb protease. by electrophoresis in sodium dodocyl sulfate polyacrylamide gel. The molecular weight of the enzyme was determined, which amounted to 42 kDa (Dalton is a unit of measurement of the molecular weight of proteins) and an isoelectric point was found at pH = 4.0 using gel filtration on Sephacryl S-200 (membrane for determining the isoelectric point). An isolated enzyme is evaluated as a glycoprotein containing amino acid residues of aspartic acid. Human serum albumin and hemoglobin were used as a substrate for the isolation of the enzyme.

The structure of the selected aspartic protease C.alb. and the data on the amino acid sequence of its chains are decoded by the author of [14, 15] and are presented in Figs. 1, 2 in the Appendix. The active center of the secretory aspartic protease C.alb. characterized by the presence of two active sites, one in each domain (linear amino acid sequence), specific for compounds of protein and synthetic nature. Also in the protease C.alb. there is one metal ion binding site, namely the amino acid residue Asp-57.

As an ionic group, aspartic acid is present in all active sites of this enzyme; therefore, C.alb protease is called secretory aspartic protease (SAP C.alb.).

The system of aspartic proteinases C.alb. is inextricably linked with the level of immunity and currently includes ten isoenzymes with various functions and determining the localization and severity of candida infection [16, 17].

Studies of secretory aspartic proteinase C.alb. (SAP) started by physicians and biologists since 1980 [4]. Shortly after the discovery of SAP1, most of the isolated C.alb allergen enzymes. deciphered as extracellular aspartic proteases. Using the properties and structures of the first enzyme SAP1 obtained by PCR-cloning as a benchmark from 1992-2000. ten isoenzymes of C.alb. allergen were isolated, which made up the system of extracellular secretory aspartic proteases of C.alb. [13, 18-23] (see Figure 3). The structure of some proteinases is presented in the international Protein Data Bank database: SAP1 doi: 10.2210 / pdb2qzw / pdb, SAP2 doi: 10.2210 / pdb1zap / pdb, SAP3 doi: 10.2210 / pdb2h6s / pdb, SAP5 doi: 10.2210 / pdb2qzx / pdb. All ten currently isolated protein substances are aspartic proteases and possess a number of SAP-specific characteristics, namely they catalyze the hydrolysis of protein substrates of hemoglybin, casein in the acidic pH range, etc.

The cell secretion scheme of the C.alb protease system has been established. [24] (see Figure 4). The action and isolation of a proteinase of proteases through secretory bridges at their pH optimum for the manifestation of maximum catalytic activity. C.alb. transfers the gap to the endoplasmic reticulum, where the signal peptide is produced by signal peptidase. The propeptide contains two active Lys-Arg sites that are targeted for Kex2 proteases in the Golgi apparatus or for alternative activation processes. The space specifically focuses on the cell membrane, guided by the enzymatic properties of the C.alb protease system contained in it. The released proteases are transported by vesicles through the cell membrane into the cell wall and secreted into the intercellular space. Induced SAP1-3 are mostly active in the range pH = 2-5, while constitutive SAPs 4-6 are active at pH = 3-7 and, thus, can act in different environments. Analysis of the secretion mechanism of SAP9 and SAP 10 suggests that both proteases are glycosulfospatidylinositol proteins (GPI proteins) and settle on the cell membrane or cell wall [25]. It is believed that Kex2 may be a key regulator of the protease SAP [26]. A mature enzyme contains a specific amino acid sequence that is characteristic of all aspartic proteases, invariably including 2 aspartate residues at a distance of hydrogen bonds from each other in the active center. Cysteine residues (Cys 45 and Cys 56), rigidly fixed in each of the ten isoenzymes, are involved in maintaining the tertiary structure of SAP [27].

The presence of a protease system is observed only for a pathogenic allergen of the Candida family: C.alb. [28, 29] and the absence of other yeast cultures, suggested that these proteases may be involved in the processing of the disease. Even the only representative of the system - SAP2 is sufficient for the rapid growth and activity of C.alb allergen. in a medium containing protein [30, 31]. At a basic level, the role of proteases of C.alb. boil down to the absorption of proteins, to provide the cells with nitrogen. At the same time, the activity of SAP2 provides the possibility of effective growth of fungi in a medium containing serum albumin or other proteins as sources of nitrogen. [27, 32]. Proteases promote and participate in adhesion and invasion, and, therefore, in the destruction of surface cellular structures and intercellular substances, the destruction of cells and molecules, weakening the resistance of the immune system to "microbial attack." Such activity for SAP2 was shown in vitro [33]. The intracellular surface and proteins such as keratin, collagen, laminin, fibronectin and mucin are actively destroyed by SAP2. In addition, proteins of the immune system, such as lactoferrin, an α-macroglobin protease inhibitor, macrophage respiratory enzymes, and an overwhelming number of immunoglobulins, including immunoglobulin A (IgA), which is usually resistant to most bacterial proteases, are destroyed by SAP. Proteases C.alb. also acts on protein proteolytic cascades with various effects that are independent of fungal specificity. For example, SAP2 can activate cascades of precursor proteins during blood coagulation [34], inactivate a cysteine protease inhibitor cystatin A [35], and break down vesicular homeostasis proteins [36]. Such activity is manifested in an increase in circulating or systemic candida infection, which was shown in experiments on mice [37]. In addition, it was proved that protease activates cellular intelikin-1β, which indicates their decisive role in the activation and maintenance of inflammatory processes on epithelial surfaces in vivo [38].

Of primary interest are two types of Candida proteinases that are interconnected with each other: those induced by SAP C.alb., Exhibiting antigenic properties and constitutive SAP C.alb., Which have predominantly sorption functions and are necessary for the subsequent secretion and functioning of the first group proteinases.

However, the entire C. alb protein system. in modern sources it is presented only by clinical and biological indicators. The possibility of mutation of DNA enzymes with subsequent adaptation to the changing environment and individual characteristics of the body designate the C.alb proteinase system. as one of the most dangerous and pathogenic active substances. Thus, suppressing the activity of the SAP C. alb system., Will effectively suppress the activity of the culture of Candida albicans with both circulating and the most dangerous systemic mycoses.

To date, anti-candidiasis preparations of several groups are widely used: derivatives of amides and allylamides (Nitrofungin), imidazole preparations (Oxyconazole, Miconazole, Clotrimazole) [39], and the most widely used triazole derivatives to date (“ Diflucan ”,“ Flucostat ”,“ Fluconazole ”“ Itraconazole ”) [40]. The mechanism of their action is the inhibition of the biosynthesis of ergosterol, which is a component of the cell wall of the membrane of fungi. The disadvantage of all three groups is high toxicity [41, 42]. Despite the fact that triazoles have an advantage over imidazoles due to better pharmacokinetics and lower toxicity, in recent years, resistance to azoles has been increasingly found among various Candida species [43]. This is especially true for C. albicans. The causes of resistance are a decrease in the permeability of the cell membrane, the presence of an active ejection system in it, or superproduction of a cytochrome target - P450 _14Dm . And the effectiveness of their action depends on the individual sensitivity of the body to the active components and the human immune status. The antibiotic Amphotericin B and its modified analogues (Metamphocin, the liposome preparation Amphotericin B + lipid complexes, Fungizon) have the most powerful fungicidal effect and slow development of resistance to them, but have a limitation in systemic use due to nephrotoxicity, possible dysfunctions of the nervous system, fever, myalgia, or thrombophlebitis [44, 45]. Thus, the drug has a limitation in use due to toxicity factor.

In such a situation, when the existing antifungal agents are not suitable for the treatment of deep mycosis, there is a need to develop agents based on a new mechanism of action on cultures of Candida pathogenic fungi, which have low toxicity and do not cause resistance to the drug. From the prior art relating to antifungal agents based on a new mechanism of action, antifungal reagents based on heterocyclic substituted pyrimidine derivatives (RU 2380365 C1 01/27/2010), 2- (1,2,4-triazol-1-ylmethyl) -6- are known Benzylidene-1b4-dioxapiro [4,5] decans (RU 2326878 C1, 11/17/2006) having the following disadvantages:

- toxicity;

- low bioavailability;

- in patent documents there is no data on the cross-interaction of compounds in the most common Candida species, namely Candida tropicalis, Candida krusei, Candida par apilosis.

Part of the pharmacological anti-candidiasis compositions is based on protein compounds. Publication WO 01/76627 describes a composition for treating mycoses in humans containing an antibody specific for a conserved epitope (a part of a macromolecule that is recognized by the immune system (antibodies, B lymphocytes, T lymphocytes). Mushroom stress protein, hsp90, in combination with known antifungal agents (amphotericin B, fluconazole, voriconazole itraconazole). This antibody (hereinafter referred to as Mycograb (RTM)) recognizes an epitope represented by a peptide having the sequence of SEQ ID NO: 1, which is conserved in many kinds of mushrooms. The disadvantage of this composition is that the azole drugs do not exhibit synergistic effect with respect to the fungi of the genus Candida.

The closest chemical compounds to the claimed technical solution are salts and mixtures based on linear polymers:

- 9-oxoacridine-10-acetic acid with 1-alkylamino-1-deoxypolyols (RU 2297246 C1, 04/20/2007), which have anti-candida activity;

- an antifungal drug based on 2-chloro-4-nitrophenolpolyethylene glycol (PEG 400) and 50% ethyl alcohol (RU 2248202 C2, 09.26.2002);

Moreover, these preparations and mixtures can only be used as part of ointments and creams, due to the high toxicity of their components, including nitrophenol. In addition, for these analogues there is no information on the specificity of these compounds to the Candida family of cultures (see above).

A common drawback of all of the above drugs and substances is the fact that their action is mainly aimed at inhibiting the components of the fungal cell wall (ergosterol, lanosterol, and squalene) of Candida albicans and does not affect its extensive enzymatic system, which determines the level of pathogenicity of Candida culture. At present, the natural compounds acetylpeptstatin and pepstatin A and some of their synthetic analogues IC50 and A70 450, the amine 2- [3-benzyl-4-n- (4-methylpiperazin-1-yl-carbonyl), are known as inhibitors of the C. albicans aspartic proteinase. ) 2-ketopiperazin-1-yl] -hexanoic acid [12].

However, these inhibitors have a significant drawback - they inhibit the activity of all proteolytic enzymes (enzymes that catalyze the hydrolysis of proteins), including those vital for the absorption of nitrogen by the human body, which can lead to poor human health.

Thus, from the prior art, technical solutions have been identified that describe compounds based on linear polymers, exhibiting anti-candida activity, which have a number of disadvantages. However, technical solutions that ensure the implementation of the tasks have not been identified. Thus, the prototype is not identified.

The claimed technical solution consists in: compounds based on complexes of hyperbranched polymers Boltorn H containing from 10 to 14 groups of propionic or acrylic acids and from 10 to 14 metal ions Co (II) and Cu (II), which have anti-candida activity against Candida albicans, Candida krusei, Candida tropicalis, Candida parapsilosis and providing effects on the Candida proteinase system and cell wall components; a method for producing compounds based on complexes of hyperbranched Boltorn H polymers with anti-candidiasis activity consisting in the synthesis of compounds containing from 10 to 14 groups of propionic or acrylic acids and from 10 to 14 metal ions using sequential esterification, substitution and addition reactions.

The objective of the proposed technical solution is the creation of compounds based on complexes of hyperbranched polymers Boltorn H, which have anti-candidiasis activity and methods for their synthesis on the basis of the claimed components, possessing at the same time the following set of properties:

- a fundamentally new mechanism of action on the Candida culture based on the simultaneous action on the Candida proteinase system and cell wall components - ergosterol, lanosterol, squalene;

- suppression of the activity of inducible and constitutive secretory aspartic proteases of Candida culture (SAP C.alb.);

- a significant increase in membrane permeability and bioavailability;

- inhibition of the biosynthesis of the components of the cell wall of the fungi of the culture of Candida, namely ergosterol, lanosterol, squalene;

- the manifestation of fungicidal properties in relation to mainly four representatives of the Candida family, namely Candida albicans, Candida krusei, Candida tropicalis, Candida parapsilosis;

- a significant reduction in the overall toxicity of drugs.

The technical result is achieved by obtaining compounds based on complexes of hyperbranched non-toxic Boltorn H polymers containing groups of propionic and acrylic acids and metal ions Co (II) and Cu (II), which have anti-candida activity against Candida albicans, Candida krusei, Candida tropicalis, Candida parapsilosis and providing effects on the Candida proteinase system and cell wall components.

A method of obtaining compounds based on complexes of hyperbranched non-toxic Boltorn H polymers with anticandidic activity consists in the synthesis of compounds containing from 10 to 14 groups of propionic or acrylic acids and from 10 to 14 metal ions using sequential esterification, substitution and addition reactions.

The claimed technical solution is illustrated by the following materials:

Лиганд -: А70,

189 - молекул воды (для наглядности α-спиральные участки представлены в виде цилиндров. β-складки - в виде лент со стрелкой, указывающей направление цепи в складке от N-конца к С-концу);figure 1 shows the structure of the secretory aspartic protease Candida albicans:

Ligand -: A70,

189 — water molecules (for clarity, the α-helical sections are presented in the form of cylinders. Β-folds are in the form of ribbons with an arrow indicating the direction of the chain in the fold from the N-end to the C-end);

- активный центр,

Протеин: 341 кислотный остаток - [: 6 колец, 23 цепей],figure 2 shows the amino acid sequence of the secretory aspartic protease:

- active center,

Protein: 341 acid residue - [: 6 rings, 23 chains],

figure 3 shows the composition of the protease system of Candida albicans;

figure 4 shows a model of cell secretion of protease systems of Candida albicans:

Table 1 shows the information characterizing the required number of components for the synthesis of chemical compounds and their technical requirements;

figure 5 is a schematic diagram of a method for producing a chemical compound C4 having anti-candidiasis activity, which is illustrated by the example of the synthesis of compounds III-VI based on hyperbranched Boltorn H polyester polyol, succinic anhydride, cobalt (II) nitrates and copper (II) and is characterized by the sequence operations and compounds of the General chemical formula I obtained as a result of the described method;

Table 2 shows the catalytic activity of C.alb-induced SAP 2. in relation to hemoglobin in the presence of the obtained compounds (C _Hb = 126 mg / L, C _SAP = 2.0 × 10 ^-6 mol / L, pH = 4.10);

Table 3. shows data on the fungicidal activity and fungus resistance of the obtained compounds to some Candida strains and provides explanations for them with respect to both fungicidal activity and their activity with respect to their ability to grow with fungi.

To assess these characteristics, the disk diffusion method was used: cellulose disks impregnated with a 10% solution of the compound were placed in the center of a Petri dish containing a Candida culture in agar-agar gel. Fungicidal activity was evaluated by the area of the lysis zone formed around the disk impregnated with the control compound.

Mushroom resistance is characterized by the parameter "Fouling", showing the degree of fouling of the disk, impregnated with the control compound, the culture of Candida.

The table shows the average results of at least five parallel measurements for each compound.

A method of producing chemical compounds C4 consists in chemical synthesis by performing the following operations, and for clarity, the applicant provides a description of the method through an explanatory flowchart shown in Fig.5.

Compound C1 is chemically modified by addition reactions with compound C2. The resulting intermediate C2 ′ compound is used to synthesize complex compounds involving C3 salts. Compound C4 obtained as a result of chemical synthesis will be a chemical compound with anticandidosis activity.

The method for producing chemical compounds with anti-candidiasis activity is illustrated by the example of the synthesis of compound C4 based on the hyperbranched Boltorn H20 polyester polyol, succinic and maleic acid anhydrides, cobalt (II) nitrates and copper (II) characterized by the sequence of operations and the compounds obtained by the described method General chemical formula I:

where A is a non-toxic hyperbranched polyether polyol Boltorn H20 (Perstorp AB, Sweden),

R = C (O) CH ₂ -CH ₂ COO; C (O) CH = HSSOO;

M = Co, Cu;

X = HO ₃ ^- , Cl ^- .

The claimed technical solution is illustrated by compounds obtained as a result of chemical synthesis of compounds consisting in the following stages:

Stage No. 1

1) A sample of the starting reagent A = Boltorn H20 should be heated to a temperature of 140 ° C and kept under heating for 30 minutes. To a heated solution of Boltorn H20 in an anhydrous solvent, add a functionalizing reagent in a molar ratio of 1: 8 to 1:16. The mixture is stirred at a temperature of 56.5 ° C-101 ° C for 16-36 hours. After cooling, treat the mixture with a precipitant. Separate the resulting product by decantation and free from solvent by vacuum.

As a solvent, you can use: acetone, chloroform, benzene, dioxane, methanol, dimethylformamide, dimethyl sulfoxide.

As a functionalizing reagent, you can use: succinic anhydride, maleic anhydride.

As a precipitant, you can use: diethyl ether, hexane, ethyl alcohol, benzene.

The obtained compounds poly-2-carboxypropionoVoltorn H20 (I, II) are shown in Fig. 5 as compounds C2 ', which are viscous amorphous substances of white or light yellow color.

The spectral characteristics and elemental analysis data in the form of the mass fraction of elements in the molecule as a percentage, the vibration frequencies of the characteristic groups in the IR spectra and the chemical shifts in the NMR spectra are given below and confirm the purity and individuality of the obtained intermediate compounds.

Stage No. 2

2) Add NaHCO ₃ to a heated solution containing poly-2-carboxypropiono Boltorn H20 (compounds I or II) in anhydrous acetone. The mixture is stirred at a temperature of 56.5 ° C for 10-12 hours. After cooling, filter out unreacted NaHCO ₃ . To the filtrate add a portion of the anhydrous salt M (NO ₃ ) ₂ , where M = Co, Cu in a molar ratio of polymer: inorganic salt of 1:16. The mixture is stirred at a temperature of 56.5 ° C for 12-16 hours. After cooling, rinse the mixture with aqueous acetone solution and treat with diethyl ether. Separate the resulting product and dry in vacuum. The reaction resulted in polynuclear complexes: compounds III-VI.

The spectral characteristics and data of elemental analysis in the form of a mass fraction of elements in a molecule as a percentage, values of vibration frequencies of characteristic groups in PC spectra are given below:

The resulting compounds III-VI inhibit the catalytic activity of inducible secretory aspartic proteinase cultures of Candida albicans culture (SAP C. alb.).

Table 2 shows the catalytic activity of the inducible proteinase Candida albicans in the presence of compounds III-VI.

The fungicidal activity and fungus resistance of compounds IV-VI to certain Candida strains are shown in Table 3.

Table 3 shows data on the fungicidal activity and fungus resistance of compounds IV-VI to some Candida strains. To assess these characteristics, the disk diffusion method was used: cellulose disks impregnated with a 10% solution of the compound were placed in the center of a Petri dish containing a Candida culture in agar-agar gel. Fungicidal activity was evaluated by the area of the lysis zone formed around the disk impregnated with the control compound. Mushroom resistance is characterized by the parameter "Fouling", showing the degree of fouling of the disk, impregnated with the control compound of the Candida culture.

Compound IV also has fungicidal activity against molds Aspergillus niger, Aspergillus fumigatus, Rhodotorula mucilaginosa (rubra).

Thus, from tables 2 and 3 it follows that the obtained compounds simultaneously suppress the growth and activity of the action on the cultures of Candida albicans, Candida tropicalis, Candida parapsilosis and Candida krusei with simultaneous inhibition of the catalytic activity of the induced proteinase Candida albicans and the components of the cell wall of Candida fungi - ergosterol, lanosterol , squalene, which is proof of the stated objectives of the technical solution.

The claimed technical solution meets the criterion of "novelty" presented to the invention, because the prior art has not identified technical solutions that have the claimed combination of features.

The claimed technical solution meets the criterion of "inventive step" for inventions, because The claimed technical solution does not follow explicitly from the prior art for a person skilled in the art.

The claimed technical solution meets the criterion of "industrial applicability", as it can be implemented in the national economy using standard equipment and tools. The resulting compounds can be used as the active substance of anti-candida pharmaceuticals.

Table 1 Component The properties BASIC STRUCTURE (C1) It has high membrane permeability and low toxicity. FUNCTIONALIZING REAGENT (C2) It has the property of destruction of the cell wall of the fungus and ligand properties COMPLEX FORMER (C3) Is an inhibitor of Candida proteinase activity

In this case, the following substances can be used as components C1, C2, C3;

C1 - hyperbranched polyether polyol Boltorn H20, H30, H40 (Perstorp AB, Sweden),

C2 - carboxylic acid anhydrides (succinic, maleic anhydrides).

C3 - nitrates or chlorides of zinc (II), cobalt (II), copper (II), nickel (II), manganese (II).

table 2 Catalytic Activity Induced by SAP C.alb. with respect to hemoglobin in the presence of modulators III-VI (C _Hb = 126 mg / L, C _SAP = 2.0 × 10 ^-6 mol / L, pH = 4.10) The concentration of the compound, mol / l Catalytic activity induced by SAP Candida albicans, mg / l × min III IV V VI 0 4.81 1 × 10 ^-3 2.3 0 3.4 0.5 1 × 10 ^-4 2.4 0 3.3 0.3 1 × 10 ^-5 2.5 0 3.6 0.6 1 × 10 ^-6 2.4 0 3.8 0.7 1 × 10 ^-7 1.8 0 3.5 0.8 1 × 10 ^-8 1.9 0 3.2 1.1 1 × 10 ^-9 2.1 0 3.3 1.1 1 × 10 ^-10 1.8 0.1 3.6 1.2 1 × 10 ^-11 1.6 0.1 4.1 1.5 1 × 10 ^-12 1.9 0.1 4.1 1.3

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Claims (2)

1. Compounds based on complexes of hyperbranched polymers Boltorn H, containing from 10 to 14 groups of propionic or acrylic acids and from 10 to 14 metal ions Co (II) and Cu (II), which have anti-candida activity against Candida albicans, Candida krusei, Candida tropicalis, Candida parapsilosis and providing effects on the Candida proteinase system and cell wall components. 2. A method of obtaining compounds based on complexes of hyperbranched polymers Boltorn H according to claim 1, having anti-candidiasis activity, which consists in the synthesis of compounds containing from 10 to 14 groups of propionic or acrylic acids and from 10 to 14 metal ions, using sequential esterification reactions, substitution and accession.

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