Primary metabolites and their producers. Topic: Secondary Metabolites

Of all products obtained through microbial processes, highest value have secondary metabolites. If the question of the physiological role of secondary metabolites in producer cells was the subject of serious discussions, then their industrial production is of undoubted interest, since these metabolites are biologically active substances: some of them have antimicrobial activity, others are specific inhibitors of enzymes, and others are growth factors. , many have pharmacological activity. Secondary metabolites include antibiotics, alkaloids and toxins. The pharmaceutical industry has developed highly complex methods for screening (mass testing) of microorganisms for the ability to produce valuable secondary metabolites.

The terms "secondary metabolites" and "secondary metabolism" entered the vocabulary of biologists in late XIX century since light hand Professor Kossel. In 1891, in Berlin, he gave a lecture at the meeting of the Physiological Society, which was called "On chemical composition cells"; the origin of the name “secondary metabolites” means secondary, “random”.

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Introduction

Of all products obtained by microbial processes, secondary metabolites are of the greatest importance. If the question of the physiological role of secondary metabolites in producer cells was the subject of serious discussions, then their industrial production is of undoubted interest, since these metabolites are biologically active substances: some of them have antimicrobial activity, others are specific inhibitors of enzymes, and others are growth factors. , many have pharmacological activity. Secondary metabolites include antibiotics, alkaloids and toxins. The pharmaceutical industry has developed highly complex methods for screening (mass testing) of microorganisms for the ability to produce valuable secondary metabolites.

The terms "secondary metabolites" and "secondary metabolism" entered the vocabulary of biologists at the end of the 19th century with the light hand of Professor Kossel. In 1891, in Berlin, he gave a lecture at the meeting of the Physiological Society, entitled "On the chemical composition of cells"; the origin of the name “secondary metabolites” means secondary, “random”.

The purpose of this work is to study the methods of synthesis, chemical structure, properties and role of secondary metabolites in human life.

To achieve this goal, the following tasks were solved:

1. Study of the processes occurring during the synthesis of secondary metabolites.
2. Analysis of the chemical structure of secondary metabolites.
3. Assessment of the role of secondary metabolites in the life of their producers, humans and higher animals.

1. Secondary metabolites of microorganisms. General information.

Secondary metabolites (idioliths) are substances of microbial (or plant) origin that are not essential for the growth and reproduction of the organism that forms them. Each secondary metabolite is produced by a relatively limited number of species. These compounds are synthesized at the end of the exponential or during the stationary phases of growth, and their formation largely depends on the growth conditions, especially the composition of the nutrient medium.

Many secondary metabolites have a chemical structure that is unusual for biological matter. These compounds belong to various classes of organic substances - aminocyclitols, coumarins, epoxides, pyrroles, nonribosomal peptides, polyenes, terpenoids, tetracyclines, polyketides, isoprenoids, steroids, gibberellins, phytoalexins, etc. In contrast to the synthesis of the primary metabolite, which occurs simultaneously with the growth and reproduction of the culture, for the producer of secondary metabolites, it is customary to speak of the trophic phase (when the culture grows and multiplies) and the idiophase (when growth slows down or stops and the synthesis of the product begins). Very little is reliably known about the mechanisms of switching metabolic pathways from primary to secondary and about the physiological role of secondary metabolites in the life of one's own producer. There are four classes of biosynthetic reactions that “remove” an intermediate (from the Latin intermediate – medium - an intermediate substance with a short lifetime, formed during a chemical reaction and then reacting further to the reaction products) to the secondary metabolism path:

1. conversion of the primary metabolite to a specific precursor for secondary metabolism;
2. modification or activation reactions leading the precursor to the path of secondary metabolism;
3. polymerization and condensation;
4. late modification reactions.

Fig. 1. Relationship between secondary and primary metabolism (VM - secondary metabolite)

Secondary metabolites include antibiotics, toxins, immunosuppressants and stimulants, as well as some reserve substances (poly-β-alkanoates). It is not known how common secondary metabolism is in nature. The very concept of "secondary metabolite" is rather vague and many researchers do not recognize it.

2. Formation of secondary metabolites

From a biotechnological point of view, the concepts of secondary metabolites or secondary exchange reactions, which are similar in all living organisms, are important. Secondary exchange reactions include those accompanied by the formation of alkaloids, antibiotics, trisporic acids, gibberellins, and some other substances that are considered insignificant for the producer. Secondary metabolites are products of reactions catalyzed by enzymes.

Figure 2. Scheme of formation of secondary metabolites.

Premetabolites in the scheme are simple nutrients coming from outside (ammonium, metal ions, carbon dioxide, sulfates, phosphates, nitrates for heterotrophs - monosaccharides and some others).

Intermediates or prometabolites include simple sugars, amino acids, nucleic bases. The information molecules of DNA and RNA are isolated from other reactions, although synthesis and decay (dashed arrows) are also catalyzed by enzymes. Unlike primary metabolites, the formation of secondary metabolites is not directly encoded by nuclear or cytoplasmic DNA. According to this concept, all living organisms synthesize their inherent secondary metabolites.

Based on the provisions formulated by V.N. Shaposhnikov (1939), each producer goes through two phases in its development, named by Zh.D. Bu'Lokkom trophophase and idiophase (from the Greek trofe-nutrition, idios-own, specific). During the trophophase period, constructive and energy metabolism actively proceed - synthetic processes predominate in cells, the number of primary metabolites-lipids, glycones, glycoconjugates increases; at the same time, the growth and reproduction rate of the organism is high, and the productivity of exogenous secondary metabolites is low, and, conversely, in the idiophase, the growth and reproduction rate is low, and the production of exogenous and endogenous secondary metabolites is high. Culture productivity can be increased by introducing metabolite precursors (predominantly during the time period at the end of the idiophase).

Rice. 3. The ratio of cell biomass (a), primary metabolites (b) and secondary metabolites (c) in cultures of Saccharomyces cerevisiae (Baker's yeast) (1), Penicillium chrysogenum (2), Nicotiana tabacum (3), keratocytes (cells of the connective tissue of the horny shells of the eye.) (4); M-mass of dried cells, M*-number of animal cells, t-time in days, I-trophophase (shaded part), II-idiophase.

Figure 3 shows that the duration of the trophophase is shorter in yeast than in penicillium and tobacco cells. The accumulation of ethanol by S.cerevisiae is accompanied by an increase in its inhibitory activity on the producer, and therefore the curves attributable to the idiophase run almost parallel, repeating the nature of the curve for primary metabolites, the biosynthesis of which began during the trophophase.

Penicillin, synthesized by P. chrysogenum, and not an inhibitory producer, accumulates markedly in the idiophase.

The alkaloid nicotine is synthesized by tobacco cells slowly, and when the culture enters the stationary phase, its yield decreases markedly.

In each of the above examples, one can note its own features of the biosynthesis of secondary metabolites. In any case, they are formed by cells as natural products during cultivation in appropriate media and under the catalytic action of enzymes.

3. Separate representatives of secondary metabolites

3.1 Antibiotics

Antibiotics are substances of biological origin that can inhibit the growth of microorganisms even at low concentrations. The term "secondary metabolites" is equivalent to the term "antibiotics" used in the broad sense of the word. The ability to form antibiotics is widespread in nature, but it is unevenly distributed among different taxonomic groups of microorganisms. The largest number of antibiotics was obtained from actinomycetes (radiant fungi) (according to various estimates, from 6000 to 10000,streptomycetes occupy the first place in terms of the chemical diversity of synthesized substances). About 1500 antibiotics have been isolated from imperfect fungi, and about a third are formed by representatives of the genera Penicillium and Aspergillus, but few of them are of practical importance. They play an important role as therapeutics, stimulants, feed additives, etc. As producers of secondary metabolites, microorganisms have acquired a huge economic importance. The discovery and research of antibiotics, as well as the production of new semi-synthetic ones, rendered invaluable services to medicine.

3.2 Formation of antibiotics

Already in the last century it was known that both symbiotic and antagonistic relationships can exist between various microorganisms. The impetus for elucidating the material basis of antibiosis was the observation of Fleming, who discovered (1928) that a colony of fungi Penicillium notatum suppressed the growth of staphylococci. The substance secreted by this fungus, which penetrated into the agar by diffusion, was called penicillin. Since then, many substances with antibiotic activity have been isolated. There are substances that inhibit the growth of microbes (bacteriostatic, fungistatic) and kill them (bactericidal, fungicidal).

3.3. Methods for detecting antibiotics

The first antibiotics were discovered by chance, by the formation of zones of growth inhibition. In nutrient agar plates densely inoculated with a test organism (indicator bacteria), there was no growth around fungal or streptomycete colonies: the antibiotic diffusing from the colony into the agar caused the formation of transparent patches in a continuous bacterial lawn (Figure 4).

Figure 4. Antibiotic release can be detected by the formation of zones of inhibition of the growth of indicator bacteria (Staphylococcus aureus), evenly dispersed on the agar.

Types - indicators in such experiments are typical representatives of groups of microorganisms. For a qualitative test of the antibiotic producer, it is enough to inoculate it in the middle of a plate with nutrient agar, and indicator bacteria in the form of radial strokes (Figure 5). After incubation, the degree of growth inhibition of various indicator organisms is used to judge the spectrum of antibiotic action. Antibiotics differ in their effect on gram-positive and gram-negative bacteria, yeast, dermatophytes and other microorganisms.

Fig.5. Determination of the spectrum of action of three antibiotics using a stroke test: 1- Staphylococcus aureus, 2- Streptococcus, 3- Escherichia coli, 4- Pseudomonas aeruginosa (Pseudomonas aeruginosa), 5- Candida albicans, 6- Trichophyton rubrum

Most antibiotics were discovered through a pre-screening process.

3.4. The most important antibiotics used in medicine

The first place among them still belongs to penicillin, which is synthesized by Penicillium notatum, P. chrysogenum and some other fungi; it was also possible to obtain semi-synthetic penicillins (by splitting natural penicillins to 6-aminopenicillanic acid, to which various side groups are then chemically attached).

For humans, penicillin is almost non-toxic and only in rare cases causes adverse allergic reactions.

Many bacteria form pencillinase, which cleaves the β-lactam ring and inactivates penicillin. By treating 6-aminopenicillanic acid with acid chlorides, hundreds of penicillins can be obtained (Figure 6). Many semi-synthetic penicillins are not broken down by penicillinase (an enzyme that has the ability to break down (inactivate) penicillins and cephalosporins) and, due to their resistance to acids, can be administered orally.

Figure 6. Obtaining semi-synthetic penicillins by the action of bacterial enzymes on penicillin.

Figure 7. Structural formulas of cephalosporin C, streptomycin A, chlormycetin, tetracycline and actinomycin D (actinomycin C 1)

Cephalosporins are products of one of the species of the fungus Cephalosporium. Cephalosporin C has a β-lactam ring and is structurally similar to penicillin (Figure 7). By splitting off the side chain and then adding other side groups to the resulting 7-aminocephalosporanic acid, semi-synthetic cephalosporins (cephalothin, cephaloridine) can be obtained, which are similar in their action to penicillin derivatives.

Streptomycin was first isolated from a culture of Streptomyces griseus, but some other Streptomyces species also synthesize it. The streptomycin molecule consists of three parts: N-methyl-L-2-glucosamine, methylpentose, and diguanidine-substituted inositol (Figure 7). The success of streptomycin is due to its action on a number of acid-fast and gram-negative bacteria that are insensitive to penicillin. However, streptomycin causes severe allergic reactions in patients. This antibiotic is also used in veterinary medicine and to combat plant diseases.

Chloromycetin (chloramphenicol) was first discovered in cultures of Streptomyces venezuelae, but it can also be obtained synthetically (Figure 7). It is extremely stable and acts on many gram-negative bacteria, including spirochetes, rickettsia and actinomycetes, as well as large viruses.

Tetracyclines are also metabolites of various streptomycetes (including Streptomyces aureofaciens). Chemically, they are very close to each other and are based on the structure of naphthacene (Figure 7). The best known are chlortetracycline (Aureomycin), oxytetracycline (Terramycin) and tetracycline. Tetracyclines are characterized by a wide spectrum of action and good tolerability.

A number of cell metabolites are of interest as target fermentation products. They are divided into primary and secondary.

Primary metabolites- These are low molecular weight compounds (molecular weight less than 1500 daltons) necessary for the growth of microorganisms. Some of them are the building blocks of macromolecules, others are involved in the synthesis of coenzymes. Among the most important metabolites for industry are amino acids, organic acids, nucleotides, vitamins, etc.

The biosynthesis of primary metabolites is carried out by various biological agents - microorganisms, plant and animal cells. In this case, not only natural organisms are used, but also specially obtained mutants. To ensure high concentrations of the product at the stage of fermentation, it is necessary to create producers that resist the regulatory mechanisms genetically inherent in their natural form. For example, it is necessary to eliminate the accumulation of an end product that represses or inhibits an important enzyme in order to obtain the target substance.

Production of amino acids.

Auxotrophs (microorganisms that require growth factors to reproduce) produce many amino acids and nucleotides during fermentations. Common objects for selection of amino acid producers are microorganisms belonging to the genera Brevibacterium, Corynebacterium, Micrococcus, Arthrobacter.

Of the 20 amino acids that make up proteins, eight cannot be synthesized in the human body (essential). These amino acids must be supplied to the human body with food. Among them, methionine and lysine are of particular importance. Methionine is produced by chemical synthesis, and more than 80% of lysine is produced by biosynthesis. The microbiological synthesis of amino acids is promising, since as a result of this process, biologically active isomers (L-amino acids) are obtained, and during chemical synthesis, both isomers are obtained in equal amounts. Since they are difficult to separate, half of the production is biologically useless.

Amino acids are used as food additives, seasonings, flavor enhancers, as well as raw materials in the chemical, perfumery and pharmaceutical industries.

The development of a technological scheme for obtaining a single amino acid is based on knowledge of the ways and mechanisms of regulation of the biosynthesis of a particular amino acid. The necessary imbalance of metabolism, which ensures the oversynthesis of the target product, is achieved by strictly controlled changes in the composition and environmental conditions. For the cultivation of strains of microorganisms in the production of amino acids, carbohydrates are the most available as carbon sources - glucose, sucrose, fructose, maltose. To reduce the cost of the nutrient medium, secondary raw materials are used: beet molasses, milk whey, starch hydrolysates. The technology of this process is being improved towards the development of cheap synthetic nutrient media based on acetic acid, methanol, ethanol, n-paraffins.

Production of organic acids.

Currently, a number of organic acids are synthesized by biotechnological methods on an industrial scale. Of these, citric, gluconic, ketogluconic and itaconic acids are obtained only by a microbiological method; milk, salicylic and acetic - both by chemical and microbiological methods; malic - chemically and enzymatically.

Acetic acid is the most important among all organic acids. It is used in the production of many chemical substances, including rubber, plastics, fibers, insecticides, pharmaceuticals. The microbiological method for producing acetic acid consists in the oxidation of ethanol to acetic acid with the participation of bacteria strains Gluconobacter and Acetobacter:

Citric acid is widely used in the food, pharmaceutical and cosmetic industries, used to clean metals. The largest producer of citric acid is the USA. The production of citric acid is the oldest industrial microbiological process (1893). For its production use the culture of the fungus Aspergillus niger, A. wentii. Nutrient media for the cultivation of citric acid producers contain cheap carbohydrate raw materials as a carbon source: molasses, starch, glucose syrup.

Lactic acid is the first of the organic acids, which began to be produced by fermentation. It is used as an oxidizing agent in the food industry, as a mordant in the textile industry, and also in the production of plastics. Microbiologically, lactic acid is obtained from the fermentation of glucose Lactobacillus delbrueckii.

Products (substances) secondary metabolism are synthesized on the basis of primary compounds and can accumulate in plants, often in significant quantities, thereby determining the specifics of their metabolism. Plants contain a huge amount of substances of secondary origin, which can be divided into various groups.

Among the biologically active substances (BAS), such extensive classes of compounds as alkaloids, isoprenoids, phenolic compounds and their derivatives are best known.

alkaloids- nitrogen-containing organic compounds of a basic nature, mainly plant origin. The structure of alkaloid molecules is very diverse and often quite complex. Nitrogen, as a rule, is located in heterocycles, but sometimes is located in the side chain. Most often, alkaloids are classified on the basis of the structure of these heterocycles or in accordance with their biogenetic precursors - amino acids. The following main groups of alkaloids are distinguished: pyrrolidine, pyridine, piperidine, pyrrolizidine, quinolizidine, quinazoline, quinoline, isoquinoline, indole, dihydroindole (betalaines), imidazole, purine, diterpene, steroid (glycoalkaloids) and alkaloids without heterocycles (protoalkaloids). Many of the alkaloids have specific, often unique physiological effects and are widely used in medicine. Some alkaloids are strong poisons (for example, curare alkaloids).

Anthracene derivatives- a group of natural compounds of yellow, orange or red color, which are based on the structure of anthracene. They may have varying degrees oxidation of the middle ring (derivatives of anthrone, anthranol and anthraquinone) and the structure of the carbon skeleton (monomeric, dimeric and condensed compounds). Most of them are derivatives of chrysacin (1,8-dihydroxyanthraquinone). Alizarin (1,2-dihydroxyanthraquinone) derivatives are less common. Anthracene derivatives can be found in plants in the free form (aglycones) or in the form of glycosides (anthraglycosides).

Withanolides- a group of phytosteroids that got their name from the Indian plant Withania somnifera (L.) Dunal (fam. Solanaceae), from which the first compound of this class, withaferin A, was isolated. Currently, several series of this class of compounds are known. Withanolides are polyoxysteroids that have a six-membered lactone ring in position 17, and a keto group at C 1 in the A ring. In some compounds, 4- beta- hydroxy-,5- beta-, 6-beta-epoxy groups.

Glycosides- widespread natural compounds that decompose under the influence of various agents (acid, alkali or enzyme) into a carbohydrate part and aglycone (genin). The glycosidic bond between sugar and aglycone can be formed with the participation of O, N or S atoms (O-, N- or S-glycosides), as well as account s-s atoms (C-glycosides). O-glycosides are the most widespread in the plant kingdom. Between themselves, glycosides can differ both in the structure of the aglycone and in the structure of the sugar chain. The carbohydrate components are represented by monosaccharides, disaccharides and oligosaccharides, and accordingly the glycosides are called monosides, biosides and oligosides. Peculiar groups of natural compounds are cyanogenic glycosides and thioglycosides (glucosinolates). Cyanogenic glycosides can be presented as derivatives alpha-hydroxynitriles containing hydrocyanic acid in their composition. They are widely distributed among plants of this family. Rosaceae, subfamily Prunoideae, concentrating mainly in their seeds (for example, the glycosides amygdalin and prunazine in the seeds of Amygdalus communis L., Armeniaca vulgaris Lam.).

Thioglycosides (glucosinolates) are currently considered as derivatives of a hypothetical anion - glucosinolate, hence the second name. Glucosinolates have been found so far only in dicotyledonous plants and are characteristic of the family. Brassicaceae, Capparidaceae, Resedaceae and other members of the order Capparales. In plants, they are found in the form of salts with alkali metals, most often with potassium (for example, sinigrin glucosinolate from the seeds of Brassica juncea (L.) Czern. and B. nigra (L.) Koch).

Isoprenoids- an extensive class of natural compounds considered as products of the biogenic transformation of isoprene. These include various terpenes, their derivatives - terpenoids and steroids. Some isoprenoids are structural fragments of antibiotics, some vitamins, alkaloids and animal hormones.

Terpenes and terpenoids- unsaturated hydrocarbons and their derivatives of the composition (C 5 H 8) n, where n \u003d 2 or n\u003e 2. According to the number of isoprene units, they are divided into several classes: mono-, sesqui-, di-, tri-, tetra- and polyterpenoids.

Monoterpenoids(C 10 H 16) and sesquiterpenoids(C 15 H 24) are common components of essential oils. The group of cyclopentanoid monoterpenoids includes iridoid glycosides (pseudoindicans), highly soluble in water and often with a bitter taste. The name "iridoids" is associated with the structural and possibly biogenetic relationship of aglycone with iridodiale, which was obtained from ants of the genus Iridomyrmex; "pseudoindicans" - with the formation of a blue color in an acidic environment. According to the number of carbon atoms in the skeleton of the aglycone part, iridoid glycosides are divided into 4 types: C 8 , C 9 , C 10 and C 14 . They are inherent only in angiosperms of the dicotyledonous class, and the families Scrophulariaceae, Rubiaceae, Lamiaceae, Verbenaceae and Bignoniaceae belong to the most rich in iridoids.

Diterpenoids(C 20 H 32) are mainly included in the composition of various resins. They are represented by acids (resinolic acids), alcohols (resinols) and hydrocarbons (resens). There are actually resins (rosin, dammar), oil-resins (turpentine, Canada balsam), gum-resins (gummigut), oil-gum-resins (incense, myrrh, asafoetida). Oil-resins, which are a solution of resins in essential oil and containing benzoic and cinnamon acids, are called balms. In medicine, Peruvian, Tolutan, Styrax balms, etc. are used.

Triterpenoids(C 30 H 48) are predominantly found in the form of saponins, the aglycones of which are represented by pentacyclic (derivatives of ursane, oleanan, lupan, hopane, etc.) or tetracyclic (derivatives of dammarane, cycloartan, zufan) compounds.

To tetraterpenoids(C 40 H 64) include fat-soluble plant pigments of yellow, orange and red color - carotenoids, precursors of vitamin A (provitamins A). They are divided into carotenes (unsaturated hydrocarbons that do not contain oxygen) and xanthophylls (oxygen-containing carotenoids having hydroxy-, methoxy-, carboxy-, keto- and epoxy groups). Widely distributed in plants alpha-, beta- and gamma-carotenes, lycopene, zeaxanthin, violaxanthin, etc.

The last group of isoprenoids of the composition (C 5 H 8) n is represented by polyterpenoids, which include natural rubber and gutta.

Cardiotonic glycosides, or cardiac glycosides, - heterosides, the aglycones of which are steroids, but differ from other steroids by the presence in the molecule instead of the side chain at C 17 of an unsaturated lactone ring: a five-membered butenolide ( cardenolides) or a six-membered cumaline ring ( bufadienolides). All aglycones of cardiotonic glycosides have hydroxyl groups at C 3 and C 14, and methyl groups at C 13. At C 10 it can be alpha-oriented methyl, aldehyde, carbinol or carboxyl groups. In addition, they may have additional hydroxyl groups at C 1 , C 2 , C 5 , C 11 , C 12 and C 16 ; the latter is sometimes acylated with formic, acetic, or isovaleric acid. Cardiotonic glycosides are used in medicine to stimulate myocardial contractions. Some of them are diuretics.

Xanthones- a class of phenolic compounds having the structure of dibenzo- gamma-pyrone. As substituents, they contain hydroxy-, methoxy-, acetoxy-, methylenedioxy- and other radicals in the molecule. Compounds containing a pyran ring are known. A feature of xanthones is the distribution of chlorine-containing derivatives. Xanthones are found in free form and as part of O- and C-glycosides. Of the xanthonic C-glycosides, the best known is mangiferin, which was one of the first to be introduced into medical practice.

Coumarins- natural compounds based on the structure of which is 9,10-benzo- alpha-pyrone. They can also be considered as acid derivatives ortho-hydroxycinnamon ( ortho-coumarova). They are classified into hydroxy- and methoxy derivatives, furo- and pyranocoumarins, 3,4-benzocoumarins and coumestans (coumestrols).

Lignans- natural phenolic substances, derivatives of dimers of phenylpropane units (C 6 -C 3), interconnected beta-carbon atoms of the side chains. The diversity of lignans is due to the presence of various substituents in the benzene rings and the nature of the bond between them, the degree of saturation of the side chains, etc. According to their structure, they are divided into several groups: diarylbutanoic (guaiaretic acid), 1-phenyltetrahydronaphthalene (podophyllotoxin, peltatins), benzylphenyltetrahydrofuran (lariciresinol and its glucoside), diphenyltetrahydrofurofuran (sesamin, syringaresinol), dibenzocyclooctane (schizandrin, schizandrol) types, etc.

Lignins are irregular three-dimensional polymers, the precursors of which are hydroxycinnamic alcohols ( pair-coumaric, coniferyl and synapic), and are building material cell walls of wood. Lignin is found in lignified plant tissues along with cellulose and hemicelluloses and is involved in the creation of the supporting elements of mechanical tissue.

Melanins- polymeric phenolic compounds, which occur sporadically in plants and represent the least studied group of natural compounds. They are painted black or black-brown and are called allomelanins. Unlike pigments of animal origin, they do not contain nitrogen (or very little). With alkaline cleavage, they form pyrocatechol, protocatechuic and salicylic acids.

Naphthoquinones- quinoid pigments of plants, which are found in various bodies(in roots, wood, bark, leaves, fruits and less often in flowers). As substituents, 1,4-naphthoquinone derivatives contain hydroxyl, methyl, prenyl and other groups. The most famous is the red pigment shikonin, found in some representatives of the family. Boraginaceae (species of the genera Arnebia Forrsk., Echium L., Lithospermum L. and Onosma L.).

Saponins (Saponisides)- glycosides with hemolytic and surface activity (detergents), as well as toxicity to cold-blooded animals. Depending on the structure of the aglycone (sapogenin), they are divided into steroid and triterpenoid. The carbohydrate part of saponins can contain from 1 to 11 monosaccharides. The most common are D-glucose, D-galactose, D-xylose, L-rhamnose, L-arabinose, D-galacturonic and D-glucuronic acids. They form straight or branched chains and can attach at the hydroxyl or carboxyl group of the aglycone.

Steroids- a class of compounds in the molecule of which there is a skeleton. Steroids include sterols, D vitamins, steroid hormones, aglycones of steroidal saponins and cardiotonic glycosides, ecdysones, withanolides, steroidal alkaloids.

Plant sterols, or phytosterols, are alcohols containing 28-30 carbon atoms. They belong to beta-sitosterol, stigmasterol, ergosterol, campesterol, spinasterol, etc. Some of them, for example beta-sitosterol, are used in medicine. Others are used to obtain steroid medicines- steroid hormones, vitamin D, etc.

Steroid saponins contain 27 carbon atoms, their side chain forms a spiroketal system of spirostanol or furanostanol types. One of the steroidal sapogenins, diosgenin, isolated from the rhizomes of Dioscorea, is a source for obtaining hormonal preparations important for medicine (cortisone, progesterone).

Stilbens can be considered as phenolic compounds with two benzene rings having the structure C 6 -C 2 -C 6 . This is a relatively small group of substances that are found mainly in wood. various kinds pines, spruces, eucalyptus, are the structural elements of tannins.

Tannins (tannins)- high-molecular compounds with an average molecular weight of about 500-5000, sometimes up to 20000, capable of precipitating proteins, alkaloids and having an astringent taste. Tannins are divided into hydrolysable, decomposing under conditions of acidic or enzymatic hydrolysis into the simplest parts (these include gallotannins, ellagitannins and non-saccharide esters of carboxylic acids), and condensed, not decomposing under the action of acids, but forming condensation products - flobaphenes. Structurally, they can be considered as derivatives of flavan-3-ols (catechins), flavan-3,4-diols (leukoanthocyanidins), and hydroxystilbenes.

Phenolic compounds are one of the most common in plant organisms and numerous classes of secondary compounds with different biological activity. These include substances of an aromatic nature, which contain one or more hydroxyl groups associated with the carbon atoms of the aromatic nucleus. These compounds are very heterogeneous in chemical structure; they occur in plants in the form of monomers, dimers, oligomers, and polymers.

The classification of natural phenols is based on the biogenetic principle. Modern concepts of biosynthesis make it possible to divide phenolic compounds into several main groups, arranging them in order of increasing complexity of the molecular structure.

The simplest are compounds with one benzene ring - simple phenols, benzoic acids, phenol alcohols, phenylacetic acids and their derivatives. According to the number of OH groups, monoatomic (phenol), diatomic (pyrocatechol, resorcinol, hydroquinone), and triatomic (pyrogallol, phloroglucinum, etc.) simple phenols are distinguished. Most often they are in a bound form in the form of glycosides or esters and are structural elements of more complex compounds, including polymeric (tannins).

More diverse phenols are derivatives of the phenylpropane series (phenylpropanoids) containing one or more C 6 -C 3 fragments in the structure. Simple phenylpropanoids include hydroxycinnamic alcohols and acids, their esters and glycosylated forms, as well as phenylpropanes and cinnamoylamides.

Compounds biogenetically related to phenylpropanoids include coumarins, flavonoids, chromones, dimeric compounds - lignans and polymeric compounds - lignins.

A few groups of phenylpropanoid compounds make up original complexes that combine derivatives of flavonoids, coumarins, xanthones and alkaloids with lignans (flavolignans, coumarinolignans, xantholignans and alkaloidolignans). Flavolignans of Silybum marianum (L.) Gaertn are a unique group of biologically active substances. (silybin, silydianin, silicristin), which exhibit hepatoprotective properties.

Phytoncides are unusual compounds of secondary biosynthesis produced by higher plants and affecting other organisms, mainly microorganisms. The most active antibacterial substances are found in onion (Allium cepa L.) and garlic (Allium sativum L.), the antibiotic compound allicin (a derivative of the amino acid alliin) has been isolated from the latter.

Flavonoids belong to the group of compounds with the structure C 6 -C 3 -C 6, and most of them are derivatives of 2-phenylbenzopyran (flavan) or 2-phenylbenzo- gamma-pyrone (flavones). Their classification is based on the degree of oxidation of the three-carbon fragment, the position of the side phenyl radical, the size of the heterocycle, and other features. Flavan derivatives include catechins, leucoanthocyanidins, and anthocyanidins; to derivatives of flavones - flavones, flavonols, flavanones, flavanonols. Flavonoids also include aurones (derivatives of 2-benzofuranone or 2-benzylidene coumaranone), chalcones and dihydrochalcones (compounds with an open pyran ring). Less common in nature are isoflavonoids (with a phenyl radical at C 3), neoflavonoids (derivatives of 4-phenylchromone), biflavonoids (dimeric compounds consisting of flavones, flavanones and flavon-flavanones linked by a C-C bond). Unusual isoflavonoid derivatives include pterocarpans and rotenoids that contain an additional heterocycle. Pterocarpans have attracted attention after it was found that many of them play a role phytoalexins that perform protective functions against phytopathogens. Rotenone and compounds close to it are toxic to insects, therefore they are effective insecticides.

chromones- compounds resulting from condensation gamma-pyrone and benzene rings (derivatives of benzo- gamma-pyrone). Usually, all compounds of this class have a methyl or hydroxymethyl (acyloxymethyl) group in position 2. They are classified according to the same principle as coumarins: according to the number and type of cycles condensed with the chromone nucleus (benzochromones, furochromones, pyranochromones, etc.).

Ecdysteroids- polyoxysteroid compounds with the activity of insect molting hormones and arthropod metamorphosis. The best known natural hormones are alpha-ecdysone and beta-ecdysone (ecdysterone). The structure of ecdysones is based on the steroid skeleton, where an aliphatic chain of 8 carbon atoms is attached at position 17. According to modern concepts, true ecdysteroids include all steroid compounds that have cis- articulation of rings A and B, 6-keto group, double bond between C 7 and C 8 and 14- alpha-hydroxyl group, regardless of their activity in the moulting hormone test. The number and position of other substituents, including OH groups, are different. Phytoecdysteroids are widely distributed secondary metabolites (more than 150 different structures have been identified) and are more variable than zooecdysteroids. The total number of carbon atoms in a compound of this group can be from 19 to 30.

Essential oils- volatile liquid mixtures of organic substances produced by plants, causing their smell. The composition of essential oils includes hydrocarbons, alcohols, esters, ketones, lactones, aromatic components. Terpenoid compounds from subclasses of monoterpenoids, sesquiterpenoids, and occasionally diterpenoids predominate; in addition, "aromatic terpenoids" and phenylpropanoids are quite common. Plants containing essential oils (ether carriers) are widely represented in the world flora. Plants of the tropics and dry subtropics are especially rich in them.

The overwhelming majority of products of secondary metabolism can be synthesized purely chemically in the laboratory, and in some cases such synthesis turns out to be economically viable. However, we should not forget that in phytotherapy the whole amount of biological substances that accumulate in the plant is important. Therefore, the possibility of synthesis in itself is not decisive in this sense.

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By metabolism, or metabolism, is meant totality chemical reactions in the body, providing it with substances for building the body and energy for maintaining life.

primary metabolism

Some of the reactions turn out to be similar for all living organisms (formation and splitting nucleic acids, proteins and peptides, as well as most carbohydrates, some carboxylic acids, etc.) and was called primary metabolism, or primary metabolism.

secondary metabolism

In addition to primary exchange reactions, there is a significant number of metabolic pathways leading to the formation of compounds that are characteristic only of certain, sometimes very few, groups of organisms. These reactions, according to I. Chapek (1921) and K. Pah (1940), are combined by the term secondary metabolism, or secondary exchange, and the products are called products of secondary metabolism, or secondary connections(sometimes, which is not entirely true, secondary metabolites). However, it should be emphasized that the differences between primary and secondary metabolism are not very sharp.

Secondary connections formed predominantly in vegetative sedentary groups living organisms - plants and fungi, as well as many prokaryotes. In animals, the products of secondary metabolism are relatively rare and often come from outside along with plant foods. The role of products of secondary metabolism and the reasons for their appearance in a particular group are different. In the most general form, they are assigned an adaptive role and, in a broad sense, protective properties.

The rapid development of the chemistry of natural compounds over the past four decades, associated with the creation of high-resolution analytical tools, has led to the fact that the world of "secondary compounds" has expanded significantly. For example, the number of alkaloids known today is approaching 5,000 (according to some sources - 10,000), phenolic compounds - to 10,000, and these numbers are growing not only every year, but also every month.

Any plant raw material always contains a complex set of primary and secondary compounds, which, as mentioned above, determine the multiple nature of the action. medicinal plants. However, the role of both in modern phytotherapy is still different. Relatively few plant objects are known, the use of which in medicine is determined primarily by the presence of primary compounds in them. However, in the future, their role in medicine and their use as sources for obtaining new immunomodulating agents cannot be ruled out.

Secondary exchange products are applied in modern medicine is much more common and wider. This is due to a tangible and often very bright pharmacological effect. Being formed on the basis of primary compounds, they can accumulate either in pure form or undergo glycosylation during exchange reactions, i.e. are attached to a sugar molecule. As a result of glycosylation, molecules are formed - heterosides, which differ from non-glycosylated secondary compounds, as a rule, in better solubility, which facilitates their participation in metabolic reactions and is of great biological importance in this sense. Glycosylated forms of any secondary compounds are called glycosides.

Src="https://present5.com/presentation/3/52712948_162925886.pdf-img/52712948_162925886.pdf-1.jpg" alt="(!LANG:> Secondary Metabolites Secondary Metabolites - organic matter synthesized by the body, but "> Secondary metabolites Secondary metabolites are organic substances synthesized by the body, but not involved in growth, development or reproduction. For their vital activity, bacteria also produce a wide range of secondary metabolites. Among them are vitamins, antibiotics, alkaloids and others. Among vitamins formed by microorganisms, riboflavin and vitamin B 12 deserve mention. large quantities flavins. The ability to form vitamin B 12 is inherent in bacteria, in the metabolism of which corrinoids play an important role (Propionibacterium, Clostridium). The same vitamin is also formed by streptomycetes. As for alkaloids, only ergot alkaloids, lysergic acid derivatives (ergotamine, ergotoxin) are extracted from a microorganism.

Src="https://present5.com/presentation/3/52712948_162925886.pdf-img/52712948_162925886.pdf-2.jpg" alt="(!LANG:> Antibiotics An antibiotic is a substance of a microbial, animal or"> Антибио тики Антибиотик - вещество микробного, животного или растительного происхождения, способное подавлять рост микроорганизмов или вызывать их гибель Антибиотики природного происхождения чаще всего продуцируются актиномицетами, реже - немицелиальными бактериями. Некоторые антибиотики оказывают сильное подавляющее действие на рост и размножение бактерий и при этом относительно мало повреждают или вовсе не повреждают клетки макроорганизма, и поэтому применяются в качестве лекарственных средств. Некоторые антибиотики используются в качестве цитостатических (противоопухолевых) препаратов при лечении онкологических заболеваний.!}

Src="https://present5.com/presentation/3/52712948_162925886.pdf-img/52712948_162925886.pdf-3.jpg" alt="(!LANG:>Classification of antibiotics A huge variety of antibiotics and their effects on the human body"> Классификация антибиотиков Огромное разнообразие антибиотиков и видов их воздействия на организм человека явилось причиной классифицирования и разделения антибиотиков на группы. По характеру воздействия на бактериальную клетку антибиотики можно разделить на две группы: бактериостатические (бактерии живы, но не в состоянии размножаться), бактерицидные (бактерии погибают, а затем выводятся из организма).!}

Src="https://present5.com/presentation/3/52712948_162925886.pdf-img/52712948_162925886.pdf-4.jpg" alt="(!LANG:>Classification of antibiotics by chemical structure Beta-lactam antibiotics (β-lactam antibiotics) antibiotics, β-lactams)"> Классификация антибиотиков по химической структуре Бета-лактамные антибиотики (β-лактамные антибиотики, β-лактамы) - группа антибиотиков, которые объединяет наличие в структуре β-лактамного кольца. В бета-лактамам относятся подгруппы пенициллинов, цефалоспоринов, карбапенемов и монобактамов. Сходство химической структуры предопределяет одинаковый механизм действия всех β- лактамов (нарушение синтеза клеточной стенки бактерий). !}

Src="https://present5.com/presentation/3/52712948_162925886.pdf-img/52712948_162925886.pdf-5.jpg" alt="(!LANG:>The structure of penicillin (1) and cephalosporin (2)">!}

Src="https://present5.com/presentation/3/52712948_162925886.pdf-img/52712948_162925886.pdf-6.jpg" alt="(!LANG:> Macrolides are a group of medicines, mostly antibiotics, the basis of the chemical structure"> Макролиды - группа лекарственных средств, большей частью антибиотиков, основой химической структуры которых является макроциклическое 14 - или 16 -членное лактонное кольцо, к которому присоединены один или несколько углеводных остатков. Макролиды относятся к классу поликетидов, соединениям естественного происхождения. Также к макролидам относят: азалиды, представляющие собой 15 -членную макроциклическую структуру, получаемую путем включения атома азота в 14 -членное лактонное кольцо между 9 и 10 атомами углерода; телитромицин азитромицин рокитамицин кетолиды - 14 -членные макролиды, у которых к лактонному кольцу при 3 атоме углерода присоединена кетогруппа. природные эритромицин олеандомицин мидекамицин спирамицин лейкомицин джозамицин, полусинтетические рокситромицин кларитромицин диритромицин флуритромицин Макролиды относятся к числу наименее токсичных антибиотиков. При применении макролидов не отмечено случаев нежелательных лекарственных реакций, свойственных другим классам антимикробных препаратов.!}

Src="https://present5.com/presentation/3/52712948_162925886.pdf-img/52712948_162925886.pdf-7.jpg" alt="(!LANG:>Erythromycin structure">!}

Src="https://present5.com/presentation/3/52712948_162925886.pdf-img/52712948_162925886.pdf-8.jpg" alt="(!LANG:> Tetracyclines are a group of antibiotics belonging to the class of polyketides that are chemically similar"> Тетрациклины - группа антибиотиков, относящихся к классу поликетидов, близких по химическому строению и биологическим свойствам. Представители данного семейства характеризуются общим спектром и механизмом антимикробного действия, полной перекрёстной устойчивостью, близкими фармакологическими характеристиками. первый представитель данной группы антибиотиков - хлортетрациклин (торговые названия ауреомицин, биомицин) - выделен из культуральной жидкости лучистого гриба Streptomyces aureofaciens; окситетрациклин (террамицин) - выделен из культуральной жидкости другого актиномицета Streptomyces rimosus; полусинтетический антибиотик тетрациклин; был выделен из культуральной жидкости Streptomyces aureofaciens.!}

Src="https://present5.com/presentation/3/52712948_162925886.pdf-img/52712948_162925886.pdf-9.jpg" alt="(!LANG:> Other important tetracyclines: semi-synthetic derivatives of oxytetracycline - doxycycline, metacycline."> Другие важные тетрациклины: полусинтетические производные окситетрациклина - доксициклин, метациклин. производные тетрациклина - гликоциклин, морфоциклин. комбинированные лекарственные формы с олеандомицином - олететрин, олеморфоциклин. а также миноциклин. Тетрациклины являются антибиотиками широкого спектра действия. Высокоактивны in vitro в отношении !} a large number gram-positive and gram-negative bacteria. In high concentrations, they act on some protozoa. Little or no activity against most viruses and molds. Not active enough against acid-fast bacteria

Src="https://present5.com/presentation/3/52712948_162925886.pdf-img/52712948_162925886.pdf-10.jpg" alt="(!LANG:>Tetracycline structure">!}

Src="https://present5.com/presentation/3/52712948_162925886.pdf-img/52712948_162925886.pdf-11.jpg" alt="(!LANG:> Aminoglycosides are a group of antibiotics whose common chemical structure is the presence"> Аминогликозиды - группа антибиотиков, общим в химическом строении которых является наличие в молекуле аминосахара, соединённого гликозидной связью с аминоциклическим кольцом. По химическому строению к аминогликозидам близок также спектиномицин, аминоциклитоловый антибиотик. Основное клиническое значение аминогликозидов заключается в их активности в отношении аэробных грамотрицательных бактерий. Аминогликозиды образуют необратимые ковалентные связи с белками 30 S-субъединицы бактериальных рибосом и нарушают биосинтез белков в рибосомах, вызывая разрыв потока генетической информации в клетке. Гентамицин так же может воздействовать на синтез белка, нарушая функции 50 S- субъединицы рибосомы!}

Src="https://present5.com/presentation/3/52712948_162925886.pdf-img/52712948_162925886.pdf-12.jpg" alt="(!LANG:> Aminoglycosides are bactericidal antibiotics, that is, they directly kill susceptible"> Аминогликозиды являются бактерицидными антибиотиками, то есть непосредственно убивают чувствительные к ним микроорганизмы (в отличие от бактериостатических антибиотиков, которые лишь тормозят размножение микроорганизмов, а справиться с их уничтожением должен иммунитет организма хозяина). Поэтому аминогликозиды проявляют быстрый эффект при большинстве тяжёлых инфекций, вызванных чувствительными к ним микроорганизмами, и их клиническая эффективность гораздо меньше зависит от состояния иммунитета больного, чем эффективность бактериостатиков Основные препараты: стрептомицин, канамицин, неомицин, гентамицин, тобрамицин, нетилмицин, сизомицин, амикацин.!}

Src="https://present5.com/presentation/3/52712948_162925886.pdf-img/52712948_162925886.pdf-13.jpg" alt="(!LANG:> Levomycetins (Chloramphenicol) - the first antibiotic obtained synthetically. Used"> Левомицетины (Хлорамфеникол) - первый антибиотик, полученный синтетически. Применяют для лечения брюшного тифа, дизентерии и других заболеваний Использование ограничено по причине повышенной опасности серьезных Хлорамфеникол (левомицетин) осложнений - поражении костного мозга, вырабатывающего клетки крови. Действие - бактериостатическое.!}

Src="https://present5.com/presentation/3/52712948_162925886.pdf-img/52712948_162925886.pdf-14.jpg" alt="(!LANG:> Glycopeptide antibiotics - consist of glycosylated cyclic or polycyclic non-ribosomal peptides."> Гликопептидные антибиотики - состоят из гликозилированных циклических или полициклических нерибосомных пептидов. Значимые гликопептидные антибиотики включают ванкомицин, тейкопланин, телаванцин, блеомицин, рамопланин и декапланин. Гликопептидные антибиотики нарушают синтез клеточной стенки бактерий. Оказывают бактерицидное действие, однако в отношении энтерококков, некоторых стрептококков и стафилококков действуют бактериостатически. Линкозамиды - группа антибиотиков, в которую входят природный антибиотик линкомицин и его полусинтетический аналог клиндамицин. Обладают бактериостатическими или бактерицидными свойствами в зависимости от концентрации в организме и чувствительности микроорганизмов. Полимиксины - группа бактерицидных антибиотиков, обладающих узким спектром активности против грамотрицательной флоры. . По химической природе это полиеновые соединения, включающие остатки полипептидов. В обычных дозах препараты этой группы действуют бактериостатически, в высоких концентрациях - оказывают бактерицидное действие. Из препаратов в основном применяются полимиксин В и полимиксин М. Обладают выраженной нефро- и нейротоксичностью.!}

Src="https://present5.com/presentation/3/52712948_162925886.pdf-img/52712948_162925886.pdf-15.jpg" alt="(!LANG:> Antibiotics of animal origin Lysocym (muramidase) - antibacterial"> Антибиотики животного происхождения Лизоци м (мурамидаза) - антибактериальный агент, фермент класса гидролаз, разрушающий клеточные стенки бактерий путём гидролиза пептидогликана клеточной стенки бактерий муреина. ферменты содержатся в организмах животных, в первую очередь, в местах соприкосновения с !} environment- in the mucous membrane gastrointestinal tract, tear fluid, breast milk, saliva, nasopharyngeal mucus, etc. Large amounts of lysozyme are found in saliva, which explains its antibacterial properties. In human breast milk, the concentration of lysozyme is very high (about 400 mg / l). This is much more than in the cow. At the same time, the concentration of lysozyme in breast milk does not decrease with time; six months after the birth of a child, it begins to increase. Ekmolin is a protein antibiotic. Has antibacterial properties. isolated from fish liver. Enhances the action of a number of bacterial antibiotics

Src="https://present5.com/presentation/3/52712948_162925886.pdf-img/52712948_162925886.pdf-16.jpg" alt="(!LANG:> Antibiotics of plant origin (phytoncides) They are very diverse in chemical nature:"> Антибиотики растительного происхождения (фитонциды) По химической природе очень разнообразны: гликозиды, терпеноиды, алкалоиды и другие вторичные метаболиты растений. Защитная роль проявляется не только в уничтожении микроорганизмов, но и в подавлении их размножения, в отрицательном хемотаксисе подвижных форм микроорганизмов, в стимулировании жизнедеятельности микроорганизмов, являющихся антагонистами патогенных форм для данного растения Например - аллейцин (род Allium - лук, чеснок,), иманин (зверобой), синигрин (хрен - р. Armorácia) и т. д.!}

Src="https://present5.com/presentation/3/52712948_162925886.pdf-img/52712948_162925886.pdf-17.jpg" alt="(!LANG:>Antibacterial agents -"> Антибактериальные вещества Сульфани лами ды - это группа химических веществ, производных пара- аминобензолсульфамида - амида сульфаниловой кислоты (пара-аминобензосульфокислоты). пара-Аминобензолсульфамид - простейшее соединение класса - также называется белым стрептоцидом. Несколько более сложный по структуре сульфаниламид пронтозил (красный стрептоцид) был первым препаратом этой группы и вообще первым в мире синтетическим антибактериальным препаратом!}

Src="https://present5.com/presentation/3/52712948_162925886.pdf-img/52712948_162925886.pdf-18.jpg" alt="(!LANG:>Antibacterial agents Available sulfa drugs differ in pharmacological parameters. Streptocide,"> Антибактериальные вещества Имеющиеся сульфаниламидные средства различаются по фармакологическим параметрам. Стрептоцид, норсульфазол, сульфазин, сульфадимезин, этазол, сульфапиридазин, сульфадиметоксин и др. относительно легко всасываются и быстро накапливатся в крови и органах в бактериостатических концентрациях, проникают через гистогематические барьеры (гематоэнцефалический, плацентарный и др.); они находят применение при лечении различных инфекционных заболеваний. Другие препараты, такие как фталазол, фтазин, сульгин, трудно всасываются, относительно долго находятся в кишечнике в высоких концентрациях и выделяются преимущественно с калом. Поэтому они применяются главным образом при инфекционных заболеваниях желудочно- кишечного тракта. Уросульфан выделяется в значительном количестве почками; он применяется преимущественно при инфекциях мочевых путей!}

Src="https://present5.com/presentation/3/52712948_162925886.pdf-img/52712948_162925886.pdf-19.jpg" alt="(!LANG:>Antibacterial agents Quinolones - group antibacterial drugs also includes fluoroquinolones. The first "> Antibacterial substances Quinolones are a group of antibacterial drugs, which also includes fluoroquinolones. The first drugs of this group, primarily nalidixic acid, have been used for many years only for urinary tract infections. Fluoroquinolones are a group of drugs with pronounced antimicrobial activity, widely used in medicine as broad-spectrum antibiotics.In terms of the breadth of the spectrum of antimicrobial activity, activity, and indications for use, they are really close to antibiotics.Fluoroquinolones are divided into first-generation drugs (pefloxacin, ofloxacin, ciprofloxacin, lomefloxacin, norfloxacin) and second-generation drugs (levofloxacin , sparfloxacin, moxifloxacin.

Src="https://present5.com/presentation/3/52712948_162925886.pdf-img/52712948_162925886.pdf-20.jpg" alt="(!LANG:>Antibacterial substances Nitrofurans are a group of antibacterial agents, derivatives of furan. K"> Антибактериальные вещества Нитрофураны - группа антибактериальных средств, производные фурана. К нитрофуранам чувствительны грамположительные и грамотрицательные бактерии, а также хламидии и некоторые простейшие (трихомонады, лямблии). Обычно Нитрофураны действуют на микроорганизмы бактериостатически, однако в высоких дозах они могут оказывать бактерицидное действие. Кроме того анибактериальное действие могут оказывать тяжелые металлы, цианиды, фенолы и т. д.!}