β-lactamides and aminoglycosides are antibiotics. Antibiotics are a large group of organic compounds with different chemical structures that have pronounced biological targeted activity. All the drugs covered here are polyfunctional compounds of complex chemical structure. The study of their physical, physicochemical and chemical properties, as well as identification of their general and particular features, is based on the knowledge of general patterns. This knowledge is acquired in the process of studying theoretical chemical and biological disciplines, as well as the pharmaceutical chemistry modules and other special disciplines covered in the previous years.
Antibiotics are chemotherapeutic substances formed by microorganisms or obtained from other natural sources, as well as their derivatives and synthetic products that have the ability to selectively suppress pathogens in the patient’s body or delay the development of malignant neoplasms.
Antibiotics differ from other drugs because of their heterogeneity, i.e., multicomponent composition. For example, the aminoglycoside gentamicin has three components; in benzylpenicillin salts, the amount of penicillins must be at least 96.0%, and the benzylpenicillin content must be at least 90.0%.
Antibiotics are characterized by a relationship to the action of certain enzyme systems. For each antibiotic, there is an enzyme that inactivates it; for example, penicillinase inactivates natural penicillin and some semi-synthetic penicillins.
Evaluation of the quality of natural and semi-synthetic antibiotics is carried out according to additional indicators: primarily their toxicity, and for some antibiotics (streptomycin sulfate, for example), determination of histamine-like substances. These indicators are determined by biological methods using animals.
Many antibiotics are produced in the form of hermetically sealed dry powder due to their instability in aqueous solutions.
Antibiotics rank first among drugs that cause adverse reactions and side effects, such as direct toxicity, dysbacteriosis, nephro- and ototoxicity (streptomycin), and allergic reactions (penicillins).
Since in most cases antibiotics are mixtures of substances, their activity is determined in units of activity (U). The biological activity of natural antibiotics is determined by the agar diffusion method. The method is based on comparing the growth inhibition of a test microorganism by certain concentrations of the test drug, with the growth inhibition caused by known concentrations of a standard antibiotic preparation.
For benzylpenicillin, 1 U corresponds to 0.5988 μg of chemically pure sodium salt of benzylpenicillin.
1 μg of chemically pure streptomycin base corresponds to a specific activity amounting to 1 U. As a rule, the content of the biological substance is indicated on the labels of most antibiotics (that are soluble salts or other soluble derivatives), usually compared to a base or acid; for example, “Oxacillin 1.0 g”.
β-lactamides
The β-lactam antibiotic group includes penicillins, cephalosporins, carbapenems, and monobactams. They have a similar chemical structure: they contain a β-lactam ring, which is necessary for the manifestation of their antimicrobial activity:
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PENICILLINS
Benzylpenicillin was discovered by A. Fleming in 1929 and is still widely used in medicine.
Russian researchers and doctors (V.A. Manassein, et al.) observed the antibiotic effect of green mold long before Fleming’s isolation of penicillin. Russian doctors A.G. Polotebnov and M.G. Tarkovsky used green mold for medicinal purposes. These remarkable discoveries of our Russian scientists were not widely known at that time (19th century).
The merit of creating Soviet penicillin and developing a method for its production from domestic strains of mold belongs to Professor, later Academician, Z. V. Ermolyeva (1942).
The All-Union Research Institute obtained semi-synthetic penicillins (methicillin, oxacillin, ampicillin, carbenicillin, etc.) as well as semisynthetic cephalosporins and a number of other antibiotics (S.M. Navashin, et al.).
A great contribution to the development of antibiotic research was made by Soviet scientists M.M. Shemyakin and A.S. Khokhlov, while academicians Yu.A. Ovchinnikov, V.A. Engelhardt and A.S. Spirin contributed to the study of the molecular mechanisms of antibiotic action.
For the industrial production of antibiotics, Penicillium notatum and Penicillium chrysogenum are of the greatest importance.
All penicillins are either natural or semi-synthetic depending on the method of production.
Natural penicillins include benzylpenicillin and phenoxymethylpenicillin.
Benzylpenicillin is a rather strong acid; it is hygroscopic, quickly inactivated, therefore it is used in the form of salts with inorganic and organic bases (sodium, potassium, novocainic, N,N’-dibenzylethylenediamine, etc.). Benzylpenicillin salts are active against gram-positive microorganisms (relatively narrow spectrum of action) and unstable to the action of acids and penicillinase, therefore they are used only parenterally.
Phenoxymethylpenicillin is more resistant to acids and penicillinase, it is used as an acid, and is an enterally administered drug.
The shortcomings of natural penicillins have stimulated the search for new antibiotics. In late 1950s, work began on the creation of active semi-synthetic antibiotics based on 6-aminopenicillanic acid (6-APA), which was isolated as a product of penicillin biosynthesis in 1959. 6-APA can also be obtained by enzymatic hydrolysis of benzylpenicillin. Acylation of 6-APA with acid chlorides of various acids made it possible to obtain a number of semi-synthetic penicillins that are resistant to acids (meaning they can be used orally) and penicillinase and have a wider spectrum of action.
Semisynthetic penicillins include: oxacillin, dicloxacillin, ampicillin, amoxicillin, carbenicillin, ticarcillin, azlocillin, piperacillin, mezlocillin.
CHEMICAL STRUCTURE, PHYSICAL AND PHYSICO-CHEMICAL PROPERTIES
The structure of penicillins is based on 6-aminopenicillanic acid (6-APA), which is a heterocyclic system consisting of 2 condensed rings:
- a four-membered β-lactam ring (B);
- a five-membered thiazolidine ring (A).