Structure Chlortetracycline

Tetracyclines are a family of antibiotics which display a characteristic 4-fused-core ring structure (Figure 1.16). They exhibit broad antimicrobial activity and induce their effect by inhibiting protein synthesis in sensitive microorganisms. Chlortetracycline was the first member of this family to be discovered (in 1948). Penicillin G and streptomycin were the only antibiotics in use at that time, and chlortetracycline was the first antibiotic employed therapeutically that retained its antimicrobial properties upon oral administration. Since then, a number of additional tetracyclines have been discovered (all produced by various strains of Streptomyces), and a variety of semi-synthetic derivatives have also been prepared (Table 1.18). 

The tetracyclines are a group of drugs with a common basic chemical structure and pharmacological activity. The first tetracycline, chlortetracycline was isolated from... 

During the course of experiments for the elucidation of the structure of the two earlier discovered compounds chlortetracycline (CTC) and oxytetracycline (OTC) it was found that hydrogenation of chlortetracycline resulted in halogenolysis and the product tetracycline (TC) retained the useful activity spectrum of the first two members of the family. TC appears to represent the first clinically successful antibiotic produced by shere chemical manipulation of preexisting antibiotic. TC was found to be present in fermentations of both cultures streptomyces aureofaciens and streptomyces rimosus as well as in streptomyces viridofaciens (1). 

Oxytetracydine Hydrochloride, USP. Early in I9.W, Finlay et al. " reported the isolation of oxytetracycline (Tei-ramycin) from S. rimosus. This compound was swai idemi-fied as a chemical analogue of chlortetracycline that showed similar antibiotic properties. The structure of oxytetracydine was elucidated by Hochstein et al.. "- and this work provided the basis fur the conllmiation of the structure of the other tetracyclines. 

After the Second World War, the effort continued to find other novel antibiotic structures. This led to the discovery of the peptide antibiotics (e.g. bacitracin (1945)), chloramphenicol (Fig. 10.72) (1947), the tetracycline antibiotics (e.g. chlortetracycline (Fig. 10.71) (1948)), the macrolide antibiotics (e.g. erythromycin (Fig. 10.73) (1952)), the cyclic peptide antibiotics (e.g. cycloserine (1955)), and in 1955 the first example of a second major group of (3-lactam antibiotics, cephalosporin C (Fig. 10.41). 

Little is known as yet about the molecular mechanisms by means of which chlortetracycline is able to control some viral diseases and penicillin (the formula of penicillin K is CuHisO S) is able to control many bacterial diseases. Knowledge of the molecular structure of chlortetracycline and penicillin does not by itself give the solution of the great problem of the molecular basis of the action of drugs and the nature of disease. We need also to know the molecular structure of the human body, of bacteria, of viruses. When these problems have been solved it will be possible to apply much of our present knowledge, as well as the new knowledge, in a way that will benefit all humanity. 

In 1952, Conover developed tetracycline (Figure 1.20) from chlortetracycline by removal of its chlorine atom by catalytic hydrogenation, and then oxytetracycline. The discovery prompted an industry-wide search for superior structurally modified antibiotics, which has provided most of the important antibiotic discoveries made since then. 

Figure 5.12. Structure of chlortetracycline-HCl extracted from ointment.

One year later, the American pharmaceutical company Pfizer discovered a related structure - christened oxytetracycline (Terramycin) - from Streptomyces rimosus. Interestingly, this was found in a soil sample located near their factory in Terre Haute, Indiana. The parent structure - tetracycline - was then obtained by chemical removal of the chlorine atom (an element only rarely found in terrestrial organisms but common in natural products from marine organisms) from chlortetracycline. This third antibacterial agent was subequently found naturally as a constituent of both Streptomyces aureofaciens and Streptomyces viridifaciens. The structures of chlortetracycline were established by R.B. Woodward in 1952 and that of oxytetracycline by Pfizer scientists (in collaboration with RBW) in 1952. 

The epoch-making discovery of chlortetracycline (aureomycin) in 1947 by Duggar paved the way for a number of structural analogues used as broad-spectrum antibiotics that belong to the tetracycline family. The tetracyclines which are found to be effective therapeutically are listed in the following table. 

The tetracyclines are a group of antibiotics with the same basic chemical structure they are derivatives of the naphthacene ring system. Compounds of the series differ in the composition of the side chains (Fig. 1). These antibiotics derived from different Streptomyces species show closely related spectra of bacteriostatic properties, with the exception of minocycline, which is very effective against most Staphylococcus strains resistant to other tetracyclines. Absorption, metabolism, and excretion of the different tetracyclines vary, however. After oral application, tetracycline, oxytetracycline, and chlortetracycline are absorbed to a much lesser degree than demethylchlortetracycline, methacycline, or the almost entirely absorbed minocycline. Maximum blood levels are found 2-6 h after oral intake and immediately in the case of intravenous infusion. Half-lives between 8 and 15 h were reported. The tetracyclines diffuse readily across the vascular barrier and are found in various tissues such as the liver, spleen, bone marrow, kidney, skin, and lungs as well as the peritoneal and pericardiac cavities. The tetracyclines are also able to... 

Fig. 1 a-h. Chemical structures of the tetracyclines, a tetracycline b oxytetracycline c chlortetracycline d methacycline e demethylchlortetracycline f 6-deoxytetracycline (doxycycline) g minocycline h roli(A -pyrrolidinomethyl)tetracycline... 

Chlortetracycline from Streptomyces aureofackns was the first tetracycline to be isolated, in 1948. Since that time there have been more than 30 new natural tetracyclines, mainly isolated from Streptomyces species, including oxytetracycline in 1950 and tetracycline in 1953 (44). Most natural tetracyclines have a common structure (Figure 1) with the 3-diketone system in rings B and C essential for antibiotic activity. Some natural tetracyclines such as terramycin X have the acetomido-group at C2 replaced by an acetyl-group, and democycline and demecycline lack the methyl-group at C6 (Table 1). 

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