Erythromycins discovery

One of the most famous examples of intramolecular attack of oxygen on the nitriUnm ion intermediate was observed in the Beckmann rearrangement of Erythromycin oxime derivatives and was used in the discovery and synthesis of the commercial macrolide antibiotic Azithromycin 464. In fact, the Beckmann rearrangement of Erythromycin A 9( )-oxime 460 produced only small amounts (5%) of the expected amide 463, along with two isomeric imino ethers (461 and 462) in a fair yield (38 and 43%) (equation 198). 

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). 

Ester derivatives of erythromycin, shown in Table 4, were synthesized soon after its discovery (124—126). They are readily prepared by acylation of the 2-hydroxyl group the neighboring 3r-dimethylamino group directs acylation to this site. Commonly used esters of erythromycin are propionate, acetate, ethyl succinate, and ethyl carbonate (30). 2r-Esters do not bind bacterial ribosomes, however, and consequently must be hydrolyzed back to the parent to exert antibacterial activity (127). Ester derivatives are still being prepared (128,129). 2,-0-Acetylerythromycin stearate, also known as erythromycin acistrate, is an example undergoing clinical trial (11,130,131). Two salts of 2,-0-propionyl-erythromycin, N-acetylcysteinate (erythromycin stinoprate) and mercaptosuccinate, were prepared to combine antibiotic and mucolytic properties in a single agent (132—134). 

The years between 1940 and 1959 have been justly called the golden era of antibiotic discovery. During this period every important class of antibacterial antibiotic now known was recognized (Table III). Indeed, many specific drugs (e.g., benzylpenicillin, streptomycin, oxytetracycline, chloramphenicol, neomycin, and erythromycin) which presently occupy major places in therapeutic practice were discovered during that period. 

With the discovery in 1951 of picromycin, followed in 1952 by erythromycin and, in 1953, of methymycin and carbomycin, it became apparent that another extensive family of antibiotic substances had been disclosed, several members of which were valuable chemotherapeutic agents. There are about 15 well characterized members of this group and about an equal number of less well characterized members. This group has been named after the most prominent structural feature of its members,... 

The search for effective and nontoxic antibiotics is unceasing. Since the discovery of penicillin in 1928, thousands of antibiotics have been isolat and studied. But relatively few are in active use. The following are among the better known and more widely used antibiotics bacitracin, chlortetracy-cline (Aureomycin), erythromycin, neomycin, nisin, nystatin, oxytetracycline (Terramycin), penicillin, pimaricin, streptomycin, and tylosin. 

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