Chloramphenicol,

Chloramphenicol (Fig. 10.72) was originally isolated from Streptomyces Venezuela, but is now prepared synthetically. It has two chiral centres, but only the i ,i -isomer is active. 

Chloramphenicol binds to the 50S subunit of ribosomes and appears to act by inhibiting the movement of ribosomes along mRNA, probably by inhibiting the peptidyl transferase reaction by which the peptide chain is extended. 

Chloramphenicol is the drug of choice against typhoid and is also used in severe bacterial infections which are insensitive to other antibacterial agents. It has also found widespread use against eye infections. However, the drug should only be used in these restricted scenarios since it is quite toxic, especially to bone marrow. The 

NO2 group is suspected to be responsible for this, although intestinal bacteria are capable of reducing this group to an amino group. 

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Dichloroacetic acid is used in the synthesis of chloramphenicol [56-75-7] and aHantoin [97-59-6]. Dichloroacetic acid has vimcidal and fungicidal activity. It was found to be active against several staphylococci (36). The oral toxicity is low the LD q in rats is 4.48 g/kg. It can, however, cause caustic bums of the skin and eyes and the vapors are very irritating and injurious (28). 

In pharmaceutical appHcations, the selectivity of sodium borohydride is ideally suited for conversion of high value iatermediates, such as steroids (qv), ia multistep syntheses. It is used ia the manufacture of a broad spectmm of products such as analgesics, antiarthritics, antibiotics (qv), prostaglandins (qv), and central nervous system suppressants. Typical examples of commercial aldehyde reductions are found ia the manufacture of vitamin A (29) (see Vitamins) and dihydrostreptomycia (30). An acyl azide is reduced ia the synthesis of the antibiotic chloramphenicol (31) and a carbon—carbon double bond is reduced ia an iatermediate ia the manufacture of the analgesic Talwia (32). 

In 1939 the isolation of a mixture of microbial products named tyrotbricin from a soil bacillus was described. Further investigation showed this material to be a mixture of gramicidin and tyrocidine. In rapid succession the isolation of actinomycin (1940), streptothricin (1942), streptomycin (1943), and neomycin (1949), produced by Streptomjces were reported and in 1942 the word antibiotic was introduced. Chloramphenicol, the first of the so-called broad spectmm antibiotics having a wide range of antimicrobial activity, was discovered in 1947. Aureomycin, the first member of the commercially important tetracycline antibiotics, was discovered in 1948. 

Chloramphenicol. Only chloramphenicol and a few closely related analogues fall iato this group. Chloramphenicol, a nitro benzene derivative of dichloroacetic acid, inhibits proteia biosyathesis. 

Table 1. Minimum Inhibitory Concentration (MIC) of Chloramphenicol and Thiamphenicol Against Sensitive Organisms...

Organism strain No. of strains tested Susceptibility Chloramphenicol Thiomphenicol Florfenicol... 

Both chloramphenicol and thiamphenicol cause reversible bone marrow suppression (9). The irreversible, often fatal, aplastic anemia, however, is only seen for chloramphenicol (9). This rare (1 in 10,000—45,000) chloramphenicol toxicity has been linked to the nitroaromatic function (1,9). Thiamphenicol, which is less toxic than chloramphenicol in regard to aplastic anemia, lacks potency as can be seen in Table 1, and thiamphenicol has never found much usage in the United States. An analogue of thiamphenicol having antimicrobial potencies equivalent to chloramphenicol was sought. Florfenicol (2) was selected for further development from a number of closely related stmctures. 

Plasmid-mediated bacterial inactivation of chloramphenicol and thiamphenicol can potentially lead to three products, the 3- 0-acetyl (3), 1-0-acetyl (4), and 1,3-di-O-acetyl (5) derivatives as shown in Figure 1. 

Fig. 1. CAT (catalyzed acetylation) of chloramphenicol (1, R = NO2), and thiamphenicol (1, R = CH2SO2) where Ac-CoA is acetyl coenzyme A [72-89-9].

Stmcture-activity and mechanism of action studies indicate that the requirements for chloramphenicol activity are the D-threo-configuration, the... 

Fig. 3. The solid-state conformations of 3- uoro-chloramphenicol (6, R = NO2) showing the corresponding rotamers and schematics of the stabilising...

Table 3. Activity of Chloramphenicol and Analogues Against Chloramphenicol-Sensitive and -Resistant Organisms...

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