Modification Of Chloramphenicol By Use Of Palminic Acid

D-Phe D-Phe D-Phe D-Tyr

Gramicidin acts as an ionophore in bacterial cell membranes to cause the loss of potassium ion from the cell.261 It is bactericidal.

Tyrothricin and gramicidin are effective primarily against Gram-positive organisms. Their use is restricted to local applications. Tyrothricin can cause lysis of erythrocytes, which makes it unsuitable for the treatment of systemic infections. Its applications should avoid direct contact with the bloodstream through open wounds or abrasions. It is ordinarily safe to use tyrothricin in troches for throat infections, as it is not absorbed from the GI tract. Gramicidin is available in various topical preparations containing other antibiotics, such as bacitracin and neomycin.

o UNCLASSIFIED ANTIBIOTICS

Among the many hundreds of antibiotics that have been evaluated for activity, several have gained significant clinical attention but do not fall into any of the previously considered groups. Some of these have quite specific activities against a narrow spectrum of microorganisms. Some have found a useful place in therapy as substitutes for other antibiotics to which resistance has developed.

Chloramphenicol

The first of the widely used broad-spectrum antibiotics, chloramphenicol (Chloromycetin, Amphicol) was isolated by Ehrlich et al.262 in 1947. They obtained it from Streptomyces venezuelae, an organism found in a sample of soil collected in Venezuela. Since then, chloramphenicol has been isolated as a product of several organisms found in soil samples from widely separated places. More importantly, its chemical structure was established quickly, and in 1949, Controulis et al.263 reported its synthesis. This opened the way for the commercial production of chloramphenicol by a totally synthetic route. It was the first and still is the only therapeutically important antibiotic to be so produced in competition with microbiological processes. Diverse synthetic procedures have been developed for chloramphenicol. The commercial process generally used starts with p-ni-troacetophenone.264

Chloramphenicol is a white, crystalline compound that is very stable. It is very soluble in alcohol and other polar organic solvents but only slightly soluble in water. It has no odor but has a very bitter taste.

Chloramphenicol possesses two chiral carbon atoms in the acylamidopropanediol chain. Biological activity resides almost exclusively in the D-threo isomer; the L-threo and the d- and L-erythro isomers are virtually inactive.

Chloramphenicol is very stable in the bulk state and in solid dosage forms. In solution, however, it slowly undergoes various hydrolytic and light-induced reactions.265 The rates of these reactions depend on pH, heat, and light. Hydrolytic reactions include general acid-base-catalyzed hydrolysis of the amide to give 1-(^-nitrophenyl)-2-amino-propan-1,3-diol and dichloroacetic acid and alkaline hydrolysis (above pH 7) of the a-chloro groups to form the corresponding a,a-dihydroxy derivative.

The metabolism of chloramphenicol has been investigated thoroughly.266 The main path involves formation of the 3-o-glucuronide. Minor reactions include reduction of the ^-nitro group to the aromatic amine, hydrolysis of the amide, and hydrolysis of the a-chloracetamido group, followed by reduction to give the corresponding a-hydroxy-acetyl derivative.

Strains of certain bacterial species are resistant to chlo-ramphenicol by virtue of the ability to produce chloram-phenicol acetyltransferase, an enzyme that acetylates the hydroxy groups at the positions 1 and 3. Both the 3-ace-toxy and the 1,3-diacetoxy metabolites lack antibacterial activity.

Numerous structural analogs of chloramphenicol have been synthesized to provide a basis for correlation of structure to antibiotic action. It appears that the ^-nitrophenyl group may be replaced by other aryl structures without appreciable loss in activity. Substitution on the phenyl ring with several different types of groups for the nitro group, a very unusual structure in biological products, does not greatly decrease activity. All such compounds yet tested are less active than chloramphenicol. As part of a QSAR study, Hansch et al.267 reported that the 2-NHCOCF3 derivative is

1.7 times as active as chloramphenicol against E. coli. Modification of the side chain shows that it possesses high specificity in structure for antibiotic action. Conversion of the alcohol group on C-1 of the side chain to a keto group causes appreciable loss in activity. The relationship of the structure of chloramphenicol to its antibiotic activity will not be seen clearly until the mode of action of this compound is known. Brock268 reports on the large amount of research that has been devoted to this problem. Chloramphenicol exerts its bacteriostatic action by a strong inhibition of protein synthesis. The details of such inhibition are as yet undetermined, and the precise point of action is unknown. Some process lying between the attachment of amino acids to sRNA and the final formation of protein appears to be involved.

The broad-spectrum activity of chloramphenicol and its singular effectiveness in the treatment of some infections not amenable to treatment by other drugs made it an extremely popular antibiotic. Unfortunately, instances of serious blood dyscrasias and other toxic reactions have resulted from the promiscuous and widespread use of chloramphenicol in the past. Because of these reactions, it is recommended that it not be used in the treatment of infections for which other antibiotics are as effective and less hazardous. When properly used, with careful observation for untoward reactions, chloramphenicol provides some of the very best therapy for the treatment of serious infections.269

Chloramphenicol is recommended specifically for the treatment of serious infections caused by strains of Grampositive and Gram-negative bacteria that have developed resistance to penicillin G and ampicillin, such as H. influenzae, Salmonella typhi, S. pneumoniae, B. fragilis, and N. meningitidis. Because of its penetration into the central nervous system, chloramphenicol is a particularly important alternative therapy for meningitis. It is not recommended for the treatment of urinary tract infections because 5% to 10% of the unconjugated form is excreted in the urine. Chloramphenicol is also used for the treatment of rickettsial infections, such as Rocky Mountain spotted fever.

Because it is bitter, this antibiotic is administered orally either in capsules or as the palmitate ester. Chloramphenicol palmitate is insoluble in water and may be suspended in aqueous vehicles for liquid dosage forms. The ester forms by reaction with the hydroxyl group on C-3. In the alimentary tract, it is hydrolyzed slowly to the active antibiotic. Chloramphenicol is administered par-enterally as an aqueous suspension of very fine crystals or as a solution of the sodium salt of the succinate ester of chloramphenicol. Sterile chloramphenicol sodium succi-nate has been used to prepare aqueous solutions for intravenous injection.

Chloramphenicol Palmitate

Chloramphenicol palmitate is the palmitic acid ester of chloramphenicol. It is a tasteless prodrug of chloramphenicol intended for pediatric use. The ester must hydrolyze in vivo following oral absorption to provide the active form. Erratic serum levels were associated with early formulations of the palmitate, but the manufacturer claims that the bioavailability of the current preparation is comparable to that of chloramphenicol itself.

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Responses

  • nibs
    Why chloramphenicol is considered as a derivative of dichloroacetic acid?
    3 years ago
  • Proserpina
    Does chloramphenicol undergoes slow amide hydrolysis in acid?
    2 years ago

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