Amphenicol

PHRM 304

Amphenicol
Amphenicols are antibiotics comprising chloramphenicol and its synthetic analogues.

Chloramphenicol

Chloramphenicol was originally produced by fermentation of Streptomyces venezuelae, but its comparatively simple chemical structure resulted in several efficient total chemical synthesis process. Chloramphenicol is introduced into clinical practice in 1949.

Mechanism of action
It is bacteriostatic. It inhibits protein synthesis both in bacteria and in eukaryotic cells. It binds reversibly to 50S ribosomal subunit and prevents binding of amino acyl tRNA to 50S ribosomal subunit. The interaction between peptidyl transferase (forms peptide links between adjacent amino acids) and amino acid substrate cant occur and thus peptide bond formation is inhibited.

Prodrug
Water solubility of chloramphenicol is enough (2.5mg/ml) to come in contact with the taste receptors on the tongue, producing an unpalatable bitterness. To mask this intense bitterness, the palmitic acid, CH3(CH2)14COOH moiety is added as an ester of chloramphenicols primary alcohol. This reduces the parent drugs water solubility (1.05mg/ml) enough so that it can be formulated as a suspension that passes over the bitter taste receptors on the tongue.

Chloramphenicol palmitate ester is inactive, and is hydrolyzed to active chloramphenicol in the small intestine by digestive esterase. There is no difference in bioavailability between chloramphenicol and chloramphenicol palmitate. R
Chloramphenicol: R=H Chloramphenicol palmitate: R= -CO(CH2)14 CH3

The intravenous (IV) preparation of chloramphenicol is the succinate ester. Succinate ester: Increase water solubility, thus volume of IV preparation will reduce

Structure-activity relationship
* *

-NO 2 group -NO2 group can be replaced by strong electron withdrawing groups without appreciable loss of activity. For example, acetyl group (CH3CO-) as in cetophenicol, methyl-sulfonyl group (CH3SO2-) as in thiamphenicol.

Cetophenicol

Thiamphenicol

 Replacement of -NO2 group by other groups like CN-, halogen, -CONH2, -OH produce inactive compound. Shifting -NO2 group from para position reduce the activity. Phenyl group Replacement of phenyl group with other aromatic or alicyclic or heterocyclic moieties give inactive compounds.

Propanediol group Chloramphenicol possesses two chiral carbon atoms (*) in the acylamino-propanediol chain as shown below:

Threo form (biologically active)

Erythro form

Thus there are two possible pairs of enantiomers. It has been observed that the biological activity resides almost exclusively in the D-Threo isomer whereas the L-Threo, and D- and L-Erythro isomers are virtually inactive. The acylamino side chain is essential for antibacterial potency, but can be widely substituted. Increases in the size of this chain cause a decrease of potency.

Therapeutic uses
The popular use of chloramphenicol is in eye drops or ointment for bacterial conjunctivitis. Should never be used for minor infections, or infections which could be treated by other drugs. The most serious side effect of chloramphenicol treatment is aplastic anaemia.

The highest risk is with oral chloramphenicol (affecting 1 in 24,00040,000) and the lowest risk occurs with eye drops (affecting less than 1 in 224,716 prescriptions). Thiamphenicol is a related compound with a similar spectrum of activity that is available in Italy and China for human use, and has never been associated with aplastic anaemia. Thiamphenicol is available in the U.S. and Europe as a veterinary antibiotic, and is not approved for use in humans.

Erythro form, threo form

For compounds with two asymmetric carbon atoms:

Threo form: the same ligands (both horizontal) at

the opposite side of Fischer projection

Erythro form: the same ligands (both horizontal) at

the same side of Fischer projection

D, L-series (sugar)
The configuration of the asymmetric carbon atom furthest from the carbonyl carbon is: identical with D-glyceraldehyde ... D-series identical with L-glyceraldehyde ... L-series

D series; 22, 25, 26, 28 and L series; 23, 24,27, 29