2-2008Dr Eman R. El-Bendary1

Amphenicols

Broad spectrum antibiotics

2-2008Dr Eman R. El-Bendary2

Mechanism of Action of Amphenicols

• Amphenicols inhibit protein synthesis.

• They bind to 50 S r-RNA and inhibit formation of peptide bond.

2-2008Dr Eman R. El-Bendary3

ChloramphenicolOH

(R)

NH

ClCl

O

(R)

N+O-

O

OH

1

2

3

1,3-propandiol

Acetamide group

2,2-dichloro-N-((1R,2R)-1,3-dihydroxy-1-(4-nitrophenyl)propan-2-yl)acetamide

D-(-)Threo isomer

p-Nitrophenyl group

2-2008Dr Eman R. El-Bendary4

Stereochemistry of chloramphenicol

O NH

(S)(R)

N+

O

O-

HO

OH

ClCl

O NH

(S)(S)

N+

O

O-

HO

OH

ClCl

The active isomer

O NH

(R)(S)

N+

O

O-

HO

OH

ClCl

OH

(R)

NH

ClCl

O

(R)

N+

O-

O

OH

2-2008Dr Eman R. El-Bendary5

Structure Activity Relationship• Replacement of phenyl group by

other aromatic systems or cyclic systems e.g. cyclohexyl, furyl, naphthyl, pyridyl or thienyl results in loss of activity.

• Replacement of NO2 by NH2, NHR, OH, SO2R, CN results in loss of activity.

• Shifting of NO2 from para‑position leads to loss of activity.

• The propanediol moiety should be in D-(-) threo-isomer. Other isomers are inactive.

• Replacement of OH, and extension or suppression of terminal CH2OH abolishes the activity.

OH

(R)

NH

ClCl

O

(R)

N+O-

O

OH

2-2008Dr Eman R. El-Bendary6

Structure Activity Relationship

• Replacement of nitro group by other electron withdrawing groups gives active compounds as

CH3SO2 (Thiamphenicol)

or CH3CO (Cetophenicol)

OH

(R)

NH

ClCl

O

(R)

SO2CH3

OH

Thiamphenicol

Cetophenicol

OH

(R)

NH

ClCl

O

(R)

COCH3

OH

2-2008Dr Eman R. El-Bendary7

Metabolism of Chloramphenicol

O

(R)

NH

ClCl

O

(R)

N+O-

O

OH

OOH

OH

COOH

OH

C-3 glucuronide conjugate

OH

(R)

NH

ClCl

O

(R)

N+O-

O

OH

OH

(R)

NH

ClCl

O

(R)

NH2

OH

OH

(R)

NH2

(R)

N+O-

O

OH

OH

(R)

NH

ClO

O

(R)

N+O-

O

OH

Chloramphenicol

OH

N+O-

O

OH

O

Major metabolite

2-2008Dr Eman R. El-Bendary8

Bacterial Resistance

OCOCH3

(R)

NH

ClCl

O

(R)

N+O-

O

OH

3- Acetoxy derivative

OH

(R)

NH

ClCl

O

(R)

N+O-

O

OCOCH3

Bacterial resistance to chloramphenicol arises from the ability of certain strains of bacteria to produce chloramphenicol acetyltransferase, an enzyme that acetylates OH at C-1 and C‑3 of the propanol moiety to produce 1-acetoxy and 3‑acetoxy derivatives, respectively, which are devoid of any activity.

1-Acetoxy derivative

2-2008Dr Eman R. El-Bendary9

Latent forms of chloramphenicol(Prodrugs of chloramphenicol)

Chloramphenicol palmitate

• Since the drug is intensively bitter, this can be masked for use as a paediatric oral suspension by use of the C‑3 palmitate, which has extremely low solubility. The ester is cleared in the duodenum to liberate the drug.

NH

Cl

ClO

N+O-

O

HO

(CH2)14COOH

O O

Chloramphenicol palmitate

Esterase EnzymeNH

Cl

ClO

N+O-

O

HO

OH

Chloramphenicol

2-2008Dr Eman R. El-Bendary10

Latent forms of chloramphenicol(Prodrugs of chloramphenicol)

Chloramphenicol hemisuccinate

• Chloramphenicol has poor water solubility and, thus is largely overcomed by conversion to the 3-hemisuccinyl ester, which forms a water‑soluble sodium salt suitable for parental preparation. This is cleaved in the body to produce active chloramphenicol. Because cleavage in muscles is too slow, this product is used intravenously rather than intramuscularly.

O

O

O

OH

HN

Cl Cl

ON+

-O

O

OH

Chloramphenicol succinate ester

Esterase Enzyme OH

HN

Cl Cl

ON+

-O

O

OH

Chloramphenicol

2-2008Dr Eman R. El-Bendary11

Uses of Chloramphenicol

• Despite of potential serious limitations, chloramphenicol is an excellent drug when used carefully. It is of special value for treatment of typhoid and parathyroid fevers, haemophilus infections, pneumococcal and meningococcal meningitis in beta lactam allergic patients. Safer antibiotics should be used whenever possible.

2-2008Dr Eman R. El-Bendary12