ZeynepAtes-Alagoz, Ph.D CHLORAMPHENICOL

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CHLORAMPHENICOL

Zeynep Ates-Alagoz, Ph.D

Ankara University, Faculty of Pharmacy

Department of Pharmaceutical Chemistry

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O H ( R ) N H C l C l O ( R ) N+ O -O O H 1 2 3 1 ,3 - p r o p a n d i ol A c e t a m i d e g r o u p 2-dichloroacetamide-1-(p-nitrophenyl)-1,3-propandiole

D-(-)Threo isomer

p - N it r o p h e n y l g r o u p

CHLORAMPHENICOL

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2-2008 Dr Eman R. El-Bendary 3

Mechanism of Action

• inhibits

protein synthesis.

• binds to 50 S r-RNA and inhibit formation

of peptide bond.

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Stereochemistry of chloramphenicol

O N H ( S ) ( R ) N+ O O -H O O H C l C l O N H ( S ) ( S ) N+ O O -H O O H C l C l

The active isomer

O N H ( R ) ( S ) N+ O O -H O O H C l C l O H ( R ) N H C l C l O ( R ) N+ O -O O H

The molecule of chloramphenicol contains two chiral centres and only one of the four

diastereoisomers with 1R, 2R configuration is active. Total synthesis produces a mixture of all four isomers, the unwanted isomers are removed before use (refer to the synthesis). Its severe potential blood dyscrasia has greatly decreased its use.

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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.

O H ( R ) N H C l C l O ( R ) N+ O -O O H

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Structure Activity Relationship

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

CH₃SO₂ (Thiamphenicol) CH₃CO (Cetophenicol)

* Replacement of dichloro group by

azido group gives active

compounds as Azidamphenicol O H ( R ) N H C l C l O ( R ) S O2C H3 O H T h i a m p h e n ic o l C e t o p h e n i c o l O H ( R ) N H C l C l O ( R ) C O C H3 O H Azidamphenicol

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Metabolism of Chloramphenicol

O ( R ) N H C l C l O ( R ) N+ O -O O H O O H O H C O O H O H C - 3 g l u c u r o n i d e c o n j u g a t e O H ( R ) N H C l C l O ( R ) N+ O -O O H O H ( R ) N H C l C l O ( R ) N H2 O H O H ( R ) N H2 ( R ) N+ O -O O H O H ( R ) N H C l O O ( R ) N+ O -O O H O H N+ O -O O H O M a j o r m e t a b o li t e CHLORAMPHENICOL

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Toxicity of Chloramphenicol

• When used for a long time → reversible agranulocytosis and thrombocytopenia

• Hematoxicity is due to the formation of nitroso and hydroxyl amines due to the reduction of the aromatic nitrogroup (reversible when the drug is discontinued) Gray baby syndrome: A syndrome due to toxicity of the antibiotic chloramphenicol in the newborn, especially the premature newborn

• because of lack the necessary liver enzymes to metabolize this drug. Chloramphenicol accumulates in the baby causing

• hypotension

• cyanosis (blue coloring of lips, nail beds, and skin from lack of oxygen in the blood),

• death

• Chloramphenicol is therefore usually not given to newborns or premature babies.

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Bacterial Resistance

O C O C H₃ ( R ) N H C l C l O ( R ) N+ O -O O H 3 - A c e to x y d e r iv a tiv e O H ( R ) N H C l C l O ( R ) N+ O -O O C O C H₃

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.

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Latent forms of chloramphenicol

(Prodrugs of chloramphenicol)

Chloramphenicol palmitate

• Since the drug is intensively bitter, this can be masked for use as a

peadiatric 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.

N H C l C l O N+ O -O H O ( C H₂)_{1 4}C O O H O O C h l o r a m p h e n ic o l p a l m it a t e E s t e r a s e E n z y m e N H C l C l O N+ O -O H O O H C h l o r a m p h e n ic o l

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Latent forms of chloramphenicol

(Prodrugs of chloramphenicol)

Chloramphenicol hemisuccinate

• Chloramphenicol has

poor water solubility

and, thus is largely overcome 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 O H H N C l C l O N+ -O O O H C h l o r a m p h e n i c o l s u c c in a t e e s t e r E s t e r a s e E n z y m e O H H N C l C l O N+ -_O O O H C h lo r a m p h e n ic o l

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Uses of Chloramphenicol

• _{Bacteriostatic or bactericidal (depending on an organism and dosage)}

• The binding site is the same as the macrolide and the linkozamides.

• Because the sites of action are same, these 3 antibiotics prevent the antibacterial

effect of each other; they should not be used together.

• Broad spectrum (especially against Gram (+) and anaerobes).

• 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.