chloramphenicol€¦ · toxicity of chloramphenicol • when used for a long time →reversible...
TRANSCRIPT
CHLORAMPHENICOL
Zeynep Ates-Alagoz, Ph.DAnkara University, Faculty of Pharmacy
Department of Pharmaceutical Chemistry
O H
(R )
N H
C lC l
O
(R )
N+
O-
O
O H
1
2
3
1 ,3 -p r o p a n d io l
A c e ta m id e g r o u p
2-dichloroacetamide-1-(p-nitrophenyl)-1,3-propandiole
D-(-)Threo isomer
p -N itro p h e n y l g r o u p
CHLORAMPHENICOL
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.
Stereochemistry of chloramphenicol
O N H
(S )(R )
N+
O
O-
H O
O H
C lC l
O N H
(S )(S )
N+
O
O-
H O
O H
C lC l
The active isomer
O N H
(R )(S )
N+
O
O-
H O
O H
C lC l
O H
(R )
N H
C lC l
O
(R )
N+
O-
O
O H
The molecule of chloramphenicol contains two chiral centres and only one of the fourdiastereoisomers with 1R, 2R configuration is active. Total synthesis produces a mixture of all fourisomers, the unwanted isomers are removed before use (refer to the synthesis). Its severe potentialblood dyscrasia has greatly decreased its use.
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 lC l
O
(R )
N+
O-
O
O H
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 lC l
O
(R )
S O 2 C H 3
O H
T h ia m p h e n ic o l
C e to p h e n ic o l
O H
(R )
N H
C lC l
O
(R )
C O C H 3
O H
Azidamphenicol
Metabolism of Chloramphenicol
O
(R )
N H
C lC l
O
(R )
N+
O-
O
O H
O
O H
O H
C O O H
O H
C -3 g lu c u r o n id e c o n ju g a teO H
(R )
N H
C lC l
O
(R )
N+
O-
O
O H
O H
(R )
N H
C lC l
O
(R )
N H 2
O H
O H
(R )
N H 2
(R )
N+
O-
O
O H
O H
(R )
N H
C lO
O
(R )
N+
O-
O
O H
O H
N+
O-
O
O H
O
M a jo r m e ta b o lite
CHLORAMPHENICOL
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 thereduction of the aromatic nitro group (reversible when the drug is discontinued)
Gray baby syndrome: A syndrome due to toxicity of the antibiotic chloramphenicol inthe 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 theblood),
• death
• Chloramphenicol is therefore usually not given to newborns or prematurebabies.
Bacterial Resistance
O C O C H 3
(R )
N H
C lC l
O
(R )
N+
O-
O
O H
3 - A c e to x y d e riv a tiv e
O H
(R )
N H
C lC l
O
(R )
N+
O-
O
O C O C H 3
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 -A c e to x y d e riv a tiv e
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 H 2 )1 4 C O O H
O O
C h lo r a m p h e n ic o l p a lm ita te
E ste r a se E n z y m e
N H
C l
C l
O
N+
O-
O
H O
O H
C h lo r a m p h e n ic o l
Latent forms of chloramphenicol(Prodrugs of chloramphenicol)
Chloramphenicol hemisuccinate
• Chloramphenicol has poor water solubility and, thus is largely overcome byconversion to the 3-hemisuccinyl ester, which forms a water-soluble sodium saltsuitable for parental preparation.
• This is cleaved in the body to produce active chloramphenicol. Because cleavagein muscles is too slow, this product is used intravenously rather thanintramuscularly.
O
O
O
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 su c c in a te e s te r
E ste r a se E n z y m e
O H
H N
C l C l
O
N+
-O
O
O H
C h lo ra m p h en ico l
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 antibacterialeffect 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 whenused carefully.
• It is of special value for treatment of typhoid and parathyroid fevers, haemophilusinfections, pneumococcal and meningococcal meningitis in beta lactam allergicpatients.
• Safer antibiotics should be used whenever possible.