Download Prodrugs of chloramphenicol

Amphenicols
Broad spectrum antibiotics
1
Dr Eman R. El-Bendary
2-2008
Mechanism of Action of
Amphenicols
• Amphenicols inhibit protein synthesis.
• They bind to 50 S r-RNA and inhibit
formation of peptide bond.
2
Dr Eman R. El-Bendary
2-2008
Chloramphenicol
1,3-propandiol
p-Nitrophenyl group
OH
OH
3
1
(R)
(R)
2
O
O-
NH
N+
Acetamide group
O
Cl
Cl
2,2-dichloro-N-((1R,2R)-1,3-dihydroxy-1-(4-nitrophenyl)propan-2-yl)acetamide
D-(-)Threo isomer
3
Dr Eman R. El-Bendary
2-2008
Stereochemistry of chloramphenicol
OH
OH
(R)
(R)
O
OH
HO
O-
NH
O
O
Cl
Cl
OH
(S)
OH
(S)
HO
O
O-
NH
+
N
Cl
4
O-
NH
N+
Cl
HO
(S)
N+
The active isomer
Cl
O
(R)
O
(S)
(R)
O-
NH
N+
O
Cl
Dr Eman R. El-Bendary
Cl
2-2008O
Cl
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.
OH
OH
(R)
• 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.
5
O
(R)
O-
NH
N+
O
Cl
Dr Eman R. El-Bendary
Cl
2-2008
Structure Activity Relationship
OH
• Replacement of nitro
group by other electron
withdrawing groups
gives active compounds
as
CH3SO2 (Thiamphenicol)
or CH3CO (Cetophenicol)
OH
(R)
(R)
O
NH
SO2CH3
Cl
Cl
Thiamphenicol
OH
OH
(R)
O
(R)
NH
COCH3
6
Cl
Dr Eman R. El-Bendary
Cl
Cetophenicol
2-2008
Metabolism of Chloramphenicol
OH
OH
(R)
COOH
(R)
OH
OH
O
O
OH
O
OH
NH
(R)
OH
(R)
O
O-
NH2
(R)
O-
NH
N+
O
Cl
(R)
NH2
OH
Cl
Cl
N+
OH
OH
O
(R)
(R)
Cl
C-3 glucuronide conjugate
O
O-
NH
N+
Major metabolite
O
OH
OH
(R)
Cl
OH
OH
Cl
Chloramphenicol
(R)
O-
O
O
+
O-
NH
N
+
N
O
O
O
7
Cl
Dr Eman R. El-Bendary
2-2008
Bacterial Resistance
OH
OCOCH3
(R)
(R)
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.
O
O-
NH
N+
O
Cl
Cl
1-Acetoxy derivative
OCOCH3 OH
(R)
O
(R)
O-
NH
N+
O
Cl
8
Dr Eman R. El-Bendary
Cl
3- Acetoxy derivative
2-2008
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.
O
O
N+
N+
O-
O-
HO
HO
Esterase Enzyme
NH
NH
O
O
OH
Cl
O
Cl
(CH2)14COOH Cl
Chloramphenicol
Chloramphenicol palmitate
9
Cl
O
Dr Eman R. El-Bendary
2-2008
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.
Cl
Cl
O
Cl
Cl
N+
O
-
N+
-
O
HN
O
O
O
HN
Esterase Enzyme
O
OH
O
OH
OH
OH
O
Chloramphenicol
Chloramphenicol succinate ester
10
Dr Eman R. El-Bendary
2-2008
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.
11
Dr Eman R. El-Bendary
2-2008
12
Dr Eman R. El-Bendary
2-2008