Download sulphonamides

Introduction
• WHO; Tuberculosis in 2002, 2,000,000
death, 1/3 of the world’s population was
infected.
• 1,900,000 children died worldwide of
respiratory infections with 70% of these
deaths in Africa and Asia.
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History of antibacterial agents
•
•
•
•
Old age
Mouldy soybean curd in Chinese
Wine, myrrh, inorganic salts in Greek
Certain type of honey in Middle age.
Identification of bacteria : van Leeuwenhoek in 1670s
Fermentation by microorganism: Pasteur
Germ theory of disease : Lister
The reason of tuberculosis is microorganism, vaccination: Koch
The principle of chemotherapy; Ehrlich’s
Magic bullet, selective toxicity, chemotherapeutic index,
therapeutic index.
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© Oxford University Press, 2013
Classification of bacteria :
Appendix 5
Difference of bacterial and
animal cells
- defined nucleus
-Organelles
-Biochemistry, e.g. vitamin
synthesis
-Cell wall, osmotic pressure,
lysis
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Five main mechanisms of antibacterial action
1.Inhibition of cell metabolism: sulphonamide
2.Inhibition of bacterial cell wall synthesis : penicillin, cephalosporins,
cycloserine, vancomycin
3.Interactions with the plasma membrane: polymyxins, tyrothricin
4.Disruption of protein synthsis: rifamycins, streptomycin, tetracyclines,
chloramphenicol
5. Inhibitions of nucleic acid transcription and replication: nalidixic acid,
proflavin, quinolones, aminoacridines
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SULPHONAMIDES
O
R1HN
S
O
NHR2
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1. Lead Compound
O
O
N
H2N
S
N
NH2
O
NH2
Pront osi l
Metabol i sm
H2N
S
O
NH2
Sul fani l ami de
Notes
•Prontosil - red dye
•Antibacterial activity in vivo (1935)
•Inactive in vitro
•Metabolised to active sulphonamide
•Acts as a prodrug
•Sulphanilamide - first synthetic antibacterial agent acting on a
wide range of infections
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2. Structure-Activity Relationships
para-Amino
group
R1HN
Aromatic
O
S
Sulphonamide
O
NHR2
•Primary amino group is essential (R1=H)
•Amide groups (R1=acyl) are allowed
•inactive in vitro, but active in vivo
•act as prodrugs
•Aromatic ring is essential
•para-Substitution is essential
•Sulphonamide group is essential
•Sulphonamide nitrogen must be primary or secondary
•R2 can be varied
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3. Prodrugs of sulfonamides
O
HN
S
2
Me
O
- CH3CO2H
O
NHR
Enzyme
H2N
S
O
NHR2
O
Notes
•Amide group lowers the polarity of the sulphonamide
•Amide cannot ionise
•Alkyl group increases the hydrophobic character
•Crosses the gut wall more easily
•Metabolised by enzymes (e.g. peptidases) in vivo
•Metabolism generates the primary amine
•Primary amine ionises and can form ionic interactions
•Ionised primary amine also acts as a strong HBD
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4. Sulphanilamide analogues
O
R1HN
S
O
NHR2
Notes
•R2 is variable
•Different aromatic and heteroaromatic rings are allowed
•Affects plasma protein binding
•Determines blood levels and lifetime of the drug
•Affects solubility
•Affects pharmacokinetics rather than pharmacodynamices
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5. Sulphanilamides - applications
Notes
•Antibacterial drugs of choice prior to penicillins (1930s)
•Superseded by penicillins
Current uses
•Treatment of urinary tract infections
•Eye lotions
•Treatment of gut infections
•Treatment of mucous membrane infections
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6. Mechanism of action
H2N
N
H2N
N
H2N
CO2H
OP P
N
H
O
N
H
N
HN
para-Aminobenzoic acid
HN
N
N
H
Dihydropteroate synthetase
_
Reversible
O
CO2H
inhibition
Dihydropteroate
Sulphonamides
H2N
H2N
H
CO2H
N
N
H
N
HN
N
H
CO2H
H
N
O
L-Glutamic acid
CO2H
Dihydrofolate
O
H2N
N
H
Dihydrofolate
reductase
NADPH
H
N
CO2H
Trimethoprim
_
H
N
HN
N
H
O
Tetrahydrofolate
(coenzyme F)
H
N
O
H
CO2H
CO2H
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6. Mechanism of action
Target enzyme
•Dihydropteroate synthetase - bacterial enzyme
•Not present in human cells
•Important in the biosynthesis of the tetrahydrofolate cofactor
•Cofactor is crucial to pyrimidine and DNA biosynthesis
•Crucial to cell growth and division
Sulphonamides
•Competitive enzyme inhibitors
•Bacteriostatic agents
•Not ideal for patients with weakened immune systems
•Mimic the enzyme substrate - para-aminobenzoic acid (PABA)
•Bind to the active site and block access to PABA
•Reversible inhibition
•Resistant strains produce more PABA
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6. Mechanism of action
Binding interactions
O
H2 N
O
C
H2 N
O
S
NR
O
Active site
Active site
H-Bond
van der Waals
interactions
Ionic bond
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6. Mechanism of action
Metabolic differences between bacterial and mammalian cells
Dihydropteroate synthetase is present only in bacterial cells
Transport protein for folic acid is only present in mammalian cells
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7. Sulphonamides - Drug Metabolism
O
H2N
S
O
O
N
N-Acetylation
HN
S
Sulphathiazole
Me
HN
S
C
HN
O
N
S
O
Insoluble metabolite
Notes
•Sulphonamides are metabolised by N-acetylation
•N-Acetylation increases hydrophobic character
•Reduces aqueous solubility
•May lead to toxic side effects
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8. Sulfonamides with reduced toxicity
O
O
H2N
S
O
H2 N
N
S
O
N
HN
HN
S
N
Sulphathiazole
Sulphadiazine
Notes
•Thiazole ring is replaced with a pyrimidine ring
•Pyrimidine ring is more electron withdrawing
•Sulphonamide NH proton is more acidic and ionisable
•Sulphadiazine and its metabolite are more water soluble
•Reduced toxicity
•Silver sulphadiazine is used topically to prevent infection of burns
H2 N
S
O
pKa 6.48
O
O
N
HN
N
H2N
S
O
N
N
N
86% I oni zed
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9. Examples of Sulphonamides
Sulphadoxine
O
H2 N
S
O
N
HN
N
MeO
OMe
•Belongs to a new generation of sulphonamides
•Long lasting antibacterial agent
•Once weekly dosing regime
•Sulphadoxine + pyrimethamine = Fanisdar
•Used for the treatment of malaria
N
NH2
H3C
N
Cl
Pyrimethamine
NH2
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9. Examples of Sulphonamides
Succinyl sulphathiazole
O
O
HN
S
HO2C
O
N
HN
O2C
O
Succinyl sulphathiazole
S
H2N
Enzyme
S
O
N
HN
CO2H
S
Succinic acid
Sulphathiazole
Notes
•Acts as a prodrug of sulphathiazole
•Ionised in the slightly acidic conditions of the intestine
•Too polar to cross the gut wall
•Concentrated in the gut
•Slowly hydrolysed by enzymes in the gut
•Used versus gut infections
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9. Examples of Sulphonamides
Benzoyl prodrugs
O
HN
S
NHR2
C
H2N
C
S
Benzoic acid
O
NHR2
O
O
Benzoyl prodrug
O
OH
O
Sulphonamide
•Too hydrophobic to cross gut wall
•Slowly hydrolysed by enzymes in gut
•Used versus gut infections
© Oxford University Press, 2013
9. Examples of Sulphonamides
NH2
N
O
H2N
H2N
N
OMe
S
O
Me
HN
N
MeO
Trimethoprim
O
OMe
Sulphamethoxazole
•Sulphamethoxazole + trimethoprim = co-trimoxazole
•Agents inhibit different enzymes in same biosynthetic pathway
•Strategy of sequential blocking
•Allows lower, safer dose levels of each agent
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10. Sulphones
NH2
N
H2N
O
S
O
N
NHR1
•Thought to inhibit dihydropteroate synthetase
•Used in the treatment of leprosy
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