SULFONAMIDES
Chapter 19
O
1
R HN
S
O
NHR2
Lead Compound
O
O
N
H2N
S
N
NH2
O
Metabolism
H2N
S
NH2
NH2
Prontosil
O
Sulfanilamide
Notes
•Prontosil - red dye
•Antibacterial activity in vivo (1935)
•Inactive in vitro
•Metabolised to active sulfonamide
•Acts as a prodrug
•Sulfanilamide - first synthetic antibacterial agent acting on a wide range of infections
Structure-Activity Relationships
para-Amino
group
R1HN
Aromatic
O
S
Sulfonamide
O
NHR2
•para-Amino group is essential (R1=H)
•para-Amido groups (R1=acyl) are allowed
•inactive in vitro, but active in vivo
•act as prodrugs
•Aromatic ring is essential
•para-Substitution is essential
•Sulfonamide group is essential
•Sulfonamide nitrogen must be primary or secondary
•R2 can be varied
Prodrugs of sulfonamides
O
HN
S
NHR2
Me
O
- CH3CO2H
O
Enzyme
O
Notes
•Amide group lowers the polarity of the sulfonamide
•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 ionizes and can form ionic interactions
•Ionised primary amine also acts as a strong HBD
H2N
S
O
NHR2
Sulfanilamide 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
Sulfanilamides - 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•Superseded by penicillins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
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
Sulfonamides
H2N
H2N
H
CO2H
CO2H
N
N
H
N
HN
N
H
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
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
Sulfonamides
•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
Mechanism of action
Binding interactions
H2 N
O
H2 N
C
O
Active site
Active site
H-Bond
van der Waals
interactions
Ionic bond
O
S
O
NR
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
Sulfonamides - Drug Metabolism
O
O
H2N
S
O
N
N-Acetylation
HN
S
Me
HN
S
C
HN
O
S
O
Sulfathiazole
Notes
•Sulfonamides are metabolised by N-acetylation
•N-Acetylation increases hydrophobic character
•Reduces aqueous solubility
•May lead to toxic side effects
N
Insoluble metabolite
Sulfonamides with reduced toxicity
O
H2N
S
O
O
H2N
N
HN
S
O
N
HN
S
N
Sulfathiazole
Sulfadiazine
Notes
•Thiazole ring is replaced with a pyrimidine ring
•Pyrimidine ring is more electron-withdrawing
•Sulfonamide NH proton is more acidic and ionizable
•Sulfadiazine and its metabolite are more water soluble
•Reduced toxicity
•Silver sulfadiazine is used topically to prevent infection of burns
H2N
S
O
pKa 6.48
O
O
N
HN
N
H2N
S
O
N
N
N
86% Ionized
Examples of Sulfonamides
Sulfadoxine
O
H2N
S
O
N
HN
N
MeO
OMe
•Belongs to a new generation of sulfonamides
•Long lasting antibacterial agent
•Once weekly dosing regime
•Sulfadoxine + pyrimethamine = Fanisdar
•Used for the treatment of malaria
N
NH2
H3C
N
Cl
NH2
Pyrimethamine
Examples of Sulfonamides
Succinyl sulfathiazole
O
O
HN
S
HO2C
O
N
H2N
Enzyme
O
Succinyl sulfathiazole
S
O
N
HN
HN
O2C
S
CO2H
Succinic acid
Notes
•Acts as a prodrug of sulfathiazole
•Ionized in the alkaline conditions of the intestine
•Too polar to cross the gut wall
•Concentrated in the gut
•Slowly hydrolysed by enzymes in the gut
•Used for gut infections
S
Sulfathiazole
Examples of Sulfonamides
Benzoyl prodrugs
O
HN
S
•Too hydrophobic to cross gut wall
•Slowly hydrolyzed by enzymes in gut
•Used for gut infections
S
Benzoic acid
O
NHR2
O
O
Benzoyl prodrug
H2N
C
NHR2
C
O
OH
O
Sulfonamide
Examples of Sulfonamides
NH2
N
O
H2N
H2N
N
OMe
S
O
Me
HN
N
MeO
Trimethoprim
O
OMe
Sulfamethoxazole
•Sulfamethoxazole + trimethoprim = co-trimoxazole
•Agents inhibit different enzymes in same biosynthetic pathway
•Strategy of sequential blocking
•Allows lower, safer dose levels of each agent
Sulfones
NH2
N
H2N
O
S
O
N
NHR1
•Thought to inhibit dihydropteroate synthetase
•Used in the treatment of leprosy