TITLE LOREM

IPSUM

PART 2
1. Lead Compound
O O
N S O Metabolism H2N S O
H2N N NH2 NH2

Prontosil
Prontosil Sulphanilamide
Sulfanilamide
NH2

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
2. Structure-Activity Relationships
Aromatic
para-Amino
group O Sulphonamide
1
R HN S 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
3. Prodrugs of sulphonamides
O
- CH3CO2H O
HN S O H2N S O
Me NHR2 Enzyme
NHR2
O
Prodrug Sulphonamide

Notes
•Amide group lowers the polarity of the sulphonamide
•Amide cannot ionize
•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
 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 pharmacodynamics
 5. Sulphanilamides - applications

Notes
•Antibacterial drugs of choice before penicillins (1930s)
•Superseded by penicillins

Current uses
•Treatment of urinary tract infections
•Eye lotions
•Treatment of gut infections
•Treatment of mucous membrane infections
6. Mechanism of action
H2N N N
H2N N N H2N CO2H
H
para-Aminobenzoic acid HN N
HN OP P N
N Dihydropteroate synthetase H
H O
O _ Reversible CO2H
inhibition
Dihydropteroate
Sulphonamides

H2N N

H
H2N CO2H HN N
N
H CO2H H H
O N CO2H
L-Glutamic acid
Dihydrofolate
H CO2H
O

Dihydrofolate
H reductase Trimethoprim
H2N N _
NADPH
H
HN N
N
H H
O N CO2H

Tetrahydrofolate H CO2H
(coenzyme F) O
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
6. Mechanism of action

Binding interactions

PABA O Sulphonamides O
H2N C H2N S NR
O O

Active site Active site

Binding interactions for PABA Binding interactions for sulphonamides

H-Bond
van der Waals
interactions
Ionic bond
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

7. Sulphonamides - Drug Metabolism

O O
H2N S O N HN S O N
N-Acetylation
HN Me C HN
S O S

Sulphathiazole Insoluble metabolite

Notes
•Sulphonamides are metabolized by N-acetylation
•N-Acetylation increases hydrophobic character
•Reduces aqueous solubility
•May lead to toxic side effects
8. Sulphonamides with reduced toxicity

O O
H2N S O N H2N 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

O
O pKa 6.48
H2N S O N
H2N S O N
N
HN
N
N 86% Ionized
 9. Examples of Sulphonamides

Sulphadoxine
O
H2N S O N
HN N

MeO OMe

•Belongs to a new generation of sulphonamides

•Long lasting antibacterial agent
•Once weekly dosing regime
•Sulphadoxine + pyrimethamine = Fansidar
•Used for the treatment of malaria

N NH2
H3C
N
Pyrimethamine

NH2
Cl
9. Examples of Sulphonamides

Succinyl sulphathiazole

O
O HO2C
H2N S O N
HN S O N Enzyme
HN
HN
CO2H S
O2C O S

Succinyl sulphathiazole 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
9. Examples of Sulphonamides

Benzoyl prodrugs

O
OH O
HN S O
C H2N S O
C NHR2
O NHR2
O

Benzoyl prodrug Benzoic acid Sulphonamide

•Too hydrophobic to cross gut wall

•Slowly hydrolysed by enzymes in gut
•Used versus gut infections
 9. Examples of Sulphonamides

NH2
N
H2N O
N O Me
H2N S
OMe HN
O
N
MeO OMe

Trimethoprim Sulphamethoxazole

•Sulphamethoxazole + trimethoprim = cotrimoxazole

•Agents inhibit different enzymes in same biosynthetic
pathway
•Strategy of sequential blocking
•Allows lower, safer dose levels of each agent
10. Sulphones

NH2
N O
H2N S O

NHR1

•Thought to inhibit dihydropteroate

synthetase
•Used in the treatment of leprosy