Untitled Quiz

Discovery of Sulfonamides

• Sulfonamides are synthetic compounds active against gram-positive and gram-negative bacteria.
• Initially synthesized as azo dyes in Germany, aiming to create antimicrobial dyes.
• Gerhard Domagk (1895-1964) discovered the antibacterial effects of Prontosil, a precursor to sulfanilamide, winning a Nobel Prize in 1939.

Folic Acid Inhibitors

• Prontosil, initially, is inactive in vitro, but highly active in vivo.
• Prontosil breaks down to release the active ingredient, sulfanilamide.
• Sulfanilamide is a first synthetic antibacterial agent.
• Sulfonamides are competitive inhibitors of dihydropteroate synthetase.
• They inhibit the bacterial enzyme that produces folic acid.
• This is crucial because bacteria, unlike humans, must synthesize folic acid for vital metabolic processes.

Mechanism of Action

• Sulfonamides resemble the structure of a substrate called para-aminobenzoic acid (PABA).
• They compete with PABA for an enzyme’s active site.
• Bacteria can't use the sulfonamide, instead it inhibits the bacterial enzyme which prevents bacteria from using folic acid.
• Resistance can emerge by bacteria producing more PABA.

Structure-Activity Relationships (SAR)

• Aromatic rings are crucial for activity.
• Changes in the structure of the aromatic rings and aromatic groups can affect the potency of the compound.
• The para position on the aminobenzoic acid is critical.
• Substituents in the para-position affect the compounds activity.
• The group at the 4 position of the structure is critical for solubility and potency.
• Sulfonamide nitrogen must be primary or secondary for activity.

Prodrugs

• Some sulfonamides are prodrugs, meaning they are inactive in their original form but are converted into active metabolites inside the body.
• N-acetylation is a common metabolic step that increases the hydrophobic nature of some sulfonamide analogs.

Side Effects

• Sulfonamides can cause kidney damage as they form crystals in the urine.
• To reduce side effects, patients should drink a lot of water, and the pH of the urine can be adjusted.