Sulfonamides: Antibacterial Sulfa Drugs

1. Introduction and History

• Sulfonamides are a group of synthetic antibacterial drugs, with a basic structure consisting of a sulfamido group (-SO2NH2) attached to an aromatic ring, usually a benzene ring.

• Prontosil (a red dye containing a sulfamido group) was discovered in 1935, becoming the first antibacterial drug.

• Prontosil was poorly soluble in water, prompting scientists to introduce a -COOH group into its structure to create more soluble sulfonamide derivatives.

• Sulfonamides have a wide range of applications in medicine, from treating respiratory and urinary tract infections to managing dermatological conditions.

2. Structure and Pharmacodynamics

• Structure-activity relationship:

• N at position 4 (N4): Essential for activity:

• Para position on the aromatic ring

• Un-substituted and free

• Directly attached to the aromatic ring

• Benzene ring: Necessary for interaction with bacterial enzymes.

• Sulfamido group: Key to antibacterial activity.

• Exception: Sulfamilon is a sulfonamide derivative where N4 isn’t directly attached to the benzene ring but still exhibits activity.

• Sulfonamide derivatives without an NH2 group: These possess activity but through a different mechanism. Examples: Chloramine T, Chloramine B.

• Replacing the benzene ring: Diminishes or eliminates activity; may result in different effects.

• Replacing the sulfamido group: Reduces or eliminates activity.

• Substitution on the benzene ring: Decreases or eliminates activity.

• Substitution on the sulfamido group: Replacing H with another substituent generally diminishes or eliminates activity. However, substitution with a heterocycle often results in improved activity.

3. Synthesis

• Three main methods for sulfonamide synthesis:

• From aniline:

• Protect the NH2 group through acetylation ((CH3CO)2O), formylation (HCOOH), or urethanization (ClCOOC2H5).

• Sulfonate with chlorosulfonic acid (HO-SO2Cl).

• Introduce the sulfamido group using NH3 or RNH2.

• From chlorobenzene:

• Reaction with a pre-existing sulfonamide.

• From existing sulfonamides:

• Substitution reactions to create new sulfonamide derivatives.

4. Physical Properties

• Low solubility in: water, benzene, chloroform.

• Soluble in: alcohol, glycerin, acetone.

• Amphoteric nature: Sulfonamides are amphoteric, capable of reacting with both acids and bases.

5. Characteristic Reactions

• Diazotization: Reaction forming diazonium salts, useful for quantification.

• Substitution reaction of the benzene ring with Br2: Reaction producing brominated substitution products.

• Reaction with p-aminobenzaldehyde (PDAB): This reaction results in color formation, used for qualitative and quantitative analysis of sulfonamides.

6. Quantitative Methods

• Nitrite determination method: Used for the NH2 group.

• Color formation method with PDAB: Color comparison for quantification.

• Acid-base method:

• Used for most sulfonamides, based on their weak acidity.

• Solvent: dimethylformamide.

• Standard: sodium methylate.

• Indicator: thymol blue.

• NH2: weak base, requires anhydrous acetic acid environment.

• Standard: HClO4.

• Indicator: crystal violet.

• Precipitation with Ag: Used for certain sulfonamides.

7. Pharmacokinetics

• Absorption: Rapid absorption through the gastrointestinal tract, except for phthalylsulfathiazole and sulfaquanidine (for intestinal infections).

• Distribution: Crosses the blood-brain barrier and placenta, reaching the fetus.

• Metabolism:

• Protein binding: Prevents sudden increases in sulfonamide levels in plasma, prolonging action.

• Acetylation: Occurs in the liver, forming poorly soluble acetylated derivatives prone to crystallization in the kidneys.

• Sulfamethoxypyridazine: low acetylation.

• Sulfadiazine: relatively easily acetylated.

• Glucuronide conjugation: Forms a derivative with activity, highly soluble, used in urinary tract infections.

• Excretion: Primarily excreted through urine.

• Note: The solubility of acetylsulfonamide increases at alkaline urine pH. Therefore, when using sulfonamides, drink plenty of water and supplement with NaHCO3.

8. Antibacterial Spectrum

• Broad antibacterial spectrum:

• Staphylococci, streptococci, pneumococci, meningococci, Shigella, Salmonella, E. coli…

9. Mechanism of Action

• Competition with PAB:

• PAB (p-aminobenzoic acid) is a constituent of folic acid, essential for bacterial replication.

• Sulfonamides compete with PAB according to the mass law, inhibiting folic acid synthesis and bacterial growth.

• Limitation: This hypothesis doesn’t explain antagonism between sulfonamides and some structures not resembling sulfonamides.

• Note: Maximal bacterial inhibition occurs when the pKa of the sulfonamide is close to the environmental pH (7).

• Sulfathiazole (pKa 6.8) > Sulfadiazine (pKa 6.4) > Sulfanilamide (pKa 10.5).

10. Bacterial Resistance Mechanisms

• Increased PAB production: Increasing PAB levels to compete with sulfonamides.

• Efficient PAB utilization: Bacteria modify enzymes to use PAB more efficiently.

• Finding alternative metabolic pathways: Bacteria find different pathways for folic acid biosynthesis.

• Inactivation of sulfonamides: Bacteria produce enzymes to convert sulfonamides into inactive forms.

11. Toxicity

• Hematopoietic system disorders:

• Independent of concentration.

• Linked to glucose-6-phosphate dehydrogenase activation.

• Kidneys: Damage, nephritis, kidney stones, hematuria.

• Seek less acetylated, less crystallizing sulfonamides to minimize toxicity.

• Hypersensitivity reactions: More frequent with slow-acting sulfonamides.

12. Classification

• Two groups: Systemic + topical.

• Three groups: Rapid, slow, intermediate.

13. Typical Sulfonamide Derivatives

• Rapid-acting sulfonamides:

• Sulfanilamide: Highly toxic, readily acetylated, used only as raw material.

• Sulfapyridine: Many acetylated derivatives are poorly soluble, prone to crystallization.

• Sulfasalazine: A prodrug, inactive, metabolized by bacteria into 5-aminosalicylic acid + sulfapyridine.

• Treats ulcerative colitis, with both local and systemic effects.

• Side effect: decreased sperm count.

• Sulfathiazole: Less toxic, rapidly absorbed, effective against staphylococci, gonococci, pneumococci, and meningococci.

• Sulfadiazine: Similar to sulfathiazole but weaker in vitro, stronger in vivo, and less toxic.

• Slow-acting sulfonamides:

• Sulfadimethoxine: Rapidly absorbed, slowly excreted, less acetylated, less prone to crystallization.

• Sulfamethoxypyridazine: Very slow excretion, disadvantageous in treating overdose.

• Sulfadoxin: Very slow excretion, administered 1g/week.

• Combined with pyrimethamine => Fansidar => treats malaria.

• Intermediate-acting sulfonamides:

• Sulfamethoxazole: Combined with trimethoprim => Bactrim => effective against typhoid fever, pneumonia, otitis media.

• Sulfacetamide: Easily absorbed, readily excreted, short-acting, used as eye drops, treating trachoma.

• Sulfamethizole: The best sulfonamide for treating urinary tract infections caused by E. coli.

• Sulfaguanidine: Not absorbed in the intestine, less toxic, administered in high doses, taken with digestive enzymes + vitB1.

• Phthalylsulfathiazole: Acts in vivo, treats dysentery and enteritis.

• Administered with vitB1, vitK due to increased clotting time.

• Succinyl sulfathiazole: Similar to phthalylsulfathiazole.

• Topical sulfonamides:

• Sulfanilamide, sulfadiazine: In the form of ointments, powders.

• Topical sulfonamides, unaffected by PAB:

• Sulfamilon:

Note:

• All slow-acting sulfonamide derivatives contain a CH3O group.

• Sulfanilamide: Not used clinically due to high toxicity.

• Sulfasalazine: Side effect of reduced sperm count.

• Sulfathiazole: Most effective in treating infections caused by staphylococci, gonococci, pneumococci, and meningococci.

• Sulfadoxin: Administered in low doses, very slow excretion.

• Phthalylsulfathiazole: Only acts in vivo, so it should be taken with vitamin B1 and K.

• Sulfamilon: Unaffected by PAB, specifically used topically.

Conclusion:

Sulfonamides are an important group of antibacterial drugs in medicine, used widely for decades. However, the development of drug-resistant bacteria has reduced their effectiveness. Scientists are researching to develop new sulfonamide derivatives that are more effective, less toxic, and more resistant to resistance.