Sulfamethoxazole: Chemical Structure, Mechanism of Action, SAR, Synthesis, Uses & Side effects

Chemical formula:

• C10H11N3O3S

Structure of Sulfamethoxazole

Mechanism of action:

• Sulfamethoxazole inhibits bacterial dihydropteroate synthase, blocking the synthesis of folate and leading to bacterial cell death.

Structure-Activity Relationship (SAR) of Sulfamethoxazole

1.Sulfonamide Group:

• Central to sulfamethoxazole's antibacterial activity is its sulfonamide group (-SO₂NH₂). This group is essential for inhibiting bacterial dihydropteroate synthase, a key enzyme in folic acid synthesis.

2.Para-Aminobenzoic Acid (PABA) Analogue:

• Sulfamethoxazole acts as a competitive inhibitor of PABA, a substrate for dihydropteroate synthase, due to its structural similarity. The effective mimicry of PABA is crucial for the drug's mechanism of action.

3.Methoxy Group:

• The presence of a methoxy group (-OCH₃) at the 5-position of the benzene ring enhances the drug's efficacy. This modification increases its lipid solubility, thereby improving tissue penetration.

4.Isopropyl Group:

• An isopropyl group at the 4-position of the benzene ring distinguishes sulfamethoxazole from other sulfonamides and contributes to its unique antibacterial profile.

Structure Activity Relationship of Sulfamethoxazole

Synthesis of Sulfamethoxazole

The synthesis of Sulfamethoxazole generally involves:

1.Synthesis of 3-Amino-5-methylisoxazole:

• The synthesis starts with the formation of 3-amino-5-methylisoxazole. This can be achieved by condensing hydroxylamine with acetoacetamide, followed by cyclization:

• Hydroxylamine + Acetoacetamide → 3-Amino-5-methylisoxazole

2.Sulfonation:

• The next step involves the introduction of the sulfonamide group. This is typically done by reacting the 3-amino-5-methylisoxazole with chlorosulfonic acid or sulfonic acid chloride:

• 3-Amino-5-methylisoxazole + Chlorosulfonic Acid → Sulfamethoxazole3-Amino-5-methylisoxazole + Chlorosulfonic Acid → Sulfamethoxazole

Uses:

• Sulfamethoxazole is often used in combination with trimethoprim (as co-trimoxazole) for the treatment of various bacterial infections, including urinary tract infections, respiratory infections, and gastrointestinal infections. It is also used for the prevention and treatment of Pneumocystis jiroveci pneumonia in immunocompromised patients.

Side effects:

• Common side effects include gastrointestinal disturbances (nausea, vomiting, diarrhea), rash, and hypersensitivity reactions. Rarely, it may cause blood dyscrasias, kidney disorders like crystalluria or interstitial nephritis, and liver toxicity.