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Sulfonamides and Sulfones

Introduction

  • Sulfonamides and sulfones are antimicrobial agents that inhibit bacterial growth by targeting folic acid synthesis, a crucial pathway for bacterial survival.

Historical Development

  • Sulfonamides were the first synthetic antibacterial agents, discovered in the 1930s.

  • Sulfones, like Dapsone, emerged later and became essential for treating leprosy and other bacterial infections.

Chemistry & Structure-Activity Relationship (SAR)

  • Sulfonamides contain a sulfonyl functional group (-SO₂NH₂) attached to an aromatic ring, crucial for antibacterial activity.

  • Modifications in the R-groups affect solubility, potency, and spectrum of activity.

  • They act as competitive inhibitors of dihydropteroate synthase, blocking folic acid synthesis.

Classification of Sulfonamides (Antibacterial Agents)

Classification of Sulfonamides (Antibacterial Agents)

1) Short-acting Sulfonamides

  • Sulphamethizole

  • Sulfisoxazole

2) Intermediate-acting Sulfonamides

  • Sulphapyridine

  • Sulphamethizine

  • Sulfacetamide

  • Sulfamethoxazole

  • Sulphadiazine

3) Topical Sulfonamides

  • Mafenide acetate

4) Anti-inflammatory Sulfonamides

  • Sulfasalazine (used for inflammatory bowel disease and rheumatoid arthritis)

SAR of Sulfonamides (Generalized class overview)

Structural Feature

SAR Insight

p-Amino group

Essential for PABA mimicry and enzyme binding. Acetylation/inactivation reduces activity.

Sulfonamide (-SO₂NH₂) group

Key for competitive inhibition of dihydropteroate synthase.

Aromatic ring

Required for optimal fit; substitutions can affect potency.

N¹-substitution (alkyl, aryl)

Modifies absorption, protein binding, and half-life.

Electron-withdrawing groups

May increase activity by stabilizing molecule/enzyme complex.

Classification of Folate Reductase Inhibitors (Potentiators of Sulfonamides)

  • These inhibit dihydrofolate reductase (DHFR), preventing bacterial DNA synthesis.

    • Trimethoprim

    • Cotrimoxazole (Combination of Sulfamethoxazole + Trimethoprim)

Classification of Sulfones (Antileprotic and Antibacterial Agents)

  • Dapsone (Used in leprosy, Pneumocystis pneumonia, and dermatitis herpetiformis)

Mechanism of Action

  • Sulfonamides act as competitive inhibitors of dihydropteroate synthase, preventing folic acid synthesis.

  • Folate reductase inhibitors (Trimethoprim, Cotrimoxazole) block dihydrofolate reductase, enhancing the antibacterial effect.

  • Sulfones, like Dapsone, have a similar mechanism but are primarily used for leprosy and certain bacterial infections.


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