SAR of Penicillin

The Structure-Activity Relationship (SAR) of penicillin reveals key insights into how modifications in its chemical structure affect its pharmacological properties. From variations in the 6-acyl side chain to the substitution patterns on the α-carbon and modifications of the thiazolidine ring, each alteration can significantly impact the antimicrobial activity, stability, and resistance profile of penicillin derivatives.

1. 6-Acyl Side Chain:

  • Substitution of R on the primary amine with an electron-withdrawing group decreases electron density and protects from acid degradation.
  • Substituents on the α-carbon, like amino, chloro, and guanidine, resist acid inactivation.
  • Benzylpenicillin is susceptible to acid and alkali degradation and known β-lactamases.
  • Varying the acyl amino side chain results in superior biological activity.
  • Substitution of α-aryl increases stability and oral absorption.

2. Bulky Groups on α-Carbon:

  • Confers β-lactamase resistance.
  • Examples: methicillin, nafcillin, oxacillin.
  • Attachment of an aromatic ring directly to the side chain amide carbonyl, with substitution at ortho positions, is crucial.
  • Size of the aromatic ring system affects penicillinase resistance.

3. Isomeric Forms:

  • D-isomer is 2–8 times more active than L-isomer of amoxicillin.
  • Introduction of polar or ionized groups into the α-position of the side chain confers activity against gram-negative bacilli.
  • Amino, hydroxyl, carboxyl, and sulfonyl groups increase gram-negative activity.
  • Examples: ampicillin and carbenicillin.

4. Replacement of Acyl Side Chain:

  • Substituting acyl side chain with hydroxymethyl groups improves gram-negative activity.
  • Introduction of C-6 α-methoxy group increases stability against β-lactamase.
  • N-acylated ampicillins (ureidopenicillins) show increased activity against Pseudomonas.

5. Ester Derivatives:

  • Esterification of carboxyl group at C-3 enhances lipophilicity and acid stability.
  • Examples: Acetoxymethyl ester derivatives used as prodrugs.

6. Thiazolidine Ring Modifications:

  • Replacing sulphur with O, CH, and CH-β-CH3 provides broad-spectrum antibacterial activity.
  • Geminal dimethyl group at the C-2 position is characteristic.
  • Doubly activated penicillin esters rapidly cleavage in vivo to generate active penicillin.
  • Examples: pivampicillin, bacampicillin.

7. In Vitro Degradation:

  • pH between 6.0 and 8.0 retards in vitro degradation.
  • More lipophilic side chains increase plasma protein binding.
  • Examples: Ampicillin (25% plasma protein bound), phenoxy methyl penicillin (75% plasma protein bound).

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