• Penicillin G and Penicillin V

  • Penicillin overview

    • Penicillin G (2D)

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      Penicillin G (3D)

       

    • Penicillin V (2D)

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      Penicillin V (3D)

     

    • Penicillins, and all β-lactam antibiotics, are defined by their unique chemical architecture.

      • The core of the penicillin molecule is a bicyclic system known as the penam nucleus. ^1,2  This structure consists of a highly strained, four-membered ring called a β-lactam ring, which is fused to a five-membered thiazolidine ring. ^1,2  

      • The β-lactam ring, a cyclic amide where the nitrogen atom is attached to the β-carbon relative to the carbonyl group, is the critical functional moiety responsible for the antibiotic's bactericidal activity.³

        • The inherent ring strain of this structure makes it chemically reactive and susceptible to nucleophilic attack, a property that is central to its mechanism of action.⁴

        • Penicillin Structure⁴

          Attribution The beta-lactam ring is essential for penicillin activity.4  The carbon atom C of the lactam C=O is very susceptible to nucleophilic attack. The carboxylic acid moiety contributes to the binding of penicillin to the active site of the transpeptidase enzyme. The reactivity of the beta-lactam ring results in penicillin being susceptible to inactivation following nucleophilic acyl substitution reactions, forming a penicilloic acid. This form does not exhibit antibiotic activity. Enhancement of penicillin stability may be accomplished by electron-withdrawing substituents at the side chain. The effect of the substitution is to make the amide carbonyl less reactive.4 An example of this effect can be illustrated using the to antibiotics under present consideration, Penicillin G and Penicillin V. Penicillin G and Penicillin V: Basis of Differences in Drug Stability when exposed to Stomach Acid4 Note the additional oxygen associated with Penicillin V (green). This oxygen has the effect of decreasing nucleophilicity of the amide carbonyl group, reducing its reactivity with the internal beta-lactam ring. A consequence of addition of this oxygen (green) is that Penicillin G is sufficiently stable in the acidic stomach environment such that this medication may be orally administered. By contrast, lacking this oxygen, Penicillin V can not maintain its structure in the acidic stomach environment and therefore must be administered by the intravenous route of administration. The top figure is a slight modification of the first figure in reference 4; whereas the second figure above corresponds to the fourth figure in reference 4, Noted below. Futurelearn Mode of Action of Penicillin. https://www.futurelearn.com/info/courses/everyday-chemistry/0/steps/22314 Future Learn:  https://www.futurelearn.com/

        • Variations in the acyl side chain attached at the 6-position of this 6-aminopenicillanic acid core determine the specific characteristics of each penicillin, including its antimicrobial spectrum, stability, and susceptibility to bacterial resistance mechanisms.^5,6  

    • Penicillin G: Structure

      • Chemically definition(2S,5R,6R)-3,3-dimethyl-7-oxo-6-[(2-phenylacetyl)amino]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid.^7,9  

        • Its empirical formula is C₁₆H₁₈N₂O₄S.^7,8  

      • A defining feature is the benzyl (phenylacetyl) group that constitutes its side chain.⁹

        • Penicillin G (Benzylpenicillin)⁹

          Attribution Benzylpenicillinic (Molecule of the Week Archive; July 9, 2018) American Chemical Society https://www.acs.org/molecule-of-the-week/archive/b/benzylpenicillin.html

        • Penicillin G has also been known as benzylpenicillin or benzylpenicillinic acid.⁹

          • In its free acid form, penicillin G is a white crystalline powder that is only sparingly soluble in water and is chemically unstable, particularly in aqueous solutions.

            •  These physicochemical limitations render the free acid impractical for clinical use.⁹

          • To overcome limitations with the free acid form, penicillin G is formulated for example, as its potassium salts, which are much more water-soluble and stable, allowing for parenteral (intravenous or intramuscular) administration.¹⁰

            •  However, even in these salt forms, aqueous penicillin G is excreted by the kidneys with extreme rapidity, resulting in a very short therapeutic half-life that necessitates frequent dosing.¹⁰ 

            • To address this pharmacokinetic challenge, long-acting "depot" or "repository" formulations were developed.

              • These involve creating salts with large organic bases, such as procaine or benzathine, which are far less soluble in water.^11,12

              • When injected intramuscularly, these salts form a depot from which the active penicillin G is slowly hydrolyzed and absorbed into the circulation over an extended period.

              • Procaine penicillin G provides therapeutic concentrations for approximately 24 hours¹¹, while benzathine penicillin G can maintain low but effective levels for two to four weeks.¹²

August, 2025