SAR of Penicillins

SAR of Penicillins

 6-Acyl side chain: The substitution of R on the primary amine with an electron withdrawing group decreases the electron density on the side chain and protects from acid degradation. Substituents on the α-carbon of the side chain, such as amino (ampicillin), chloro, and guanidine exerts good resistance to inactivation by acids. Benzyl penicillin undergoes acid and alkali degradation and is susceptible to all known β-lactamase. The increased latitude in varying the acyl amino side chain through acylation of 6APA results with superior biological activity. Substitution of α-aryl of the alkyl group in the side chain gives increased stability and oral absorption.

1.           Substitution of bulky groups on α-carbon of the side chain confers β-lactamase resistance. Examples: methicillin, nafcillin, oxacillin, etc. In all these penicillins, an aromatic ring is attached directly to the side chain amide carbonyl, and there is substitution at both positions ortho to the point of attachment. The size of the ring systems play an important role in determining the ability of the ortho substitutent to confer penicillinase resistance.

2.           The isomeric forms of penicillins differs in their activity. Example: _D-isomer is 2–8 times more active than _L-isomer of amoxicillin. The introduction of polar group or ionized molecule into the α-position of the side chain in the benzyl carbon atom of penicillin-G confers against the gram-negative bacilli. Amino, hydroxyl, carboxyl, and sulphonyl increases gram-negative activity. Example: ampicillin and carbenicillin.

3.           Replacement of acyl side chain with hydroxymethyl groups shows improved gram-negative activity and introduction of C-6 α-methoxy group produces greater stability against β-lactamase. N-acylated ampicillins (ureidopenicillins) have increased activity against Pseudomonas.

4.           Many esters of the carboxyl group attached to C-3 have been prepared as prodrugs to increase lipophilicity and acid stability. Example: Acetoxymethyl ester derivatives are used for preparing prodrugs.

5.           The sulphur of the thiazolidine ring with O, CH , and CH-β-CH₃ gives broad-spectrum antibacterial activity. The geminal dimethyl group at C-2 position is a characteristic of the penicillin. In general, derivatization of the C-3 carboxylic acid functionality is not tolerated unless the free penicillin carboxylic acid can be generated in vivo. Doubly activated penicillin esters, undergo rapid cleavage in vivo to generate active penicillin. Example: pivampicillin and becampicillin. The antibacterial activity is evidented by N-4 atom at ring junction.

6.           In vitro degradation is retarded by keeping the pH of the solution between 6.0 and 8.0. More lipophilic side chain increases the plasma protein binding. Example: Ampicillin: 25% plasma protein bound and phenoxy methyl penicillin: 75% plasma protein bound.